riikka laitinen physical modification of drug release … · laitinen, riikka. physical...

RIIKKA LAITINEN

Physical Modification of Drug ReleaseControlling Structures

Hydrophobic Matrices and Fast Dissolving Particles

JOKAKUOPIO 2009

KUOPION YLIOPISTON JULKAISUJA A. FARMASEUTTISET TIETEET 117KUOPIO UNIVERSITY PUBLICATIONS A. PHARMACEUTICAL SCIENCES 117

Doctoral dissertation

To be presented by permission of the Faculty of Pharmacy of the University of Kuopio

for public examination in Auditorium, Mediteknia building, University of Kuopio,

on Saturday 27th June 2009, at 12 noon

Department of PharmaceuticsFaculty of PharmacyUniversity of Kuopio

Distributor : Kuopio University Library P.O. Box 1627 FI-70211 KUOPIO FINLAND Tel. +358 40 355 3430 Fax +358 17 163 410 http://www.uku.fi/kirjasto/julkaisutoiminta/julkmyyn.shtml

Series Editor : Docent Pekka Jarho, Ph.D. Department of Pharmaceutical Chemistry

Author’s address: Department of Pharmaceutics University of Kuopio P.O. Box 1627 FI-70211 KUOPIO FINLAND Tel. +358 40 355 3881 Fax +358 17 162 252 E-mail : [email protected]

Supervisors: Professor Jarkko Ketolainen, Ph.D. Department of Pharmaceutics University of Kuopio

Docent Eero Suihko, Ph.D. Orion Oyj Kuopio

Reviewers: Professor Henderik W. Frij l ink, Ph.D. Department of Pharmaceutical Technology and Biopharmacy Groningen University Institute for Drug Exploration (GUIDE) The Netherlands

Professor Thomas Rades, Ph.D. The New Zealand National School of Pharmacy University of Otago New Zealand

Opponent: Professor Robert T. Forbes, Ph.D. School of Life Sciences University of Bradford UK

ISBN 978-951-27-0855-0ISBN 978-951-27-1148-2 (PDF)ISSN 1235-0478

KopijyväKuopio 2009Finland

Laitinen, Riikka. Physical modification of drug release controlling structures –hydrophobic matrices andfast dissolving particles. Kuopio University Publications A. Pharmaceutical Sciences 117. 2009. 138 p.ISBN 978-951-27-0855-0ISBN 978-951-27-1148-2 (PDF)ISSN 1235-0478

ABSTRACT

An oral drug delivery system (e.g. tablet or capsule) is required for administration, which must ensuredelivery to the site of absorption in the gastrointestinal (GI) tract and release control of the active drugsubstance in a safe, effective and reliable way. However, many drug compounds are either ineffectively orincompletely absorbed after oral administration. Fortunately, biopharmaceutical performance of drugcompounds suffering from such limitations can be effectively improved by modified-release formulationtechnologies. The objective of this study was to evaluate different modified-release technologies both for controllingthe drug release properties of a hydrophobic matrix system and for improving the dissolution properties ofa poorly soluble drug, in order to allow its intraoral delivery, i.e. to formulate an orally fast disintegratingtablet (FDT). Matrix systems, which allow retarding the drug dissolution from the dosage form, are themost commonly used controlled drug delivery dosage forms due to their robustness and low productioncosts. This can beneficial in the case that the required dosing frequency is too high to enable once or twicea day administration due to the excessively short pharmacokinetic half-life of the drug. On the other hand,from a FDT the drug releases in the oral cavity and it can be absorbed through the oral mucosa anddelivered directly into the systemic circulation, avoiding first pass metabolism, by ensuring that the drug israpidly released and dissolved in the oral cavity. Another advantage of the intraoral route is the very fastonset of drug action. First, the ability of hydrophobic starch acetate (SA) and ethyl cellulose (EC) matrices for controlling therelease of water soluble model drugs was studied. In the study, the release properties of highly watersoluble saccharides were found to be similar with SA and commercially available EC. It was shown thatsimply by altering tablet porosity and the relative amount of the excipient in the tablet, the release ofsaccharides could be controlled over a wide time scale. Subsequently, a simple dry powder agglomerationpreparation process for drug/SA mixtures was developed. It was observed that changing the organization ofthe powder mixture by this process, the release rate of water soluble model drugs from SA matrix and tabletproperties could be modified. The extent of the change in the mixture structure was found to be dependenton the size and the surface roughness of the drug particles. Finally, an extremely fast dissolution rate of a poorly water soluble drug in a small volume of liquid (pH6.8) was obtained by utilizing a solid dispersion (SD) approach. The amorphous SD with the bestdissolution and stability characteristics was formulated as a FDT. The formulation prepared with directcompression, underwent fast disintegration and displayed a fast and immediate onset of the release of thedrug and also possessed sufficient tensile strength. In conclusion, simple formulation and processing modifications, which do not require any expensive andcomplicated equipment or process stages, or new chemical entities, displayed a great potential in controlledmodification of release and dissolution of physicochemically diverse drugs. These simple methods may behelpful in solving the future challenges of developing innovative formulations and dosage forms, e.g.enhancing the drug solubility and dissolution rate of new, more hydrophobic lead molecules that otherwisewould have limited biavailabilities. The results can also be useful for developing dosage forms for elderlypatients and children, two patient groups who suffer problems in swallowing conventional dosage forms.

National Library of Medicine Classification: QV 785, QV 787, WB 350Medical Subject Headings: Drug Delivery Systems; Administration, Oral; Dosage Forms; Delayed-ActionPreparations; Tablets; Solubility; Hydrophobicity; Starch/analogs & derivatives; Cellulose/analogs &derivatives; Porosity; Excipients; Powders; Particle Size; Tensile Strength

Imagination is more important than knowledgeAlbert Einstein

ACKNOWLEDGEMENTS

The present study was carried out in the Department of Pharmaceutics, University of

Kuopio during the years 2002-2009. This study was financially supported by the Finnish

Foundation for Technology and Innovation (TEKES), European Regional Development

Fund (ERDF), Kuopio University Pharmacy, The Finnish Cultural Foundation, Kuopio

University Foundation and The Finnish Pharmaceutical Society, which are gratefully

acknowledged.

I wish to warmly thank my principal supervisor, Professor Jarkko Ketolainen for giving

me the opportunity to work in his research group and for giving me the possibility to

grow into an independent scientist. I am also grateful to my second supervisor, Docent

Eero Suihko, for his invaluable contribution to my study and for always finding time for

me in his busy schedule.

Professors Kristiina Järvinen and Arto Urtti, present and former heads of the

Department of Pharmaceutics, and Professor Jukka Mönkkönen, dean of the Faculty of

Pharmacy, are acknowledged for providing facilities and pleasant working environment.

Kristiina, I highly appreciate your expertise and optimism which has been a great help,

especially in finishing the last two parts of my study.

I am grateful to my co-authors Mikko Björkqvist, Ph. D., Minna Heiskanen, M. Sc.

(Pharm.), Olli-Pekka Hämäläinen, M. Sc., Ossi Korhonen Ph. D. (Pharm.), Docent Vesa-

Pekka Lehto, Marko Lehtonen M.Sc., Matti Murtomaa, Ph. D., Riku Niemi, Ph. D.

(Pharm.), Heli Pitkänen, M.Sc. (Pharm.), Joakim Riikonen M.Sc., Ms. Susanne Rost and

Kaisa Toukola, M.Sc. (Pharm.) for their valuable collaboration. Ewen MacDonald, Ph.D.

is acknowledged for revising the language of my publications and this thesis. I also wish

to warmly thank all the personnel in the Faculty of Pharmacy who have contributed to

this work or helped me in any way during my career: especially Ms. Pirjo Hakkarainen

for her highly skillfull technical assistance and support at the beginning of my study; Ossi

Korhonen for introducing me to the research field of pharmacy and for guidance and

invaluable expert help during my work; Kristiina Heikkilä M.Sc. (Pharm) for laboratory

assistance; Docent Pekka Jarho, Professor Tomi Järvinen and Elina Turunen, M.Sc.

(Pharm.) for pleasant collaboration during the NOPPA-project and Tarja Toropainen,

Ph.D. (Pharm) for helping me with many practical things related to Ph.D. thesis project.

I am grateful to the official reviewers: Professor Henderik W. Frijlink from the

Groningen University Institute for Drug Exploration (GUIDE) and Professor Thomas

Rades from the University of Otago, for their useful comments to improve this thesis. I

also warmly thank Professor Robert T. Forbes from the University of Bradford for

agreeing to be the opponent in the public examination of my thesis.

My warmest thanks go to my friends and colleagues in the Department of

Pharmaceutics. Most of all I would like to thank the fabulous and highly talented TeTu-

team: Katri Levonen, M. Sc. (Pharm), Juha Mönkäre, M. Sc. (Pharm), Jari Pajander, M.

Sc. (Pharm) and Sami Poutiainen, M. Sc., for all of your cheer-ups and many

unforgettable moments during these years. Jari, it has been a privilege to be your

roommate. Your invaluable help and outstanding sense of humor will never be forgotten.

Cordial thanks for sharing the highs and lows of my Ph.D. studies, espresso breaks and

discussions varying from the scientific to the often very unscientific. I wish you the best

success with your own thesis.

I thank my parents Anja and Timo for always supporting the choices I have made. You

have given me a solid ground for life. I am also very grateful to my childhood friends and

the closest friends from the student days, that you have not forgotten me in spite of the

long distance between us.

Finally, I would like to express my sincere thanks to my beloved husband Mika.

Having you by my side has given me strength every single day. Your love and support

mean everything to me. Thank you for being there, you are my dearest!

Kuopio, May 2009

Riikka Laitinen

ABBREVIATIONS

A surface areaASES aerosol solvent extraction systemATR attenuated total reflectanceC concentrationCp heat capacityCs solubilityCD cyclodextrinCP crospovidoneCS calcium silicateD diffusion constantDEA dielectric analysisDMA dynamical mechanic analysisDS degree of substitutionDSC differential scanning calorimetry� solubility parameterε matrix porosityEC ethyl celluloseELS evaporative light scatteringf2 similarity factorFDT fast disintegrating tabletFRET fluorescence resonance energy transferFTIR fourier-transform infraredGAS gas antisolventGI gastrointestinalH enthalpyh thickness of the diffusion layerHEC hydroxyethylcelluloseHPC hydroxypropylcelluloseHPLC high performance liquid chromatographyHPMC hydroxypropylmethylcelluloseHPMCAS hydroxypropylmethylcellulose acetate succinateHSM hot-stage microscopyHTS high throughput screeningIGC inverse gas chromatographyIMC isothermal microcalorimetryIR infraredk release rate constant incorporating the matrix structurem massMt amount of drug released at time tM� amount of drug released at time t=�MTDSC modulated temperature differential scanning calorimetryn diffusional exponentNAG N-acetyl-D-glucosamineNCE new chemical entityNIR near-infrared

MW molecular weightPAA polyacrylic acidPE polyethylenePEG polyethylene glycolPEO poly (ethylene oxide)PGSS particles from gas saturated solutionsPLGA copolylactic acid/ glycolic acidPLS partial least squares regression analysisPLS-DA partial least squares discriminant analysisPP polypropylenePPZ perphenazinePVC polyvinyl chloridePVP polyvinyl pyrrolidonePVP/VA poly (vinylpyrrolidone-co-vinylacetate)Q the amount of drug released� densityRESS rapid expansion of supercritical solutionRH relative humiditySA starch acetateSAS supercritical antisolventSAXS small-angle X-ray scatteringSCF supercritical fluidSD solid dispersionsd standard deviationSDS sodium dodecyl sulfateSEDS solution enhanced dispersion by supercritical fluidsSEM scanning electron microscopySS stainless steelssNMR solid-state nuclear magnetic resonancet timeτ matrix tortuosity� mean molecular relaxation timesTEM transmission electron microscopyTg glass transition temperatureTK Kauzmann temperature (or temperature of zero mobility)Tm melting (fusion) temperatureT50% time required for dissolution of 50% of the substanceV (specific) volumew weight fractionXRD X-ray diffractionXRPD X-ray powder diffractometry

LIST OF ORIGINAL PUBLICATIONS

This doctoral thesis is based on the following original publications referred in the text by

Roman numerals I-IV.

I Mäki R, Suihko E, Korhonen O, Pitkänen H, Niemi R, Lehtonen M, Ketolainen J:

Controlled release of saccharides from matrix tablets. Eur J Pharm Biopharm 62:

163-170, 2006.

II Mäki R, Suihko E, Rost S, Heiskanen M, Murtomaa M, Lehto VP, Ketolainen J:

Modifying drug release and tablet properties of starch acetate tablets by dry

powder agglomeration. J Pharm Sci 96: 438-447, 2007.

III Laitinen R, Suihko E, Toukola K, Björkqvist M, Riikonen J, Lehto VP, Järvinen

K, Ketolainen J: Intraorally fast dissolving particles of a poorly soluble drug:

preparation and in vitro characterization. Eur J Pharm Biopharm 71: 271-281,

2009

IV Laitinen R, Suihko E, Björkqvist M, Riikonen J, Lehto VP, Järvinen K,

Ketolainen J: Perphenazine solid dispersions for orally fast disintegrating tablets:

physical stability and formulation. Drug Dev Ind Pharm, submitted

CONTENTS

1 INTRODUCTION ........................................................................................................... 17

2 BACKGROUND OF THE STUDY .............................................................................. 19

2.1 Oral drug delivery ...................................................................................................... 19

2.2 Matrix tablets for oral controlled release .................................................................. 21

2.2.1 Hydrophobic matrices ......................................................................................... 21

2.2.2 Hydrophilic matrices ........................................................................................... 23

2.2.3 Matrix tablet preparation ..................................................................................... 23

2.2.3.1 Tablet formation ............................................................................................... 23

2.2.3.2 Tablet structure and strength............................................................................ 24

2.2.3.3 Effect of solid state properties of the materials on tablet properties ............. 25

2.2.3.4 Importance of powder mixing on tableting and tablet properties .................. 26

2.2.4 Drug release mechanisms .................................................................................... 29

2.2.4.1 Diffusion ........................................................................................................... 29

2.2.4.2 Swelling............................................................................................................. 30

2.2.4.3 Erosion .............................................................................................................. 31

2.3 Intraoral drug formulations ........................................................................................ 31

2.3.1 Intraoral drug delivery ......................................................................................... 31

2.3.2 Orally fast disintegrating tablets ......................................................................... 33

2.3.2.1 Preparation by freeze-drying ........................................................................... 33

2.3.2.2 Preparation by compression ............................................................................. 35

2.3.2.3 Other preparation techniques ........................................................................... 36

2.3.2.4 Pharmacokinetic advantages of fast disintegrating tablets ............................ 36

2.4 Improvement of the dissolution rate of poorly soluble drugs .................................. 37

2.4.1 Solubility and dissolution rate ............................................................................ 37

2.4.2 Enhancement of the dissolution by using amorphous forms ............................ 40

2.4.2.1 Formation and properties of the amorphous state .......................................... 40

2.4.2.2 Characterization of the amorphous state ......................................................... 43

2.4.2.3 Stability of amorphous drugs ........................................................................... 46

2.4.3 Enhancing the dissolution by using solid dispersions ....................................... 48

2.4.3.1 Preparation of solid dispersions ....................................................................... 50

2.4.3.2 Carrier materials ............................................................................................... 53

2.4.3.3 Physical characterization of solid dispersions ................................................ 56

2.4.3.4 Dissolution of solid dispersions ....................................................................... 58

2.4.3.5 Stability and formulation of solid dispersions ................................................ 59

3 AIMS OF THE STUDY ................................................................................................. 63

4 EXPERIMENTAL .......................................................................................................... 64

4.1 Materials...................................................................................................................... 64

4.1.1 Excipients and model drugs (I-IV) ..................................................................... 64

4.1.2 Other chemicals (I-IV) ........................................................................................ 64

4.2 Methods ...................................................................................................................... 65

4.2.1 Particle and powder properties (I-IV) ................................................................ 65

4.2.2 Tableting (I, II, IV) .............................................................................................. 65

4.2.3 Tablet properties (I, II, IV).................................................................................. 66

4.2.4 Preparation of solid dispersions (III, IV) ........................................................... 67

4.2.5 Physicochemical characterization (I-IV) ............................................................ 67

4.2.5.1 Polarized light microscopy (I) ......................................................................... 67

4.2.5.2 Differential Scanning Calorimetry (I, III, IV) ................................................ 67

4.2.5.3 X-ray Powder Diffractiometry (III, IV) .......................................................... 69

4.2.5.4 Fourier Transform Infrared Spectroscopy (III, IV) ........................................ 69

4.2.5.5 Small-angle X-ray scattering (III, IV) ............................................................. 69

4.2.6 Solubility and dissolution testing (I-IV)............................................................. 70

4.2.7 Stability testing (IV) ............................................................................................ 72

4.2.8 Statistical analysis (I, II)...................................................................................... 72

5 RESULTS AND DISCUSSION..................................................................................... 74

5.1 Factors affecting release of highly water soluble compounds from hydrophobic

matrices (I) ................................................................................................................. 74

5.1.1 Dissolution characteristics of N-acetyl-D-glucosamine (I) .............................. 74

5.1.2 Dissolution characteristics of saccharides and oligosaccharides (I)................. 76

5.2 Effect of organization of powder mixture on the release rate of drugs from starch

acetate matrix (II) ...................................................................................................... 81

5.2.1 Triboelectrification of the materials (II)............................................................. 81

5.2.2 Dry powder agglomeration (II) ........................................................................... 82

5.2.3 Dissolution and tablet characteristics (II) .......................................................... 83

5.2.4 Summary and future prospectives (I, II) ............................................................ 88

5.3 Fast dissolving particles of a poorly soluble drug for intraoral preparations (III,

IV) ............................................................................................................................ 90

5.3.1 Improvement of drug dissolution by solid dispersion approach (III) ............... 90

5.3.1.1 Polymer selection by the solubility parameter approach (III) ....................... 90

5.3.1.2 Dissolution properties of the solid dispersions (III, IV) ................................ 91

5.3.2 Physical properties and stability of the solid dispersions (III, IV) ................... 93

5.3.3 Performance of fast disintegrating tablets containing solid dispersions (IV) 100

5.3.4 Summary and future prospectives (III, IV) ...................................................... 102

6 CONCLUSIONS............................................................................................................ 105

7 REFERENCES .............................................................................................................. 107

ORIGINAL PUBLICATIONS ........................................................................................ 138

17

1 INTRODUCTION

Solid oral dosage forms offer robustness, low manufacturing costs, ease of product

handling and convenience of use making them the most commonly used drug

administration systems (Rudnic and Kottke 1996, Venkatraman et al. 2000). However, in

oral drug delivery, as in all other categories of treatment, one major challenge for drug

development is to define optimal dose, time, rate and site of delivery in order to produce

safe and more efficient drugs. Thus, properties both of the drug and the delivery system

must be optimized.

The drug’s bioavailability can be effectively optimized by modified-release formulation

technologies. Within the context of this doctoral thesis, by the term modified-release is

referred to oral controlled release systems, oral delivery systems for modifying the

release of poorly water soluble drugs as well as fast dissolving dosage forms from which

drug absorption may occur through the oral mucosa or the gastrointestinal (GI) tract.

Controlled drug delivery techniques are a feasible way of improving the efficacy of the

drug when the solubility, dose, stability and cell membrane permeability of the drug are

appropriate (Qiu and Zhang 2000). Typically, a controlled release system is designed to

provide a desired release rate for a certain drug over an extended period of time in order

to achieve constant drug levels in plasma. Hydrophobic or hydrophilic polymeric matrix

tablets are common controlled release dosage forms due to the ease and economy of their

production (Qiu and Zhang 2000). However, the drug release rate from simple polymeric

matrix systems tends to decrease as a function of time and to overcome this problem

various methods, such as geometric configurations (e.g. donut shaped systems (Kim

1995a, Sundy and Danckwerts 2004)) and multiple unit dosage forms (Kendall 1989),

have been developed. Unfortunately, the dosage form per se is not always sufficient to

produce desirable drug release properties.

High throughput receptor based screens (HTS) and combinatorial chemistry are

producing increasing amounts of drug candidates with high lipophilicity and thus, good

permeability, but poor aqueous solubility (Alsenz and Kansy 2007). This leads to slow

dissolution of the drug in GI fluids and a reduction in the rate of the first step in the oral

absorption process. After a certain point, the solubility limitations cannot be overcome

18

with dosage form design and thus strategies, such as micronization of the drug (McInnes

et al. 1982, Mosharraf and Nyström 1995, Vogt et al. 2008), use of a faster dissolving

salt, polymorphic or amorphous form of the drug (Kobayashi et al. 2000, Huang and

Tong 2004, Blagden et al. 2007, Serajuddin 2007), complexation with cyclodextrins

(Rajewski and Stella 1996, Brewster and Loftsson 2007) and formation of a solid

dispersion (Chiou and Riegelman 1971, Leuner and Dressman 2000, Sethia and

Squillante 2003) are needed if one wishes to improve the solubility and dissolution rate of

the drug itself. Fast dissolution of the drug is also needed when formulating a drug for

dispensing in orally fast dissolving tablets from which the drug is released in the oral

cavity and absorbed through oral mucosa (Seager 1998).

In the present study, different modified-release technologies were applied for

improving the drug release properties of a controlled release drug delivery system and the

dissolution properties of a poorly soluble drug in order to enable its usage in orally fast

disintegrating formulations. First, the release rate and profile of highly water soluble

drugs from starch acetate matrix tablets were controlled by simple formulation

approaches. Then, the dissolution properties of a poorly soluble drug were improved with

a solid dispersion technique, after which the fast dissolving dispersion was formulated as

an orally fast disintegrating tablet.

19

2 BACKGROUND OF THE STUDY

2.1 Oral drug delivery

The majority of drug substances exist as crystalline or amorphous powders. A delivery

system (e.g. tablet or capsule) is required for delivering and releasing the drug substance

to its absorption site in the GI tract safely, effectively and reliably. In addition to the

delivery of the drug to its absorption site, transposition of a drug from an oral dosage

form into the bloodstream requires dissolving of the drug followed by movement of the

dissolved drug through the membranes of the GI tract into the general blood circulation.

Unfortunately, many drug compounds are either incompletely or ineffectively absorbed

after oral administration, i.e. they have low bioavailability due to low solubility or cell

membrane permeability, or because they are metabolized by the liver into an inactive

form (first-pass metabolism) (Löbenberg et al. 2000, Hillery 2001). On the other hand,

the required dosing frequency might be too high to enable once or twice a day

administration if the drug has a very short pharmacokinetic half-life. Nonetheless, the

biopharmaceutical performance of many drug compounds suffering from these kinds of

limitations can be effectively improved by resorting to modified-release formulation

technologies.

The term controlled drug delivery refers to dosage forms which provide a specifically

designed dissolution profile of the drug from the dosage form. Various physical and

chemical approaches can be applied to produce a dosage form displaying the desired

release profile and thereby control over the drugs’ absorption into the systemic

circulation (Qiu and Zhang 2000). Some of the systems utilized include: insoluble, slowly

eroding or swelling matrices; polymer-coated tablets, pellets or granules; osmotically

driven systems; systems controlled by ion exchange mechanisms and various

combinations of these approaches (Saikh et al. 1987a and b, Tahara et al. 1995, Charman

and Charman 2002, Jeong and Park 2008). With respect to controlled release dosage

forms, the focus in this thesis will be restricted to the matrix structures (Chapter 2.2).

Matrix systems are the most commonly used type of controlled drug delivery systems

due to their robustness and low production costs. A matrix system is simply a

20

homogenous mixture of drug particles within a polymer matrix, often manufactured by

direct compression. However, one disadvantage of a simple monolithic matrix is the

decrease in dissolution rate as a function of time, resulting from an increase in the

diffusion path length and a decrease in effective diffusion area, even when hydrophilic

polymers (swelling/erodible) are used. This leads to a square-root of time release profile

of the drug (Venkatraman et al. 2000, Charman and Charman 2002). However, zero-order

drug release is often desired since it offers several therapeutic advantages, such as

minimized peak plasma levels leading to reduced risk of adverse reactions and

predictable and extended duration of action (Breimer 1998). Therefore, numerous

approaches, such as matrices with modified geometry and the surface area available for

diffusion (Bayomi 1994, Kim 1995a, Chopra 2002, Zerbe and Kumme 2002, Sundy and

Danckwerts 2004) or multiple unit delivery systems consisting of small subunits such as

granules, pellets or minitablets (Efentakis and Koutilis 2001, Verhoeven et al. 2006,

Hayashi et al. 2007) have been examined as ways to modify the release rate of the drug.

Manufacturing of the multiple-unit preparations, however, is a relatively complicated and

expensive involving numerous process variables. Thus, the pharmaceutical industry

prefers to design of directly compressed monolithic delivery systems in controlling the

drug release. Furthermore, if one considers the pharmaceutical variables, then the

physicochemical properties of the drug are crucial, since after released from the dosage

form, the drug has to be dissolved into surrounding fluids in order to be absorbed. Drugs

that can be formulated to controlled release dosage forms have reasonable solubilities,

relatively low dose, short elimination half-lives, and low first pass metabolism (Qiu and

Zhang 2000, Chrzanowski 2008a,b). However, hydrophobic matrix systems are not

suitable for very poorly water-soluble compounds, since the concentration gradient

generated is insufficient for providing satisfactory drug release and in vivo exposure (Liu

et al. 2005). Instead, hydrophilic matrices may be designed where polymer erosion is

modulated to further aid release control of poorly soluble drugs (Liu et al. 2005).

Sufficient drug release is attained as long as the drug molecules dissolve before polymers

erode from the dosage form.

The physicochemical properties of the drugs, such as low solubility, might represent a

barrier for absorption. The ongoing trend in drug development towards lower solubility

21

drug candidates, attributed to HTS which was initiated in the late 1980s and the use of

combinatorial chemistry approaches to drug design and discovery of new targets

requiring more lipophilic molecules for target affinity (Lipinski 2000, Alsenz and Kansy

2007), poses challenges to development of controlled release dosage forms. It has been

estimated that over 40 percent of all new chemical entities (NCEs) entering drug

development programs have insufficient aqueous solubility to allow them to be absorbed

adequately from the GI tract in order to ensure therapeutic efficacy (Hauss 2007,

Stegemann et al. 2007). In addition, the previously mentioned first-pass effect can be

significant for some drug substances, leading to low bioavailability of the drug. In this

case, a dosage form redesign cannot improve the situation. Instead, only by changing the

absorption site or the entire administration route can the first-pass effect be avoided. If

one attempts intraoral drug delivery, e.g. with orally fast disintegrating/dissolving tablets

(Chapter 2.3), then the drug can be delivered directly into the systemic circulation, but

this requires that the drug is rapidly released and dissolved in saliva and can be absorbed

through the oral mucosa (Seager 1998, Kellaway et al. 2002, Bredenberg et al 2003). This

can represent an obstacle for lipophilic drugs and thus, facilitation of the solubility and/or

dissolution of poorly soluble compounds is required, and this can be approached by

several physical and chemical techniques, which are discussed in Chapter 2.4. Other

advantages of the intraoral route include fast onset of drug action and overcoming of

swallowing difficulties, which may be a real problem with pediatric and geriatric patients

(Kellaway et al. 2002, Strickley et al. 2008).

2.2 Matrix tablets for oral controlled release

Polymers from natural products, chemically modified natural products and synthetic

products are used in matrix-type dosage forms. Drugs are generally dispersed into

polymers which can be either hydrophobic or hydrophilic.

2.2.1 Hydrophobic matrices

In hydrophobic matrix tablets, the release rate controlling components are water

insoluble materials (Liu et al. 2005) such as waxes, glycerides, fatty acids and polymers

22

such as ethyl cellulose (EC) (Rekhi and Jambhekar 1995), starch acetate (SA) (Korhonen

et al. 2000) or ammonio methacrylate copolymers (Eudragit®) (Caraballo et al. 1999).

Due to the insoluble nature of the matrix, the formulation maintains its dimensions during

drug release.

EC is a commercially available, inert polymer widely used for the preparation of matrix

tablets with both water soluble and poorly soluble drugs (Saikh et al. 1987a,b, Rekhi and

Jambhekar 1995). Starch acetates (SA) are prepared from native starch polymers by

esterification (Paronen et al. 1997). SAs with different degrees of substitution (DS) can

be produced by controlling the reaction conditions (Figure 2.1). SAs having the highest

DS values (i.e. 2.1-3) form a strong tablet matrix with sustained drug release properties

and they are suitable for direct compression (Korhonen et al. 2000). The drug release rate

from starch acetate tablets can be controlled by the DS value and the amount of SA in the

tablet.

Figure 2.1. Native starch consists mainly of linear amylose, which is shown here, andbranched amylopectin units. Esterification replaces the hydrogen atoms with an acetylgroup producing SAs with DS values up to 3 (modified from Rowe et al. 2006).

In the case of a hydrophobic polymer matrix, such as EC and SA, the drug release

occurs by dissolution and diffusion of the drug through water-filled capillaries within the

matrix’s pore network (Crowley et al. 2004, Pohja et al. 2004). According to the

percolation theory, the particle size of the hydrophobic polymer significantly affects the

drug release, since the more polymer particles present (i.e. the smaller the particle size)

the fewer drug clusters can be formed leading to slower drug release (Leuenberger et al.

1987, Holman and Leuenberger 1988, Crowley et al. 2004).

R RR

R R R

CH2OR CH2OR CH2OR

n = 300 to 1000R = COCH3

23

2.2.2 Hydrophilic matrices

The primary drug release rate controlling ingredients in a hydrophilic matrix are

polymers that swell on contact with the aqueous medium and form a gel layer on the

surface of the system. Polymers such as cellulose ethers (hydroxypropylmethylcellulose

(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC)) (Colombo 1993,

Ferrero Rodriquez et al. 2000), xanthan gum (Talukdar et al. 1998), sodium alginate

(Efentakis and Buckton 2002) and poly(ethylene oxide) (Kim 1995b) are commonly used

in the production of compressed hydrophilic matrices. Due to their good compression

characteristics and adequate swelling properties, HPMCs are most widely used in

controlled release tablets (Ferrero Rodriquez et al. 2000). High viscosity grades of HPMC

are suitable for delaying the drug release from the matrix (Rowe et al. 2006). The

formulation variables which have the greatest impact on the release rate are matrix

dimension and shape, amount of polymer and its molecular weight, drug load and drug

solubility (Velasco et al. 1999, Liu et al. 2005). The release of a water soluble compound

from an HPMC matrix involves the successive processes of penetration of a liquid into

the matrix, hydration and swelling of the matrix, dissolution of the drug in the matrix and

diffusion of the drug through the channels in the matrix (Tahara et al. 1995, Colombo

1999).

2.2.3 Matrix tablet preparation

2.2.3.1 Tablet formation

Tablets are produced by applying a force on a powder material in a die, which

transforms the powder into a porous, coherent compact product with a well-defined

shape. The compression process can be considered to occur in four sequential or parallel

stages: particle rearrangement, deformation, fragmentation and bonding (Parrott 1981,

Nyström and Karehill 1996, Patel et al. 2006). During compression, the particles are first

rearranged, resulting in closer packing. This particle movement is prevented at a certain

load by the packing characteristics of the particles or a high interparticulate friction and

24

thus the further reduction of the compaction volume occurs by elastic (reversible) and

plastic (irreversible) deformation of the particles. Subsequently, the particles are

fragmented into smaller parts which fill in the empty positions, decreasing further the

compact volume. Thus, the compaction process results in increased contact area and

interparticulate attraction or bonding occurs. The dominating bonding mechanisms in the

case of dry powders are: attraction between solid particles (molecular (van der Waals,

hydrogen bonding) and electrostatic forces), mechanical interlocking between irregularly

shaped particles and the formation of solid bridges (due to e.g. melting) (Nyström and

Karehill 1996, Patel et al. 2006).

The properties of the produced tablets are strongly dependent on the mechanical

characteristics of the powder constituents and the particle-particle interactions (Patel et al.

2006). In addition, geometric factors such as surface rugosity, shape and size distribution

of the materials all contribute to tablet properties. These factors interact with the process

parameters applied during manufacturing, such as the compaction force, to govern the

tablet structure and strength (Sinka et al. 2009).

2.2.3.2 Tablet structure and strength

A tablet can be described as an aggregate of smaller particles which are strongly

adhered to each other. The gas phase in the compact (air) can be described as a three

dimensional network of connected pores. With normal compaction pressures (i.e. smaller

than 300-500 MPa), the porosity of the final compact is from 5% to 25%, depending on

the powder compressibility (Alderborn 1996). The strength of a tablet is dependent on

both the characteristics of the interparticulate pore system (e.g. porosity, pore size

distribution and pore surface area), the properties of the particles forming the compact

(e.g. surface area and morphology, particle size distribution and the packing

characteristics or relative positions of the particles) in conjunction with the interactions

between the particles (Alderborn 1996, Juppo 1996, Mattsson 2001, Wu et al. 2001, van

Veen et al. 2002).

In a tablet consisting of a mixture of two different materials, three different types of

interparticle bonding exist: cohesive forces between the particles of the same component

25

and adhesive forces between the particles of the two different components (Fell 1996).

When the ratio of the two components in a formulation is changed, also the

interparticulate bonding and the structure of the tablet will be altered (Fell 1996, van

Veen 2002). The structure of tablets consisting of a binary mixture can be described by

the percolation theory (Leuenberger et al. 1987, Holman 1991, Bonny and Leuenberger

1993, Fernández-Hervás et al. 1996) according to which the particles either form a

continuous matrix or exist in separate clusters. At a certain component concentration in

the tablet (i.e. the percolation threshold), a continuous matrix is formed, instead of

clusters, leading to changes in tablet properties (e.g. strength) (Bonny and Leuenberger

1993, Amin and Fell 2004).

The strength of a tablet is also related to the particle size of the materials used and the

way they pack together under compaction (Alderborn 1996, Gane et al. 2006). Particle

dimensions affect both the degree of fragmentation and the degree of deformation during

compression and thus the number and strength of the interparticulate bonds (Alderborn

1996). In general, a decreased original powder particle size leads to increased tablet

strength (McKenna and McCafferty 1982). In contrast, the effect of particle shape is

relevant only when the material fragments to a limited degree during compression, and

then the more irregular shape of the particles will increase the strength of the tablets

(Alderborn 1996).

The dominant process parameter that determines tablet strength is the compression

pressure. As the compression pressure is increased, the tensile strength of a material

increases for most pharmaceutical materials due to the increased degree of fragmentation

and the number of interparticulate bonds or due to the increased degree of particle

deformation and the bonding force. This continues until a certain force threshold is

passed, after which cracking and lamination might occur (Alderborn 1996, Sinka et al.

2009).

2.2.3.3 Effect of solid state properties of the materials on tablet properties

In the solid state, a drug can exist in different physical forms. Two forms with the

same molecular structure but different crystal packing are called polymorphs.

26

Pseudopolymorphs (i.e. hydrates and solvates) differ from each other in terms of the

amount of solvent of crystallization (i.e. water in the case of a hydrate) incorporated into

the crystal lattice (Florence and Attwood 1998, Byrn et al. 1999a). Instead, amorphous

forms lack the long-range molecular order, but may possess some short-range order e.g.

due to hydrogen bonds (Byrn et al. 1999b). Amorphous forms are thermodynamically

unstable and they will eventually transform into the crystalline form by nucleation and

growth of crystals.

The different solid state properties of the physical forms of a drug or excipients can

have a significant effect on tableting and tablet properties, such as flow, densification or

binding properties (Fachaux et al. 1995, Bolhuis and Chowhan 1996, Sun and Grant

2001, Joiris et al. 2008, Sinka et al. 2009). In addition, metastable forms in

pharmaceutical products might crystallize, convert to another crystal form or change

between an unsolvated and a solvated form during processing or storage (Craig et al.

1999, Kaushal et al. 2004, Zhang et al. 2004, Tantry et al. 2007, Feng et al. 2008).

Furthermore, processes involving mechanical stress (i.e. grinding, milling, wet

granulation, drying and compression) can, intentionally or unintentionally, convert a

crystalline material into either fully or partially amorphous form (mechanical activation)

(Ketolainen et al. 1995, Guinot and Leveiller 1999, Yonemochi et al. 1999a, Morris et al.

2001, Mura et al. 2002), leading to development problems and altered product

performance (Hüttenrauch et al. 1985, Bhugra et al. 2008, Feng et al. 2008). Furthermore,

metastable forms of the drug might have considerably different dissolution rates from the

tablets than the stable form of a drug (Phadnis and Suryanarayanan 1997), and a rapid

phase transition during dissolution (e.g. from anhydrate to monohydrate) can negate the

potential dissolution advantage of the metastable forms (Debnath and Suryanarayanan

2004, Li et al. 2007).

2.2.3.4 Importance of powder mixing on tableting and tablet properties

Mixing of powders is an important operation in the production of tablets in order to

obtain a homogenous mixture of a drug and excipient(s). Powder mixing has been

described by several theories. In the random mixing theory, the mixing process is treated

27

as a statistical process where the bed of particles is repeatedly split and combined until a

binomial distribution is reached (Lacey 1954). This approach requires that all particles

are equal in every physical respect (except colour) and that all particles are non-

interacting, i.e. particles in a random mix are mainly influenced by gravity. However, it is

well known that the materials involved in a mixing process interact with each other

through capillary, electrostatic and van der Waals forces (Zeng et al. 2000b) and may

produce ordered mixtures, where fine particles adhere or cohere to form ordered units

(Hersey 1974). In an ordered mix, it is the ordered units that are influenced by gravity.

Within the unit, the fine particles are bound to the coarse ones by interparticulate forces

which result from surface electrical attractions (Staniforth 1981). The force of gravity and

surface electrical forces vary with the particle size distribution of the materials; the

smaller the particles, the greater will be the influence of the surface electrical forces

(Staniforth 1981, Venables and Wells 2001).

The forces arising from the particle surfaces, along with gravity, define the organization

of a blend, not the bulk properties of the materials (i.e. parameters related to molecules)

(Barra et al. 1998). It has been observed that the adhesion force between two particles of

different materials will be maximum if they have same polarity and very different particle

sizes (Staniforth 1981, Barra et al. 1998). This causes adhesion of the small particles on

the surfaces of the larger particles. However in practice, rugosity of the particle surfaces

also affects adhesion (de Boer et al. 2005, Dickhoff et al. 2005). For example, if one of

the materials is porous, its surface will contain a large number of active adhesion sites

able to entrap smaller particles of the other material (Staniforth 1981, Barra et al. 1998).

Furthermore, the surface of contact available between the particles also depends on their

shapes (Venables and Wells 2001).

During mixing, powder particles come into contact with each other and with solid

surfaces (e.g. particle and a container wall) which leads to contact electrification of the

surface of the materials. The term triboelectrification is used when charges are transferred

between the contacting surfaces and the contact involves frictional effects e.g. due to

sliding and rolling (Staniforth 1981, Bailey 1993, Rowley 2001). The increasing number

of contacts and collisions between surfaces leads to accumulation of electrostatic charge

which in the case of a particle is positive or negative depending on the separation

28

energies, or work functions, of the outer electrons in the atoms of the powder particles

relative to those of the container wall (Staniforth and Rees 1981, Kulvanich and Stewart

1987). The particle size, shape, surface nature, purity and roughness, the electrical and

mechanical properties of the powder and the contact surface in addition to the

atmospheric conditions, e.g. relative humidity (RH), all affect the extent of

triboelectrification (Carter et al. 1992, Bennett et al. 1999, Rowley 2001, Murtomaa et al.

2004). Charging of powders, leading to agglomeration during processing is often

undesirable, but it can be also utilized e.g. in stabilizing ordered mixtures (Staniforth

1981, Staniforth and Rees 1981, Venables and Wells 2001). The increased electrostatic

attraction between oppositely charged drug and excipient particles brings two particles

into a close surface contact which might permanently increase van der Waals adhesion

forces compared to the situation with uncharged particles (Staniforth 1981).

Different organizations of the powder mixtures have been found to influence powder

compactibility and the tensile strength of the compacts. In the case of interacting

materials, the adhering material (i.e. the material with the lowest particle size) forms a

percolating network, and the mixture has the compactibility and the tensile strength of the

adhering material (Barra et al. 1999). This observation can be put into use in

pharmaceutical preparations by artificially increasing the compactibility of a mixture

without changing its composition. Furthermore, drug-excipient interactions can affect the

drug dissolution rate, i.e. it has been observed that inclusion of the drug in the excipient

agglomerates and adhesion of small-sized magnesium stearate on the surface of the drug

particles and agglomerates resulted in hydrophobic coating and reduced water

penetration, hindering the drug dissolution from the filled capsules (Chowhan and Chi

1986). In addition, by using ordered mixtures of fine drug particles attached to coarser

excipient carrier particles, optimal drug exposure and thus potentially immediate drug

dissolution can be achieved e.g. in the design of rapidly disintegrating tablets

(Bredenberg et al. 2003). Thus, the use of ordered mixtures might also provide a potential

way of controlling drug release rate from monolithic matrix formulations (Barra et al.

2000).

29

2.2.4 Drug release mechanisms

Factors affecting the drug release may vary depending on the drug release mechanism

of the delivery system. Thus knowledge of the mechanism of the delivery system is an

essential part of drug development process. The most important drug release controlling

mechanisms are diffusion, swelling and erosion which involve drug diffusion through

tortuous channels or a viscous gel layer, or drug dissolution due to system erosion.

2.2.4.1 Diffusion

Drug release from a porous monolithic matrix where the drug is dispersed in a

hydrophobic polymer, such as EC and SA, involves the simultaneous processes of

penetration of the surrounding liquid, dissolution of the drug and diffusion of the drug

through channels or pores of the matrix (Qiu and Zhang 2000, Crowley et al. 2004, Pohja

et al. 2004). The Higuchi model (Higuchi 1961) is the most frequently used model to

describe the drug release from such systems (Eq. 1):

(1)

where Q is the amount of drug released in time t, Cs is the drug solubility in the matrix, C

is the initial concentration of the drug and D is the diffusion constant of the drug

molecules in the medium. Since the volume and length of the pores in the matrix must be

taken into account, Eq. 1 is further modified as:

(2)

where ε and τ are the porosity and the tortuosity of the matrix, respectively (Higuchi

1963). The assumptions when this equation is valid are that perfect sink conditions

prevail and swelling of the matrix is negligible, i.e. the matrix retains its dimensions.

Thus, according to Eq. 2, square-root of time kinetics is expected for drug release, since

there will be an increasing diffusion path length as drug release proceeds.

DtCCCQ ss )2( −=

τεε tDCCCQ ss )2( −=

30

The Higuchi equation was originally developed for planar diffusion. Later, a simple

exponential equation was introduced by Korsmeyer and Peppas (Korsmeyer and Peppas

1983) for describing the general release behavior from hydrophobic matrices with other

geometries, such as slabs, spheres and cylinders (Eq. 3):

(3)

where Q (Mt/M�) is the fractional release, k is a constant and n is the diffusional

exponent. The n value can be used for characterization of different release mechanisms

(Costa and Sousa Lobo 2001). In the case of a cylinder, the exponent n has values of 0.45

for Fickian diffusion (leading to square root of time release kinetics), from 0.45 to 0.89

for non-Fickian anomalous transport (leading to first-order release kinetics) and 0.89 for

non-Fickian Case-II transport (leading to zero-order kinetics).

2.2.4.2 Swelling

Drug release controlled by swelling is a complex process due to diverse

macromolecular changes occurring in the polymer during release. Swelling controlled

systems consist of water soluble drugs dispersed in a glassy polymer matrix, such as

HPMC (Colombo 1993, Narasimhan 2000). Once it makes contact with water, the

polymer swells and transforms from a glassy to a rubbery state, forming a gel layer in

which the dissolved drug can be transported due to increased mobility of the polymeric

chains. The gel layer prevents matrix disintegration and controls additional water

penetration. Thus, water penetration, swelling, drug dissolution and diffusion, and matrix

erosion are the factors controlling formation of the gel layer and, consequently, drug

dissolution (Colombo et al. 1996, 2000). The drug release kinetics can be modified by the

gel layer thickness and the rate at which it is formed (Kanjickal and Lopina 2004). As the

proportion of the polymer in the tablet increases, the gel formed reduces diffusion of the

drug and delays the erosion of the matrix (Ford et al. 1985a).

nt ktMMQ ==

∞

31

2.2.4.3 Erosion

Also in erosion-controlled systems, the drug is dispersed uniformly throughout the

hydrophilic polymer matrix. Once in contact with water, these systems swell and this is

followed by polymer and drug dissolution. However, the diffusion of the drug in the gel

layer formed is slower than the polymer dissolution rate or erosion of the gel (Lee 1985,

Ford et al. 1987). In the erodible hydrophilic matrix, the drug release can be controlled

either by erosion in the case of poorly soluble drugs or by diffusion of the drug through

the gel layer and erosion of the gel in the case of highly water soluble drugs (Ford et al.

1985a, 1985b, 1987, Lee 1985). In addition, the strength of the gel layer influences drug

release: using polymers of low viscosity grades leads to erosion-controlled release and

zero-order kinetics (Zuleger and Lippold 2001). Instead, if one uses polymers of high

viscosity or high amounts of a polymer in the tablet then a stable matrix is created where

polymer dissolution is negligible, in which case the drug is released primarily by Fickian

diffusion following square-root of time kinetics (Pham and Lee 1994, Katzhendler et al.

1997, Zuleger and Lippold 2001). Often both diffusion and erosion contribute to the drug

release leading to “anomalous transport”, i.e. kinetics between zero-order and square-root

of time (Zuleger and Lippold 2001).

Two types of matrix erosion behavior, surface erosion and bulk erosion, can be

identified (Kanjickal and Lopina 2004). Polymers with highly reactive functional groups

(e.g. polyanhydrides) undergo faster degradation than the diffusion of water into the

matrix, leading to surface erosion. In contrast, in a bulk eroding system, degradation of a

polymer with less reactive groups (e.g. PLGA (copoly lactic acid/ glycolic acid)) is much

slower than the diffusion of water. Thus, water is present throughout the system and the

polymer erodes in a homogenous manner.

2.3 Intraoral drug formulations

2.3.1 Intraoral drug delivery

The per oral route has some considerable disadvantages in terms of effective drug

delivery. After absorption from the GI tract, the drug is subjected to first-pass

metabolism. For some drugs, the extent of first pass metabolism might be so considerable

32

as to substantially reduce the drug’s bioavailability. Thus, there is a growing interest in

exploiting the oral cavity as a site for delivering drugs subject to extensive first-pass

metabolism since this is a way of gaining direct access to the systemic circulation (Sastry

et al. 2000, Kellaway et al. 2002). However, the differences in relative thickness of the

tissues as well as degree of keratinization of sublingual, gingival and buccal membranes

result in different permeability characteristics (Kellaway et al. 2002). It has been reported

that the sublinqual route is more permeable than the buccal or gingival routes (Harris and

Robinson 1992). In addition, even though oral administration of tablets is considered as a

convenient way of drug delivery, it has also been increasingly recognized that

compliance issues with solid oral dosage forms can be significant for those individuals

who have difficulty in swallowing conventional tablets or capsules (dysphagia).

Dysphagia is common among all age groups, but especially in elderly people and children

(Sastry et al. 2000, Kearney 2002, Strickley et al. 2008). The disorder can be associated

with many medical conditions, such as stroke, Parkinson’s disease or radiation therapy to

the neck and head area (Sastry et al. 2000). It has been estimated that as much as 35% of

general population suffer from dysphagia (Sastry et al. 2000, Kearney 2002). In addition,

the inconvenience associated with administering conventional oral dosage forms

concerns people not having access to potable water. In this respect, modified-release

technology, viz. orally fast disintegrating tablets (FDTs), offers possibilities for avoiding

the abovementioned problems.

According to the European Pharmacopoeia (2007), FDTs should disintegrate or

dissolve in the oral cavity into the saliva in less than three minutes without chewing or

need of excess water. However, in many studies the limit for tablet disintegration in the

oral cavity has been considered as less than one minute (Habib et al. 2000, Fu et al. 2004)

or even less than 30 s (Shimizu et al. 2003). In addition to improving patient compliance,

FDTs produce rapidly concentrated saliva drug solutions, able to coat the oral mucosa

easily, and thus, to be absorbed directly into the systemic circulation avoiding the first-

pass metabolism (Kellaway et al. 2002). Therefore, an added advantage of these

formulations is their rapid onset of action. However, unless the drug does not have an

undesirable taste, the use of taste-masking techniques becomes critical to patiet

acceptance. Taste-masking is accomplished simply by use of flavoring agents and

33

sweeteners or by microencapsulation, i.e. covering the drug particles by polymers

through spray-drying or coacervation (Habib et al. 2000, Sastry et al. 2000, Pather et al.

2002, Bora et al. 2008).

2.3.2 Orally fast disintegrating tablets

There are several formulation types of FDTs, e.g. fast melting, fast dispersing, rapid

dissolve and rapid melt. The fast disintegration is generally achieved either by choosing

fast dissolving tablet excipients, inclusion of effervescents in order to produce rapid

disintegration in contact with saliva or by using a freeze-drying process in order to

produce a highly porous tablet structure (Sastry et al. 2000, Dobetti 2001, Fu et al. 2004).

There are several technologies available for producing FDTs, however, not all of them

have succeeded in being applied in commercially marketed products. These technologies

utilize either freeze-drying, molding or compression as a production method, from which

compression supplemented with modifications is the most widely used (Dobetti 2001, Fu

et al. 2004). One common characteristic of all these methods is that selection of the

materials used is based on their rapid dissolution or ability to disintegrate in water, sweet

taste, low viscosity in order to provide a smooth texture in the mouth as well as

compressibility (Kearney 2002, Pather et al. 2002, Di Martino et al. 2005). This has led to

wide use of saccharides in FDTs. However, in order to attain fast disintegration, the

dosage forms need to be very porous and/or compressed at very low compression forces.

Thus, they are soft, friable and often require special packaging (Sugimoto et al. 2006). In

general, FDTs with tensile strength higher than 1 MPa (Takeuchi et al. 2005, Sugimoto et

al. 2006) are considered strong enough to be handled and packed normally.

2.3.2.1 Preparation by freeze-drying

In preparing FDTs by freeze-drying (i.e. lyophilization), the solvent is removed by

sublimation from a frozen drug solution or a suspension containing structure-forming

excipients (Dobetti 2001, Fu et al. 2004). The advantage of this technology is that the

tablets produced have a highly porous structure leading to extremely fast (< 5s)

dissolution/disintegration and release of the drug when the tablet is placed on the tongue

34

(Dobetti 2001). The process may also lead to formation of a glassy or rubbery amorphous

structure of excipients and the drug, further enhancing the dissolution rate. In addition,

tablet production is conducted at low temperatures, which may prevent stability problems

during processing. During the shelf life of the product, stability problems are avoided by

storing the tablets in a dry environment. The disadvantages of the method include the

poor stability of the formulation in elevated temperature and humidity, physical weakness

of the tablets (requiring special packaging) and high cost of the manufacturing process

(Dobetti 2001, Fu et al. 2004).

The Zydis® technology is a pioneering technique and the most well known example of

the freeze-drying method (Habib et al. 2000, Kearney 2002). There are several

commercialized products based on this technology, such as Claritin® RediTabs® (an

antihistamine (loratadine) preparation from Schering Corporation), Maxalt®-MLT® (an

antimigraine (rizatriptan benzoate) preparation from Merck) and Zyprexa® Zydis® (an

antipsychotic (olanzapine) preparation from Eli Lilly).

In the Zydis® process, the active incredient is dissolved or suspended in an aqueous

solution of water-soluble structure formers (typically gelatin and mannitol). The mixture

is poured into preformed blister pockets and freeze-dried. The Zydis® process is most

suitable for low-solubility drugs in doses up to 400 mg. The suitable dose for a soluble

drug depends on the intrinsic properties of the drug and is usually less than 60 mg.

Generally the drug particle size should be limited to 50 µm. Absorption from the oral

cavity can be achieved, if the characteristics of the drug are optimal (Kearney 2002,

Dobetti 2001).

Other techniques based on freeze-drying include Quicksolv®, Lyoc® and

NanoCrystal™. Quicksolv®, for example, is obtained by freezing an aqueous dispersion

or solution of the active-containing matrix and subsequently drying it by solvent

extraction (Dobetti 2001, Fu et al. 2004). The method produces a very rapidly

disintegrating tablet with uniform porosity and adequate strength for handling (Fu et al.

2004). A commercial product of a peristaltic stimulant cisapride monohydrate

(Propulsid®Quicksolv® from Janssen Pharma) is available based on this technology.

35

2.3.2.2 Preparation by compression

Conventional tablet processing methods and equipment can also be used in the

preparation of FDTs. However, achieving high porosity and adequate tablet strength

requires some modifications compared to the preparation of conventional tablets. Wet

granulation, dry granulation, spray drying and flash heating in addition to various after-

treatments, such as humidity treatment or sublimation, have been used in the preparation

of FDTs (Fu et al. 2004, Mizumoto et al. 2005). However, direct compression is still the

preferable technique due to its simplicity and cost efficiency and thus it is discussed here

in more detail.

Direct compression requires the incorporation of one or more superdisintegrants into

the formulation or the use of highly water-soluble excipients to achieve adequate tablet

disintegration (Dobetti 2001, Rawas-Qalaji et al. 2006). Saccharides are widely used as

excipients due to their solubility, sweetness and a pleasant oral texture (Fu et al. 2004).

The disintegration times achieved with this method are not as fast as can be obtained with

e.g. lyophilized tablets, and the disintegration and dissolution process is extremely

dependent on the tablet size, porosity and hardness, and the type(s) and amount(s) of the

disintegrants used (Dobetti 2001, Sunada and Bi 2002, DiMartino et al. 2005, Rawas-

Qalaji et al. 2006). In direct compression method the use of water or heat is not required

and therefore it is suitable for moisture and heat sensitive materials.

For example, OraSolv® and DuraSolv® technologies are based on direct compression

(Habib et al. 2000). In OraSolv® technology, a pair of effervescent materials (i.e. an acid

source and a carbonate source) acts as a disintegrating agent, as well as assisting with

taste-masking and providing a pleasant “fizzing” sensation in the mouth (Pather et al.

2002, Fu et al. 2004). The fast disintegration (in 6 to 40 s) is achieved by compressing

water soluble excipients at lower compression forces than those used with conventional

tablets. Instead, in DuraSolv®, it is the large amounts of fast-dissolving excipients (e.g.

dextrose, mannitol, sorbitol, lactose or sucrose) in fine particle form that are responsible

for the fast dissolution of the tablet (Pather et al. 2002, Fu et al. 2004). DuraSolv® tablets

are harder and less friable than OraSolv® tablets, thus they can be packed into bottles or

blisters (Habib et al. 2000). For example, Remeron SolTab®, a product with the

antidepressant mirtazapine from Organon, is based on these technologies.

36

2.3.2.3 Other preparation techniques

In compression molding, the powder mixture of the drug and water-soluble excipients

is moistened with a solvent (ethanol or water) and then molded into tablets at low

compression forces (Bi et al. 1999, Fu et al. 2004). Instead, in heat molding, the drug is

dissolved or dispersed in a molten matrix or in no-vacuum lyophilization, the solvent

from a drug solution or suspension is evaporated at ambient pressure (Dobetti 2001, Fu et

al. 2004). In these cases, the drug remains dispersed as discrete particles or microparticles

in the matrix. These techniques produce relatively fast disintegrating (5-15 s), but weak

tablets. The manufacturing costs are high and the formulation may suffer from stability

problems (Dobetti 2001). In Flashdose® technology, an amorphous candyfloss or

shearform matrix, formed from saccharides or polysaccharides by simultaneous flash

melting and centrifugal force, is partially recrystallized in order to provide a compound

with good flowability and compressibility suitable for tableting (Habib et al. 2000,

Dobetti et al. 2001, Fu et al. 2004). The floss fibers are blended with the drug and

conventional excipients and compressed into tablets. The drug can be added to the floss

also before the flash heat process (Sastry et al. 2000).

2.3.2.4 Pharmacokinetic advantages of fast disintegrating tablets

The drugs typically formulated as FDTs are often intended for treating of allergy, pain

or mental disorders (Sastry et al. 2000, Fu et al. 2004), where a rapid onset of action

and/or ease of administration due to the patients’ age (pediatrics or geriatrics) and/or

physical condition are crucial. Immediate absorption of the drug from FDTs through oral

mucosa into the systemic circulation also produces high bioavailability for the kinds of

drugs that are subjected to extensive first pass metabolism. Increased bioavailability has

been observed with FDTs (Fu et al. 2004). For example, the bioavailability of selegiline

has been improved when it is administered in a Zydis® formulation due to the avoidance

of first-pass metabolism as a result of drug absorption in the pregastric region (Kearney

2002). Extremely fast tablet disintegration is required for rapid absorption of the drug

through the buccal or sublingual mucosa, but in addition to the formulation requirements,

37

the properties of the drug itself have to be appropriate. The drug has to be soluble, fast

dissolving and stable, but also small and lipophilic in order to pass through the oral

membranes (Bredenberg et al. 2003). Furthermore, due to the small volume of saliva in

the oral cavity, the therapeutic dose of an intraoral drug must be relatively small and in

most cases, dissolution enhancers must be applied (Jain et al. 2002). Thus, the difficulty

lies in resolving the problem of somehow dissolving a lipophilic drug rapidly in a small

volume of saliva. There are several approaches which can be utilized to overcome drug

solubility problems; these are discussed in the following sections.

2.4 Improvement of the dissolution rate of poorly soluble drugs

2.4.1 Solubility and dissolution rate

Solubility may be defined as the amount of a substance that dissolves in a given volume

of solvent at a specified temperature. Compound solubility can be defined as unbuffered

(i.e. in water), buffered (i.e. at a given pH) and intrinsic (i.e. solubility of the neutral form

of an ionizable compound) solubility (Alsenz and Kansy 2007). Dissolution is the process

by which the drug dissolves in a liquid and the rate at which this process takes place is

the dissolution rate. However, the difference between solubility and dissolution should be

noted: solubility implies that the dissolution process is completed and the solution is

saturated.

The relationship between the dissolution rate (dm/dt) and solubility (Cs) can be

expressed by the Noyes-Whitney equation (Eq. 4):

(4)

where m is the mass, t time, A the surface area of the dissolving solid, D the diffusion

coefficient, h the thickness of the diffusion layer and C the concentration in the

dissolution medium (Noyes and Whitney 1897). From Eq. 4, it can be seen that

parameters affecting the dissolution rate are the drug solubility, particle size of the drug

(since it affects the surface area of the drug solid) and the thickness of the diffusion layer.

)( CChDA

dtdm

s −×=

38

Thus, increasing the dissolution rate of a drug can be achieved by increasing the

solubility of the drug or the surface area available for dissolution (i.e. decreasing the

particle size). Solubility is an intrinsic material property and it can only be influenced by

chemical modification of the molecule, i.e. by making salt form (Bogardus and

Blackwood 1979, Huang and Tong 2004, Serajuddin 2007) or prodrug formation (Stella

and Nti-Addae 2007). In contrast, dissolution which is an extrinsic material property, can

be affected by various chemical, physical or crystallographic techniques, such as

complexation, modification of particle size, surface properties or solid state, or

solubilization enhancing formulation strategies (Table 2.1). With respect to approaches

used in dissolution enhancement of poorly soluble drugs, the focus in this thesis will be

on amorphous forms, particularly amorphous solid dispersions.

39Ta

ble

2.1.

App

roac

hes f

or im

prov

ing

solu

bilit

y an

d/or

diss

olut

ion

and

bioa

vaila

bilit

y of

poo

rly so

lubl

e dr

ugs.

Met

hod

Adv

anta

ges

Lim

itatio

nsR

efer

ence

sRe

duct

ion

ofpa

rticl

e si

ze(m

icro

niza

tion,

nano

sizin

g).

Nan

osiz

ing

(e.g

. by

high

pre

ssur

eho

mog

eniz

atio

n) m

ight

als

o in

crea

seth

e sa

tura

tion

solu

bilit

y of

a d

rug,

furth

er e

nhan

cing

the

diss

olut

ion

rate

.

Poor

flow

pro

perti

es, g

ener

atio

n of

stat

ic c

harg

es a

ndpa

rticl

e ad

hesi

on. M

icro

niza

tion

limit

of 2

-5 µ

mw

hich

is o

ften

not e

noug

h to

to im

prov

e th

e dr

ugdi

ssol

utio

n an

d bi

oava

ilabi

lity.

Pro

blem

s pro

duci

ngpa

rticl

es sm

alle

r tha

n 10

0 nm

(nan

osiz

ing)

.

Farin

ha e

t al.

2000

, Kar

avas

et a

l.20

06, K

esis

oglo

u 20

07, M

ülle

r and

Pete

rs 1

998,

Pat

rava

le e

t al.

2004

Com

plex

atio

n (e

.g.

by c

yclo

dext

rins

(CD

s))

Com

plex

atio

n w

ith

nativ

e or

chem

ical

ly m

odifi

ed C

Ds

incr

ease

s th

eap

pare

nt so

lubi

lity

of d

rugs

.

CD

s inc

reas

e th

e fo

rmul

atio

n bu

lk m

ass.

The

rate

at

whi

ch th

e dr

ug is

rele

ased

from

CD

mig

ht re

stric

tdr

ug a

bsor

ptio

n.

Bre

wst

er e

t al.

2007

, Bre

wste

r and

Lofts

son

2007

, Irie

and

Uek

ama

1997

, Raj

ewsk

i and

Ste

lla 1

996

Mod

ifica

tion

of th

eso

lid st

ate

(pol

ymor

phs,

pseu

dopo

lym

orph

s)

Diss

olut

ion

adva

ntag

e du

e to

diff

eren

tla

ttice

ene

rgie

s of d

rug

phys

ical

form

s.R

elat

ivel

y sm

all s

olub

ility

ben

efit

(less

than

10-

fold

)an

d th

e po

ssib

le c

onve

rsio

n to

mor

e st

able

and

less

solu

ble

form

s dur

ing

proc

essin

g, st

orag

e or w

hen

inco

ntac

t with

GI l

iqui

ds li

mit

the

expl

oita

bilit

y.To

xici

ty is

sues

with

solv

ates

.

Hua

ng a

nd T

ong

2004

, Kob

ayas

hi e

tal

. 200

0, M

urph

y et

al.

2002

, Sin

ghal

and

Cura

tolo

200

4, Z

hang

et a

l. 20

04

Mod

ifica

tion

of th

eso

lid st

ate

(am

orph

ous f

orm

s)

Adv

anta

ge u

p to

seve

ral h

undr

ed ti

mes

in d

isso

lutio

n be

twee

n am

orph

ous a

ndco

rres

pond

ing

crys

talli

ne fo

rm.

Prob

lem

s ass

ocia

ted

with

phy

sica

l and

che

mic

alsta

bilit

y du

ring

stor

age.

Dis

solu

tion

rate

adv

anta

ge o

fth

e am

orph

ous d

rug

form

mig

ht b

e lo

st d

ue to

solv

ent-m

edia

ted

crys

talli

zatio

n up

on d

isso

lutio

n.

Han

cock

and

Par

ks 2

000,

Hua

ng a

ndTo

ng 2

004,

Mos

harr

af e

t al.

1999

,Sa

vola

inen

et a

l. 20

09

Dru

g di

sper

sion

inca

rrie

rs (s

olid

disp

ersio

ns (S

Ds)

)

One

of t

he m

ost w

idel

y us

ed a

ndsu

cces

sful

stra

tegi

es to

impr

ove

the

diss

olut

ion

of p

oorly

solu

ble

drug

s.

Scal

e up

and

stab

ility

issu

es (s

olve

nt-m

edia

ted

devi

trific

atio

n, cr

ysta

lliza

tion

upon

pro

cess

ing

and

stora

ge).

Leun

er a

nd D

ress

man

200

0,Se

raju

ddin

199

9, S

ethi

a an

dSq

uilla

nte 2

003

Form

atio

n of

salts

D

rugs

with

ioni

zabl

e gr

oups

, suc

h as

carb

oxyl

ic a

cids

or a

min

es, f

orm

salts

with

app

ropr

iate

coun

terio

ns. T

hese

salts

hav

e hi

gher

solu

bilit

ies t

han

thei

rco

rres

pond

ing

acid

or b

asic

form

s.

Suita

ble

only

for w

eakl

y ac

idic

/bas

ic d

rugs

. Com

mon

ion

effe

ct m

ay lo

wer

solu

bilit

y/di

ssol

utio

n ra

te o

fH

Cl s

alts.

In v

ivo

conv

ersi

on o

f sal

t int

o ac

idic

/bas

icfo

rms m

ay in

hibi

t the

impr

ovem

ent o

f bio

avai

labi

lity.

A sa

lt fo

rm re

prer

esen

ts a

NC

E, th

us c

linic

al tr

ials

have

to b

e pe

rform

ed.

Bar

ich

et a

l. 20

05, B

ogar

dus a

ndB

lack

woo

d 19

79, C

harm

an a

ndC

harm

an 2

002,

Kar

avas

et a

l. 20

06,

Sera

judd

in 2

007

Prod

rugs

Use

of a

pol

ar p

rom

oiet

y m

ay b

e us

eful

whe

n us

ual a

ppro

ache

s fai

l.A

pro

drug

repr

esen

ts a

NC

E (c

linic

al tr

ials)

.St

ella

and

Nti-

Add

ae 2

007

40

2.4.2 Enhancement of the dissolution by using amorphous forms

2.4.2.1 Formation and properties of the amorphous state

There are two ways how a material may behave when a melt is cooled, which can be

seen from the enthalpy (H) (or specific volume (V)) –temperature diagram (Figure 2.2).

At Tm, the liquid state usually crystallizes, which leads to a contraction of the system due

to decrease in V and H. Alternatively, if the cooling rate is too fast to permit

crystallization, H and V may follow the equilibrium line of the liquid beyond the Tm into

the supercooled liquid region without showing any discontinuity in H and V. The

supercooled liquid is a nonequilibrium state relative to the crystalline state, but it is an

equilibrium state with respect to structural changes with temperature (Kawakami and

Pikal 2005). Thus, cooling causes direct corresponding changes in structure and

thermodynamic properties. As the viscosity of the material increases there is a reduction

in the molecular motions until the molecules move so slowly that they have no time to

rearrange themselves before the temperature is lowered further. Thus, a change in slope

(Figure 2.2) can be seen at the glass transition temperature (Tg), when the material enters

a glassy state where the disorder of the molecules is reduced (Hancock and Zografi 1997,

Craig et al. 1999, Kaushal et al. 2004). The real glass approaches the equilibrium glassy

state by spontaneous relaxation which decreases the energy (arrow a in Figure 2.2). When

the sample is heated near Tg (arrow b in Figure 2.2), the molecular mobility increases and

H recovers to the supercooled liquid state as shown by arrow c in Figure 2.2 (Kawakami

and Pikal 2005).

The amorphous state is characterized by the absence of the long-range three

dimensional molecular order. However, an amorphous solid may have a short-range

molecular order, i.e. a relationship between neighboring molecules (Hancock and Zografi

1997, Yu 2001). As a result of the higher internal energy, the amorphous state generally

has greater molecular motion and enhanced thermodynamic properties compared to the

crystalline state (e.g. solubility which can lead to enhanced dissolution and

bioavailability) (Hancock and Zografi 1997, Hancock and Parks 2000, Kaushal et al.

2004). The high internal energy and specific volume of the amorphous state are also

responsible for greater chemical reactivity and the tendency to crystallize (i.e. entry to a

41

lower energy state), possibly at different rates below and above Tg (Hancock and Zografi

1997, Yu 2001).

Figure 2.2. Schematic representation of enthalpy (or volume) versus temperature for aliquid capable of crystallizing and glass formation, where TK is the Kauzmanntemperature (or temperature of zero mobility), Tg is the glass transition temperature andTm the fusion temperature (Modified from Kawakami and Pikal 2005). Arrows a, b and cindicate the real glass approaching the equilibrium glassy state by spontaneous relaxation,heating the sample near to Tg and subsequent enthalpy recovery to the supercooled liquidstate, respectively.

Amorphous drugs can be prepared by a variety of technologies (Table 2.2) such as

rapid cooling from the melt, rapid precipitation from solution and mechanical activation

of the crystalline material (Hancock and Zografi 1997, Craig et al. 1999, Yu 2001,

Kaushal et al. 2004). Rapid precipitation from solution can be made by freeze-drying

(Guo et al. 2000, Surana et al. 2004, Abdul-Fattah et al. 2007) or spray drying

(Yonemochi et al. 1999a, Surana et al. 2004, Ohta and Buckton 2005, Vogt et al. 2008),

where process conditions can strongly influence the amount of amorphous material in the

end product and the physical properties of the final product (Corrigan et al. 2003, Ohta

and Buckton 2005, Moran and Buckton 2007).

Equilibrium glass

Ent

halp

y/vo

lum

e

Temperature

Real glass

Crystal

Supercooledliquid

Liquid

TmT

gT

K

ab

c

42Ta

ble

2.2.

Met

hods

for

pre

para

tion

of a

mor

phou

s fo

rms.

The

amor

phiz

atio

n m

echa

nism

s an

d so

me

deta

ils o

f th

e m

etho

ds a

repr

esen

ted.

Met

hod

Am

orph

izat

ion

mec

hani

smSp

ecifi

c in

form

atio

nR

efer

ence

sCo

olin

g fro

m th

em

elt

Cry

stalli

zatio

n is

avoi

ded

sinc

e th

e co

olin

g ra

te is

too

fast

or t

he c

ryst

alliz

atio

n its

elf i

s not

favo

red

beca

use

of m

olec

ular

shap

e, s

ize

or o

rient

atio

n (e

.g. w

ithpr

otei

ns).

Am

orph

ous c

elec

oxib

pre

pare

d in

situ

in D

SC w

asre

sista

nt to

cry

stal

lizat

ion

unde

r the

influ

ence

of

tem

pera

ture

and

/or p

ress

ure,

due

to it

s pro

tect

ion

from

the

exte

rnal

env

ironm

ent d

urin

g pr

epar

atio

n.Po

tent

ial f

or c

hem

ical

deg

rada

tion

of th

e dr

ug is

adr

awba

ck.

Han

cock

and

Zog

rafi

1997

, Gup

ta a

nd B

ansa

l20

05, P

atte

rson

et a

l.20

05

Free

ze-d

ryin

gEx

trem

ely

low

tem

pera

ture

s lim

it th

e m

olec

ular

mob

ility

and

pre

vent

nuc

leat

ion

of th

e m

ater

ial.

Proc

ess c

ondi

tions

, suc

h as

ann

ealin

g tim

e an

dte

mpe

ratu

re, m

ight

aff

ect e

.g. s

tabi

lity

of th

e en

dpr

oduc

t.

Abd

ul-F

atta

h et

al.

2007

,M

orris

et a

l. 20

01, Z

hang

et a

l. 20

04

Spra

y dr

ying

Fast

rem

oval

of s

olve

nt fr

om d

ropl

ets b

y ho

t air

lead

sto

form

atio

n of

am

orph

ous m

ater

ial o

r rap

idcr

ysta

lliza

tion

of a

met

asta

ble

phas

e.

Var

iatio

ns in

pro

cess

con

ditio

ns, s

uch

as fe

edso

lutio

n co

ncen

tratio

n or

inle

t-air

tem

pera

ture

, mig

htaf

fect

the

parti

cle

size

or s

urfa

ce p

rope

rties

and

thus

phys

ical

stab

ility

of a

mor

phou

s end

pro

duct

s.

Mor

an a

nd B

uckt

on20

07, O

hta

and

Buc

kton

2005

, Zen

g et

al.

2000

a

Grin

ding

/mill

ing

Mec

hani

cal s

tress

indu

ces d

efec

ts in

the

crys

tal l

attic

e.

The

effe

ctiv

enes

s of b

all m

illin

g is

depe

nden

t on

the

unit

cell

stru

ctur

e of

the

com

poun

d as

show

n w

ithca

rbam

azep

ine.

Mill

ing

perfo

rmed

far b

elow

Tg (

athi

gh e

noug

h in

tens

ity) h

as b

een

obse

rved

to re

sult

inam

orph

izat

ion

whi

le m

illin

g pe

rform

ed a

bove

Tg m

ayre

sult

in p

olym

orph

ic tr

ansf

orm

atio

ns. I

n th

e T

g

rang

e, b

oth

type

s of t

rans

form

atio

ns c

an o

ccur

depe

ndin

g on

the

mill

ing

inte

nsity

.

Des

cam

ps e

t al.

2007

,H

ütte

nrau

ch e

t al.

1985

,M

ura

et a

l. 20

02,

Patte

rson

et a

l. 20

05,

Yon

emoc

hi e

t al.

1999

a,b

43

2.4.2.2 Characterization of the amorphous state

A wide selection of techniques is available for the physical characterization of

amorphous solids, though they do not all provide the same information (Table 2.3). Basic

characterization can be conducted by X-ray diffractometry (XRD) techniques and

differential scanning calorimetry (DSC). The specificity and accurate quantitative nature

of XRD in detecting long-range molecular order has made it a standard method for

studying amorphous/crystalline systems. Temperature and environmental control makes

it possible to follow the kinetics of phase transformations (e.g. crystallization) (Byrn et al.

1999d). DSC is widely used for studying fundamental thermodynamic properties, such as

glass transitions, heat capacities and enthalpy changes of the amorphous state. However,

the influences of several experimental variables (e.g. sample size, heating and cooling

rate) can effect the type and quality of the data obtained (Bhugra et al. 2006, Vyazovkin

and Dranca 2006, Bhugra et al. 2008).

If one wishes to study pharmaceutical systems containing a few weight percent of

amorphous material, then isothermal microcalorimetry (IMC), solution calorimetry and

water vapour sorption techniques are the preferred means (Saleki-Gerhardt 1994, Mackin

et al. 2002, Ramos et al. 2005). If one wishes to quantify of the degree of crystallinity,

also solid state nuclear magnetic resonance spectroscopy (ssNMR) can be used. Instead

of recognizing long-range molecular order (like XRD), ssNMR is more sensitive to local

or “short-range” order, thus differences between the results obtained with XRD and

ssNMR are to be expected (Stephenson et al. 2001). In addition to quantifying the degree

of crystallinity, Fourier-transform infrared spectroscopy (FTIR), near-infrared

spectroscopy (NIR) and Raman spectroscopy have been used for determining the glass

transition temperature and mean molecular relaxation times (�) as a function of

temperature (Oksanen and Zografi 1993, Taylor and Zografi 1998, Stephenson et al.

2001, Lubach et al. 2007, Imamura et al. 2008). Due to enhanced sensitivity of FT-

Raman spectroscopy and its advantages, such as minimum sample preparation and

greater specificity relative to NIR, its application in quantitative analysis is predicted to

increase in the future (Stephenson et al. 2001). However, interpretation of spectral data is

often quite complex and thus supporting information obtained by other techniques may

44Ta

ble

2.3.

Tec

hniq

ues

for p

hysic

al c

hara

cter

izat

ion

of a

mor

phou

s sol

ids.

Met

hod

Obs

erva

tions

Spec

ific

info

rmat

ion

Ref

eren

ces

X-r

ay D

iffra

ctio

n(X

RD)

Shar

p di

ffrac

tion

peak

s ar

e vi

sibl

e in

the

case

of

crys

talli

ne m

ater

ial.

Am

orph

ous m

ater

ial s

how

s aha

lo p

atte

rn. S

uita

ble

for d

etec

ting

and

quan

tifyi

ngm

olec

ular

ord

er d

own

to le

vels

of a

bout

5%

.

Conv

entio

nal (

with

tem

pera

ture

and

envi

ronm

enta

l con

trol,

wid

e-an

gle

and

smal

l-ang

le te

chni

ques

(SA

XS)

are

appl

icab

le. N

onde

struc

tive.

Han

cock

and

Zog

rafi

1997

, Men

et a

l. 20

05, P

luta

and

Gal

eski

2007

, Roe

and

Cur

ro 1

983,

Sale

ki-G

erha

rdt e

t al.

1994

Vib

ratio

nal

spec

trosc

opy

(FTI

R, N

IR a

ndR

aman

)

Shar

p vi

brat

iona

l ban

ds o

bser

ved

in th

e ca

se o

fcr

ysta

lline

mat

eria

l. Fo

r am

orph

ous s

ampl

es, t

heba

nds a

re b

road

er.

Non

-des

truct

ive.

Ofte

n th

e sp

ectra

lfe

atur

es o

f diff

eren

t sol

id-s

tate

form

sov

erla

p in

whi

ch c

ase

spec

ial a

ppro

ache

sar

e ne

eded

in o

rder

to o

btai

n a

calib

ratio

ncu

rve

to q

uant

ify th

e de

gree

of

crys

talli

nity

.

Bug

ay 2

001,

Ste

phen

son

2001

,Ta

ylor

and

Zog

rafi

1998

Solid

-sta

teN

ucle

ar M

agne

ticR

eson

ance

Spec

trosc

opy

(ssN

MR

)

Peak

s are

shar

p fo

r cry

stal

line

solid

s and

bro

ad fo

ram

orph

ous s

olid

s. Q

uant

itativ

e an

alys

is o

fcr

ysta

lline

/am

orph

ous m

ixtu

res c

an b

e ac

hiev

edw

ithou

t the

nee

d fo

r sta

ndar

d cu

rve

prep

arat

ion.

Non

-des

truct

ive.

Eve

n w

hole

tabl

ets c

anbe

stud

ied

with

out d

isrup

ting

the

tabl

etstr

uctu

re a

nd th

e ph

ysic

al st

ate

of it

sco

nten

ts.

Luba

ch e

t al.

2007

, Tisc

mac

k et

al. 2

003

Diff

eren

tial

Scan

ning

Cal

orim

etry

(DSC

)

Shar

p fu

sion

endo

ther

m is

obs

erve

d fo

r cry

stal

line

solid

s. A

mor

phou

s/par

tially

am

orph

ous s

ampl

essh

ow g

lass

tran

sitio

n (T

g) w

ith/w

ithou

tre

crys

talli

zatio

n en

doth

erm

and

fusio

n en

doth

erm

.

Diff

icul

t to

quan

tify

low

leve

ls of

amor

phou

s con

tent

(i.e

. bel

ow 1

0%) w

ithco

nven

tiona

l DSC

. By

usin

g hi

gh sp

eed

DSC

(Hyp

er-D

SC) a

mor

phou

s con

tent

s as

low

as 1

.5%

can

be

dete

cted

.

Han

cock

and

Zog

rafi

1997

,Sa

leki

-Ger

hard

t et a

l. 19

94,

Saun

ders

et a

l. 20

04

Mod

ulat

edte

mpe

ratu

re D

SC(M

TDSC

)

The h

eat f

low

sig

nal i

s sep

arat

ed in

to re

vers

ing

(sho

win

g T g

) and

non

-rev

ersi

ng (s

how

ing

rela

xatio

nen

doth

erm

, rec

ryst

alliz

atio

n ex

othe

rm a

nd fu

sion

endo

ther

m) c

ompo

nent

s.

Enab

les t

he d

etec

tion

of h

idde

nph

enom

ena,

such

as o

verla

ppin

g T g

and

crys

talli

zatio

n. A

ble

to d

etec

t and

qua

ntify

low

am

orph

ous c

onte

nts.

Col

eman

and

Cra

ig 1

996,

Gui

not a

nd L

evei

ller 1

999,

Sakl

atva

la e

t al.

1999

Isot

herm

alM

icro

calo

rimet

ry(IM

C)

No

resp

onse

for c

ryst

allin

e sa

mpl

e, fo

r am

orph

ous

mat

eria

l a re

crys

talli

zatio

n ex

othe

rm is

obs

erve

d.M

easu

rem

ents

in c

onsta

nt re

lativ

ehu

mid

ity (R

H) o

r lin

earl

y ra

mpi

ng th

e RH

from

0 to

100

% a

re p

ossib

le. A

mor

phou

sco

nten

ts as

smal

l as 0

.5%

can

be

dete

cted

.

Lech

uga-

Bal

lest

eros

et a

l. 20

03,

Mac

kin

et a

l. 20

02, S

amra

and

Buc

kton

200

4

45So

lutio

nca

lorim

etry

Hig

h he

at o

f sol

utio

n fo

r cry

stal

line

mat

eria

ls an

dlo

w h

eat o

f sol

utio

n fo

r am

orph

ous m

ater

ials.

Am

orph

ous c

onte

nts a

s sm

all a

s 0.5

% c

anbe

det

ecte

d. F

or e

xam

ple,

for l

acto

seso

lutio

n ca

lorim

etry

has

bee

n re

porte

d to

give

mor

e pre

cise

resu

lts th

an IM

C.

Hog

an a

nd B

uckt

on 2

000,

Ram

os e

t al.

2005

Die

lect

ricA

naly

sis (

DEA

)N

o re

spon

se fo

r cry

stal

line

sam

ple,

die

lect

ric lo

ss a

tT g

for a

mor

phou

s mat

eria

ls.

Poss

ible

to m

onito

r a ra

nge

of lo

wte

mpe

ratu

re tr

ansi

tions

ass

ocia

ted

with

chan

ges

in m

olec

ular

mob

ility

.

Cra

ig 1

996,

Dud

du a

ndSo

kolo

ski 1

995

Dyn

amic

alM

echa

nic

Ana

lysi

s (D

MA

)

The m

echa

nica

l pro

perti

es o

f a sa

mpl

e ar

e m

easu

red

as a

func

tion

of te

mpe

ratu

re. A

mor

phou

s sam

ple

show

s a la

rge

chan

ge in

thes

e pr

oper

ties a

t Tg.

Ver

y se

nsiti

ve te

chni

que

for t

heid

entif

icat

ion

and

char

acte

rizat

ion

of g

lass

trans

ition

s, us

ually

with

pol

ymer

s.

Roy

all e

t al.

2005

Visc

omet

ryD

ecre

ase

in v

isco

sity

is c

ontin

uous

for c

ryst

allin

em

ater

ials

, whi

le a

sudd

en d

ecre

ase

in v

iscos

ity is

seen

abo

ve T

g for

am

orph

ous s

ampl

es.

Expe

rimen

tal d

iffic

ultie

s hav

e re

stric

ted

the u

se o

f the

met

hod.

And

roni

s and

Zog

rafi

1997

,H

anco

ck a

nd Z

ogra

fi 19

97

Den

sity

Den

sity

of a

cry

stal

line

mat

eria

l is h

ighe

r tha

n th

atof

the

corr

espo

ndin

g am

orph

ous

form

.Y

u 20

01

Gra

vim

etric

wat

erab

sorp

tion

An

over

all m

ass l

oss i

s obs

erve

d as

a c

lear

hum

p in

the

sorp

tion

diag

ram

in th

e ca

se o

f cry

stal

lizat

ion.

Cry

stal

lizat

ion

proc

ess c

an b

e st

udie

d by

mon

itorin

g th

e m

ass c

hang

e of t

he m

ater

ial

as a

func

tion

of ti

me

at g

iven

con

ditio

ns,

since

am

orph

ous m

ater

ial a

dsor

bsre

lativ

ely

larg

e am

ount

s of w

ater

vap

oran

d, w

hen

crys

talli

zing

, giv

es u

p th

e ex

tram

oist

ure

due

to d

ecre

ased

sorp

tion

capa

city

of t

he c

ryst

allin

e m

ater

ial.

Bur

nett

et a

l. 20

04, N

ewm

an e

tal

. 200

8

Pola

rized

ligh

tm

icro

scop

eB

irefr

inge

ncy

in th

e ca

se o

f cry

stal

line

mat

eria

lun

der p

olar

ized

ligh

t.Po

lariz

ed li

ght i

s ref

ract

ed fr

om th

e cr

ysta

lpl

anes

and

is se

en a

s brig

ht a

reas

in th

ein

spec

tion

unde

r the

mic

rosc

ope.

Byr

n et

al.

1999

c

46

be needed (Bugay 2001). Raman spectroscopy is sensitive to changes in intramolecular

conformations and intermolecular interactions arising from changes in solid state

structure. The changes in the spectra between the different solid-state forms are often

very small, but when combined with suitable data-analysis method (e.g. partial least

squares discriminant analysis, PLS-DA, and partial least squares regression analysis,

PLS), Raman spectroscopy can be used for monitoring and quantifying the solid-phase

transition occurring during the dissolution of amorphous drugs (Savolainen et al. 2009).

Thus, there are many suitable methods available for the characterization of amorphous

materials. However, none of these methods is sufficient per se, instead a detailed

characterization of an amorphous material should always involve the combination of

spectroscopic, X-ray diffraction and thermal methods.

2.4.2.3 Stability of amorphous drugs

Since the amorphous forms are unstable, they tend to revert back to a crystalline form

with the passage of time. Prediction of the crystallization timescale is very important and

it can be achieved by understanding the physicochemical properties of the drug in

question combined with some knowledge of the general principles of crystallization.

Based on these parameters, optimized storage conditions can be determined and shelf-life

predicted.

Crystallization from the amorphous state is primarily governed by the same factors that

determine crystallization from the melt (Hancock and Zografi 1997). As can be seen from

Figure 2.3, in the case of amorphous materials, the rate of nucleation increases as the

temperature decreases due to increased viscosity. However, molecular motion decreases

as the temperature decreases (particularly below Tg), which slows the molecular diffusion

and reduces the crystallization rate. Thus, the maximum rate of crystallization occurs

somewhere between Tm and Tg (Hancock and Zografi 1997, Craig et al. 1999). Storing

the amorphous material below Tg should lower the risk of devitrification due to low

molecular mobility (Saleki-Gerhardt and Zografi 1994). However, this is far from a

guarantee of stability, since molecular mobility is present also below Tg and it might be

sufficient to result in devitrification during the typical storage times for pharmaceutical

products (Craig et al. 1999). Furthermore, amorphous materials with similar Tg values

47

might show different stability profiles when stored below their Tg values, e.g. due to

variations in their steric structure and hydrogen bonding of the molecules within the

materials (Fukuoka et al. 1989). Furthermore, the presence of water in storage conditions

may plasticize the material sufficiently to lower the Tg value to that of the storage

temperature, increasing the rate of crystallization and reducing the crystallization

temperature (Hancock and Zografi 1994, Ward and Schultz 1995, Jouppila et al. 1998). It

has been suggested that storage at TK, i.e. at the temperature of zero mobility, would

ensure sufficient physical stability for amorphous materials (Craig et al. 1999, Yu 2001,

Kaushal et al. 2004). For many fragile glasses, TK is approximately 50 K below Tg and

for strong glass formers it is even lower (Yu 2001). Unfortunately, for the majority of

compounds, TK lies near to refridgeration temperature which is impractical for product

handling and storage (Craig et al. 1999, Kaushal et al. 2004). However, this approach can

be used as a way of estimating possible stability problems. A more concrete perspective

on stability characteristics of the material can be achieved by estimation of �-values over

a range of conditions, which allows an insight into the relationship between molecular

mobility and temperature (Hancock et al 1995).

Figure 2.3. Schematic representation of the temperature dependence of the crystallizationprocess for an amorphous system (modified from Hancock and Zografi 1997).

The use of amorphous drugs in dosage forms is restricted by problems associated with

changes in physical and chemical stability during their storage. Furthermore, regardless

Tg Tm Temperature

Nucleation

Molecular motion

48

of possible stability in dry conditions, the solubility and dissolution rate advantage of the

amorphous drug form might be lost due to solvent-mediated crystallization upon

dissolution (Mosharraf et al. 1999, Hancock and Parks 2000, Savolainen et al. 2009).

Thus, one must find ways for stabilizing the amorphous drug forms during their shelf-life

and inhibiting their crystallization after administration. It is known that inclusion of

materials with high Tg values may improve the physical stability of amorphous drugs by

raising the Tg of the binary system (Yoshioka et al. 1995, Kakumanu and Bansal 2002).

Therefore, possibility of formulating the high-energy amorphous drugs in the form of

solid dispersions has generated huge interest. In addition to improved stability, solid

dispersion systems may demonstrate increases in solubility in the range of orders of

magnitude and provide markedly increased dissolution and absorption properties (Chiou

and Riegelman 1971, Serajuddin 1999, Leuner and Dressman 2000, Sethia and Squillante

2003, Vasconcelos et al. 2007).

2.4.3 Enhancing the dissolution by using solid dispersions

Solid dispersions (SDs) are defined as a range of pharmaceutical products with one or

more drugs homogenously dispersed in an inert carrier or matrix in a solid state, prepared

by the melting, solvent or melting-solvent methods (Craig 2002, Sethia and Squillante

2003, Kaushal et al. 2004).

SDs are divided into different types according to their physicochemical properties. A

broad distinction can be made based on the physical state of the drug within the system,

i.e. is it crystalline or amorphous. In eutectic and monotectic systems, both the drug and

carrier are present in the crystalline state. In eutectic systems, the drug and carrier are

completely miscible in the liquid (molten) state, and when cooling their mixture with the

eutectic composition they form a microfine physical mixture with a lower melting point

than the drug or the carrier alone (Leuner and Dressman 2000, Craig 2002, Vippagunta et

al. 2007). In monotectic systems, the melting point of the carrier does not change in the

presence of the drug (Vippagunta 2007). In eutectic drug/hydrophilic carrier systems, the

highly water soluble carrier dissolves quickly in an aqueous medium, releasing very fine

drug crystals and this drug size reduction has been noted to be responsible for improved

49

dissolution rate e.g. as observed for fenofibrate and loperamide in SDs with poly(ethylene

glycols) (PEGs) (Law et al. 2003, Weuts et al. 2005a).

In the second SD type, the drug may be dispersed as a separate amorphous or

crystalline phase (or some combination of the two) in a glassy matrix (i.e. solid

suspensions) (Craig 2002, Vasconcelos et al. 2007). These types of SDs are typically

formed with amorphous polymers, such as polyvinyl pyrrolidone (PVP) (Van den Mooter

et al. 1998, Sethia and Squillante 2004), or with semicrystalline materials, such as PEG

(Van den Mooter et al. 1998, Nair et al. 2002, Verheyen et al. 2002, Karavas et al.

2007b). In addition, complex formation might be possible with some carriers, such as

PVP (Garekani et al. 2003).

The third SD type is a solid solution in which the drug and carrier are totally miscible

with each other, and as a result of specific molecular interactions, the drug is present as a

molecular dispersion within the carrier (Leuner and Dressman 2000, Craig 2002, Sethia

and Squillante 2003, Kaushal et al. 2004, Vasconcelos et al. 2007). Solid solutions can be

further subdivided either according to their miscibility (continuous or discontinuous solid

solutions) or according to the way in which the drug molecules are distributed in the

matrix (substitutional, interstitial or amorphous) (Leuner and Dressman 2000). Few

drug/carrier systems have been observed to be continuous solid solutions, i.e. the

situation when the components are miscible with each other in all proportions (Shamblin

et al. 1998, Konno and Taylor 2006). Instead, discontinuous solid solutions are more

common, where the miscibility of the components with each other is limited (Craig 1990,

Leuner and Dressman 2000). For example, the solid solubility of trehalose in dextrose

has been found to be less than 10 % (w/w) (Vasathavada et al. 2004) and the solubility of

different drug molecules with PEGs has been reported as being less than 15% (Law et al.

2001, Urbanetz and Lippold 2005).

In addition to these classical SDs, "third generation" SDs, i.e ternary SDs, which

contain a mixture of polymers and/or surfactants as carriers (Mura et al. 1999, Mura et al.

2005, Vasconcelos et al. 2007) have been prepared. In these SDs, the carrier properties

are tailored to the needs of the drug in order to keep the drug molecularly dispersed at

higher drug loads (Janssens et al. 2008a-c).

50

2.4.3.1 Preparation of solid dispersions

The preparation methods of SDs can be roughly separated into two categories: melt

(fusion) methods and solvent evaporation methods (Table 2.4). Melt methods include

traditional hot melting, melt extrusion, direct capsule filling, compression moulding and

hot spin melting (Leuner and Dressman 2001). The solvent methods include traditional

solvent evaporation e.g. by spray or freeze-drying, supercritical fluid (SCF) technology,

co-precipitation and spin-coating. SDs prepared by solvent methods are often called

coprecipitates instead of coevaporates, even though this term is only correct for SDs

prepared by precipitation methods. The most widely used techniques in the small-scale

preparation of SDs are traditional melting or solvent evaporation methods, but their scale-

up problems have led to the development of new methods which are suitable for large-

scale production, such as melt extrusion or SCF technology (Leuner and Dressman 2001).

There are only a few studies which have compared the traditional methods to the newer

ones, e.g. coevaporation has been observed to result in a higher amorphous content of the

drug than SCF technology, which in turn resulted in smaller amount of residual solvent

and thus more free flowing powders (Sethia and Squillante 2002, Majerick et al. 2007).

In addition to the methods reviewed in Table 2.4, simple kneading (Modi and Tayade

2006) and spray freeze drying, a potential method for incorporating labile drugs in a

stabilizing carrier (van Drooge et al. 2005), have been used in the preparation of SDs.

Furthermore, techniques such as a combustion dryer system (Xu et al. 2007) and a pulse

dropping method (Bashiri-Shahroodi et al. 2008) have been studied as novel, potential

preparation methods for SDs.

51Ta

ble

2.4.

An

over

view

of p

repa

ratio

n m

etho

ds o

f sol

id d

ispe

rsio

ns.

Met

hod

Spec

ific

info

rmat

ion

Lim

itatio

nsR

efer

ence

sH

ot m

eltin

gPh

ysic

al m

ixtu

re o

f the

dru

g an

d ca

rrie

r is

mel

ted

or th

e dr

ug is

mix

ed w

ith m

olte

n ca

rrie

r,th

e m

elt i

s coo

led

and

then

pul

veriz

ed. R

apid

cool

ing

lead

s to

supe

rsat

urat

ion

of th

e dr

ug in

the

carr

ier m

atrix

. Sim

ple

and

econ

omic

alm

etho

d.

Man

y dr

ugs

mig

ht b

e de

grad

ed o

rev

apor

ated

at t

he h

igh

tem

pera

ture

s use

d.M

iscib

ility

of t

he d

rug

and

carr

ier i

n th

em

olte

n fo

rm is

nec

essa

ry. M

isci

bilit

y ga

psle

ad to

a p

rodu

ct th

at is

not

mol

ecul

arly

disp

erse

d. N

ot id

eal f

or sc

ale-

up.

Aso

and

Yos

hiok

a 20

05, B

rom

an e

tal

. 200

1, L

eune

r and

Dre

ssm

an20

00, M

ura

et a

l. 19

99, S

ethi

a an

dSq

uilla

nte 2

003,

Urb

anet

z an

dLi

ppol

d 20

05, V

asco

ncel

os e

t al.

2007

, Ver

heye

n et

al.

2001

Hot

mel

t ext

rusi

on

The d

rug-

carr

ier m

ixtu

re is

sim

ulta

neou

sly

mel

ted

and

hom

ogen

ized

, typ

ical

ly in

a c

o-ro

tatin

g tw

in-s

crew

ext

rude

r, th

en e

xtru

ded

and

shap

ed a

s gra

nule

s, pe

llets,

shee

t or t

able

ts in

ash

apin

g de

vice

. Sho

rt ex

posu

re to

hig

hte

mpe

ratu

res a

llow

s pro

cess

ing

of re

lativ

ely

ther

mol

abile

dru

gs. A

bsen

ce o

f org

anic

solv

ents

, con

tinuo

us o

pera

tion

poss

ibili

ty,

min

umun

pro

duct

was

tage

, goo

d co

ntro

l of

oper

atio

n pa

ram

eter

s and

thus

goo

d po

tent

ial f

orsc

ale-

up. M

elt e

xtru

sion

of m

isci

ble

com

pone

nts l

eads

to fo

rmat

ion

of a

sol

idso

lutio

n.

Extru

sion

tem

pera

ture

s 10-

20°C

abo

ve th

eT g

or T

m o

f the

pol

ymer

are

requ

ired

toas

sure

pro

per m

ater

ial f

low

in th

e ex

trude

r→

eff

ectiv

e pl

astiz

atio

n of

the

poly

mer

is a

chal

leng

e. L

abor

ator

y sc

ale

extru

ders

requ

ire la

rge

amou

nts o

f dru

g.

Bro

man

et a

l. 20

01, C

hoks

hi e

t al.

2005

, For

ster

et a

l. 20

01,

Ghe

brem

eske

l et a

l. 20

07, L

eune

ran

d D

ress

man

200

0, S

ethi

a an

dSq

uilla

nte 2

002,

Set

hia

and

Squi

llant

e 200

3

Dire

ct c

apsu

lefil

ling

Dire

ct fi

lling

of h

ard

gela

tin c

apsu

les w

ith th

em

elt o

f sol

id d

ispe

rsio

ns. P

ossib

le g

rindi

ng-

indu

ced

chan

ges i

n th

e cr

ysta

llini

ty o

f the

dru

gar

e av

oide

d. L

arge

-sca

le m

anuf

actu

reeq

uipm

ent c

omm

erci

ally

ava

ilabl

e.

Not

suita

ble

for t

herm

olab

ile d

rugs

.So

lubi

lity

of th

e dr

ug in

the

carri

er is

requ

ired.

Row

ley

et a

l. 19

98, S

ethi

a an

dSq

illan

te 2

003

Com

pres

sion

mou

ldin

gM

ixtu

re o

f the

dru

g an

d ca

rrie

r is c

ompr

esse

dun

der e

leva

ted

tem

pera

ture

. Pro

duce

s an

intim

ate

cont

act a

nd m

ixin

g of

the

mol

ten

com

pone

nts.

Suita

ble

for l

arge

-sca

le p

rodu

ctio

nof

SD

s.

Not

suita

ble

for t

herm

olab

ile d

rugs

.B

rom

an e

t al.

2001

c

ont.

52Ta

ble

2.4.

An

over

view

of p

repa

ratio

n m

etho

ds o

f sol

id d

ispe

rsio

ns (c

ont.)

.M

etho

dSp

ecifi

c in

form

atio

nLi

mita

tions

Ref

eren

ces

Solv

ent

evap

orat

ion

The d

rug

and

carr

ier a

re d

isso

lved

in a

com

mon

solv

ent f

ollo

wed

by

solv

ent e

vapo

ratio

n, e

.g. b

yro

tary

eva

pora

tor,

nitro

gen

stre

am, v

acuu

mdr

ying

, spr

ay d

ryin

g an

d fre

eze-

dryi

ng, i

n or

der

to o

btai

n a

solid

resi

due.

Low

ope

ratio

nte

mpe

ratu

re p

reve

nts t

herm

al d

egra

datio

n.A

llow

s for

pre

para

tion

of so

lid so

lutio

ns.

Diff

icul

ties t

o fin

d a

com

mon

solv

ent.

The

use

of o

rgan

ic so

lven

ts an

d di

fficu

lties

into

tally

rem

ovin

g th

em (e

nviro

nmen

tal a

ndto

xici

ty is

sues

). H

igh

prep

arat

ion

cost

s.Sm

all v

aria

tions

in p

roce

ssin

g co

nditi

ons

may

lead

to la

rge

chan

ges i

n pr

oduc

tpe

rform

ance

.

Am

bike

et a

l. 20

05, B

rom

an et

al.

2001

, Kar

avas

et a

l. 20

07b,

Leu

ner

and

Dre

ssm

an 2

001,

Van

den

Moo

ter

et a

l. 19

98, S

ethi

a an

d Sq

illan

te 2

003,

Shah

et a

l. 19

95, S

ham

blin

et a

l.19

98, v

an D

roog

e et

al.

2004

a,V

asan

thav

ada

et a

l. 20

04,

Vas

conc

elos

et a

l. 20

07Su

perc

ritic

al fl

uid

(SCF

) tec

hnol

ogy

CO

2 is

the

mos

t com

mon

SC

F us

ed si

nce

it is

nont

oxic

, non

-flam

mab

le, i

nexp

ensiv

e, an

d ha

sa

low

crit

ical

tem

pera

ture

whi

ch m

akes

itsu

itabl

e fo

r hea

t-lab

ile m

olec

ules

. Sev

eral

tech

niqu

es, e

.g.

RES

S, G

AS,

SA

S, A

SES,

SED

S an

d PG

SS h

ave

been

use

d fo

r pre

para

tion

of S

Ds.

Sing

le st

ep p

roce

ssin

g gi

ves

mic

roni

zed

and

solv

ent-f

ree

parti

cles

. Dru

gs se

nsiti

ve to

heat

, lig

ht o

xida

tion

or h

ydro

lysis

can

be

proc

esse

d. S

cale

up

is po

ssib

le.

Proc

ess d

esig

n an

d sc

ale-

up re

quire

sfu

ndam

enta

l und

ersta

ndin

g of

the

ther

mop

hysi

cal p

roce

ss.T

he a

pplic

abili

ty o

fR

ESS

is lim

ited

by th

e ve

ry lo

w so

lubi

lity

ofm

ost d

rugs

and

pol

ymer

s in

CO

2.

Jun

et a

l. 20

05, J

uppo

et a

l. 20

03,

Ker�

et a

l. 19

99, L

ee e

t al.

2005

,M

ajer

ick

et a

l. 20

07, M

oneg

hini

et a

l.20

01, S

ethi

a an

d Sq

uilla

nte

2003

,W

on et

al.

2005

Co-

prec

ipita

tion

A n

on-s

olve

nt is

add

ed d

ropw

ise to

the

drug

and

carr

ier s

olut

ion

unde

r con

stant

stir

ring.

Even

tual

ly, t

he d

rug

and

carr

ier a

re c

o-pr

ecip

itate

d as

mic

ropa

rticl

es.

Vas

conc

elos

et a

l. 20

07

Spin

-coa

ting

Solu

tion

of th

e dr

ug a

nd c

arrie

r in

a co

mm

onso

lven

t is e

vapo

rate

d by

dro

ppin

g th

e so

lutio

non

a sp

inni

ng su

bstra

te. H

eatin

g is

requ

ired

tore

mov

e re

sidua

l sol

vent

. The

resu

lt is

anop

tical

ly tr

ansp

aren

t thi

n fil

m. S

uita

ble

for

moi

stur

e-se

nsiti

ve d

rugs

sinc

e it

is p

erfo

rmed

unde

r dry

con

ditio

ns.

Kon

no a

nd T

aylo

r 200

6, M

arsa

c et

al.

2006

a, V

asco

ncel

os e

t al.

2007

53

2.4.3.2 Carrier materials

Carrier materials used in SDs are generally hydrophilic substances with varying

physicochemical properties, ranging from low molecular weight sugars to high molecular

weight polymers. Several factors should be considered when selecting a carrier, e.g. the

solubility of the drug in the carrier, mechanism of the inhibition of the crystal growth,

carrier's ability to enhance the dissolution rate and possible toxicity.

The carrier materials commonly used for preparation of SDs are presented in Table 2.5,

though different grades of PVP and PEG, either alone or in combinbation of surface

active ingredients, have become the most popular carriers (Leuner and Dressman 2001,

Sethia and Squillante 2003, Kaushal et al. 2004). In addition to the carriers shown in

Table 2.5, other polymers such as HPC (Ambike et al. 2004), poly (acrylic acid) (PAA)

(Broman et al. 2001, Weuts et al. 2005c), poly (vinylpyrrolidone-co-vinylacetate)

(PVP/VA) (Matsumoto and Zografi 1999, Weuts et al. 2005b), povidone (Nair et al.

2002); block copolymers such as Lutrol F127 (Poloxamer) and Pluronic F68 (Vippagunta

et al. 2002, Ahuja et al. 2007); sugars such as chitosan, inulin, mannitol and sorbitol

(Asada et al. 2004, van Drooge et al. 2004b, Ahuja et al. 2007); organic acids such as

citric acid and urea (Lu and Zografi 1998, Ahuja et al. 2007) have been used as carriers in

the preparation of SDs. In order to improve the miscibility of the drug in the carrier

matrix and the dissolution rate of the drug, ternary SDs with carrier combinations of e.g.

PEG and surfactants (sodium dodecyl sulfate (SDS), Tween 60, Tween 80) (Mura et al.

1999, 2005), and PEG and HPMC (Janssens et al. 2008a, 2008c) have been successfully

prepared.

54Ta

ble

2.5.

Car

riers

com

mon

ly u

sed

in so

lid d

ispe

rsio

ns.

Car

rier

Prop

ertie

s/ad

vant

ages

Lim

itatio

nsR

efer

ence

sPo

lyet

hyle

ne g

lyco

l(P

EG)

PEG

s in

mol

ecul

ar w

eigh

t ra

nge

of 1

500-

2000

0 ar

e us

ually

em

poly

ed.

PEG

s in

thi

sM

W

rang

e ar

e se

mi-c

ryst

allin

e an

d w

ater

solu

ble.

Th

e cr

ysta

lline

pa

rt m

ay

exist

in

exte

nded

or

fold

ed f

orm

s. PE

Gs

are

suita

ble

for

mel

ting

and

solv

ent

prep

arat

ion

met

hods

.So

lubi

lizat

ion

and

impr

oved

wet

tabi

lity

of th

edr

ug im

prov

e di

ssol

utio

n.

Mol

ecul

ar

disp

ersio

ns

with

PE

G

(with

limite

d dr

ug s

olub

ility

in

PEG

) ha

ve b

een

prep

ared

for

onl

y a

few

dru

gs.

The

drug

rele

ase

is de

pend

ent

on P

EG M

W a

nd t

heam

ount

of

PE

G

in

the

SD.

Stab

ility

prob

lem

s dur

ing

prep

arat

ion

or s

tora

ge. U

seof

low

MW

PEG

s an

d/or

a d

rug

havi

ngpl

astic

izin

g ef

fect

mig

ht r

esul

t in

sof

t an

dta

cky

prod

uct.

Ang

uian

o-Ig

ea

et

al.

1995

, C

raig

1990

, Dam

ian

et a

l. 20

00, D

ordu

noo

et a

l. 19

97,

Kar

avas

et

al.

2007

b,K

hoo

et a

l. 20

00,

Law

et

al.

2001

,20

03,

Mon

eghi

ni e

t al

. 20

01,

Van

den

Moo

ter

et a

l. 19

98, N

air

et a

l.20

02, P

erng

et a

l. 19

98, U

rban

etz

etal

. 20

05,

Urb

anet

z 20

06,

Ver

heye

net

al.

2001

, 200

2, W

euts

et a

l. 20

05a

Poly

viny

l pyr

rolid

one

(PV

P)A

mor

phou

s pol

ymer

, gra

des

from

K12

to K

30(M

W 2

500

to 5

0000

) hav

e be

en u

sed

for S

Ds.

Goo

d so

lubi

lity

in w

ater

or

orga

nic

solv

ents,

solu

bilit

y in

wat

er d

ecre

ases

with

inc

reas

ing

MW

. G

ood

for

prep

arat

ion

of

SDs

with

solv

ent

met

hod.

Sol

ubili

zatio

n an

d im

prov

edw

etta

bilit

y of

the

dru

g im

prov

e di

ssol

utio

n.A

ntip

last

izat

ion

and

hydr

ogen

bo

ndin

gin

tera

ctio

ns

stab

ilize

dr

ug/P

VP

SDs.

Mol

ecul

ar d

isper

sions

with

man

y dr

ugs

have

been

pre

pare

d.

Use

in h

ot m

elt m

etho

d lim

ited

due

to h

igh

T g.

The

drug

rel

ease

is

depe

nden

t on

PV

PM

W

sinc

e in

crea

sed

visc

osity

w

ithin

crea

sed

MW

reta

rds

drug

dis

solu

tion,

and

on t

he a

mou

nt o

f PV

P in

the

SD

, sin

cehi

gher

pro

porti

on o

f PV

P re

sults

in

drug

amor

phiz

atio

n an

d hi

gher

solu

biliz

atio

n.

Am

bike

et

al.

2004

, C

row

ley

and

Zogr

afi

2003

, K

arav

as e

t al

. 20

05,

2007

b,

Kon

no

and

Tayl

or

2006

,M

atsu

mot

o an

d Zo

graf

i 19

99,

Van

den

Moo

ter

et a

l. 19

98,

Van

den

Moo

ter

2001

, Pa

radk

ar e

t al

. 20

04,

Pern

g et

al

. 19

98,

Seth

ia

and

Squi

llant

e 20

04,

Sham

blin

et

al

.19

98,

Tant

ishai

yaku

l et

al

. 19

99,

Tayl

or

and

Zogr

afi

1997

,V

asan

thav

ada

et a

l. 20

04,

2005

HPM

C/H

PMCA

STh

e m

olec

ular

wei

ght r

ange

s of

HPM

Cs fr

om10

000

to 1

5000

00 a

re u

sed.

SD

s bo

th w

ithso

lven

t and

mel

t met

hods

hav

e be

en p

repa

red.

Add

ition

of s

hort

chai

n le

ngth

PEG

s to

HPM

Cha

s be

en

obse

rved

to

le

ad

to

a fu

rther

impr

ovem

ent

of

drug

di

ssol

utio

n w

ithou

tco

mpr

omisi

ng st

abili

ty.

Jans

sens

et a

l. 20

08a,

200

8c, K

onno

et a

l. 20

08, S

ix e

t al.

2003

, Tan

no e

tal

. 200

4, W

on e

t al.

2005

55G

eluc

ires

Satu

rate

d po

lygl

ycol

ized

gly

cerid

es c

onsi

sting

of a

wel

l-def

ined

mix

ture

of

mon

o-,

di-

and

trigl

ycer

ides

an

d m

ono-

an

d di

-fat

ty

acid

este

rs o

f PE

G 1

500.

Gra

des

of 4

4/14

and

50/1

3, h

ave

been

use

d. S

uita

ble

for

mel

ting

and

solv

ent

met

hods

. So

lubi

lize

lipop

hilic

drug

s in

co

ntac

t w

ith

aque

ous

med

ium

faci

litat

ing

drug

abs

orpt

ion.

Agi

ng e

ffect

due

to li

pidi

c na

ture

whi

ch c

anbe

red

uced

by

form

ulat

ing

Gel

ucire

s w

ithot

her c

arrie

rs e

g. P

VP.

Ahu

ja e

t al.

2007

, Dam

ian

et a

l.20

00, K

hoo

et a

l. 20

00, S

ethi

a an

dSq

uilla

nte

2002

, 200

4, S

him

pi e

t al.

2005

, Vip

pagu

nta

et a

l. 20

02

Vita

min

E T

PGS

Prep

ared

by

este

rific

atio

n of

the

acid

gro

up o

fd-α

-toco

pher

yl a

cid

succ

inat

e by

PEG

100

0.Su

rface

act

ive

and

mis

cibl

e w

ith w

ater

in a

llpa

rts.

Low

crit

ical

mic

elle

con

cent

ratio

n an

dm

eltin

g po

int.

Suita

ble

for

mel

ting

and

solu

tion

met

hods

.

May

req

uire

mix

ing

with

oth

er c

arrie

rs i

nor

der

to i

ncre

ase

the

mel

ting

poin

t of

the

SD.

Kho

o et

al

. 20

00,

Seth

ia

and

Squi

llant

e 20

02,

2004

, Sh

in

and

Kim

200

3

Poly

(eth

ylen

e ox

ide)

(PEO

)C

ryst

allin

e,

non-

ioni

c hy

drop

hilic

po

lym

er.

The

chem

ical

stru

ctur

e of

the

repe

atin

g un

it is

iden

tical

to

th

at

of

PEG

, bu

t th

e PE

Om

olec

ular

wei

ght i

s sig

nific

antly

hig

her.

Low

proc

essi

ng t

empe

ratu

re i

n m

eltin

g m

etho

d is

an a

dvan

tage

.

Poss

ible

stab

ility

pro

blem

s due

tocr

ysta

lline

nat

ure o

f PEO

.B

rom

an e

t al.

2001

, Li e

t al.

2006

,Sc

hach

ter e

t al.

2004

56

2.4.3.3 Physical characterization of solid dispersions

The basic questions in the physical characterization of SDs are: what are the changes

occurring in the physical state of the drug during preparation and storage of the SD, and

are there interactions present between the drug and the carrier? The methods for

characterization of the amorphous state, the basic features of which were discussed in

Table 2.3, are suitable and also widely used for general characterization of the SDs

(Leuner and Dressman 2000, Sethia and Squillante 2003). However, the sensitivities of

the methods are different, the obtained results might be conflicting and thus care is

required in their accurate interpretation. For example, a lack of drug melting endotherm

usually points to the presence of the drug in amorphous form in the SD. However, in PEG

SDs, PEG often has a lower melting point than the drug, and thus a crystalline drug might

dissolve in the melted PEG during the DSC scan (Damian 2000, Nair et al. 2002, Mura et

al. 2005). Thus, the lack of a drug melting endotherm might be misinterpreted as the

presence of an amorphous form. However, by performing hot stage-microscopy (HSM)

measurements, the possible drug dissolution in PEG can be visually confirmed (Mura et

al. 2005). In addition, the true drug physical state must be verified with XRPD (Nair et al.

2002).

IR-spectroscopy is mainly used for the assessment of molecular interactions (i.e.

hydrogen bonding) within the SDs (Taylor and Zografi 1997), since these interactions

give rise to band shifts and broadening of the peaks which are characteristic for the

interacting groups compared to the IR spectra of the corresponding physical mixtures.

For example, in the case of PVP SDs, shifts of the absorption band of the PVP carbonyl

group towards lower wavenumbers are evidence of hydrogen bonding interactions with

the drug molecule (Van den Mooter et al. 1998, Nair et al. 2001, Bansal et al. 2007).

Shifts towards higher wavenumbers, indicative of specific drug-PVP interactions, have

also been observed (Taylor and Zografi 1997, Khougaz and Clas 2000, Nair et al. 2001,

Karavas 2005). Instead, in the case of PEG SDs, the interactions have been more difficult

to demonstrate (Anguiano-Igea et al. 1995, Van den Mooter et al. 1998). In addition to

IR, interactions evoke band shifts also in Raman spectra (Taylor and Zografi 1997,

Shamblin et al. 1998, Li et al. 2006) and in ssNMR spectroscopy the interactions are

57

visualized by chemical shift variations (Aso and Yoshioka 2006, Van den Mooter et al.

2001, Schachter et al. 2004).

The miscibility of the drug and polymer can be predicted by the solubility parameter

approach (Hancock et al. 1997, Greenhalgh et al. 1999, Forster et al. 2001, Nair et al.

2001, Marsac et al. 2006b, Ghebremeskel et al. 2007). The solubility parameter (�) is one

way to quantify the cohesive energy of a material, which in turn determines many of the

critical physico-chemical properties (e.g. solubility, melting point) of drugs and

excipients. There are group contribution methods, such as the Hansen’s approach, by

which solubility parameters can be calculated. The Hansen solubility parameters for a

compound are calculated from its chemical structure using the approaches of

Hoftyzer/Van Krevelen and Hoy (Van Krevelen 1997) where the square root is taken of

the sum of squares of the contributions of dispersive, polar and hydrogen bonding. These

individual components are calculated using the contributions of the functional groups of

the molecule. The value of � can also be determined experimentally e.g. by measuring the

solubility/miscibility of a material in liquids with known cohesive energies (Reuteler-

Faoro et al. 1988) or by inverse gas chromatography (IGC) experiments (Huu-Phuoc et

al. 1986, Adamska et al. 2008). Compounds with similar values for � are likely to be

miscible, since the energy required for mixing of the components is compensated by the

energy released by the interaction between the components (Greenhalgh et al. 1999). It

has been estimated that if the difference between the solubility parameters of two

components (Δ�) is smaller than 7 MPa1/2, then the components are likely to be miscible,

and when Δδ is smaller than 2.0 MPa1/2 the components might form a solid solution

(Greenhalgh et al. 1999, Forster et al. 2001, Ghebremeskel et al. 2007).

Differentiating whether a solid dispersion or a solid solution is formed, is generally

based on DSC analysis, where in the case of solid solutions, a single, composition-

dependent Tg between the Tgs of the pure substances is observed as evidence of the

miscibility of the components (Matsumoto and Zografi 1999, Forster et al. 2001, Nair et

al. 2001, Vasanthavada et al. 2004, Marsac et al. 2006a). The Tg value of the different

compositions can be predicted with Gordon-Taylor equation (Gordon and Taylor 1952,

Van den Mooter 1998, Nair et al. 2001) (Eq. 5):

58

(5)

where Tg12 is the glass transition temperature of the drug-polymer blend, w1, w2, Tg1 and

Tg2 are the weight fractions and glass transition temperatures (K) of the pure drug and

polymer, respectively. K is a constant describing the interaction between the components

and it can be approximated using the following equation (Simha-Boyer rule, Eq. 6):

(6)

where ρ1 and ρ2 are the true densities of the components. Deviations of the

experimentally determined Tgs from the theoretical Tgs are indicative of differences in the

strengths of the intermolecular interactions between the individual components and those

of the blend (Nair et al. 2001).

However, there is a lack of a proper characterization tool which could determine the

actual dispersion of the drug and its particle size within a polymer matrix. Microscopic

methods, e.g. SEM, TEM, and MTDSC in combination to gravimetric water sorption

have been used for this purpose (Dordunoo et al. 1997, van Drooge et al. 2006b, Karavas

et al. 2007a,b), however they are not able to detect molecular dispersions. Instead,

alternative techniques such as micro-Raman and fluorescence resonance energy transfer

(FRET) might be capable of distinguishing between nanodispersions and solid solutions

(van Drooge et al. 2006a, Karavas 2007b).

2.4.3.4 Dissolution of solid dispersions

The mechanisms of dissolution enhancement in SDs are not yet completely understood

in spite of intensive research. There are several factors that are known to contribute to the

enhancement of drug solubility and dissolution rate from SDs. Reduced particle size and

thus increased surface area of the drug within the dispersion, especially in the case of

eutectics and solid solutions, leads to faster dissolution of the drug. In addition, improved

21

221112 Kww

TKwTwT gg

g ++

=

22

11

g

g

TT

Kρρ

≈

59

wettability of the hydrophobic drug particles, the absence of aggregation of the drug

particles and possible solubilization by the carrier are all factors that improve the drug

dissolution (Craig 2002, Sethia and Squillante 2003, Kaushal et al. 2004, Vasconcelos et

al. 2007). Furthermore, enhancement of drug solubility is achieved by converting the

drug to the amorphous state, since then no energy is required to break up the crystal

lattice during dissolution (Taylor and Zografi 1997, Kaushal et al. 2004). After

dissolution, the drug is present as a supersaturated solution which might precipitate with

the passage of time (Kaushal et al 2004, Vasconcelos et al. 2007). In addition,

intermolecular interactions between the drug and carrier promote drug dissolution from

SDs, since they control the physical state and the particle size of the drug in SDs (Bansal

et al. 2007, Karavas et al. 2007b). In the case where the effects of particle size reduction,

polymer hydrophilicity and wettability have been assumed to be the same, the major

contribution to the dissolution enhancement has appeared to be due to intermolecular

interactions between the drug and the polymer (Bansal et al. 2007). In addition, the

intensity of the interactions has been observed to modify the dissolution mechanism from

being carrier controlled to drug controlled for high polymer concentrations in the case of

felodipine/PVP dispersions (Karavas et al. 2006). However, the benefits attributed to

these factors are opposed by solvent-mediated devitrification and the overall solubility

benefit is a balance between these opposing forces (Bansal et al. 2007).

Enhanced in vitro dissolution by SD technique has been demonstrated to lead to

increased bioavailability of many drugs (Khoo et al. 2000, Ambike et al. 2005, Shimpi et

al. 2005, Piao et al. 2007). For example, SDs are more efficient than micronization in

increasing bioavailability. Micronization has a limited size reduction capacity and thus

might achieve only a marginal improvement of the drug solubility or release in the small

intestine (Serajuddin 1999, Dannenfelser et al. 2004).

2.4.3.5 Stability and formulation of solid dispersions

Improved stability has been observed for many drugs, which have been formulated in

amorphous SDs with different polymers, under accelerated conditions (Perng et al. 1998,

Khoo et al. 2000, Law et al. 2001, Ambike et al. 2004, 2005, Vasathavada et al. 2004,

60

Karavas et al. 2005, Shimpi 2005). In spite of extensive research into the stabilizing

effect of SDs, there is no consensus of what is the dominant mechanism of stabilization,

although it is generally considered that achieving miscibility between the drug and the

carrier is important (Marsac et al. 2006b).

Restricting molecular mobility by increasing the Tg of the system (antiplasticization) by

using carriers with high Tg values has been proposed to be the stabilizing mechanism for

SDs containing PVP (Van den Mooter et al. 2001). In addition, salt formation between

the polymer and the drug compound has resulted in high Tg values of the system (Weuts

et al. 2005c). However, a significant reduction in crystallization rates or inhibition of

crystallization has been observed for many amorphous drugs at PVP amounts which were

too low to increase the Tg of the system or when the Tg of the SD was even lower than the

amorphous drug alone (Matsumoto and Zografi 1999, Khougaz and Clas 2000, Crowley

and Zografi 2003) suggesting that antiplasticization is not the only factor affecting the

physical stability of the SDs. Furthermore, two polymers might have different effects on

crystallization even when the Tgs of the SDs with these polymers are similar (Miyazaki et

al. 2004). The stability of the SDs in these cases has been attributed to the interactions

formed between the drug and the polymer (Matsumoto and Zografi 1999, Khougaz and

Clas 2000, Miyazaki et al. 2004). Specific drug-polymer interactions have been observed

to lead to inhibition of drug crystallization in many cases (Perng et al. 1998, Karavas et

al. 2005), although it has been argued that interactions per se are not a prerequisite for

stabilization (Van den Mooter 2001). Since some level of adhesive interactions, such as

van der Waals forces, hydrogen bonds and ion-dipole interactions, is required between

the drug and the polymer to achieve the formation of a molecular level mixture of the

drug, the true role of these interactions in crystallization inhibition has been hard to

evaluate (Konno and Taylor 2006). However, hydrogen bonding (e.g. between the

carbonyl group of PVP and the drug) has been observed to reduce enthalpy relaxation

indicative of decreased molecular mobility of the system (Ambike et al. 2004, Aso and

Yoshioka 2006, Bansal et al. 2007). Furthermore, crystallization has been observed to be

effectively inhibited by a strong intermolecular interaction due to proton transfer between

acidic and basic functional groups of the drug and the polymer (polyacrylic acid (PAA))

(Weuts et al. 2005c, Miyazaki et al. 2006). However in some cases, the crystallization

61

tendency has been found to be dependent on the relative crystallization tendencies of the

pure substances (Marsac et al. 2006a). Thus, if an amorphous drug is stable in the

absence of the polymer, it will remain stable in the presence of polymer whether or not

there are any specific interactions present (Law et al. 2001).

In their studies with three chemically different polymers (PVP, HPMC and HPMCAS),

Konno and Taylor (2006) found these polymers to be equally effective in decreasing the

nucleation rate of amorphous felodipine at given weight percentages of the polymer. No

correlation between the nucleation rate and the Tgs of the pure polymers, the Tgs of the

SDs or the strength of the hydrogen bond interactions could be established. Instead, the

stability was attributed to the polymers’ ability to increase the kinetic barrier to

nucleation with the scale of the effect being related to the polymer concentration and for

the three specific polymers studied, it was independent of the polymer physicochemical

properties.

From the above discussion, it is apparent that the physicochemical factors governing

the stability of SDs are not fully understood. Thus, crystallization of the amorphous drug

during processing (mechanical stress) or storage (temperature and humidity stress) can

not be fully controlled (Serajuddin 1999, Sethia and Squillante 2003, Kaushal et al. 2004,

Vasconcelos et al. 2007). Despite the clear advantages achieved by SD technology, the

above stability issues are one major reason why there are so few SD-based products on

the market. A striking example of the unpredictability of SD based products is the

ritonavir capsule (Norvir®, Abbott) which was withdrawn from the market due to

crystallization of ritonavir from the supersaturated solution in a SD system during the

product's shelf life (Bauer et al. 2001). Furthermore, lack of predictability of the

dissolution behaviour of SDs due to lack of understanding of their molecular behavior,

manufacturing and scale up limitations, and cost of preparation are all factors that have

limited the commercialization of the SDs (Craig 2002, Sethia end Squillante 2003, Bansal

et al. 2007). Nonetheless, products of griseofulvin/PEG (Gris-PEG®, Novartis),

nabilone/povidone (Cesamet®, Lilly) and itraconazole/HPMC (Sporanox®, Janssen

Pharmaceutica/Johnson and Johnson) are available on the US market.

Formulating SDs into tablets or capsules presents many formulation challenges. Solid

dispersions might be soft and tacky, making pulverization, sieving and tabletting difficult

62

(Serajuddin 1999, Sethia and Squillante 2003). In addition, often a high amount of carrier

is required in order to achieve fast dissolution of the drug from the SD which might mean

that the amount of SD required to administer the drug dose becomes too large to produce

a tablet of reasonable size (Leuner and Dressman 2000). This can be prevented by using

better carriers, e.g. gelucires, which are needed in smaller amounts in order to produce

satisfactory dissolution and stabilization of the drug (Shimpi 2007). However, direct

compression has been found to be suitable for tabletting of SDs, and there are ways to

avoid possible sticking problems e.g. by adding magnesium stearate to the powder

mixture (Liu and Desai 2005, Shibata et al. 2006). The improved dissolution by SD was

maintained in these tablet formulations, leading to better performance of the SD

containing tablets in comparison to conventional tablets.

In addition, rapidly disintegrating tablet formulations have been successfully prepared

using SDs. In these tablets, disintegration within the time range of 60 to 780 seconds is

effectively combined with a fast dissolution rate of the drug from the SDs, leading to a

fast release of the drug from the tablets (Valleri et al. 2004, Sammour et al. 2006,

Goddeeris et al. 2008). These SDs have been shown to be stable during preparation and

storage of these tablet formulations (Valleri et al. 2004, Shibata et al. 2006).

63

3 AIMS OF THE STUDY

I. To examine the ability of hydrophobic excipients (starch acetate and ethyl

cellulose) to act as a release controlling matrix for highly water soluble

saccharides in order to design a tablet that would release the saccharides within 2–

4 h, starting already in the stomach but mainly in the upper part of the small

intestine.

II. To modify the drug release rate of water soluble model drugs without changing

the composition of the drug/starch acetate mixture. For this purpose, a dry powder

agglomeration, induced by triboelectrification on a mixing plate, was used for

drug and starch acetate mixtures prior to direct compression.

III. To improve the release rate of a poorly water soluble drug by the solid dispersion

approach in order to allow usage of the drug in intraoral preparations from which

the drug would be released and dissolved fast enough to allow absorption through

oral mucosa.

IV. To prepare a fast disintegrating tablet for intraoral administration, containing the

solid dispersion with acceptable dissolution properties, stability and size of the

product.

64

4 EXPERIMENTAL

4.1 Materials

4.1.1 Excipients and model drugs (I-IV)

N-acetyl-D-glucosamine (NAG (I, II), Sigma Aldrich Chemie, Germany),

maltopentaose (I) and maltose monohydrate (I, sieved through a 1 mm sieve) (Seikagaku,

Japan) were used as highly water soluble model saccharides. Anhydrous caffeine (II) and

propranolol hydrochloride (II) (Sigma-Aldrich Chemie, Steinheim, Germany) were used

as water soluble model drugs. Perphenazine (III, IV) (PPZ, Sigma-Aldrich Chemie,

Steinheim, Germany) was used as a poorly water soluble model drug. Hydrophobic

matrix formers starch acetate (SA) with degree of substitution 2.7 (VTT, Rajamäki,

Finland) (I, II) with sieve fractions of < 500 µm (I), 500–297 µm (I), <149 µm (I) and

<53 µm (II) and ethyl cellulose (EC) (I) (Ethocel Standard 10 Premium, gift sample from

DOW Europe (Germany)); hydrophilic matrix former mannitol (IV) (Pearlitol 400 DC,

Roquette Frères, Lestrem, France); disintegrants crospovidone (CP) (II, IV),

(Polyplasdone XL-10, ISP Technologies, Inc.,Calvert City, KY, USA) and calcium

silicate (CS) (IV) were used in the tabletting studies.

4.1.2 Other chemicals (I-IV)

Chemicals used in the preparation of dissolution mediums and in HPLC analysis of the

model drugs were all obtained from commercial suppliers. Chemicals for HPLC analysis

(i.e. acetonitrile and triethylamine) were of HPLC grade, other chemicals were at least of

analytical grade.

65

4.2 Methods

4.2.1 Particle and powder properties (I-IV)

The particle size distribution of powders (I, II) was determined with a laser

diffractometer (Mastersizer 2000, Malvern Instruments Inc., Worchestershire, UK), either

by the particle in air method (I, II) or by the particle in liquid (ethanol) method (I).

Material densities (I-IV) were measured in five parallel determinations with a Multi

pycnometer (Quanta Chrome, NY, USA) using helium as the measuring gas.

Scanning electron microscopy was used for visual examination of powders (I-III). The

SEM micrographs were taken with a XL 30 ESEM TMP microscope (FEI Co., Czech

Republic).

The contact charging of powders with different materials was studied by performing

triboelectric measurements (II). The measurements were made by sliding the neutralized

powders through tubes of 50 cm in length into a Faraday’s cup where the generated

charge was measured using an electrometer (Keithley 6517A, Keithley Instruments Inc.,

USA) (Murtomaa and Laine 2000). Subsequently, the samples were weighed and the total

charge per unit mass, i.e. the specific charge, was calculated. The tube materials were

stainless steel (SS), glass, polyvinyl chloride (PVC), acrylic, polyethylene (PE) and

polypropylene (PP). The measurements were repeated five times per each powder/tube

material pair. For SA, a larger particle size fraction of SA (53-149 µm) was used in these

measurements instead of cohesive fraction < 53 µm (which was used in the tabletting

studies).

4.2.2 Tableting (I, II, IV)

Powder mixtures for tableting were prepared by mixing carefully in a mortar (I, II IV).

The relative amounts of the mixture components were calculated on a mass basis. Dry

powder agglomeration prior to tableting (II) was conducted on a stainless steel plate

(diameter 39 cm) which was attached to Erweka AR 400 apparatus (Erweka Apparatebau

G.m.b.H., Germany) where the mixture of drug and SA was placed. The plate was rotated

for 10 minutes at a rotation speed of 14 rpm. If CP was added to the formulation, it was

scattered on the agglomerated powder and the plate was rotated for an additional 5

66

minutes. The agglomeration process using a PP container (diameter 27 cm) was

conducted as described above with the PP container placed on the steel plate.

The powder mixtures were compacted with a compaction simulator (PCS-1, PuuMan

Ltd., Kuopio, Finland) (I, II, IV). Tablet formulations (I) were designed by using an

experimental design program (Design-Expert 5, StatEase Corp., Minneapolis, USA). The

tablets were cylindrical, with diameters of 8, 10 or 13 mm. Tablets were compressed to

the desired porosity. The compression profiles were sine waves for both punches or only

for the upper punch, in which case the lower punch was stationary. The compression

pressures varied between 42 and 345 MPa.

The compression profiles (II) were double sided sine waves. The tablets were

cylindrical, with a diameter of 13 mm and mass of 500 mg. The tablets were compressed

to the desired porosity (20 % for NAG and caffeine, and 15% for propranolol

formulations). The compression pressures varied between 72 and 293 MPa.

Four different formulations (IV), containing 10% of either 1/5 PPZ/PEG or 1/5

PPZ/PVP SD, mannitol and disintegrants (CS and/or CP) were prepared (i.e. each tablet

had 4 mg of PPZ). The compression profiles were double sided sine waves. The tablets

were cylindrical, with a diameter of 10 mm and a mass of 200 mg. The compaction

pressures were 64 or 127 MPa.

4.2.3 Tablet properties (I, II, IV)

Tablet volumetric dimensions and weights (I, II, IV) were measured 24 h after

compression. Crushing strengths of tablets (I, II, IV) were measured with a universal

tester (CT-5 tester, Engineering Systems, Nottingham, England). The tensile strengths of

the tablets (I, II, IV) were calculated according to Fell and Newton (1970).

Disintegration times for the tablets (IV) were determined on a petri dish without agitation

by immersing the tablet in 20 ml of distilled water and recording the time passing until

the tablet had visually disintegrated.

67

4.2.4 Preparation of solid dispersions (III, IV)

The carrier selection was based on a comparison of the solubility parameter of PPZ

(estimated according to the group contribution method (David and Misra 1999) using the

Matprop©-program (Material Property Estimator and Database, SF Technologies,

Amherst, MA)) to the solubility parameters of different polymers and polymer grades,

found in the literature (Hancock et al. 1997, Greenhalgh et al. 1999, Forster et al 2001,

Marsac et al. 2006b).

SDs with different drug/polymer weight ratios (5/1, 1/5 and 1/20) were prepared by

freeze-drying. Thus, the SDs contained 80, 20 and 5 % (m/m) of PPZ, respectively. Also

pure PPZ was processed similarly. 0.1 N HCl-solutions with an overall solid

concentration (drug + polymer) of 5% (w/w) in the case of 1/5 and 1/20 dispersions were

prepared, 3% solutions in the case of 5/1 dispersions and 2% solutions in the case of pure

PPZ. After freezing, the samples were dried (Modulyod-230, Thermo Savant, Savant

NY) for 2-4 days. The prepared particles were stored in dessicator over silica gel at a

temperature below 10°C.

4.2.5 Physicochemical characterization (I-IV)

4.2.5.1 Polarized light microscopy (I)

The existence of a crystalline part of maltopentaose was qualitiatively confirmed by

using polarized light microscopy (Nikon Microphot-Fxa, Nikon, Tokyo, Japan).

4.2.5.2 Differential Scanning Calorimetry (I, III, IV)

DSC was used in the determination of melting points (I, III, IV) and glass transition

temperatures (III, IV) of the materials. The measurements conducted with Perkin-Elmer

DSC7 (I) (Perkin-Elmer Co., Norwalk, CT, USA) were made in duplicate using a heating

rate of 10°C/min and a temperature scale of 10-250°C. Samples of 4-6 mg in weight were

crimped in 50 µl aluminium pans with pierced lids. All runs were performed under an

atmosphere of dry nitrogen. The temperature axis was calibrated with Ga and In.

68

The cooling/heating programs when using a Mettler Toledo DSC823e equipped with an

intercooler (Mettler Toledo, Schwerzenbach, Switzerland) and an autosampler (Mettler

Toledo, TS080IRO, Sample Robot, Schwerzenbach, Switzerland) (III, IV) are shown in

Table 4.1. Sine-wave temperature modulation had to be used in the case of 1/5- and 1/20

PPZ/PVP-formulations in order to separate the overlying water evaporation endotherm

from the other thermal events, such as glass transition (Table 4.1).

Table 4.1. DSC cooling/heating programs for PPZ, PVP K30 and PEG 8000, freeze-driedPPZ, the prepared solid dispersions (SDs) and the corresponding physical mixtures (PM).

Sample Phase 1 (heating) Phase 2 (cooling) Phase 3 (heating)Temperaturemodulation

PPZ from 25°C to115°C, 10°C/min

from 115°Cimmediately to -40°C, 15 min at -40°C

from -40°C to120°C, 10°C/min

-

PVP K30 from 25°C to140°C, 10°C/min,10 min at 140°C

from 140°Cimmediately to25°C, 10 min at25°C

from 25°C to190°C, 10°C/min

-

PEG 8000 from 25°C to100°C, 10°C/min,3 min at 100°C

from 100°C to -75°C, 10°C/min, 15min at -75°C

from -75°C to100°C, 10°C/min

-

freeze-dried PPZ,5/1 PPZ/PVP PMand SD

from 0°C to125°C, 10°C/min

- - -

1/5 and 1/20PPZ/PVP PMand SD

From 0°C to200°C, 1°C/min

- - Amplitude ±1°C,frequency 1 min

5/1 PPZ/PEG PMand SD

- at -40°C 10 min from -40°C to55°C or to 125°C,10°C/min

-

1/5 and 1/20PPZ/PEG PMand SD

- at -75°C 30 min from -75°C to -10°C or to 125°C,10°C/min

-

The samples were weighed (weight range 2-11 mg) with an analytical balance (Mettler

Toledo AT261, Mettler Toledo Ag, Schwerzenbach, Switzerland) and analyzed in sealed

40 µl aluminium sample pans with a pierced lid. Measurements for each material were

performed in triplicate. H2O, In, Pb and Zn were used for temperature scale and enthalpy

response calibration, however for the temperature modulated runs, no further calibration

69

was done, thus the ΔCp-values could not be compared between the different materials.

The results were analysed with STARe software (Mettler Toledo Schwerzenbach,

Switzerland). Melting points were determined as onset-values and the glass transition

temperatures as midpoint-values. In the case of temperature modulated measurements,

the Tg-values were determined from the reversing heat flow signal as midpoint-values.

4.2.5.3 X-ray Powder Diffractiometry (III, IV)

X-ray powder diffraction analysis (XRPD) was performed using a Philips PW 1830

diffractometer (Philips, Amelo, The Netherlands) with Bragg-Brentano geometry (θ-2θ)

(III, IV). The radiation used was nickel filtered CuK�, which was generated using an

acceleration voltage of 40 kV and a cathode current of 50 mA. The samples were scanned

over a 2θ range of 3°-30°, step size being 0.04° and counting time 3s per step.

For the SDs stored in 40°C/silica (IV), a Philips PW1050 diffractometer (Philips,

Amelo, The Netherlands) was used, since the measurements were conducted at ∼5% RH

(the measurement chamber contained silica). In that case, the acceleration voltage was

45 kV and the cathode current was 35 mA. The samples were placed into copper sample

holders and scanned over 2θ range of 3°-30°, with the step size being 0.04° and counting

time 3s per step.

4.2.5.4 Fourier Transform Infrared Spectroscopy (III, IV)

A Nicolet Nexus 870 FTIR spectrometer (Thermo Electron Corp, Madison, WI)

equipped with an Attenuated Total Reflectance (ATR) accessory (Smart Endurance,

Single-reflection ATR diamond composite crystal) was used for obtaining the IR-spectra.

For each spectrum, 32 scans were performed with a resolution of 4 cm-1.

4.2.5.5 Small-angle X-ray scattering (III, IV)

SAXS permits the measurement of the size of inhomogeneity regions, arising from the

electron density inhomogeneities within the sample, in a range from 1 to 100 nm

70

(Guozhong 2004). In the measurements, the X-ray radiation generated by PW 1830 X-ray

generator (Philips, Amelo, The Netherlands, operated at 40 kV and 50 mA) was limited

to a narrow line. This permitted the determination of scattering of the radiation which

penetrated through the sample starting from small angles. The intensity of the scattered

radiation was measured by a proportional counter by changing the angle in a stepwise

manner (Kratky-camera, Anton Paar, Graz, Austria). The measuring times were

approximately 20 hours per sample (5 min/step). The measurements were carried out by

measuring the scattering of the transmitted radiation at small angles. When analyzing the

data, the shape of the areas of different electron densities (i.e. particles) was assumed to

be spherical and their size distribution was estimated to be from 0 to 100 nm. The pair

density distribution functions (particularly the location of the maximum (nm)),

determined from the original data, provide information on the size of the electron density

areas in the sample.

4.2.6 Solubility and dissolution testing (I-IV)

The drug release from tablets (I) was determined in triplicate by the USP XXVIII

rotating basket method, with a rotation speed of 100 rpm (Sotax AT6, Switzerland). The

dissolution medium was 900 ml of pH 1.2 HCl-solution for the first two hours, after

which the tablets were transferred into 900 ml of distilled water for the next 22 hours.

Both media were maintained at 37 ± 0.5°C. The amount of dissolved NAG was

determined with a Gilson HPLC system (Gilson, France) with UV-detection (UV/Vis-

151 detector Gilson, USA) at the wavelength of 210 nm (method adapted from Sashiwa

et al. 2002) using an amino column (Asahipak NH2P, 4.6x 250 mm, Shodex, Japan)

operating at 40°C. The sample injection volume was 20 µl, the mobile phase was

acetonitrile-water (70:30) and its flow rate was 1 ml/min. The retention time of NAG was

5 min.

The amount of dissolved maltose and maltopentaose was determined with a Merck

LaChrom HPLC system (Hitachi, Tokyo, Japan) with evaporative light scattering (ELS)

detection (Sedex 55 ELS detector, Sedere, Vitry-Sur-Seine, France) using the Asahipak

NH2P column. The sample injection volume was 10 µl, the mobile phase was

71

acetonitrile-water (48:52) and its flow rate was 1 ml/min (method adapted from Shodex

2003). The detector temperature was 42°C and the pressure of the nebulizing gas (dry and

filtered air) was 2.2 bar. The retention times of maltose and maltopentaose were 3.55 min

and 4 min, respectively.

The drug release from six parallel SA tablets (II) was determined by using the USP

XXVIII rotating basket method, with a rotation speed of 100 rpm. The dissolution

medium was 900 ml of simulated gastric fluid without enzymes (USP XXIV, pH 1.2),

maintained at 37 ± 0.5 °C. The amount of dissolved drug was determined by UV-

spectrophotometry (Genesys 10uv, ThermoSpectronic, Rochester, NY, USA). The

wavelengths used for NAG, caffeine and propranolol were 210, 272 and 289 nm,

respectively.

The PPZ equilibrium solubility (III) at pH 6.8 was determined by adding excess

amounts of the drug to 1 ml of buffer solution (pH unchanged during the experiment) at

room temperature. The suspensions were equilibrated in a shaker (at speed 300 rpm) for

three days and then filtered through a 0.45 µm membrane filter. For the phase-solubility

studies, solutions containing 10, 7.5, 5, 2.5 and 1 % (w/v) of PVP or PEG in pH 6.8

phosphate buffer (pH was unchanged during the experiment) were prepared. Otherwise

the phase-solubility study was carried out similarly as the solubility studies, with the

exception that the solution volume was 10 ml. A 150 µl sample of the filtered test

solution was taken, mixed with 350 µl of ACN and analyzed with Gilson HPLC -system

with UV-detection at the wavelength of 254 nm. A reverse-phase column (Inertsil ODS-

3, 4.0x150 mm, GL Sciences Inc.,Tokyo, Japan) was used. The sample injection volume

was 20 µl, the mobile phase was acetonitrile-water (70/30) with 0.03% (v/v)

triethylamine (TEA), and its flow rate was 1 ml/min. The retention time of PPZ was 3.75

min.

The dissolution rates of the materials (III, IV) were determined in a small volume (3 ml

of pH 6.8 phosphate buffer), in order to simulate the small liquid volumes present in the

mouth. The powder was weighed in the bottom of the test tubes in such a way that there

was always 4 mg of PPZ. Three parallel samples were prepared for each time point. The

test tubes were placed on a shaker at a speed of 300 rpm (KS125basic, IKA

Labortechnik, IKA-Werke Gmbh & Co., Straufen, Germany) and 3 ml of the pH 6.8

72

buffer was added to the test tube. The samples were taken at 15, 30 and 45 s, 1, 2 and 4

min time points by pouring the solution into a syringe equipped with a 0.45 µm

membrane filter on the head, filtering it immediately and diluting it with phosphate buffer

prior to analysis with HPLC. The dissolution rates of PPZ (d(0.5) = 30 µm) and PPZ

micronized (< 15 µm) were also determined under sink conditions (i.e. the PPZ sample

amount was such that the maximum amount of the dissolved PPZ was 5% of its

equilibrium solubility) using the USP XXVIII rotating paddle method, with a rotation

speed of 50 rpm. The dissolution medium (900 ml of pH 6.8 phosphate buffer) was

maintained at 37.0 ± 0.5 °C.

The dissolution profiles of PPZ from the prepared tablet formulations (IV) were

determined using the USP XXVIII rotating basket method, with a rotation speed of 50

rpm. The dissolution medium was 500 ml of phosphate buffer pH 6.8, maintained at 37.0

± 0.5 °C. Three parallel tablets from each formulation were tested. The amount of

dissolved PPZ was determined with HPLC as described above.

4.2.7 Stability testing (IV)

Fresh samples of solid dispersions were exposed to the following conditions: 40°C/75%

RH and 40°C/∼5% RH (silica) for four weeks after which the FTIR, DSC and XRPD

measurements and dissolution studies were conducted for the SDs. However, freeze-dried

PPZ, 5/1 PPZ/PEG and all of PPZ/PVP became deliquesced during the storage at

40°C/75 % RH and no measurements for these samples could be conducted. In addition,

a total of 20 tablets from each formulation were stored at room temperature (21°C)/60%

RH for four weeks. After that time, the tablet weights, crushing strengths and

disintegration times were measured and dissolution profiles of PPZ were determined.

4.2.8 Statistical analysis (I, II)

The experimental design program (Design-Expert 5, StatEase Corp., Minneapolis,

USA) was used for designing the tablet formulations (I) with a Plackett-Burman 2-level

factorial design. With this program the factors affecting the drug release rate (T50%) and

73

mechanism (n-value from Korsmeyer-Peppas model (Costa and Sousa Lobo 2001)) were

evaluated. Also a full 2-level factorial design was used for optimization of the drug

release.

Statistical significance for the differences between the melting points of maltose

monohydrate in the tablet prior to the dissolution test and after 2h of dissolution test (I),

and the tensile strengths of the unagglomerated and agglomerated formulations (II) were

evaluated by using Student’s t-test. Dissolution profiles were evaluated by calculating the

similarity factors (f2). Only one timepoint after 85% of drug released was included in f2-

value calculations. Should the f2-value be less than 50, then the dissolution profiles were

considered to be different.

74

5 RESULTS AND DISCUSSION

5.1 Factors affecting release of highly water soluble compounds from hydrophobic

matrices (I)

Generally, it is desirable that one has water-soluble drugs in the development of

immediate release dosage forms. However, retarding the release of these kinds of

molecules can be a challenging task (Pillay and Fassihi 2000, Liu et al. 2005). In this

study, SA and EC were used as hydrophobic matrix formers in order to obtain release of

model saccharides (NAG, maltose and maltopentaose) within 2-4 hours. The physical

properties of the drugs and excipients are shown in Table 5.1.

Table 5.1. Physical properties of tablet excipients (starch acetate with different particlesize fractions (I-II) and ethyl cellulose (I)) and model drugs (N-acetyl-D-glucosamine (I,II), maltose monohydrate (I), maltopentaose (I), anhydrous caffeine (II) and propranololHCl (II)).

Material Particle density(mean ± sd) (g/cm3)

Volume mean particlesize (µm)

Melting point (°C)

SA < 500 µm 1.326 ± 0.004 131b ndSA 297-500 µm 1.358 ± 0.005 372b ndSA <149 µm 1.310 ± 0.011 23b ndSA < 53 µm 1.341a 12 ndEC 1.192 ± 0.005 227b ndNAG 1.483 ± 0.008 141c 213.7 ± 0.7maltose monohydrate 1.525 ± 0.004 138c 125.5 ± 0.6maltopentaose 1.481 ± 0.008 nd 116d

anhydrous caffeine 1.452 ± 0.003 46 ndpropranolol HCl 1.211 ± 0.003 14 nda data from van Veen et al. 2005; b Particle in air method; c Particle in ethanol method; d Partiallyamorphous (confirmed by polarized light microscopy), melting point of the crystalline part; nd = notdetermined.

5.1.1 Dissolution characteristics of N-acetyl-D-glucosamine (I)

In order to achieve controlled release of highly water soluble saccharides, the effect of

different formulation and process variables (Table 5.2) on the release rate and mechanism

of NAG from SA tablets were evaluated. Plackett-Burman 2-level factorial design of

experiment was used for designing eight different formulations (Table 5.2).

75

Table 5.2. Tablet formulations designed by Plackett-Burman design of experiment forevaluation of the effect of six process and formulation variables on the release rate andmechanism of N-acetyl-D-glucosamine (NAG) from the starch acetate (SA) tablets.Formulationcode(NAG/SA)

Amountof NAG(mg)

Tabletmass(mg)

Duration ofcompression(ms)

Type ofcompressiona

Tabletporosity(%)

SA particlesize fraction(µm)

A1 (25/75) 150 600 500 -1 7.5 297-500A8 (25/75) 150 600 1500 1 15 297-500B2 (50/50) 150 300 500 1 7.5 <149B7 (50/50) 150 300 1500 -1 15 <149C3 (17/83) 50 300 500 -1 15 297-500C6 (17/83) 50 300 1500 1 7.5 297-500D4 (8/92) 50 600 500 1 15 <149D5 (8/92) 50 600 1500 -1 7.5 <149a-1 = one sided; 1 = double sided

The dissolution studies of these formulations demonstrated that the dissolution rate of

the drug was fastest from formulation B7, which contained the higher amount of NAG in

the tablet and possessed a higher porosity of the tablet and lower tablet weight (T50%

values shown in Table 5.3). Three formulations studied (A8, B2 and B7) released NAG

within the desired time, i.e. within 2-4 hours.

The release rate (T50%) could be modeled (R2=0.999) and predicted (Q2=0.998) well

and the model showed that the four most significant factors affecting the release rate were

the amount of NAG in the tablet (P<0.0001), the porosity of the tablet (P<0.001), the

duration of compression (P<0.001) and the tablet mass (P<0.01).

In the case of high amount of drug in the tablet, the excipient was not able to form a

percolating network inside the tablet (Bonny and Leuenberger 1993, Amin and Fell 2004)

and thus, in the tablets of the formulations A1, A8, B2 and B7, the matrix was probably

formed by NAG, leading to lower tensile strengths and faster release (Table 5.3). The

higher porosity of the tables led to a weaker structure of the tablets and thus faster release

(Table 5.3). The longer duration of compression might have led to formation of a higher

amount of stronger bonds inside the tablet and thus to higher tensile strength and slower

release (Table 5.3). In the smaller tablet, the shorter diffusion path might have caused

faster release of the drug (Table 5.3). However, the particle size of SA did not seem to

have a significant effect on the drug release, which is in contradiction with general

observations about hydrophobic matrix formers (Leuenberger et al. 1987, Holman and

76

Leuenberger 1988, Crowley et al. 2004). This might be due to that the difference between

the two particle size fractions should have been larger in order to show a significant

effect on the release rate.

The release kinetics of NAG from the SA matrices was evaluated by using Korsmeyer-

Peppas model (Eq. 3). The resulting n values, indicative of drug release kinetics, are

shown in Table 5.3. It was found that according to Eq. 3, the release of NAG from three

formulations (B2, D5 and probably also B7) followed square root of time kinetics (i.e.

�0.45), while with the other formulations, NAG release kinetics was anomalous

transport. In the B2 and D5 formulations, the smaller SA particle size fraction was used

and the tablet porosity was 7.5 % meaning that there was a tighter tablet structure and

purely diffusion-controlled release. Unfortunately, it was not possible to construct a

reliable model for predicting NAG release kinetics from the studied matrix tablets.

Table 5.3. Times required for 50 % of drug release (T50%), n values from theKorsmeyer-Peppas equation and tensile strengths (± sd) of the tablets (Table 5.2).

Formulation T50% (h) Tensile strength (MPa) nA1 2.5 4.15 ± 0.11 0.55A8 1.1 2.87 ± 0.20 0.63B2 1.2 4.60 ± 0.31 0.49B7 0.7 1.86 ± 0.12 0.40C3 3.8 2.73 ± 0.60 0.53C6 8.0 5.97 ± 0.51 0.56D4 4.4 4.17 ± 0.24 0.63D5 9.2 5.04 ± 0.09 0.46

5.1.2 Dissolution characteristics of saccharides and oligosaccharides (I)

After defining the most significant factors affecting NAG release, the release from SA

tablets was optimized by using a full 2-level factorial design, where the two variable

factors were the amount of drug in the tablet and tablet porosity (Table 5.4). The same

design was used for studying the release of NAG from hydrophobic EC matrices, and

also for studying the release of maltose monohydrate from SA and EC matrices.

77

Table 5.4. Formulations designed by a full 2-level factorial design for NAG and maltosemonohydrate in SA and EC matrices and the tensile strengths (± sd) of the preparedtablets.

Tensile strength (MPa)NAG Maltose

FormulationTabletporosity(%)

Amount ofsaccharide(%)a

SAb EC SAb EC

1 20 50 1.16 ± 0.08 0.50 ± 0.02 2.16 ± 0.20 1.05 ± 0.072 25 75 0.17 ± 0.06 nd 0.37 ± 0.04 0.22 ± 0.033 15 25 3.46 ± 0.29 1.59 ± 0.06 4.68 ± 0.31 2.71 ± 0.064 25 25 1.57 ± 0.06 0.49 ± 0.02 1.91 ± 0.10 0.89 ± 0.035 15 75 0.18 ± 0.06 0.70 ± 0.35 1.86 ± 0.06 1.51 ± 0.16aThe amount of saccharide in the tablet was always 50 mg; b Since SA particle size found not to effect onthe NAG release, the SA fraction < 500 µm was used; nd = not able to measure

In the dissolution studies with these formulations, two formulations, 2 and 5,

disintegrated in the dissolution bath and released the saccharide immediately (not shown).

Instead, formulations 1, 3 and 4 released the saccharides mainly within the desired 2-4

hours (Figure 5.1 a-d). Thus, for optimal release, either lower porosity and a higher

amount of the saccharide in the tablet or higher porosity and a lower amount of the

saccharide in the tablet was required. The release characteristics of EC were observed to

be very similar to SA (Figure 5.1 a-d). This is probably due to the fact that there were

identical mechanisms of drug release from these matrices in the case of water soluble

drugs, i.e. the release occurs by dissolution and diffusion of the drug through water-filled

capillaries of the pore network (Crowley et al. 2004, Pohja et al. 2004). Thus, in the case

of similar SA and EC formulations, the saccharide release rate depends mainly on the

properties of the molecule which was clearly shown by that the release of maltose

monohydrate was considerably slower from formulations 3 and 4 than NAG release from

similar formulations (Figure 5.1 a-d). This is probably due to the fact that maltose is a

hydrate and thus its dissolution rate in water is slower (Khankari and Grant 1995,

Florence and Attwood 1998, Murphy et al. 2002).

The release profiles of maltose monohydrate from SA/EC -formulations 3 and 4 (Figure

5.1 c, d) were found to consist of two linear phases with different release rates. The

release rate slowed at the time point of two hours, where the medium was changed.

However, also when the whole dissolution study was performed in pH 1.2 HCl-solution

78

or in water (not shown), a similar behavior was observed, indicating that the medium

change was not the reason for this behavior.

Figure 5.1. The dissolution profiles of NAG from; (a) starch acetate formulations 1 (),3 (�) and 4 (�); (b) ethyl cellulose formulations 1 (), 3 (�) and 4 (�); and maltosemonohydrate released from; (c) starch acetate formulations 1 (), 3 (�) and 4 (�); (d)ethyl cellulose formulations 1 (), 3 (�) and 4 (�).

It is well known that polymorphic transitions or the formation of amorphous regions on

particles can be induced by the application of mechanochemical stress, such as occurs

during tabletting (Chan and Doelker 1985, Saleki-Gerhardt et al. 1994), and that this can

have an effect on the dissolution rate of the drug (Phadnis and Suryanarayanan 1997).

During the tabletting process, maltose monohydrate could have been converted to a

metastable (more soluble) form and during the dissolution test it could have reverted back

to the monohydrate (less soluble) after a certain lag time, which could explain the initial

faster dissolution and consequent reduction of release rate at the two hour measurement

point. A biphasic dissolution caused by similar phenomenon has been previously reported

for calcium carbonate (Mosharraf et al. 1999). Evidence of activation of maltose

monohydrate during tablet compression was found by taking starch acetate tablets with

a b

c d

79

maltose monohydrate out of dissolution medium at 0.5, 1, 2, 2.5 and 4 hour timepoints

and analyzing 1) these tablets, 2) the corresponding physical mixture and 3) the tablet

before dissolution with DSC. There was a statistically significant difference (P<0.01 with

t-test) between the melting points of maltose monohydrate determined from dispersed

tablets prior to the dissolution test and after keeping the tablet for two hours in the

dissolution bath (average 130.2°C) and those determined from the physical mixture and

from tablets taken out of the dissolution bath after 2.5 hours or later (average 131.3°C)

(Table 5.5). The metastable solid-state structure, formation of which had been induced by

tabletting, had reverted or at least started to revert back to its original condition when the

tablets had been in the dissolution bath for more than two hours.

Table 5.5. Melting point ranges (n=2) of physical mixture of maltose monohydrate andSA, tablets before dissolution and tablets removed from the dissolution bath at varioustimepoints. Physical mixture and tablets are based on formulation 3 (Table 5.4).

Sample Time in the dissolution bath (hours) Melting point (°C)a

Physical mixture ⎯ 131.4 – 132.2

Tablet ⎯ 130.2 – 130.2Tablet 0.5 129.2 – 130.3Tablet 1 129.7 – 131.7Tablet 2 129.8 – 130.2Tablet 2.5 130.7 – 131.5Tablet 4 130.0 – 132.0

a Peak-values were used due to the large water dehydration peak, which interfered with onset-valuedetermination.

SA formulations 3 and 4 (Table 5.4) were also prepared by using maltopentaose, an

oligomer of maltose, in order to evaluate the effect of molecular size of the saccharides

on the release. Maltopentaose was observed to be released slightly faster than maltose

monohydrate (Figures 5.1 c and 5.2) presumably due to its mainly amorphous nature, this

being observed by using polarized light microscopy (Figure 5.3). In addition, the small

particle size (observed visually by SEM) could also mask the effect of molecular size on

the release rate. Once again, a biphasic release was seen, which could be due to the

existence of a small crystalline fraction in the maltopentaose particles (Figure 5.3, Table

5.1), dissolving slower than the amorphous component. In addition, the slowing of the

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release rate of maltopentaose formulations could also be due to recrystallisation of the

amorphous maltopentaose in the dissolution medium during the dissolution test

(Mosharraf et al. 1999).

Figure 5.2. Dissolution of maltopentaose from SA formulations 3 () and 4 ( ).

Figure 5.3. Photographs of maltopentaose particles in polarized light microscopeshowing the crystalline fractions as bright areas (left). When polarization is not in use, nobright areas are seen (right).

81

5.2 Effect of organization of powder mixture on the release rate of drugs from

starch acetate matrix (II)

5.2.1 Triboelectrification of the materials (II)

It is known that ordered powder mixtures can be stabilized by charging the particles

with opposite polarity by triboelectrification (Chapter 2.2.3.4). In this study,

triboelectrification and the agglomeration tendencies of drugs with different particle sizes

(NAG, caffeine and propranolol HCl, Table 5.1) and a disintegrant (CP) with SA with a

small particle size fraction (Table 5.1) were studied. The triboelectric charging of the

powders in contact with different materials (Table 5.6) was measured. This revealed that

if NAG and caffeine were in contact with a stainless steel (SS) plate they became charged

with an opposite polarity to SA. In contrast, propranolol HCl was charged with the same

polarity as SA when it was in contact with all the tested materials. Thus, in the case of

NAG and caffeine, triboelectrification of powders might promote the drug-SA attraction,

i.e. increase in adhesion and agglomeration, but in the case of propranolol it would hinder

these processes. However, adhesion between caffeine and SA should be stronger than

between NAG and SA due to caffeine’s larger negative charge on SS. CP became

charged positively when it was in contact with SS, thus it might adhere similarly to SA to

the surfaces of negatively charged NAG and caffeine. Based on these results, the

agglomeration process was carried out on a SS plate. In addition, a PP plate was used in

the case of NAG, since on this material NAG charged with similar polarity to SA (which

was expected to hinder adhesion and agglomeration).

Table 5.6. Charging of powders (starch acetate (SA), crospovidone (CP), N-acetyl-D-glucosamine (NAG), caffeine and propranolol HCl) in contact with stainless steel (SS),glass, polyvinyl chloride (PVC), acrylic, polyethylene (PE) and polypropylene (PP).

Charge of powders (nC/g)Material SS PP PE PVC Acrylic GlassSAa 12.27 3.53 -3.67 21.11 -11.46 14.64CP 15.57 12.32 - - - 6.64NAG -0.3 6 -1.09b 8.92 -1.1b -0.93Caffeine -3.72 8.39 -4.6 2.43 -4.92 -4.21Propranolol HCl 16.28 16.11 -0.87 22.98 -5.2 14.97

a sieve fraction 53-149 µm; b both polarities

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5.2.2 Dry powder agglomeration (II)

The formation of agglomerates was carried out by mixing powders with different

compositions (Table 5.7) on a rolling plate placed at an angle, which created a "snowball"

effect, i.e. as the particles rolled along the slope on the surface of the powder, they

increased in size. The scanning electron micrographs of agglomerated powders (examples

shown in Figure 5.4) revealed that in both SS and PP-agglomerated NAG-SA

formulations, agglomerates of large, flaky NAG particles (mean particle size of 141 µm,

Table 5.1) and small, round SA particles (mean particle size 12 µm, Table 5.1) with small

CP particles (mean particle size 21 µm, Table 5.1) on the surface were formed (Figure

5.4 a, d). Instead, in the case of caffeine formulations, the particle size of caffeine is only

slightly greater (mean particle size of 46 µm, Table 5.1) than that of SA. Thus, the

adhesion of SA particles onto the surface of caffeine is not favored due to the rather small

difference in the particle size. This leads to to a weaker adhesion between the two

particles (Staniforth 1981) and the formation of smaller agglomerates with also some

caffeine particles on the surface (Figure 5.4 b). However, the opposite charging of

caffeine and SA on the SS plate favored agglomeration, as also is the case for NAG

(Table 5.6). In contrast, in the case of propranolol HCl, no agglomerates could be seen

(Figure 5.4 c). The mean particle size of propranolol (14 µm, Table 5.1) and the charge

generated on SS was similar to those of SA, and therefore no adhesion promoted by a

particle size difference occurred in the mixture.

These results indicate that though the opposite polarities of the particle charges might

promote adhesion and agglomeration, the particle size difference between two materials

seems to be a more significant factor in determining the extent of particle interaction, as

is evidenced by the agglomeration of NAG and SA on the PP plate, in spite of the similar

charges of the particles (Figure 5.4 d). In addition, the particle distribution in a powder

mixture is affected by the surface properties of the particles. Surface roughness, surface

impurities and adhering moisture all contribute to the magnitude of the interparticulate

forces (Zeng et al. 2001). In general, large and irregular particles should exhibit higher

adhesion forces since they possess a higher contact area (Hersey 1975, Staniforth 1987).

The experimental results revealed that agglomeration was most effective with NAG in

83

spite of the polarity of tribocharging (Figure 5.4 a, d) due to its ability to store smaller SA

particles within the surface discontinuities (deBoer et al. 2005, Dickhoff et al. 2005).

Figure 5.4. Scanning electron micrographs of: (a) SS-agglomerated NAG formulationA5, showing an agglomerate consisting of NAG, starch acetate and crospovidone on thesurface; (b) SS-agglomerated caffeine formulation B8, showing an agglomerateconsisting of SA, caffeine and CP; (c) SS-agglomerated propranolol HCl formulation C4showing no agglomerates; (d) PP-agglomerated NAG formulation A, showing anagglomerate consisting of NAG, starch acetate and crospovidone on the surface.

5.2.3 Dissolution and tablet characteristics (II)

The dissolution profiles of SS and PP-agglomerated NAG formulations and SS-

agglomerated caffeine and propranolol formulations together with the corresponding

unagglomerated formulations are shown in Figure 5.5 (formulation codes in Table 5.7).

In the case of NAG (Figure 5.5 a), it can be seen that the more CP present in the SS-

agglomerated formulation, the faster was the release of NAG. However, even with quite a

high amount of CP (i. e. 10%), NAG was not released immediately even though the tablet

disintegrated rapidly. In a comparison of the agglomerated formulation A5 with the

a b

c d

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unagglomerated formulation A6 which had an identical material composition (containing

7.5 % of CP), it can be noted that agglomeration had slowed down the dissolution of

NAG (Figure 5.5 a). The calculated f2-value for formulations A5 and A6 was 35 which

indicates that they can be considered as being different. Furthermore, the initial burst

release, typical for uncoated SA matrix tablets (Pohja et al. 2004, Korhonen et al. 2005),

seen at the beginning of the dissolution curves, was less extensive with the agglomerated

formulation A5 than with the corresponding unagglomerated formulation A6. However,

these effects were not seen when comparing formulations A and A7, which did not

contain CP (Figure 5.5 a). The f2-value for these formulations was 72, indicating that the

formulations can be considered as being similar. When comparing the dissolution profiles

of PP-agglomerated formulations (A, A5) to the profiles of SS-agglomerated

formulations (Figure 5.5 b), no differences between SS and PP agglomerated

formulations were observed (f2-values 63 and 50, respectively). This confirms the

observation made with SEM (Figure 5.4), that NAG does form agglomerates with SA

despite the polarity of the charge generated on the particles.

In the case of caffeine (Figure 5.5 c), no significant difference was found between the

agglomerated (B5, B6) and unagglomerated (B1, B2) formulations when CP was present

in amounts of 0 and 1% (f2-values 73 and 59, respectively). However, much less CP

could be used in the formulations than in the case of NAG. The agglomerated

formulation B7 (contained 2% of CP) released caffeine slower than the corresponding

unagglomerated formulation B3. The formulations can be considered different, since the

f2-value was 47. However, the agglomerated formulation B8 (contained 3% of CP)

released caffeine faster than the corresponding unagglomerated formulation B4. The

difference is quite significant since the f2-value was 38. In addition, more extensive burst

release from the agglomerated formulation B8 compared to the unagglomerated B4 was

observed.

In the case of propranolol HCl –SA formulations, the porosity of the tablets had to be

small (15%) and only very small amounts of CP (0.5%) could be used in order to achieve

sustained release of propranolol. The release profiles of propranolol HCl from the

agglomerated and the unagglomerated formulations were the same (Figure 5.5 d) with f2-

85

values of 94 (C1 vs. C3) and 96 (C2 vs. C4), supporting the results obtained by SEM

(Figure 5.4 c), evidence that no agglomeration had occurred.

Table 5.7. N-acetyl-D-glucosamine (NAG), caffeine and propranolol hydrochlorideformulations and tensile strengths (± sd) of the prepared tablets.

Drug Formulation code Amount of CP in the tablet(%)

Tensile strength of the tablets(MPa)

NAG Aa 0 3.33 ± 0.19A1 2 3.17 ± 0.23A2 3 3.15 ± 0.18A3 5 2.94 ± 0.27A4 10 3.13 ± 0.15A5a 7.5 2.87 ± 0.08A6b 7.5 3.33 ± 0.15A7b 0 3.07 ± 0.17

caffeine B1b 0 3.56 ± 0.22B2b 1 3.75 ± 0.15B3b 2 3.80 ± 0.26B4b 3 4.29 ± 0.35B5 0 3.85 ± 0.25B6 1 3.93 ± 0.13B7 2 3.95 ± 0.19B8 3 3.69 ± 0.29

propranolol HCl C1b 0 5.23 ± 0.21C2b 0.5 5.34 ± 0.28C3 0 5.28 ± 0.13C4 0.5 5.52 ± 0.28

a agglomerated also on a PP plate; b unagglomerated formulation

86

Figure 5.5. Dissolution profiles of: (a) agglomerated (A (�), A1 (�), A2 (�), A3 (�), A4(+) and A5(×)) and unagglomerated (A6(�), A7(�)) formulations of NAG; (b) SSagglomerated (A ( ), A5 ()) and PP agglomerated (A (�), A5 (�)) formulations of NAG;(c) agglomerated (B5 (�), B6 (�), B7(�) and B8 (�)) and unagglomerated (B1( ), B2(�), B3 () and B4(�)) formulations of caffeine; (d) (C3 (�) and C4 (�)) andunagglomerated (C1 ( ) and C2 ()) formulations of propranolol HCl.

Thus, the most pronounced effects on dissolution were seen with NAG with a mean

particle size of 141 µm, minor effects with caffeine (46 µm) and no effects with

propranolol (14 µm) (Figure 5.5). This can be explained by the differences in the

organization of the binary and tertiary powder mixtures, caused by the different particle

sizes of the drugs. The larger the particles, the more rough and the greater storage

capacity of the discontinuities of the drug particles (DeBoer et al. 2005, Dickhoff 2005).

In the case of NAG formulations, the SA particles were initially completely obscured in

the discontinuities of NAG and a percolating SA network could not be formed during

compaction of the tablet, since SA was only present in clusters in the NAG matrix

a

dc

b

87

(formulation A7). The agglomeration process caused spreading of SA particles more

evenly over the large NAG particles and thus the particle contacts formed during

tabletting would be mainly SA-SA contacts, creating a continuous SA matrix inside the

tablet (observed also by SEM, not shown) (formulation A). This led to the formation of

stronger tablets than the tablets of unagglomerated A7 formulation (p < 0.05, Table 5.7).

In fact, as a consequence of the powder agglomeration, the tensile strengths of the tablets

A (Table 5.7) approached the values of pure SA tablets (3.62 ± 0.37 MPa) which were

much higher than the tensile strengths of pure NAG tablets (0.52 ± 0.09 MPa). This is in

accordance with the fact that the tensile strength and drug dissolution of a binary mix

have been observed to be dependent on its organization, i.e. governed by the adhering

material (Barra et al. 1999, 2000).

The effect of CP on the dissolution can be explained by the disruption of the SA matrix

in the tablet, which could be seen when 3% or more CP was present in the formulations

(Figure 5.5 a, c). Below this concentration, the SA matrix was not affected by the

presence of CP which was only present in minor clusters at lower concentrations (and had

only a minor effect on the tablet strength, Table 5.7). Thus, CP was unable to disrupt the

SA matrix during dissolution. In the agglomerated NAG formulations, SA and CP were

well distributed on the surfaces of the NAG particles (Figure 5.4 a) and the SA matrix

determined the strength of the tablets (Table 5.7). However, the addition of increasing

amounts of CP resulted in weaker tablets than the tablets of formulation A (contained 0%

of CP) and tablets of the unagglomerated A7 (Table 5.7), since it is known that SA-CP

binding is weaker than SA-SA binding (VanVeen et al. 2002, 2004). Interestingly,

despite the fact that as a result of the agglomeration process, the tensile strength values

decreased, there was still a reduction in the drug release rate (Figure 5.5). This might

indicate that, when the hydrophobic SA particles coated NAG particles, water penetration

and the subsequent contact with NAG was hindered and the release rate declined. This is

in accordance with that the dissolution properties of the tablet are governed by the

percolating material (Barra et al. 2000). The slowing of the dissolution rate as a result of

hydrophobic excipient coating of the drug particles has been previously observed with

filled capsules (Chowhan and Chi 1986).

88

In the case of caffeine, the storage capacity of the discontinuities was insufficient to

hide all SA and a percolating SA network was almost invariably formed when the tablets

were compressed. The agglomeration process only improved the SA network and thus

only minor effects were observed on dissolution (Figure 5.5 c) and tensile strength of the

tablets (Table 5.7). Finally, the propranolol particles were so small that the discontinuities

could not hide any SA particles and the mixtures were almost identical, whether or not an

agglomeration process had been carried out (Figure 5.5 d and Table 5.7).

5.2.4 Summary and future prospectives (I, II)

The study showed that controlling the release rate of highly water soluble saccharides

from hydrophobic matrices over a wide time scale is possible simply by altering the tablet

porosity and the relative amount of the matrix former in the tablet. Using these means in

the present study, the saccharide release type could be designed to be in the range of

intermediate to prolonged release. The desired saccharide release in 2-4 hours was

obtained with SA and EC matrices that had either relatively low porosity and a high

amount of saccharide in the tablet or high porosity and a low amount of saccharide in the

tablet. In addition, these hydrophobic matrices may be potential vehicles for oral delivery

of larger molecules (e.g. macromolecules), suggested by their ability to control the

release of an oligosaccharide (maltopentaose).

However, the physicochemical properties and process induced phase transformations

can affect significantly the dissolution rate of even highly water soluble substances, as

shown by the observed biphasic dissolution profile of maltose and maltopentaose,

attributable to water mediated phase transitions of the metastable phases present in these

materials. Thus, this observation emphasizes how important it is to understand crystal

forms and the amorphous phase of the drug (and excipients), since e.g. incorporation of a

metastable phase in the dosage form can lead to development problems.

Furthermore, in this study it has been shown that the dissolution characteristics and

tablet properties of a hydrophobic matrix tablet could be modified without changing the

composition of the powder mixture or other formulation parameters. A simple mixing

process prior to tabletting may be sufficient to change the mixture organization in a way

89

that the dissolution rate is modified, providing that certain conditions are fulfilled. By

choosing the right container material for the mixing, adhesion and agglomeration of the

drug with exipients can be promoted by triboelectic charging. However, drug-excipient

combinations that are sensitive to tribocharging can also be problematic in regular large

scale production since minor changes in the environmental humidity and powder

movements could lead to undesired variations in drug release. It is claimed that generally

excipient powders become negatively charged when they are in contact with metal or

glass and positively in contact with plastic (Staniforth and Rees 1982). However, in this

study, the excipients (SA and CP) became positively charged in contact with metal (SS),

glass and plastic materials of PP and PVC. SA charged negatively in contact with plastic

materials of PE and acrylic. Thus triboelectric measurements need to be conducted for

excipients and the drugs used in order to find a material where surface charges of

opposite signs are generated to allow interparticle attraction to occur. Unfortunately,

many pharmaceutical materials lose electrostatic charge through earth leakage relatively

quickly (Staniforth 1987). Thus, the stability of agglomerates generated by electrostatic

interactions may not be good.

However, the extent of particle organization in the tablets is dependent also on the size

and the surface roughness of the particles. In the present study, the most pronounced

effects were seen with the drug with the largest particle size (NAG) since initially, SA

particles were able to be stored within the discontinuities on the NAG surface and no SA

matrix was formed. Agglomeration caused spreading of SA particles over larger NAG

particles, promoting formation of the SA matrix and leading to slower dissolution rate of

NAG. In the case of drugs with smaller particle sizes (caffeine, propranolol), the storage

capacity of the surface discontinuities was insufficient to obscure all SA and the SA

matrix was almost invariably formed, leading to less pronounced changes in the tablet

properties.

For some time now, advances in oral-modified release technology have been largely

driven by significant improvements in manufacturing equipment and technologies as well

as the development of improved biocompatible and biodegradable polymeric materials

for controlling release rates (Charman and Charman 2002). It can be expected that this

trend will continue in the future. In the scientific literature, various examples of complex

90

oral-modified release systems can be found, but in many cases their commercial

applicability has not been proved. It needs to be remembered that the drug product

manufacturing process has to be both reproducible and capable of being conducted at

reasonable cost. It seems that the simple modifications and preparation processes for

tailoring the drug release properties of the hydrophobic matrices, examined in this study,

meet these criteria.

5.3 Fast dissolving particles of a poorly soluble drug for intraoral preparations

(III, IV)

5.3.1 Improvement of drug dissolution by solid dispersion approach (III)

As described in Chapter 2.3, there is a growing interest in developing dosage forms,

e.g. orally fast disintegrating tablets, which allow a rapidly dissolving drug to absorb

directly into the systemic circulation through the oral mucosa. The inherent advantages of

the SD approach in enhancing drug dissolution and stability (described in chapter 2.4.3)

might mean that even a poorly soluble drug could be administerd in such a formulation.

The model drug used (PPZ) was found to have poor dissolution properties in conditions

simulating the buccal cavity (i.e. low liquid volume (3 ml), with pH 6.8). The solubility

of PPZ was found to be 149 ± 3 µg/ml and its dissolution rate was poor, i.e. within 4

minutes only 2% of PPZ had dissolved (Figure 5.6 a). Reducing the particle size of PPZ

did not markedly change the situation, viz. only 13% of PPZ <15 µm had dissolved

within 4 minutes (Figure 5.6 a). Furthermore, even when sink conditions prevailed, only

43 % of PPZ and 88 % of PPZ <15µm had dissolved after 20 minutes (results shown up

to 4 min in Figure 5.6 a).

5.3.1.1 Polymer selection by the solubility parameter approach (III)

As described in section 2.4.3.3, two materials are considered to be miscible with each

other when Δδ is smaller than 2.0 MPa1/2 which might lead to the formation of a solid

solution. The δ value for PPZ was estimated to be 22.4 MPa1/2. Evaluation of a wide

selection of polymers and their different grades (Hancock et al. 1997, Greenhalgh et al.

91

1999, Forster et al. 2001, Marsac et al. 2006b) revealed that two hydrophilic polymers,

PVP K 30 and PEG 8000, possessed solubility parameter values nearest to that of PPZ,

i.e. 22.4 (Δδ = 0) and 21.6 MPa1/2 (Δδ = 0.8) respectively, and thus they were predicted to

provide the most favorable conditions for molecular level mixing with PPZ.

5.3.1.2 Dissolution properties of the solid dispersions (III, IV)

In phase solubility studies, increasing concentrations of PVP and PEG increased

linearly the PPZ solubility in pH 6.8 buffer, however PVP was considerably better than

PEG (Figure 5.6 b). PPZ solubility was increased over fivefold in 10% (w/v) PVP

solution whereas in 10% (w/v) PEG solution, the increase was a mere doubling. Similar

behavior has been observed previously for the other model drugs (Sethia and Squillante

2004, Mura et al. 2005, Ruan et al. 2005).

Figure 5.6. Dissolution curves of (a) PPZ (d(0.5) = 30 µm) in supersaturated (�) and insink conditions (�), and micronized (<15 µm) PPZ) in supersaturated ( ) and in sinkconditions (�); (b) phase solubility diagrams of PPZ in solutions PVP (�) and PEG ( ) inpH 6.8 buffer solution at room temperature.

The dissolution rates of freeze-dried PPZ and PPZ from prepared PPZ/PVP and

PPZ/PEG dispersions were determined in supersaturated conditions due to the small

dissolution volume (3 ml), i.e. complete dissolution of PPZ would result in 9-times the

equilibrium solubility of crystalline PPZ (Table 5.8). With freeze-dried PPZ, a rapid

dissolution at the beginning of the experiment (over 70 % of PPZ dissolved already after

15 seconds) was seen leading to over 7-fold supersaturation of PPZ. The supersaturated

a b

92

PPZ started to precipitate after one minute and the amount of dissolved PPZ declined

down to 60 %.

Instead, in the case of PPZ/polymer SDs, the ability of the polymers to inhibit

precipitation of PPZ was seen (Table 5.8). In the case of PPZ/PVP SDs, no precipitation

of supersaturated PPZ was observed. After 15 seconds, 20, 35 and 10 % of PPZ had

dissolved from 5/1, 1/5 and 1/20 PPZ/PVP, respectively, increasing up to 40, 90 and 40%

after four minutes. In the case of PPZ/PEG SDs, no precipitation of the supersaturated

PPZ was observed with 5/1 and 1/5-formulations. However, only 40% of PPZ dissolved

from the 5/1 PPZ/PEG after four minutes. The most remarkable improvement in the

dissolution rate was seen with 1/5 PPZ/PEG SD which dissolved within one minute

without precipitation of the supersaturated PPZ.

Thus, the dissolution rates of PPZ/PVP SDs were not as fast as those of PPZ/PEG SDs,

probably due to their surprisingly poor wettability which was observed visually

(PPZ/PVP powders remained floating on the liquid surface). On the other hand, at high

polymer contents, PVP might form a viscous layer during dissolution, hindering the

dissolution of the drug (Craig 2002) or it might act as a binder with some drugs which

could cause a decrease in the dissolution rate (Bansal et al. 2007).

The dissolution rates (in 3 ml of pH 6.8 buffer) of freeze-dried PPZ and PPZ/PVP SDs

were found to be changed after four weeks of storage at 40°C/silica gel (Table 5.8). In the

case of fresh samples, freeze-dried PPZ and 1/5 PPZ/PVP had a faster dissolution, while

5/1 and 1/20 PPZ/PVP dissolved clearly more slowly. In contrast, the best dissolution

after storage was found with freeze-dried PPZ (50% of PPZ dissolved in 4 min) and 5/1

PPZ/PVP (60% of PPZ dissolved in 4 min), while the dissolution of 1/5 and 1/20

PPZ/PVP was considerably poorer that encountered with the fresh SDs. In fact, the

dissolution rate of PPZ from 1/20 PPZ/PVP had declined back to the level of crystalline

PPZ, i.e. 2% PPZ dissolved in four minutes.

In the case of PPZ/PEG SDs, the dissolution profiles were also found to be somewhat

different than the profiles of fresh samples (Table 5.8). After storage at 40°C/silica gel,

1/5 PPZ/PEG formulation still had the best dissolution properties (i.e. over 60% of PPZ

dissolved in 4 min). The dissolution of 5/1 PPZ/PEG had remained almost unchanged,

93

but there was a reduction in the dissolution rate of 1/20 PPZ/PEG. After storage at

40°C/75%, the dissolution of PPZ from 1/5 and 1/20 PPZ/PEG had further declined.

Table 5.8. The amount (%) of PPZ dissolved in the freeze-dried PPZ and from the SDs ofPPZ before and after four weeks’ storage at 40°C/silica or 40°C/75 % RH (n=3 ± sd.).

% of perphenazine dissolving at time t (min)Dispersion Storage t=0.25 t=0.5 t=0.75 t=1 t=2 t=4freeze-driedPPZ

- 72 ± 21 72 ± 3 78 ± 8 77 ± 12 61 ± 12 61 ± 9

freeze-driedPPZ

40/silica 40 ± 6 52 ± 1 57 ± 11 52 ± 5 66 ± 3 51 ± 6

5/1 PPZ/PVP - 22 ± 8 26 ± 5 32 ± 5 39 ± 13 42 ± 5 44 ± 95/1 PPZ/PVP 40/silica 41 ± 1 50 ± 5 56 ± 3 55 ± 4 56 ± 3 59 ± 3

1/5 PPZ/PVP - 35 ± 3 36 ± 5 46 ± 6 60 ± 10 75 ± 11 86 ± 61/5 PPZ/PVP 40/silica 8.4 ± 2 9.6 ± 3 9.5 ± 3 12 ± 1 13 ± 1 15 ± 1

1/20 PPZ/PVP - 10 ± 1 15 ± 2 18 ± 1 20 ± 1 24 ± 3 37 ± 31/20 PPZ/PVP 40/silica 1.7 ± 2.1 1.2 ± 0.3 1.3 ± 0.3 1.1 ± 0.2 1.4 ± 0.1 2.4 ± 0.3

5/1 PPZ/PEG - 26 ± 6 33 ± 4 36 ± 5 - 36 ± 3 38 ± 35/1 PPZ/PEG 40/silica 22 ± 5 25 ± 1 38 ± 5 45 ± 4 43 ± 9 57 ± 3

1/5 PPZ/PEG - 79 ± 8 83 ± 6 82 ± 5 98 ± 6 98 ± 6 96 ± 161/5 PPZ/PEG 40/silica 68 ± 4 64 ± 3 68 ± 2 68 ± 7 67 ± 3 64 ± 31/5 PPZ/PEG 40/75% RH 47 ± 8 52 ± 5 46 ± 8 44 ± 3 49 ± 5 56 ± 11

1/20 PPZ/PEG - 72 ± 2 76 ± 2 75 ± 1 107 ± 1 73 ± 7 77 ± 81/20 PPZ/PEG 40/silica 48 ± 2 47 ± 7 54 ± 4 56 ± 6 63 ± 4 53 ± 11/20 PPZ/PEG 40/75% RH 39 ± 1 50 ± 1 53 ± 6 45 ± 1 54 ± 3 53 ± 2

5.3.2 Physical properties and stability of the solid dispersions (III, IV)

It has been suggested that in SDs, drug areas with dimensions of 50-100 nm can be

considered as drug particles that have not achieved molecular-level dispersion in the

polymer (Karavas et al. 2007a). When studying the distribution of PPZ in 1/5 and 1/20

PPZ/polymer SDs by SAXS using similarly processed PVP and PEG as references, there

was no evidence of these kinds of PPZ areas. In the pair density distribution curves of

PVP, PEG and their 1/5 and 1/20 SDs with PPZ (Figure 5.7 a, b), one large maximum

(approx. 25 nm) and another much smaller maximum (approx. 90 nm) can be seen, which

did not change in spite of addition of different amounts of PPZ (i.e. the case of 1/5 and

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1/20 SDs). Thus, PPZ was uniformly distributed in the polymer matrices suggesting that

a molecular dispersion had been formed irrespective of the PPZ/polymer ratio.

However, the drug particle size in a SD might increase during storage due to phase

separation and crystallization of the drug (Dordunoo et al. 1997). After four weeks of

storage at 25°C/60% RH, determination of the distribution of the inhomogeneity regions

revealed that with the PVP SDs, the maxima had been shifted from 24 nm to 26-27 nm

and from 89 nm to 70 nm (1/20 PPZ/PVP) (Figure 5.7 a). However, similar shifts were

visible with the freeze-dried PVP. In the case of PPZ/PEG SDs, the maxima were found

to be exactly the same in both the fresh and stored samples (i.e. 26 and 80 nm) (Figure

5.7 b). No increase in the size of the inhomogeneity regions (in the region up to 100 nm)

in the SDs had occurred during storage and thus, it was considered unlikely that phase

separation and crystallization had taken place.

Figure 5.7. Pair density distribution functions of (a) freeze-dried PVP ( ) and 1/5 (×) and1/20 (-) perphenazine/PVP fresh solid dispersions compared to the dispersions stored at25°C/60% RH for four weeks (corresponding symbols in grey); (b) freeze-dried PEG ( )and 1/5 (×) and 1/20 (-) perphenazine/PEG fresh solid dispersions compared to thedispersions stored at 25°C/60% RH for four weeks (corresponding symbols in grey),determined from SAXS measurements.

The formation of solid solutions was confirmed by XRPD and DSC studies (Figures 5.8

a,b, Table 5.9) which revealed that PPZ was present in an amorphous form in the

dispersions in all mixture ratios and that all the SDs had a single Tg, in contrast to many

studies with other drugs where amorphization of the drug has occurred only at higher

polymer contents (Shah et al. 1995, Lin and Cham 1996, Paradkar et al. 2004). This was

probably due to the complete miscibility of PPZ with the carriers, as indicated by the

a b

95

similarity of their solubility parameters. Thus, in the case of PVP (initially amorphous,

Figure 5.8 a, Table 5.9), PPZ formed amorphous molecular dispersions with fully

amorphous PVP.

Figure 5.8. X-ray diffraction patterns of: (a) PPZ (a), PEG (b), PVP (c) and freeze-driedPPZ (d); (b) fresh PPZ/polymer SDs (PVP a-c, PEG d-e); (c) freeze dried PPZ (a) andPPZ/PVP SDs (b-d) stored at 40°C/silica gel; (d) 1/5 PPZ/PEG SD before (a) and afterstorage at 40°C/silica gel (b) and 40°C/75% RH (c).

However, the situation with PEG (initially crystalline, Figure 5.8 a, Table 5.10) was

found to be different. A decrease in PEG crystallinity as a function of the increasing PPZ

content indicative of lattice distortion of the carrier due to the formation of a solid

solution (Law et al. 2001), was seen in DSC (�H values in Table 5.10). Furthermore, the

melting temperature of PEG was higher in the SDs compared to the physical mixtures

(Table 5.10) which might be attributable to the fact that the higher melting (extended

chain) form of PEG remained crystalline while the lower melting, once-folded

modification had transformed into the amorphous form (Craig 1990) during the SD

preparation process. The amount of amorphized PEG was found to be 94, 21 and 13 %

5 10 15 20 25 300

1000

2000

3000

4000

5000

Inte

nsity

(cts

)

2theta (°)

PPZ

PPZ

PPZ

PPZ

PPZPEG

PEG

a

bc

5 10 15 20 25 300

5000

10000

d

c

bInte

nsity

(cts

)

2theta (°)

a

5 10 15 20 25 300

20000

40000

60000

Inte

nsity

(cts

)

2theta (°)

bcdef

a5 10 15 20 25 30

0

25000

50000

75000

Inte

nsity

(cts

)

2 theta (°)

a

b

c

da b

c d

96

for 5/1, 1/5 and 1/20 dispersions, respectively, as can be calculated from the ΔH values of

PEG in the dispersions and the ΔH value for pure PEG, shown in Table 5.10. Thus, the

SDs consisted of two phases; one composed of crystalline PEG and one of amorphous

PPZ/PEG containing 19, 38 and 65 % of amorphous PEG, respectively.

Table 5.9. Glass transition (Tg) and heat capacity (ΔCp) values (n= 3 ± sd) for freeze-dried perphenazine and the solid dispersions of perphenazine before and after the fourweeks of storage at 40°C/silica gel.

SampleTg (°C) beforestorage

ΔCp (J/gK) beforestorage

Tg (°C),after storage at40°C/silica gel

ΔCp ( J/gK)after storage at40°C/silica gel

PPZ 15.3 ± 0.3 0.49 ± 0.06 - -

PVP 172 ± 0.3 0.22 ± 0.03 - -

PEG nd. nd. - -

freeze-dried PPZ 53.8 ± 2.5 0.82 ± 0.24 62.3 ± 0.3 0.10 ± 0.06

5/1 PPZ/PVP 58.9 ± 0.6 0.68 ± 0.14 60.9 ± 0.8 0.46 ± 0.10

1/5 PPZ/PVP 155.1 ± 2.4 0.17 ± 0.08 151.4 ± 0.3 0.30 ± 0.01

1/20 PPZ/PVP 170.3 ± 1.4 0.13 ± 0.03 165.7 ± 1.6 0.26 ± 0.02

5/1 PPZ/PEG 22.2 ± 0.7 0.48 ± 0.03 15.6 ± 1.0 0.47 ± 0.04

1/5 PPZ/PEG -44.9 ± 0.2 0.02 ± 0.01 nd. nd

1/20 PPZ/PEG nd. nd. nd. nd - = not measured; nd. = not detected

Table 5.10. The melting points (Tm,°C) and enthalpies (ΔH, J/g) (n= 3 ± sd) of PEG inthe prepared PPZ/PEG physical mixtures (PM), and solid dispersions (SD) before andafter the four weeks of storage at 40°C/silica gel and 40°C/75% RH.Sample Tm/°C,

ΔΗ/J/ga

of PEG in PMb

Tm/°C,ΔΗ/J/ga

of PEG in SD

Tm/°C,ΔΗ/J/ga of PEG inSD after storage at 40°C/silica gel

Tm/°C,ΔΗ/J/ga of PEG after storage at 40°C/75%RH

5/1 PPZ/PEG 59.7 ± 0.1,165 ± 20

62.9 ± 0.1,9.4 ± 2

64.0 ± 0.4,3.6 ± 0.7

-

1/5 PPZ/PEG 59.3 ± 0.1,198 ± 7

61.4 ± 1.2,157 ± 6

60.8 ± 0.7,190 ± 10

62.7 ± 1.6,190 ± 5

1/20 PPZ/PEG 59.4 ± 0.1,193 ± 1

61.2 ± 0.3,168 ± 2

61.0 ± 0.2,196 ± 2

63.3 ± 0.3,194 ± 1

a ΔH is corrected for the amount of PEG in the mixture; b ΔH of pure PEG is 186 ± 3 J/g; - = not measured

97

The unexpectedly high Tg value observed for the amorphous, freeze-dried PPZ (Table

5.9) was attributed to the formation of an amorphous PPZ dihydrochloride salt due to the

preparation method, this being confirmed by the FTIR data. In fact, PPZ was found to be

present as an HCl salt in all of the SDs (example spectra in Figure 5.9 a, b), evidenced by

the appearance of a new absorption band at approx. 2400 cm-1 (HCl absorption) in freeze-

dried PPZ and in the SDs.

The theoretical Tg-value for each of the PPZ/polymer blends was calculated according

to the Gordon–Taylor equation (Eq. 5) and Simha-Boyer rule (Eq. 6). The Tgs of the

freeze-dried PPZ and PVP measured by DSC (Table 5.9) and the Tg value from literature

for PEG (Forster et al. 2001) were used for the calculations. The true density of the

components was measured by helium pycnometry, obtained values being 1.31, 1.17 and

1.48 g/cm3 for PPZ; PVP and PEG, respectively. In the calculations for PPZ/PEG SDs,

the true compositions of amorphous PPZ/PEG phase were used. The Tg-values observed

by DSC (Table 5.9) were found to be in reasonable agreement with the values predicted

for the SDs by the Eq. 5 (74, 144 and 165°C for 5/1, 1/5 and 1/20 PPZ/PVP, and 28, 5

and -24°C for 5/1, 1/5 and 1/20 PPZ/PEG, respectively), except the value for 1/5

PPZ/PEG. Generally, deviation from ideal behavior would be caused by differences in

strength of intermolecular interactions between the individual components and those of

the blend (Nair et al. 2001).

Figure 5.9. The FTIR spectra of (a) 1/5 perphenazine/PVP solid dispersion before (a) andafter storage at 40°/silica (b); (b) 5/1 perphenazine/PEG before (a) and after storage at40°/silica (b) and 1/5 perphenazine/PEG solid dispersions before (c) and after storage at40°/silica (d) and at 40°/75% RH (e).

4000 3500 3000 2500 2000 1500 1000

e

d

c

bAbso

rban

ce

Wavenumber (cm-1)

a

4000 3500 3000 2500 2000 1500 1000

b

Abso

rban

ce

Wavenumber (cm-1)

a

a b

98

In addition, FTIR results revealed that hydrogen bonding between PPZ and PVP and/or

HCl was promoting the formation of PPZ/PVP solid solutions (Figure 5.9 a). In the SDs

of PVP, interactions between the OH-group of PPZ (band at approx. 3400 cm-1) and the

carbonyl group of PVP (band at approx. 1665 cm-1) were observed (example spectrum

shown in Figure 5.9 a) as shifts of the carbonyl band of PVP at to 1670, 1663 and 1662

cm-1 in the 5/1, 1/5 and 1/20 dispersions, respectively, compared to 1655 cm-1 in the

physical mixtures. Usually the carbonyl shift occurs to lower wave numbers (Nair et al.

2001), but similar shifts to higher wave numbers, indicative of specific drug-PVP

interactions, have been also observed (Taylor and Zografi 1997, Karavas et al. 2005). In

the case of SDs of PEG, interactions were present with the OH-group of PPZ and the

ether oxygen of PEG (band at approx. 1095 cm-1), observed as a small shift of the C-O

stretching band (∼2 cm-1 to the higher wavenumbers) in the case of 5/1 and 1/5

formulations compared to the physical mixtures (Figure 5.9 b). Hydrogen bonding

between PPZ and PEG was more difficult to demonstrate from the FTIR spectra than

between PPZ and PVP, in accordance with previous studies (Anguiano-Igea et al. 1995,

Van den Mooter et al. 1998).

These results indicate that the formation of a solid solution of PPZ and the presence of

PPZ HCl salt in the SDs, which created a microenvironment around the dissolving

particles leading to a high supersaturation of PPZ were the factors promoting the

dissolution of PPZ. Previously, simultaneous modulation of the microenvironmental pH

and drug crystallinity in solid dispersions has been claimed to be a useful way to increase

the dissolution rate of an ionizable drug (Usui et al. 1998, Tran et al. 2008). In

conjunction with hydrogen bonding between PPZ and polymers, these factors may also

improve the physical stability of the solid dispersions.

As a consequence of four weeks of storage of 1/5 and 1/20 PPZ/PEG SDs at accelerated

conditions (40°C/75%), a breakdown of the stabilizing drug/polymer interactions was

observed by FTIR (Figure 5.9 b) which probably led to crystallization of the amorphous

part of PEG into a higher melting modification (Table 5.10, Figure 5.8 d), which has been

observed previously with PEGs (Dordunoo et al. 1997, Weuts et al. 2005). This led to at

least partial crystallization of PPZ which was observed by XRPD (Figure 5.8 d) and DSC

(i.e. no Tg was observed). Thus, the decline in dissolution rate after storage at 40°C/75%

99

was most probably attributable to the increase in the amount of crystalline PPZ in the

SDs during storage. However, the capacity of PEG to create a local micro-environment

allowing more rapid dissolution probably compensated for the transformation of the drug

from an amorphous into the crystalline state, preventing the dissolution rate from

reverting back to the level of crystalline PPZ (Weuts et al. 2005). Furthermore, the

dissolution of PPZ from 1/5 and 1/20 PPZ/PEG had somewhat declined also after storage

at 40°C/silica (Table 5.8), even though PPZ had remained in an amorphous state

according to XRPD (example diffractograms are displayed in Figure 5.8 d) and FTIR

demonstrated that the hydrogen bonding interactions between PPZ and PEG were stable

(example spectra shown in Figure 5.9 b). However, PEG had crystallized also in these

conditions (Table 5.10) from which it can be proposed that the ability of crystalline PEG

to preserve the supersaturated PPZ during dissolution is not as good as that of amorphous

PEG (Khougaz and Clas 2000, Konno and Taylor 2006). Regardless, it should be noted

that the dissolution properties after storage were still much better than those of the

crystalline PPZ with all PPZ/PEG formulations.

The PPZ/PVP SDs were found to be stable (observed by DSC and XRPD, Table 5.9

and Figure 5.8 c) during storage at 40°C/silica, due to the antiplasticizing effect of PVP

and stabilizing hydrogen bonding interactions (observed by FTIR, Figure 5.9 a). In spite

of this, a significant decline was seen in the dissolution rate of PPZ from the 1/5 and 1/20

PPZ/PVP (Table 5.8). Similarly, a small decline in the dissolution rate of drugs has been

observed in other studies with PVP SDs when they are stored, in spite of the physical

stability of the SD (Ambike et al. 2004).

On the contrary, 5/1 PPZ/polymer SDs were found to be stable during storage at

40°C/silica (Figures 5.8 c and 5.9 b, Tables 5.9 and 5.10) and the dissolution rate of PPZ

from these preparations was even slightly improved (Table 5.8). This phenomenon has

been claimed to be attributable to improved hydrogen bonding between the drug and

polymer due to increased molecular mobility during storage at elevated temperatures

(Gupta et al. 2002). In addition, freeze-dried PPZ remained stable during storage at

40°C/silica (Table 5.9, Figure 5.8 c) but its dissolution rate became slightly slower (Table

5.8). The stability might be due to HCl salt formation, increasing the Tg of the drug, and

it might promote the stability of PPZ also in the SDs, since the stability of some SDs has

100

been claimed to originate mainly from the physicochemical properties of the amorphous

drug (Law et al. 2001, Marsac et al. 2006).

5.3.3 Performance of fast disintegrating tablets containing solid dispersions (IV)

As discussed in chapter 2.3.2, FDTs can be prepared by variety of technologies, though

direct compression is relatively simple and economical. However, tabletting by direct

compression requires optimization of the type and amount of excipients and the

compression force in order to produce tablets which have sufficient hardness (i.e. > 1

MPa) but still disintegrate quickly (< 30s). In this study, this was examined by using a

combination of mannitol and disintegrants (CS and/or CP).

The 1/5 PPZ/PEG SD was selected for evaluation in the orally fast disintegrating tablet

formulation study considering the size of the dose (i.e. equivalent of 4 mg of PPZ) and

the results from physical characterization, dissolution rate and the stability studies. For

comparison, similar tablets were prepared with the 1/5 PPZ/PVP SD. Four different

formulations were prepared, the compositions and properties of which are shown in Table

5.11. A formulation containing 10% of 1/5 PPZ/PEG, 60% of mannitol, 15 % CS and

15% of CP (formulation 2) displayed a fast disintegration in 37 seconds even though it

had a tensile strength as high as 1.3 MPa (Table 5.11).

Furthermore, formulation 2 had the best PPZ dissolution properties (i.e. PPZ released

34 % in four minutes) (Figure 5.10 a), followed by formulations 1, 4 and 3, respectively.

Thus, PPZ release from the FDTs seemed to follow the order of the dissolution rates of

the SDs (Table 5.8). The tensile strengths of formulations 2 and 4 (containing CP and

CS) were higher (i.e. ≥ 1 MPa) than those of formulations 1 and 3 (containing only CS)

due to the higher compression force (Table 5.11). In spite of this, the disintegration times

of formulations 2 and 4 were considerably shorter than those of formulations 1 and 3.

This is due to CS’s ability (alone or as a combination of superdisintegrants) to produce

tablets that retain their fast disintegration properties in spite of having being subjected to

a higher compression force (Rxcipients 2007). Furthermore, the disintegration time of

formulation 2, containing 1/5 PPZ/PEG, was 20 seconds shorter than the disintegration

time of the similar formulation 4, containing 1/5 PPZ/PVP, probably due to the lower

101

tensile strength of formulation 2 than that of formulation 4. This in turn might be

attributable to the SD’s ability to resist deformation under the compaction force, which in

this case was better with PPZ/PEG, leading to the formation of weaker tablets (Sadeghi et

al. 2004).

Table 5.11. Formulation compositions, compression forces and resulting porosity (n=50)of the FDTs containing either 10 % (w/w) 1/5 PPZ/PEG SD or 1/5 PPZ/PVP SD. Inaddition, mass uniformity (n=50 (before) ± sd and n=20 ± sd (after)), tensile strength(n=6 ± sd), disintegration time (n=6 ± sd) of the tablets before and after storage at21°C/60 % RH are shown.

Formulation

Property 1 2 3 4SD 1/5 PPZ/PEG 1/5 PPZ/PEG 1/5 PPZ/PVP 1/5 PPZ/PVPMannitol % (w/w) 60 60 60 60Calcium silicate % (w/w) 30 15 30 15Crospovidone % (w/w) - 15 - 15Compaction force (kN) 5 10 5 10Tablet porosity (%) 29 19 32 22

Fresh tabletsMean weight (mg) 199.6 ± 0.5 200.5 ± 0.6 198.7 ± 0.5 198.4 ±1.0Tensile strength (MPa) 0.40 ± 0.04 1.28 ± 0.06 0.62 ± 0.07 1.58 ± 0.06Disintegration time (s) 104 ± 17 37 ± 3 >120 58 ± 2

After storageMean weight (mg) 199.0 ± 0.4 200.4 ± 0.5 200.9 ± 0.5 204.8 ± 1.1Tensile strength (MPa) 0.70 ± 0.11 1.11 ± 0.04 1.73 ± 0.14 1.29 ± 0.07Disintegration time (s) >120 36 ± 4 >120 68 ± 4

Figure 5.10. Dissolution properties of the tablet formulations containing solid dispersions1/5 of perphenazine with PEG (formulations 1 ( ) and 2 (�)) and PVP (formulations 3��) and 4 (�)) (a) before and (b) after storage at 21°C760% RH.

ba

102

Formulation 2 was the best at maintaining its performance during storage at 25°C/60%

RH (Table 5.1, Figure 5.10 b). The release properties of formulations 1 and 2 had

remained unchanged (or had become somewhat faster) throughout the storage (Figure

5.10 b), with formulation 2 still being the fastest releasing formulation. Instead, the

release of PPZ was slower from formulations 3 and 4 after storage (Figure 5.10 b). These

changes in dissolution properties were probably attributable to the changes in the tablet

properties occurring during storage (Table 5.11).

Due to the hygroscopicity of 1/5 PPZ/PVP, the weight of the tablets of formulations 3

and 4 had increased whereas the weight of the tablets containing 1/5 PPZ/PEG

(formulations 1 and 2) had remained constant during the storage (Table 5.11). The tensile

strength values had increased with formulations 1 and 3 but decreased with formulations

2 and 4 which can be attributable to several factors. The tensile strength during storage at

high relative humidity can decrease due to moisture uptake with a subsequent weakening

of the binder bridges (Carstensen 2000). Formulations 2 and 4 contained CP, for which

this behavior has been observed before (Engineer et al. 2004). In contrast, an increase in

tensile strength might occur when the sorbed moisture causes recrystallization of a tablet

component or its softening or deliquescence and subsequent filling of the pores of the

tablets (Serajuddin 1999, Carstensen 2000, Sunada and Bi 2002, Marsac et al. 2006a,

Sugimoto et al. 2006), which might be the case with formulation 3. This would also

account for the poorer release of PPZ from the tablet after storage. The increase in tensile

strength led to an increase in the disintegration time with formulation 1. The

disintegration time of formulation 2 remained the same whereas that of formulation 4

increased, in spite of the decrease in tensile strength, which might explain the slightly

slower release of PPZ.

5.3.4 Summary and future prospectives (III, IV)

In this study, freeze-drying of solutions of a poorly water soluble PPZ with 0, 20, 80 or

95% of a polymer led to an improved PPZ solubility and extremely fast dissolution rate

in a small liquid (pH 6.8) volume compared to crystalline or micronized PPZ. The most

remarkable improvement in the dissolution rate was seen with 1/5 PPZ/PEG formulation

103

which dissolved within one minute without precipitation of the supersaturated PPZ.

Dissolution of PPZ was enhanced by solid solution formation, which in turn was

promoted by hydrogen bonding interactions between the drug and polymers, and the

formation of HCl salt of PPZ in the SDs. These factors, in addition to hydrogen bonding

between PPZ and both polymers, probably promoted the stability of PPZ in all solid

dispersions when they were stored for four weeks at 40°C/silica. Nonetheless, the

dissolution rate of PPZ from the solid dispersions was found to be changed, with 1/5

PPZ/PEG still exhibiting the fastest dissolution of PPZ.

When formulating the 1/5 PPZ/polymer SDs into FDTs, a fast and immediate onset of

the release of PPZ (i.e. 34 % of perphenazine in 4 minutes) was provided by the

formulation containing 10% of 1/5 PPZ/PEG, 60% of mannitol, 15 % CS and 15% of CP.

This might mean, however, that the remaining solid material (i.e. approx. 60% of the

drug) is not dissolved in the oral cavity as intended, but is simply swallowed and will be

absorbed via the GI-tract. The formulation showed a fast disintegration in 36 seconds and

had sufficient tensile strength (i.e. >1 MPa) to permit normal handling and packaging,

which is better than the disintegration times reported previously for FDTs containing

SDs, i.e. from 60 to 780 seconds (Valleri et al. 2004, Sammour et al. 2006, Goddeeris et

al. 2008). The formulation also maintained its performance during the four weeks of

storage at 25°C/60% RH, as also in some previous studies with tablet formulations

containing SDs (Hirasawa et al. 2004, Valleri et al. 2004, Shibata et al. 2005).

The absorption of PPZ in vivo has been studied in rabbits after sublingual

administration of 1/5 PPZ/PEG SD powder, in addition to a solid PPZ/�-CD complex,

plain micronized PPZ and after oral administration of an aqueous PPZ solution (Turunen

et al. 2008). The absorption of PPZ (AUC0-360min) was observed to decrease in the

following order: sublingual micronized PPZ > sublingual 1/5 PPZ/PEG SD > sublingual

solid PPZ/�-CD complex > oral aqueous PPZ solution. Thus, the SD formation improved

more the sublingual absorption of PPZ in comparison to CD complexation, but was still

less effective than drug micronization, possibly due to larger bulk volume of the SD.

Today, approx. over 40% of the lead compounds have poor solubility, seriously

limiting their bioavailability (Hauss 2007, Stegemann et al. 2007). This figure is not

likely to decrease in the future, meaning that innovative dosage forms for enhancing the

104

solubility and dissolution rate, such as the amorphous systems, are increasingly needed.

In this study, the suitablility of the solid dispersion approach for formulation of a poorly

soluble drug (PPZ) into an intraoral FDT formulation was assessed. The need for

sophisticated drug delivery systems, such as those presented in this study, is expected to

increase in the future due to the increasing proportion of elderly patients. These types of

formulations are also suitable for pediatric patients (Danish and Kottke 2002). Moreover,

FDTs offer a means for extension of the patent life and market exclusivity for

pharmaceutical companies (Chandrasekhar et al. 2009).

In addition, as pointed out in this study, a thorough understanding of the way in which

solid state properties influence solubility, stability and other properties of the drug

substance is critical when developing drug formulations. In spite of intensive research

e.g. in the field of amorphous drugs and SDs there is still a lack of deep understanding of

the behaviour of these systems. In addition, optimized (new) manufacturing techniques

that are easily scalable remain a field where work is needed in the SD research. However,

control over the amorphous state represents a challenge also in the field of delivery of

macromolecules (e.g. peptides and proteins), since many of these formulations are at least

partially amorphous (Byrappa et al. 2008, Daugherty and Mrsny 2006, Shoyele and

Cawthorne 2006).

105

6 CONCLUSIONS

I. Hydrophobic starch acetate and ethyl cellulose matrices were shown to be capable

of controlling the release of highly water soluble saccharides over a wide time

scale simply by altering tablet porosity and the relative amount of the excipient in

the tablet. The desired saccharide release was achieved with matrices that had

either relatively low porosity and a high amount of saccharide in the tablet or high

porosity and a low amount of saccharide in the tablet.

II. The drug release rate of water soluble model drugs from starch acetate matrix was

modified by dry powder agglomeration. The agglomeration process affected the

particle distribution in the mixtures, this being dependent on the size and the

surface roughness of the drug particles, leading to changes in tensile strength and

drug release properties of the tablets.

III. An extremely fast dissolution rate of a poorly water soluble perphenazine (PPZ)

in a small liquid (pH 6.8) volume was obtained by the formation of solid solutions

of HCl salt of PPZ with polyvinylpyrrolidone (PVP) or polyethyleneglycol

(PEG). The 1/5 PPZ/PEG solid dispersion powder, which dissolved within one

minute, was found to be the most promising candidate for usage in intraoral

formulations.

IV. PPZ remained amorphous in the prepared PVP and PEG solid dispersions when

stored protected from humidity, but nonetheless the dissolution of PPZ had

declined to a greater or lesser extent. In the formulation study of an orally fast

disintegrating tablet, a formulation containing 10% of 1/5 PPZ/PEG, 60% of

mannitol, 15 % calcium silicate and 15% of crospovidone underwent fast

disintegration, displayed a fast and immediate onset of the release of PPZ and had

sufficient tensile strength. The formulation also maintained its performance

during four weeks of storage at 25°C/60% RH.

106

V. In this study, simple formulation and processing modifications, needing no

expensive and complicated equipment or process stages, or new chemical entities,

showed great potential in achieving controlled modification of release and

dissolution of physicochemically diverse drugs. These simple methods can be

helpful in solving the future challenges of developing innovative formulations and

dosage forms, e.g. enhancing the drug solubility and dissolution rate of new, more

hydrophobic lead molecules that otherwise would have limited bioavailability.

The results can also be useful for developing dosage forms for the increasing

proportion of elderly patients as well as for children, two patient groups who

experience problems in swallowing conventional dosage forms.

107

7 REFERENCES

Adamska K, Bellinghausen R, Voelkel A: New procedure for the determination ofHansen solubility parameters by means of inverse gas chromatography. J Chormatogr A1195: 146-149, 2008

Ahuja N, Katare OP, Singh B: Studies on dissolution enhancement and mathematicalmodeling of drug release of a poorly water-soluble drug using water-soluble carriers. EurJ Pharm Biopharm 65: 26-38, 2007

Alderborn G: Particle dimensions. In: Pharmaceutical Powder Compaction Technology,pp. 245-282. Eds. G Alderborn, C Nyström, Marcel Dekker Inc., New York, NY, USA,1996

Alsenz J, Kansy M: High throughput solubility measurement in drug discovery anddevelopment. Adv Drug Deliv Rev 59: 546-567, 2007

Ambike AA, Mahadik KR, Paradkar A: Stability study of amorphous valdecoxib. Int JPharm 282: 151-162, 2004

Ambike AA, Mahadik KR, Paradkar A: Spray-dried amorphous solid dispersions ofsimvastatin, a low Tg drug: in vitro and in vivo evaluations. Pharm Res 22: 990-998, 2005

Amin MCI, Fell JT: Comparison studies on the percolation thresholds of binary mixturetablets containing excipients of plastic/brittle and plastic/plastic deformation properties.Drug Dev Ind Pharm 30: 937-345, 2004

Andronis V, Zografi G: Molecular mobility of supercooled amorphous indomethacin,determined by dynamic mechanical analysis. Pharm Res 14: 410-414, 1997

Anguiano-Igea S, Otero-Espinar FJ, Vila-Jato JL, Blanco-Mendéz: The properties ofsolid dispresions of clofibate in polyethylene glycols. Pharm Acta Helv 70: 57-66, 1995

Asada M, Takahashi H, Okamoto H, Tanino H, Danjo K: Theophylline particle designusing chitosan by the spray drying. Int J Pharm 270: 167-174, 2004

Aso Y, Yoshioka S: Molecular mobility of nifedipine-PVP and phenobarbital-PVP soliddispersions as measured by 13C-NMR spin lattice relaxation time. J Pharm Sci 95: 318-325, 2006

108

Bailey AG: Charging of solids and powders. J Electrostat 30: 167-180, 1993

Bansal SS, Kaushal AM, Bansal AK: Molecular and thermodynamic aspects of solubilityadvantage from solid dispersions. Mol Pharm 4: 794-802, 2007

Barich DH, Munson EJ, Zell MT: Physicochemical properties, formulation and drugdelivery. In: Drug Delivery: Priciples and Applications, pp. 57-71. Ed. B. Wang, JohnWiley & Sons Inc., Hoboken, NJ, USA, 2005

Barra J, Falson-Rieg F, Doelker E: Influence of the organization of binary mixes on theircompactibility. Pharm Res 16: 1449-1455, 1999

Barra J, Falson-Rieg F, Doelker E: Modified drug release from inert matrix tabletsprepared from formulations of identical composition but different organizations. JControl Rel 65: 419-428, 2000

Barra J, Lescure F, Falson-Rieg F, Doelker E: Can the organization of a binary mix bepredicted from the surface energy, cohesion parameter and particle size of itscomponents? Pharm Res 15: 1727-1736, 1998

Bashiri-Shahroodi A, Nassab PR, Szabó-Révész P, Rajkó R: Preparation of a soliddispersion by a dropping method to improve the rate of dissolution of meloxicam. DrugDev Ind Pharm 34: 781-788, 2008

Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J: Ritonavir: anextraordinary example of conformational polymorphism. Pharm Res 18: 859-866, 2001

Bayomi MA: Geometric approach for zero-order release of drugs dispersed in an inertmatrix. Pharm Res 11: 914-916, 1994

Bennett FS, Carter PA, Rowley G, Dandiker Y: Modification of electrostatic charge oninhaled carrier lactose particles by addition of fine particles. Drug Dev Ind Pharm 25: 99-103, 1999

Bhugra C, Shmeis R, Krill SL, Pikal MJ: Predictions of onset of crystallization fromexperimental relaxation times I – Correlation of molecular mobility from temperaturesabove the glass transition to temperatures below the glass transition. Pharm Res 23: 2277-2290, 2006

109

Bhugra C, Shmeis R, Pikal MJ: Role of mechanical stress in crystallization and relaxationbehavior of amorphous indomethacin. J Pharm Sci 97, 4446-4458, 2008

Bi Y, Yonezawa Y, Sunada H: Rapidly disintegrating tablets prepared by the wetcompression method: Mechanism and optimization. J Pharm Sci 88: 1004-1010, 1999

Blagden N, de Matas M, Gavan PT, York P: Crystal engineering of active pharmaceuticalingredients to improve solubility and dissolution rates, Adv Drug Deliv Rev 59: 617-630,2007

Bogardus JB, Blackwood RK Jr.: Dissolution rates of doxycycline free base andhydrochloride salts. J Pharm Sci 68: 1183-1184, 1979

Bolhuis GK, Chowhan ZT: Materials for direct compaction. In: Pharmaceutical PowderCompaction Technology, pp. 419-500. Eds. G Alderborn, C Nyström, Marcel DekkerInc., New York, NY, USA, 1996

Bonny JD, Leuenberger H: Matrix type controlled release systems. Pharm Acta Helv 68:25-33, 1993

Bora D, Borude P, Bhise K: Taste masking by spray-drying technique. AAPSPharmSciTech 9: 1159-1164, 2008

Bredenberg S, Duberg M, Lennernäs B, Lennernäs H, Pettersson A, Westerberg M,Nyström C: In vitro and in vivo evaluation of a new sublingual tablet system for rapidoromucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci 20:327-334, 2003

Breimer DD: Future challenges for drug delivery research. Adv Drug Deliv Rev 33: 265-268, 1998

Brewster ME, Loftsson T: Cyclodextrins as pharmaceutical solubilizers. Adv Drug DevRev 59: 645-666, 2007

Broman E, Khoo C, Taylor LS: A comparison of alternative polymer excipients andprocessing methods for making solid dispersions of a poorly water soluble drug. Int JPharm 222: 139-151, 2001

Bugay DE: Characterization of the solid state: spectroscopic techniques. Adv Drug DelivRev 48: 43-65, 2001

110

Burnett DJ, Thielmann F, Booth J: Determining the critical relative humidity formoisture-induced phase transitions. Int J Pharm 287: 123-133, 2004

Byrappa K, Ohara S, Adschiri T: Nanoparticles synthesis using supercritical fluidtechnology –towards biomedical applications. Adv Drug Deliv Rev 60: 299-327, 2008

Byrn SR, Pfeiffer RR, Stowell JG: Polymorphs. In: Solid-State Chemistry of Drugs, pp.143-232. Eds. SR Byrn, RR Pfeiffer, JG Stowell, SSCI, Inc., West Lafayette, USA,1999a

Byrn SR, Pfeiffer RR, Stowell JG: Amorphous solids. In: Solid-State Chemistry ofDrugs, pp. 249-258. Eds. SR Byrn, RR Pfeiffer, JG Stowell, SSCI, Inc., West Lafayette,USA, 1999b

Byrn SR, Pfeiffer RR, Stowell JG: Microscopy. In: Solid-State Chemistry of Drugs, p.71. Eds. SR Byrn, RR Pfeiffer, JG Stowell, SSCI, Inc., West Lafayette, USA, 1999c

Byrn SR, Pfeiffer RR, Stowell JG: The powder diffraction method. In: Solid-StateChemistry of Drugs, p. 71. Eds. SR Byrn, RR Pfeiffer, JG Stowell, SSCI, Inc., WestLafayette, USA, 1999d

Caraballo I, Melgoza LM, Alvarez-Fuentes J, Soriano MC, Rabasco AM: Design ofcontrolled release inert matrices of naltrexone hydrochloride based on percolationconcepts. Int J Pharm 181: 23-30, 1999

Carstensen JT: Physical testing. In: Drug stability. Principles and practices, 3th Ed, pp.293-314. Eds. JT Carstensen, CT Rhodes, Marcel Dekker, Inc., New York, 2000

Carter PA, Rowley G, Fletcher EJ, Hill EA: An experimental investigation oftriboelectrification in cohesive and non-cohesive pharmaceutical powders. Drug Dev IndPharm 18: 1505-1526, 1992

Chan HK, Doelker E: Polymorphic transformation of some drugs under compression.Drug Dev Ind Pharm 11: 315-332, 1985

Chandrasekhar R, Hassan Z, AlHusban F, Smith AM, Mohammed AR: The role offormulation excipients in the development of lyophilized fast disintegrating tablets. Eur JPharm Biopharm 72: 119-129, 2009

111

Charman SA, Charman WN: Oral modified release delivery systems. In: Modified-Release Drug Delivery Technology, pp. 1-10. Ed. M Rathbone, Marcel Dekker Inc., NewYork, NY, USA, 2002

Chiou WL, Riegelman S: Pharmaceutical applications of solid dispersion systems. JPharm Sci 60: 1281-1302, 1971

Chokshi RJ, Sandhru HK, Iyer RM, Shah NH, Malick AW, Zia H: Characterization ofphysico-mechanical properties of indomethacin and polymers ta assess their suitabilityfor hot-melt extrusion process as a means to manufacture solid dispersion/solution. JPharm Sci 94: 2463-2474, 2005

Chopra SK: Procise: Drug delivery systems based on geometric configuration. In:Modified-Release Drug Delivery Technology, pp. 35-48. Ed. M Rathbone, MarcelDekker Inc., New York, NY, USA, 2002

Chowhan ZT, Chi LH: Drug-excipient interations resulting from powder mixing III:Solid state properties and their effect on drug dissolution. J Pharm Sci 75: 534-541, 1986

Chrzanowski F: Preformulation condiderations for controlled release dosage forms: Part Iselecting candidates. AAPS Pharm Sci Tech 9: 635-638, 2008a

Chrzanowski F: Preformulation condiderations for controlled release dosage forms: PartII –selected candidate support. AAPS Pharm Sci Tech 9: 639-645, 2008b

Colombo P: Swelling-controlled release in hydrogel matrices for oral route. Adv DrugDeliv Rev 11: 37-57, 1993

Colombo P, Bettini R, Santi P, De Ascentiis A, Peppas NA: Analysis of the swelling andrelease mechanisms from drug delivery systems with emphasis on drug solubility andwater transport. J Control Rel 39: 231-237, 1996

Colombo P, Bettini R, Peppas NA: Observation of swelling process and diffusion frontposition during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containinga soluble drug. J Control Rel 61: 83-91, 1999

Colombo P, Santi P, Bettini R, Brazel CS, Peppas NA: Drug release from swelling-controlled systems. In: Handbook of Pharmaceutical Controlled Release Technology, pp.183-224. Ed. DL Wise, Marcel Dekker Inc., New York, NY, USA, 2000

112

Coleman NJ, Craig DQM: Modulated temperature differential scanning calorimetry: anovel approach to pharmaceutical thermal analysis. Int J Pharm 135: 13-29, 1996

Corrigan DO, Healy AM, Corrigan OI: The effect of spray drying solutions ofbendroflumethiazide/polyethylene glycol on the physicochemical properties of theresultant materials. Int J Pharm 262: 125-137, 2003

Costa P, Sousa Lobo JM: Modeling and comparison of dissolution profiles. Eur J PharmSci 13: 123-133, 2001

Craig D: Dielectric analysis of solids. In: Dielectric Analysis of Pharmaceutical Systems,pp. 123-145. Ed. D: Craig, Taylor and Francis, Ltd, London, Great Britain, 1996

Craig DQM: Polyethylene glycols and drug release. Drug Dev Ind Pharm 16: 2501-2526,1990

Craig DQM: The mechanisms of drug release from solid dispersions in water solublepolymers. Int J Pharm 231: 131-144, 2002

Craig DQM, Royall PG, Kett VL, Hopton ML: The relevance of the amorphous state topharmaceutical dosage forms: glassy drugs and freeze dried systems. Int J Pharm 179:179-207, 1999

Crowley MM, Schroeder B, Fredersdorf A, Obara S, Talarico M, Kucera S, McGinityJW: Physicochemical properties and mechanism of drug release from ethyl cellulosematrix tablets prepared by direct compression and hot-melt extrusion. Int J Pharm 269:509-522, 2004

Crowley KJ, Zografi G: The effect of low concentrations of molecularly dispersedpoly(vinylpyrrolidone) on indomethacin crystallization from the amorphous state. PharmRes 20: 1417-1422, 2003

Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, Van den Mooter G:Physicochemical characterization of solid dispersions of the antiviral agent UC-781 withpolyethylene glycol 6000 and Gelucire 44/14. Eur J Pharm Sci 10: 311-322, 2000

Danish M, Kottke MK: Pediatric and geriatric aspects of pharmaceutics. In: ModernPharmaceutics, pp.667-693. Ed. Banker GS, Marcel Dekker Inc., New York, NY, USA,2002

113

Dannenfelser RM, He H, Joshi Y, Bateman S, Serajuddin ATM: Development of clinicaldosage forms for a poorly water soluble drug I: application of polyethylene glycol-polysorbate 80 solid dispersion carrier system. J Pharm Sci 93: 1165-1175, 2004

Daugherty AL, Mrsny RJ: Formulation and delivery issues for monoclonal antibodytherapeutics. Adv Drug Deliv Rev 58: 686-706, 2006

David DJ, Misra A, Cohesive properties and solubility parameter concepts. In: Relatingmaterials properties to structure. Handbook and software for polymer calculations andmaterials properties, pp. 287-304. Eds. DJ David, A Misra, Technomic Publishing CoInc., Lancaster, USA, 1999

Debnath S, Suryanarayanan R: Influence of processing-induced phase transformations onthe dissolution of theophylline tablets. AAPS Pharm Sci Tech Feb 12 5: E8, 2004

De Boer AH, Dickhoff BHJ, Hagedoorn P, Gjaltema D, Goede J, Lambregts D, FrijlinkHW: A critical evaluation of the relevant parameters for drug redispersion from adhesivemixtures during inhalation. Int J Pharm 294: 173-184, 2005

Descamps M, Willart JF, Dudognon E, Caron V: Transformation of pharmaceuticalcompounds upon milling and comilling: The role of Tg. J Pharm Sci 96: 1398-1407, 2007

Dickhoff BHJ, de Boer AH, Lambregts D, Frijlink HW: The interaction between carrierrugosity and carrier payload, and its effect on drug particle redispersion from adhesivemixtures during inhalation. Eur J Pharm Biopharm 59: 197-205, 2005

Di Martino P, Martelli S, Wehrlé P: Evaluation of different fast melting disintegrants bymeans of a central composite design. Drug Dev Ind Pharm 31: 109-121, 2005

Dobetti L: Fast-melting tablets: Developments and technologies, Phar. Tech. Feb 2: 44-50, 2001

Dordunoo SK, Ford JL, Rubinstein MH: Physical stability of solid dispersions containingtriamtrene or temazepam in polyethylene glycols. J Pharm Pharmacol 49: 390-396, 1997

Duddu SP, Sokoloski TD: Dielectric analysis in the characterization of amorphouspharmaceutical solids. 1. Molecular modility in poly(vinylpyrrolidone)-water systems inthe glassy state. J Pharm Sci 84: 773-776, 1995

114

Efentakis M, Buckton G: The effect of erosion and swelling on the dissolution oftheophylline from low and high viscosity sodium alginate matrices. Pharm Dev Technol7: 69-77, 2002

Efentakis M, Koutlis A: Release of furosemide from multiple-unit and single-unitpreparations containing different viscosity grades of sodium alginate. Pharm DevTechnol 6: 91-98, 2001

Engineer S, Shao ZJ, Khagani NA: Temperature/humidity sensitivity of sustained-releaseformulations containing Kollidon®SR. Drug Dev Ind Pharm 30: 1089-1094, 2004

European Pharmacopoeia, 6th Ed., 2007. Council of Europe, Strasbourg, France.

Fachaux JM, Guyot-Hermann AM, Guyot JC, Conflant P, Drache M, Veesler S, BoistelleR: Pure paracetamol for direct compression Part II. Study of the physicochemical andmechanical properties of sintered-like crystals of paracetamol. Powder Technol 82: 129-133, 1995

Farinha A, Bica A, Tavares P: Improved bioavailability of a micronized megestrol acetatetablet formulation in humans. Drug Dev Ind Pharm 26: 567-570, 2000

Fell JT: Compaction properties in binary mixtures. In: Pharmaceutical PowderCompaction Technology, pp. 501-515. Eds. G Alderborn, C Nyström, Marcel DekkerInc., New York, NY, USA, 1996

Fell JT, Newton JM: Determination of tablet strength by the diametrical-compressiontest. J Pharm Sci 59: 688-691, 1970

Feng T, Pinal R, Carvajal MT: Process induced disorder in crystalline materials:Differentiating defective crystals from the amorphous form of griseofulvin J Pharm Sci97: 3207-3221, 2008

Ferrero Rodriquez C, Bruneau N, Barra J, Alfonso D, Doelker E: Hydrophilic cellulosederivatives as drug delivery carriers: influence of substitution type on the properties ofcompressed matrix tablets. In: Handbook of Pharmaceutical Controlled ReleaseTechnology, pp. 465- 503. Ed. DL Wise, Marcel Dekker Inc., New York, NY, USA,2000

115

Fernández-Hervás MJ, Vela MT, Arias MJ, Rabasco AM: Percolation theory: Evaluationand interest of percolation thresholds determination in inert matrix tablets. Pharm ActaHelv 71: 259-264, 1996

Florence AT, Attwood D: Properties of the solid state. In: Physicochemical Principles ofPharmacy, pp. 11-21. Ed. AT Florence, D Attwood, MacMillan Press Ltd., London,Great Britain.

Ford JL, Rubinstein MH, Hogan JE: Propranolol hydrochloride and aminophyllinerelease from matrix tablets containing hydroxypropylmethylcellulose. Int J Pharm 24:339-350, 1985a

Ford JL, Rubinstein MH, Hogan JE: Formulation of sustained release promethazinehydrochloride tablets using hydroxypropyl-methylcellulose matrices. Int J Pharm 24:327-338, 1985b

Ford JL, Rubinstein MH, McCaul F, Hogan JE, Edgar PJ: Importance of drug type, tabletshape and added diluents on drug release kinetics from hydroxyprpylmethylcellulosematrix tablets. Int J Pharm 40: 223-234, 1987

Forster A, Hempenstall J, Tucker I, Rades T: Selection of excipients for melt extrusionwith two poorly water-soluble drugs by solubility parameter calculation and thermalanalysis. Int J Pharm 226: 147-161, 2001

Fu Y, Yang S, Jeong, SH, Kimura S, Park K: Orally fast disintegrating tablets:developments, technologies, taste masking and clinical studies. Crit Rev Ther DrugCarrier Syst 21: 433-476, 2004

Fukuoka E, Makita M, Yamamura S: Glassy state of pharmaceuticals III: Thermalproperties and stability of glassy pharmaceuticals and their binary glass systems. ChemPharm Bull 37: 1047-1050, 1989

Gane PAC, Ridgway CJ, Barcelo E: Analysis of pore structure enables improved tabletdelivery systems. Powder Technol 169: 77-83, 2006

Garekani HA, Sadeghi F, Ghazi A: Increasing the aqueous solubility of acetaminophen inthe presence of polyvinylpyrrolidone and investigation of the mechanisms involved. DrugDev Ind Pharm 29: 173-179, 2003

116

Ghebremeskel AN, Vemavarapu C, Lodaya M: Use of surfactants as plasticizers inpreparing solid dispersions of poorly suluble API: Selection of polymer-surfactantcombinations using solubility parameters and testing the processability. Int J Pharm 328:119-129, 2007

Goddeeris C, Willems T, Van den Mooter G: Formulation of fast disintegrating tablets ofternary solid dispersions consisting of TPGS 1000 and HPMC 2910 or PVPVA 64 toimprove the dissolution of the anti-HIV drug UC 781. Eur J Pharm Sci 34: 293-302, 2008

Gordon M, Taylor JS: Ideal copolymers and the second order transition of syntheticrubbers 1. Non-crystalline co-polymers. J Appl Chem 2: 493-500, 1952

Greenhalgh DJ, Williams AC, Timmins P, York P: Solubility parameters as predictors ofmiscibility in solid dispersions. J Pharm Sci 88: 1182-1190, 1999

Guinot S, Leveiller F: The use of MTDSC to assess the amorphous phase content of amicronized drug substance. Int J Pharm 192: 63-75, 1999

Guozhong C: Characterization and properties of nanomaterials. In: Nanostructures andnanomaterials, pp. 333-336. Ed. C Guozhong, World scientific publishing company Inc.,Singapore, 2004

Gupta P, Bansal AK: Devitrification of amorphous celecixib. AAPS Pharm Sci Tech 6:article 32, 2005

Gupta MK, Bogner RH, Goldman D, TsengYC: Mechanisms for further enhancement indrug dissolution from solid-dispersion granules upon storage. Pharm Dev Technol 7, 103-112, 2002

Habib W, Khankari R, Hontz J: Fast-dissolve drug delivery systems. Crit Rev Ther DrugCarrier Syst 17: 61-72, 2000

Hancock BC, Parks M: What is the true solubility advantage for amorphouspharmaceuticals? Pharm Res 17: 397-404, 2000

Hancock B, York P, Rowe R: The use of solubility parameters in pharmaceutical dosageform design. Int J Pharm 148: 1-21, 1997

Hancock BC, Zografi G: The relationship between the glass transition temperature andthe water content of amorphous pharmaceutical solids. Pharm Res 11: 471-477, 1994

117

Hancock BC, Zografi G: Characteristics and significance of the amorphous state inpharmaceutical systems. J Pharm Sci 86: 1-12, 1997

Harris D, Robinson JR: Drug delivery via the mucous membranes of the oral cavity. JPharm Sci 81: 1-10, 1992

Hauss DJ: Oral lipid-based formulations. Adv Drug Deliv Rev 59: 667-676, 2007

Hayashi T, Hideyoshi K, Okada M, Kawase I, Ikeda Y, Onuki Y, Kaneko T, Sonobe T:In vitro and in vivo sustained-release characteristics of theophylline matrix tablets andnovel cluster tablets. Int J Pharm 341: 105-113, 2007

Hersey JA: Ordered Mixing: a new concept in powder mixing practice. Powder Technol11: 41-44, 1975

Higuchi T: Rate of release of medicaments from ointment bases containing drugs insuspension. J Pharm Sci 50: 847-875, 1961

Higuchi T: Mechanism of sustained-action medication. Theoretical analysis of rate ofrelease of solid drugs dispersed in solid matrices. J Pharm Sci 52: 1145-1149, 1963

Hillery AM: Drug delivery: the basic concepts. In: Drug delivery and targeting, pp.1-48.Eds. AM Hiilery, AW Lloyd, J Swarbrick, Tylor and Francis, London, UK, 2001

Hirasawa N, Ishise S, Miyata H, Danjo K: Application of nivaldipine solid dispersion totablet formulation and manufacturing using crospovidone and methylcellulose asdispersion carriers. Chem Pharm Bull 52: 244-247, 2004

Hogan SE, Buckton G: The quantification of small degrees of disorder in lactose usingsolution calorimetry. Int J Pharm 207: 57-64, 2000

Holman LE: The compaction behaviour of particulate materials. An elucidation based onpercolation theory. Powder Technol 66: 265-280, 1991

Holman LE, Leuenberger H: The relationship between solid fraction and mechanicalproperties of compacts –the percolation theory model approach. Int J Pharm 46: 35-44,1988

118

Huang LF, Tong WQ: Impact of solid state properties on developability assessment ofdrug candidates. Adv Drug Deliv Rev 56: 321-334, 2004

Huu-Phuoc N, Luu RPT, Munafo A, Ruelle P, Nam-Tran H, Buchmann M, KesselringUW: Determination of partial solubility parameters of lactose by gas-solidchromatography. J Pharm Sci 75: 68-72, 1986

Hüttenrauch R, Fricke S, Zielke P: Mechanical activation of pharmaceutical systems.Pharm Res 2: 302-306, 1985

Imamura K, Ohyama K, Yukoyama T, Maruyama Y, Imanaka H, Nakanishi K:Temperature scanning FTIR analysis of interactions between sugar and polymer additivein amorphous sugar-polymer mixtures. J Pharm Sci 97: 519-528, 2008

Irie T, Uekama K: Pharmaceutical applications of cyclodextrins. III. Toxicological issuesand safety evaluation. J Pharm Sci 86: 147-162, 1997

Jain AC, Aungst BJ, Adeyeye MC: Development and in vivo evaluation of buccal tabletsprepared using danazol-sulfobutylether 7 β-cyclodextrin (SBE 7) complexes. J Pharm Sci91: 1659-1668, 2002

Janssens S, Denivell S, Rombaut P, Van den Mooter G: Influence of polyethylene glycolchain length on compatibility and release characteristics of ternary solid dispersions ofitraconazole in polyethylene glycol/hydroxypropylmethylcellulose 2910 E5 blends. Eur JPharm Sci 35: 203-210, 2008a

Janssens S, Humbeeck JV, Van den Mooter G: Evaluation of the formulation of soliddispersions by co-spray drying itraconazole with Inutec SP1, a polymeric surfactant, incombination with PVPVA 64. Eur J Pharm Biopharm 70: 500-505, 2008b

Janssens S, Novoa de Armas H, Roberts CJ, Van den Mooter G: Characterization ofternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5. J Pharm Sci97: 2110-2120, 2008c

Jeong SH, Park K: Development of sustained release fast-disintegrating tablets usingvarious polymer-coated ion-exchange resin complexes. Int J Pharm 353: 195-204, 2008

Joiris E, Di Martino P, Malaj L, Censi R, Barthélémy C, Odou P: Influence of crystalhydration on the mechanical propertied of sodium naproxen. Eur J Pharm Biopharm 70:345-356, 2008

119

Jouppila K, Kansikas J, Roos YH: Crystallization and x-ray diffraction of crystals formedin water-plasticized amorphous lactose. Biotechnol Prog 14: 347-350, 1998

Jun SW, Kim MS, Jo GH, Lee S, Woo JS, Park JS, Hwang SJ: Cefuroxime axetil soliddispersion prepared using solution enhanced dispersion by supercritical fluids. J PharmPharmacol 57: 1529-1537, 2005

Juppo AM: Relationship between breaking force and pore structure of lactose, glucoseand mannitol tablets. Int J Pharm 127: 95-102, 1996

Juppo AM, Boissier C, Khoo C: Evaluation of solid dispersion particles prepared withSEDS. Int J Pharm 16: 385-401, 2003

Kakumanu VK, Bansal AK: Enthalpy relaxation studies of celecoxib amorphousmixtures. Pharm Res 19: 1873-1878, 2002

Kanjickal DG, Lopina ST: Modeling of drug release from polymeric delivery systems-Areview. Crit Rev Ther Drug Carrier Syst 21: 345-386, 2004

Karavas E, Georgarakis E, Docoslis A, Bikiaris D: Combining SEM, TEM, and micro-Raman techniques to differentate between the amorphous molecular level dispersions andnanodispersions of a poorly water-soluble drug within a polymer matrix. Int J Pharm 340:76-83, 2007a

Karavas E, Georgarakis E, Sigalas MP, Avgoustakis K, Bikiaris D: Investigation of therelease mechanism of a sparingly water-soluble drug from solid dispersions inhydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions. Eur J Pharm Biopharm 66: 334-347, 2007b

Karavas E, Ktistis G, Xenakis A, Georgarakis E: Miscibility behavior and formationmechanism of stabilized felodipine-polyvinylpyrrolidone amorphous solid dispersions.Drug Dev Ind Pharm 31: 473-489, 2005

Karavas E, Ktistis G, Xenakis A, Georgarakis E: Effect of hydogen bonding interactionson the release mechanism of felodipine from nanodispersions with polyvinylpyrrolidone.Eur J Pharm Biopharm 63: 103-114, 2006

Katzhendler I, Hoffman A, Goldberger A, Friedman M: Modeling of drug release fromerodible tablets. J Pharm Sci 86: 110-115, 1997

120

Kaushal AM, Gupta P, Bansal AK: Amorphous drug delivery systems: Molecularaspects, design and performance. Crit Rev Ther Drug Carrier Syst 21: 133-193, 2004

Kawakami K, Pikal MJ: Calorimetric investigation of the structural relaxation ofamorphous materials: evaluating validity of the methodologies. J Pharm Sci 94: 948-965,2005

Kearney P: The Zydis oral fast-dissolving dosage form. In: Modified-Release DrugDelivery Technology, pp. 191-216. Ed. M Rathbone, Marcel Dekker Inc., New York,NY, USA, 2002

Kellaway IW, Ponchel G, Duchene D: Oral mucosal drug delivery. In: Modified-ReleaseDrug Delivery Technology, pp. 349-364. Ed. M Rathbone, Marcel Dekker Inc., NewYork, NY, USA, 2002

Kendall MJ: Metoprolol – controlled release, zero-order kinetics. J Clin Pharm Ther 24:159-179, 1989

Ker� J, Sr�� S, Knez Ž, Sen�ar-Boži� P: Micronization of drugs using supercriticalcarbon dioxide. Int J Pharm 182: 33-39, 1999

Kesisoglou F, Panmai S Wu Y: Nanosizing – Oral formulation development andbiopharmaceutical evaluation. Adv Drug Deliv Rev 59: 631-644, 2007

Ketolainen J, Poso A, Viitasaari V, Gynther J, Pirttimäki J, Laine E, Paronen P: Changesin solid-state structure of cyclophosphamide monohydrate induced by mechanicaltreatment and storage. Pharm Res 12: 299-304, 1995

Khankari RK, Grant DJW: Pharmaceutical hydrates. Thermochim Acta 248: 61-79, 1995

Khoo SM, Porter CJH, Charman WN: The formulation of halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability andabsolute bioavailability assessment. Int J Pharm 205: 65-78, 2000

Khougaz K, Clas SD: Crystallization inhibition in solid dispersions of MK-0591 andpoly(vinylpyrrolidone) polymers. J Pharm Sci 89: 13251334, 2000

Kim CJ: Compressed donut-shaped tablets with zero-order release kinetics. Pharm Res12: 1045-1048, 1995a

121

Kim CJ: Drug release from compressed hydrophilic POLYOX-WSR tablets. J Pharm Sci84: 303-306, 1995b

Kobayashi Y, Ito S, Itai S, Yamamoto K: Physicochemical properties and bioavailabilityof carbamazepine polymorphs and dihydrate. Int J Pharm 193: 137-146, 2000

Konno H, Handa T, Alonzo DE, Taylor LS: Effect of polymer type on the dissolutionprofile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm 70:493-499, 2008

Konno H, Taylor LS: Influence of different polymers on the crystallization tendency ofmolecularly dispersed amorphous felodipine. J Pharm Sci 95: 2692-2705, 2006

Korhonen O, Raatikainen P, Harjunen P, Nakari J, Suihko E, Peltonen S,Vidgren M,Paronen P: Starch acetates -multifunctional direct compression excipients. Pharm Res 17:1138-1143, 2000

Korhonen O, Matero S, Poso A, Ketolainen J: Partial least square projections to latentstructures analysis (PLS) in evaluating and predicting drug release from starch acetatematrix tablets. J Pharm Sci 94: 2716-2730, 2005

Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA: Mechanisms of solute releasefrom porous hydrophilic polymers. Int J Pharm 15: 25-35, 1983

Kulvanich P, Stewart PJ: The effect of mixing time on particle adhesion in a modelinteractive system. J Pharm Pharmacol 39: 732-733, 1987

Lacey PMC: Developments in the theory of particle mixing. J Appl Chem 4: 257-268,1954

Law D, Krill SL, Schmitt EA, Fort JJ, Qiu Y, Wang W, Porter WR: Physicochemicalconsiderations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 soliddispersions. J Pharm Sci 1015-1025, 2001

Law D, Wang W, Schmitt EA, Qiu Y, Krill S, Fort JJ: Properties of rapidly dissolvingeutectic mixtures of poly (ethylene)glycol and fenofibrate; The eutectic microstructure. JPharm Sci 92: 505-515, 2003

122

Lechuga-Ballesteros D, Bakri A, Miller DP: Microcalorimertic measurement of theinteractions between water vapor and amorphous pharmaceutical solids. Pharm Res 20:308-318, 2003

Lee PI: Kinetics of drug release from hydrogel matrices. J Control Rel 2: 277-288, 1985

Lee S, Nam K, Kim MS, Jun SW, Park JS, Woo JS, Hwang SJ: Preparation andcharacterization of solid dispersions of itraconazole by using aerosol solvent extractionsystem for improvement in drug solubility and bioavailability. Arch Pharm Res 28: 866-874, 2005

Leuenberger H, Rohera BD, Haas CH: Percolation theory –a novel approach to soliddosage form design. Int J Pharm 38: 109-115, 1987

Leuner C, Dressman J: Improving drug solubility for oral delivery using soliddispersions. Eur J Pharm Biopharm 50: 47-60, 2000

Li L, AbuBaker O, Shao Z: Characterization of poly(ethylene oxide) as a drug carrier inhot-melt extrusion. Drug Dev Ind Pharm 2006, 991-1002, 2006

Li X, Zhi F, Hu Y: Investigation of excipient and processing on solid phasetransformation and dissolution of ciprofloxacin. Int J Pharm 328: 177-182, 2007

Lin CW, Cham TM: Effect of particle size on the available surface area of nifedipinefrom nifedipine-polyethylene glycol 600 solid dispersions. Int J Pharm 127: 61-272, 1996

Lipinski CA: Drug-like properties and the causes of poor solubility and poorpermeability. J Pharmacol Toxicol Methods 44: 235-249, 2000

Liu C, Desai KG: Characteristics of rofecoxib-polyethylene glycol 4000 solid dispersionsand tablets based on solid dispersions. Drug Dev Technol 10: 467-477, 2005

Liu P, Ju T, Qiu Y: Diffusion-controlled drug delivery systems. In: Design of ControlledRelease Drug Delivery Systems, pp. 107-137. Eds. X Li and BR Jasti, McGraw-HillProfessional Publishing, Inc., Blacklick, OH, USA, 2005

Lu Q, Zografi G: Phase behavior of binary and ternary amorphous mixtures containingindomethacin, citric acid and PVP. Pharm Res 15: 1202-1206, 1998

123

Lubach JW, Xu D, Segmuller BE, Munson EJ: Investigation of the effects ofpharmaceutical processing upon solid-state NMR relaxation times and implications tosolid-state formulation stability. J Pharm Sci 96: 777-787, 2007

Löbenberg R, Amidon GL, Vieira M: Solubility as a limiting factor to drug absorption.In: Oral Drug Absorption: Prediction and Assessment, pp. 137-154. Eds. JB Dressman, HLennernäs, Marcel Dekker Inc., New York, NY USA, 2000

Mackin L, Zanon R, Park JM, Foster K, Opalenik H, Demonte M: Quantification of lowlevels (<10%) of amorphous content in micronised active batches using dynamic vapoursorption and isothermal microcalorimetry. Int J Pharm 231: 227-236, 2002

Majerick V, Horvath G, Szokonya L, Charbit G, Badens E, Bosc N, Teillaud E:Supercritical antisolvent versus coevaporation -preparation and characterization of soliddispersions. Drug Dev Ind Pharm 33: 975-983, 2007

Marsac PJ, Konno H, Taylor LS: A comparison of the physical stability of amorphousfelodipine and nifedipine systems. Pharm Res 23: 2306-2316, 2006a

Marsac PJ, Shamblin SL, Taylor LS: Theoretical and practical approaches for predictionof drug-polymer miscibility and solubility. Pharm Res 23: 2417-2426, 2006b

Matsumoto T, Zografi G: Physical properties of solid molecular dispersions ofindomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) inrelation to indomethacin crystallization. Pharm Res 16: 1722-1728, 1999

Mattsson S, Nyström C: The use of mercury porosimetry in assessing the effect ofdifferent binders on the pore structure and bonding properties of tablets. Eur J PharmBiopharm 52: 237-247, 2001

McInnes GT, Asbury MJ, Ramsay LE, Shelton JR, Harrison IR: Effect of micronizationon the bioavailability and pharmacologic activity of spironolactone. J Clin Pharmacol 22:410-417, 1982

McKenna A, McCafferty DF: Effect of particle size on the compaction mechanism andtensile strength of tablets. J Pharm Pharmacol 34: 347-351, 1982

Men Y, Rieger J, Lindner P, Enderle HF, Lilge D, Kristen MO, Mihan S, Jiang S:Structural changes and chain radius of gyration in cold-drawn polyethylene after

124

annealing: Small- and wide-angle X-ray scattering and small-angle neutron scatteringstudies. J Phys Chem B 109: 16650-16657, 2005

Miyazaki T, Yoshioka S, Aso Y: Physical stability of amorphous acetanilide derivativesimproved by polymer excipients. Chem Pharm Bull 54: 1207-1210, 2006

Miyazaki T, Yoshioka S, Aso Y, Kojima S: Ability of polyvinylpyrrolidone andpolyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J Pharm Sci93: 2710-2717, 2004

Mizumoto T, Masuda Y, Yamamoto T, Yonemochi E, Terada K: Formulation design of anovel fast-disintegrating tablet. Int J Pharm 306: 83-90, 2005

Modi A, Tayade P: Enhancement of dissolution profile by solid dispersion (kneading)technique. AAPS Phar Sci Tech 7: article 68, 2006

Moneghini M, Kikic I, Voinovich D, Perissutti B, Filipovi�-Gr�� J: Processing ofcarbamazepine-PEG 4000 solid dispersions with supercritical carbon dioxide:preparation, characterization, and in vitro dissolution. Int J Pharm 222: 129-138, 2001

Moran A, Buckton G: Adjusting and understanding the properties and crystallizationbehaviour of amorphous trehalose as a function of spray drying feed concentration. Int JPharm 343: 12-17, 2007

Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG: Theoretical approaches to physicaltransformations of active pharmaceutical ingredients during manufacturing processes.Adv Drug Deliv Rev 48: 91-114, 2001

Mosharraf M, Nyström C: The effect of particle size and shape on the surface specificdissolution rate of microsized practically insoluble drugs. Int J Pharm 122: 35-47, 1995

Mosharraf M, Sebhatu T, Nyström C: The effects of disordered structure on the solubilityand dissolution rates of some hydrophilic, sparingly soluble drugs. Int J Pharm 177: 29-51, 1999

Mura P, Cirri M, MT Faucci, Gines-Dorado JM, Bettinetti GP: Investigation of theeffects of grinding and co-grinding on physicochemical properties of glisentide. J PharmBiomed Anal 30: 227-237, 2002

125

Mura P, Faucci MT, Manderioli A, Bramanti G, Parrini P: Thermal behavior anddissolution properties of naproxen from binary and ternary solid dispersions. Drug DevInd Pharm 25: 257-264, 1999

Mura P, Moyano JR, Gonzales-Rodriques ML, Rabasco-Alvarez AM, Cirri M, MaestrelliF: Characterization and dissolution properties of ketoprofen in binary and ternary soliddispersions with polyethylene glycol and surfactants. Drug Dev Ind Pharm 31: 425-434,2005

Murphy D, Rodriguez-Cintron F, Langevin B, Kelly N, Rodriquez-Hornedo N: Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect oflattice disorder. Int J Pharm 246: 121-134, 2002

Murtomaa M, Laine E: Electrostatic measurements on lactose-glucose mixtures. JElectrostatics 48: 155-162, 2000

Murtomaa M, Mellin V, Harjunen P, Lankinen T, Laine E, Lehto VP: Effect of particlemorphology on the triboelectrification in dry powder inhalers. Int J Pharm 282: 107-114,2004

Müller RH, Peters K: Nanosuspensions for formulation of poorly soluble drugs I:Preparation by a size-reduction technique. Int J Pharm 160: 229-237, 1998

Nair R, Nyamweya N, Gönen S, Martinez-Miranda LJ, Hoag SW: Influence of variousdrugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic andspectroscopic investigation. Int J Pharm 225: 83-96, 2001

Nair R, Gonen S, Hoag SW: Influence of polyethylene glycol and povidone on thepolymorphic transformation and solubility of carbamazepine. Int J Pharm 240: 11-22,2002

Narasimhan B: Accurate models in drug delivery systems. In: Handbook ofPharmaceutical Controlled Release Technology, pp. 155-181. Ed. DL Wise, MarcelDekker Inc., New York, NY, USA, 2000

Newman AW, Reutzel-Edens SM, Zografi G: Characterization of the “hygroscopic”properties of active pharmaceutical ingredients. J Pharm Sci 97: 1047-1059, 2008

Noyes AA, Whitney WR: The rate of solution of solid substances in their own solutions.J Am Chem Soc 19: 930-934, 1897

126

Nyström C, Karehill PG: The importance of intermolecular bonding forces and theconcept of bonding surface area. In: Pharmaceutical Powder Compaction Technology,pp. 17-53. Eds. G Alderborn, C Nyström, Marcel Dekker Inc., New York, NY, USA,1996

Ohta M, Buckton G: A study of the differences between two amorphous spray-driedsamples of cefditoren pivoxil which exhibited different physical stabilities. Int J Pharm289: 31-38, 2005

Oksanen CA, Zografi G: Molecular mobility in mixtures of absorbed water and solidpoly(vinylpyrrolidone). Pharm Res 10: 791-799, 1993

Paradkar A, Ambike AA, Jadhav BK, Mahadik KR: Characterization of curcumin-PVPsolid dispersion obtained by spray drying. Int J Pharm 271: 281-286, 2004

Paronen TP, Peltonen SH, Urtti AO, Nakari LJ, Starch acetate composition withmodifiable properties, method for preparation and usage thereof. US Patent 5.667.803,1997

Parrott EL: Compression. In: Pharmaceutical Dosage Forms: Tablets Vol 2, pp. 153-184.Eds. HA Lieberman, L Lachman, Marcel Dekker, Inc., New York, NY, USA, 1981

Patel S, Kaushal AM, Bansal AK: Compression physics in the formulation developmentof tablets. Crit Rev Ther Drug Carrier Syst 23: 1-65, 2006

Pather SI, Khankari RK, Moe DV: OraSolv and DuraSolv: Efficient technologies for theproduction of orally disintegrating tablets. In: Modified-Release Drug DeliveryTechnology, pp. 203-216. Ed. M Rathbone, Marcel Dekker Inc., New York, NY, USA,2002

Patravale VB, Date AA, Kulkarni RM: Nanosuspensions: a promising drug deliverystrategy. J Pharm Pharmacol 56: 827-840, 2004

Patterson JE, James MB, Forster AH, Lancaster RW, Butler JM, Rades T: The influenceof thermal and mechanical preparative techniques on the amorphous state of four poorlysoluble compounds. J Pharm Sci 94: 1998-2012, 2005

127

Perng CY, Kearney AS, Patel K, Palepu NR, Zuber G: Investigation of formulationapproaches to improve the dissolution of SB-210661, a poorly water soluble 5-lipoxygenase inhibitor. Int J Pharm 176: 31-38, 1998

Phadnis NV, Suryanarayanan R: Polymorphism in anhydrous theophylline -implicationson the dissolution rate of theophylline tablets. J Pharm Sci 86: 1256-1263, 1997

Pham AT, Lee PI: Probing the mechanisms of drug release from hydroxypropylmethylcellulose marices. Pharm Res 11: 1379-1384, 1994

Piao MG, Kim JH, Kim JO, Lyoo WS, Lee MH, Yong CS, Choi HG: Enhanced oralbioavailability of piroxicam in rats by hyaluronate microspheres. Drug Dev Ind Pharm33: 485-491, 2007

Pillay V, Fassihi R: A novel approach for constant rate delivery of highly solublebioactives from a simple monolithithic system. J Control Rel 67: 67-78, 2000

Pluta M, Galeski A: Plastic deformation of amorphous poly (L/DL-lactide): Stuctureevolution and physical properties. Biomacromolecules 8: 1836-1843, 2007

Pohja S, Suihko E, Vidgren M, Paronen P, Ketolainen J: Starch acetate as a tablet matrixfor sustained drug release. J Control Rel 94: 293-302, 2004

Qiu Y, Zhang G: Research and development aspects of oral controlled release dosageforms. In: Handbook of Pharmaceutical Controlled Release Technology, pp. 465- 503.Ed. DL Wise, Marcel Dekker Inc., New York, NY, USA, 2000

Rajewski RA, Stella VJ: Pharmaceutical applications of cyclodextrins. 2. In vivo drugdelivery. J Pharm Sci 85: 1142-1169, 1996.

Ramos R, Gaisford S, Buckton G: Calorimetric determination of amorphous content inlactose: A note on the preparation of calibration curves. Int J Pharm 300: 13-21, 2005

Rawas-Qalaji MM, Simons FER, Simons KJ: Fast disintegrating sublingual tablets:Effect of epinephrine load on tablet characteristics. AAPS Pharm Sci Tech 7: Article 41,2006

Rekhi, GS, Jambhekar SS: Ethylcellulose –a polymer review. Drug Dev Ind Pharm 21:61-77, 1995

128

Reuteler-Faoro D, Ruelle P, Nam-Tran H, de Reyff C, Buchmann M, Negre JC,Kesslring UW: A new equation for calculating partial cohesion parameters of solidsubstances from solubilities. J Phys Chem 1988: 92, 6144-6148

Roe R, Curro JJ: Small-Angle X-ray Scattering study of density fluctuation inpolystyrene annealed below the glass transition temperature. Macromolecules 16: 428-434, 1983

Rowe RC, Sheskey PJ, Owen SC: Pharmaceutical excipients. Pharmaceutical Press andAmerican Pharmacists Association 2006 (Online). Available at:www.medicinescomplete.com (Accessed March. 2008)

Rowley G: Quantifying electrostatic interactions in pharmaceutical solid systems. Int JPharm 227: 47-55, 2001

Rowley G, Hawley AR, Dobson CL, Chatham S: Rheology and filling characteristics ofparticulate disperions in polymer melt formulations for liquid fill hard gelatin capsules.Drug Dev Ind Pharm 24: 605-611, 1998

Royall PG, Huang C, Tang SJ, Duncan J, Van-de-Velde G, Brown MB: The developmentof DMA for the detection of amorphous content in pharmaceutical powdered materials.301: 181-191, 2005

Ruan LP, Yu BY, Fu GM, Zhu D: Improving the solubility of ampelopsin by soliddispersions and inclusion complexes. J Pharm Biomed Anal.38 457-464, 2005

Rudnic EM, Kottke MK: Tablet dosage forms. In: Modern Pharmaceutics, pp. 333-394,3nd edn. Ed. Banker GS, Rhodes CT, Marcel Dekker Inc., New York, NY, USA, 1996

Rxcipients: Rxcipients Application bulletin: Fast melt with mannnitol-30%RxCIPIENTS FM1000 / PVPXL System, 2007. http://www.rxcipients.com (AccessedSeptember 2006)

Sadeghi F, Afrasiabi Garekani H, Goli F: Tableting of Eudragit RS and propranololhydrochloride solid dispersion: Effect of particle size, compaction force and plasticizeraddition on drug release. Drug Dev Ind Pharm 30: 759-766, 2004

Saikh NA, Abidi SE, Block LH: Evaluation of ethyl cellulose as a matrix for prolongedrelease formulations. I. Water soluble drugs: acetaminophen and theophylline. Drug DevInd Pharm 13: 1345-1369, 1987a

129

Saikh NA, Abidi SE, Block LH: Evaluation of ethyl cellulose as a matrix for prolongedrelease formulations. II. Sparingly water-soluble drugs –ibuprofen and indomethacin.Drug Dev Ind Pharm 13: 2495-2518, 1987b

Saklatvala R, Royall PG, Craig DQM: The detection of amorphous material in anominally crystalline drug using modulated temperature DSC – a case study. Int J Pharm192: 55-62, 1999

Saleki-Gerhardt A, Ahlneck C, Zografi G: Assessment of disorder in crystalline solids.Int J Pharm 101: 237-247, 1994

Saleki-Gerhardt A, Zografi G: Non-isothermal and isothermal crystallization of sucrosefrom the amorphous state. Pharm Res 11: 1166-1173, 1994

Sammour OA, Hammad MA, Megrab NA, Zidan AS: Formulation and optimization ofmouth dissolve tablets containing rofecoxib solid dispersion. AAPS Pharm Sci Tech 7:article 55, 2006

Samra RM, Buckton G: The crystallization of a model hydrophobic drug (terfenadine)following exposure to humidity and organic vapours. Int J Pharm 284: 53-60, 2004

Sashiwa H, Fujishima S, Yamano N, Kawasaki N, Nakayama A, Muraki E, Hiraga K,Oda K Aiba S: Production of N-acetyl-D-glucosamine from �-chitin by crude enzymesfrom Aeromonas hydrophila H-2330. Carbohydr Res 337: 761-763, 2002

Sastry SV, Nyshadham JM Fix JA: Recent technological advances in oral drug delivery –a review. Pharm Sci Tech Today 3: 138-145, 2000

Saunders M, Podluii K, Shergill S, Buckton G, Royall P: The potential of high-speedDSC (Hyper-DSC) for the detection and quantification of small amounts of amorphouscontent in predominantly crystalline samples. Int J Pharm 274: 35-40, 2004

Savolainen M, Kogermann K, Heinz A, Aaltonen J, Peltonen L, Strachan C, Yliruusi J:Better understanding of dissolution behaviour of amorphous drugs by in situ solid-stateanalysis using Raman spectroscopy. Eur J Pharm Biopharm 71: 71-79, 2009

Schachter DM, Xiong J, Tirol G: Solid state NMR perspective of drug-polymer solidsolutions: a model system based on poly(ethylene oxide). Int J Pharm 281: 89-101, 2004

130

Seager H: Drug-delivery products and the Zydis fast-dissolving dosage form. J PharmPharmacol 50: 375-382, 1998

Serajuddin ATM: Solid dispersion of poorly water-soluble drugs: early promises andrecent breakthroughs. J Pharm Sci 88: 1058-1066, 1999

Serajuddin ATM: Salt formation to improve drug solubility. Adv Drug Deliv Rev 59:603-616, 2007

Sethia S, Squillante E: Physicochemical characterization of solid dispersions ofcarbamazepine formulated by supercritical carbon dioxide and conventional solventevaporation method. J Pharm Sci 91: 1948-1957, 2002

Sethia S, Squillante E: Solid dispersions: Revival with greater possibilities andapplications in oral drug delivery. Crit Rev Ther Drug Carrier Syst 20: 215-247, 2003

Sethia S, Squillante E: Solid dispersion of carbamazepine in PVP K30 by conventionalsolvent evaporation and supercritical methods. Int J Pharm 272: 1-10, 2004

Shah JC, Chen JR, Chow D: Preformulation study of etoposide: II. Increased solubilityand dissolution rate by solid-solid dispersions. Int J Pharm 113: 103-111, 1995

Shamblin SL, Taylor LS, Zografi G: Mixing behavior of colyophilized binary systems. JPharm Sci 87: 694-701, 1998

Shibata Y, Fujii M, Noda S, Kokudai M, Okada H, Kondoh M, Watanabe Y: Fluidity andtableting characteristics of a powder solid dispersion of the low melting drugs ketoprofenand ibuprofen with crospovidone. Drug Dev Ind Pharm 32: 449-456, 2006

Shimizu T, Sugaya M, Nakano Y, Izutsu D, Mizukami Y, Okochi K, Tabata T,Hamaguchi N, Igari Y: Formulation study for lansoprazole fast-disintegrating tablet. III.Design of rapidly disintegrating tablets. Chem Pharm Bull 51: 1121-1127, 2003

Shimpi SL, Chauhan B, Mahadik KR, Paradkar A: Stabilization and improved in vivoperformance of amorphous etoricoxib using Gelucire 50/13. Pharm Res 22: 1727-1734,2005

Shimpi SL, Mahadik KR, Takada K, Paradkar A: Application of polyglycolizedglycerides in protection of amorphous form of etoricixib during compression. ChemPharm Bull 55: 1448-1451, 2007

131

Shin SC, Kim J: Physicochemical characterization of solid dispersion of furosemide withTPGS. Int J Pharm 251: 79-84, 2003

Shodex: Oligosaccharide analysis = chitooligosaccharides.http://www.shodex.com/english/dc030314.html (Accessed November 2002)

Shoyele SA, Cawthorne S: Particle engineering techniques for inhaledbiopharmaceuticals. Adv Drug Deliv Rev 58: 1009-1029, 2006

Sinka IC, Motazedian F, Cocks ACF, Pitt KG: The effect of processing parameters onpharmaceutical tablet properties. Powder Technol 189: 276-284, 2009

Singhal D, Curatolo W: Drug polymorphism and dosage form design: a practicalperspective. Adv Drug Deliv Rev 56: 335-347, 2004

Six K, Berghmans H, Leuner C, Dressman J, Van Werde K, Mullens J, Benoist L,Thimon M, Meublet L, Verreck G, Peeters J, Brewster M, Van den Mooter G:Characterization of solid dispersions of itraconazole and hydroxypropylmethylcelluloseprepared by melt extrusion, part II. Pharm Res 20: 1047-1054, 2003

Staniforth JN: Total mixing. Int J Pharm Tech & Prod Mfr 2: 7-12, 1981

Staniforth JN: Order out of chaos. J Pharm Pharmacol 39: 329-334, 1987

Staniforth JN, Rees JE: Powder mixing by triboelectrification. Powder Technol 30: 255-256, 1981

Staniforth JN, Rees JE: Electrostatic charge interactions in ordered powder mixes. J PharPharmacol 34: 69-76, 1982

Stegemann S, Leveiller F, Franchi D, de Jong H, Linden H: When poor solubilitybecomes an issue: From early stage to proof of concept. Eur J Pharm Sci 31: 249-261,2007

Stella VJ, Nti-Addae KW: Prodrug strategies to overcome poor water solubility. AdvDrug Deliv Rev 59: 677-694, 2007

Stephenson GA, Forbes RA, Reutzel-Edens SM: Characterization of the solid state:quantitative issues. Adv Drug Deliv Rev 48: 67-90, 2001

132

Strickley RG, Iwata Q, Wu S, Dahl TC: Pediatric drugs-A review of commerciallyavailable oral formulations. J Pharm Sci 97: 1731-1774, 2008

Sugimoto M, Narisawa S, Matsubara K, Yoshino H, Nakano M, Handa T: Effect offormulated ingredients on rapidly disintegrating oral tablets prepared by the crystallinetransition method. Chem Pharm Bull 54: 175-180, 2006

Sun C, Grant DJW: Influence of crystal structure on the tableting properties ofsulfamerazine polymorphs. Pharm Res 18: 274-280, 2001

Sunada H, Bi Y: Preparation, evaluation and optimization of rapidly disintegratingtablets. Powder Technol 122: 188-198, 2002

Sundy E, Danckwerts MP: A novel compression-coated doughnut-shaped tablet designfor zero-order sustained release. Eur J Pharm Sci 22: 477-485, 2004.

Surana R, Pyne A, Suryanarayanan R: Effect of preparation method on physicalproperties of amorphous trehalose. Pharm Res 21: 1167-1176, 2004

Tahara K, Yamamoto K, Nishihata T: Overall mechanism behind matrix sustainedrelease (SR) tablets prepared with hyroxypropyl methylcellulose 2910. J Control Rel 35:59-66, 1995

Takeuchi H, Nagira S, Tanimura S, Yamamoto H, Kawashima Y: Tabletting of soliddispersion particles consisting of indomethacin and porous silica particles. Chem PharmBull 53: 487-491, 2005

Taludkar MM, Rombaut P, Kinget R: The release mechanism of an oral controlled-release delivery system for indomethacin. Pharm Dev Technol 3: 1-6, 1998

Tanno F, Nishiyama Y, Kokubo H, Obara S: Evaluation of hypromellose acetate(HPMCAS) as a carrier in solid dispersions. Drug Dev Ind Pharm 2004: 9-17, 2004

Tantishaiyakul V, Kaewonopparat N, Ingkatawornwong S: Properties of solid dispersionsof piroxicam in polyvinylpyrrolidone. Int J Pharm 181: 143-151, 1999

Tantry JS, Tank J, Suryanarayanan R: Processing-induced phase transitions oftheophylline –implications on the dissolution on theophylline tablets. J Pharm Sci 96:1434-1444, 2007

133

Taylor LS, Zografi G: Spectroscopic characterization of interactions between PVP andindomethacin in amorphous molecular dispersions. Pharm Res 14: 1691-1698, 1997

Taylor LS, Zografi G: The quatitative analysis of crystallinity using FT-Ramanspectroscopy. Pharm Res 15: 755-761, 1998

Tishmack PA, Bugay DE, Byrn SR: Solid-state nuclear magnetic resonance spectroscopy–pharmaceutical applications. J Pharm Sci 92: 441-474, 2003

Tran PH, Tran HT, Lee BJ: Modulation of microenvironmental pH and crystallinity ofionizable telmisartan using alkalizers in solid dispersions for controlled release. J ControlRel 129: 59-65, 2008

Turunen E, Mannila J, Laitinen R, Riikonen J, Lehto VP, Järvinen T, Ketolainen J,Järvinen K, Jarho P: Sublingual absorption of perphenazine from fast-dissolvingformulations. J Pharm Sci, submitted

Urbanetz NA, Lippold BC: Solid dispersions of nimodipine and polyethylene glycol2000: dissolution properties and physico-chemical characterization. Eur J PharmBiopharm 59: 107-118, 2005

Urbanetz NA: Stabilization of solid dispersions of nimodipine and polyethylene glycol2000. Eur J Pharm Sci 28: 67-76, 2006

Valleri M, Mura P, Maestrelli F, Cirri M, Ballerini R: Development and evaluation ofglyburide fast dissolving tablets using solid dispersion technique. Drug Dev Ind Pharm30: 525-534, 2004

Van den Mooter G, Augustijns P, Blaton N, Kinget R: Physico-chemical characterizationof solid dispersions of temazepam with polyethylene glycol 6000 and PVP K 30. Int JPharm 164: 67-80, 1998

Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, Kinget R:Physical stabilization of amorphous ketoconazole in solid dispersions withpolyvinylpyrrolidone K25. Eur J Pharm Sci 12: 261-269, 2001

Van Drooge DJ, Braeckmans K, Hinrichs WLJ, Remaut K, De Smedt SC, Frijlink HW:Characterization of the mode of incorporation of lipophilic compounds in solid

134

dispersions at the nanoscale using fluorescence resonance energy transfer (FRET).Macromol Rapid Commun 27: 1149-1155, 2006a

Van Drooge DJ, Hinrichs WLJ, Dickhoff BHJ, Elli MNA, Visser MR, Zijlstra GS,Frijlink HW: Spray freeze drying to produce a stable �9-tetrahydrocannabinol containinginulin-based solid dispersion powder suitable for inhalation. Eur J Pharm Sci 26: 231-240, 2005

Van Drooge DJ, Hinrichs WLJ, Frijlink HW: Incorporation of lipophilic drugs in sugarglasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent. JPharm Sci 93: 713-725, 2004a

Van Drooge DJ, Hinrichs WLJ, Visser MR, Frijlink HW: Characterization of themolecular distribution of drugs in glassy solid dispersions at the nano-meter scale, usingdifferential scanning calorimetry and gravimetric water vapour sorption techniques. Int JPharm 310: 220-229, 2006b

Van Drooge DJ, Hinrichs WLJ, Wegman KAM, Visser MR, Eissens AC, Frijlink HW:Solid dispersions based on inulin for the stabilisation and formulation of �9-tetrahydrocannabinol. Eur J Pharm Sci 21: 511-518, 2004b

Van Krevelen DW: Cohesive properties and solubility. In: Properties of polymers. Theircorrelation with chemical structure: their numerical estimation and prediction fromadditive group contributions, pp. 189-225. Ed. DW Van Krevelen, Elsevier, Amsterdam,The Netherlands, 1997

Vasathavada M, Tong WQ, Joshi Y, Kislalioglu MS: Phase behavior of amorphousmolecular dispersions I: Determination of the degree and mechanism of solid solubility.Pharm Res 21: 1598-1606, 2004

Vasathavada M, Tong WQ, Joshi Y, Kislalioglu MS: Phase behavior of amorphousmolecular dispersions II: role of hydrogen bonding in solid solubility and phaseseparation kinetics. Pharm Res 22: 440-448, 2005

Vasconcelos T, Sarmento B, Costa P: Solid dispersions as strategy to improve oralbioavailability of poor water soluble drugs. Drug Discov Today 12: 1068-1075, 2007

van Veen B, Pajander J, Zuurman K, Lappalainen R, Poso A, Frijlink HW, Ketolainen J:The effect of powder blend and tablet structure on drug release mechanisms ofhydrophobic starch acetate matrix tablets. Eur J Pharm Biopharm 61: 149-157, 2005

135

van Veen B, Van der Voort Maarschalk K, Bolhuis GK, Frijlink HW: Predictingmechanical properties of compacts containing two components. Powder Technol 139:156-164, 2004

van Veen B, Van der Voort Maarschalk K, Bolhuis GK, Gons M, Zuurman K, FrijlinkHW: The influence of particles of a minor component on the matrix strength of sodiumchloride. Eur J Pharm Sci 16: 229-235, 2002

Velasco MV, Ford JL, Rowe P, Rajabi-Siahboomi AR: Influence ofdrug:hydroxypropylmethylcellulose ratio, drug and polymer particle size andcompression force on the release of diclofenac sodium from HPMC tablets. Journal ofControlled Release 57: 75–85, 1999

Venables HJ, Wells JI: Powder mixing. Drug Dev Ind Pharm 27: 599-612, 2001

Venkatraman S, Davar N, Chester A, Kleiner L: An overview of controlled releasesystems. In: Handbook of Pharmaceutical Controlled Release Technology, pp. 431- 463.Ed. DL Wise, Marcel Dekker Inc., New York, NY, USA, 2000

Verheyen S, Augustijns P, Kinget R, Van den Mooter G: Melting behavior of purepolyethylene glycol 6000 and polyethylene glycol 6000 in solid dispersions containingdiazepam or temazepam: a DSC study. Thermochim Acta 380: 153-164, 2001

Verheyen S, Blaton N, Kinget R, Van den Mooter G: Mechanism of increased dissolutionof diazepam and temazepam from polyethylene glycol 6000 solid dispersions. Int JPharm 249: 45-58, 2002

Verhoeven E, Vervaet C, Remon JP: Xanthan gum to tailor drug release of sustained-release ethylcellulose mini-matrices prepared via hot-melt extrusion: in vitro and in vivoevaluation. Eur J Pharm Biopharm 63: 320-330, 2006

Vippagunta SR, Wang Z, Hornung S, Krill SL: Factors affecting the formation of eutecticsolid dispersions and their dissolution behavior. J Pharm Sci 96: 294-304, 2007

Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW: Solid-state characterization ofnifedipine solid dispersions. Int J Pharm 236: 111-123, 2002

136

Vogt M, Kunath K, Dressman: Dissolution enhancement of fenofibrate by micronization,cogrinding and spray-drying: Comparison with commercial preparations. Eur J PharmBiopharm 68: 283-288, 2008

Vyazovkin S, Dranca I: Probing beta relaxation in pharmaceutically relevant glasses byusing DSC. Pharm Res 23: 422-428, 2006

Ward GH, Scultz RK: Process-induced crystallinity changes in albuterol sulfate and itseffect on powder physical stability. Pharm Res 12: 773-779, 1995

Weuts I, Kempen D, Verreck G, Decorte A, Heymans K, Peeters J, Brewster M, Van denMooter G: Study of the physicochemical properties and stability of solid dispersions ofloperamide and PEG6000 prepared by spray drying. Eur J Pharm Biopharm 59: 119-126,2005a

Weuts I, Kempen D, Decorte A, Verreck G, Peeters J, Brewster M, Van den MooterG:Physical stability of the amorphous state of loperamide and two fragment molecules insolid dispersions with the polymers PVP-K30 and PVP-VA64. Eur J Pharm Sci 25: 313-320, 2005b

Weuts I, Kempen D, Verreck G, Peeters J, Brewster M, Blaton N, Van den Mooter G:Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and threebasic model compounds resulting in very high glass transition temperatures and constantdissolution properties upon storage. Eur J Pharm Sci 25: 387-393, 2005c

Won DH, Kim MS, Lee S, Park JS, Hwang SJ: Improved physicochemical characteristicsof felodipine solid dispersion particles by supercritical anti-solvent precipitation process.Int J Pharm 301: 1999-208, 2005

Wu JS, Ho HO, Sheu MT: A statistical design to evaluate the influence of manufacturingfactors and material properties on the mechanical performances of microcrystallinecellulose. Powder Technol 118: 219-228, 2001

Xu L, Li SM, Sunada H: Preparation and evaluation of ibuprofen solid dispersionsystems with kollidon particles using a pulse combustion dryer system. Chem PharmBull: 1545-1550, 2007

Yonemochi E, Kitahara S, Maeda S, Yamamura S, Oguchi T, Yamamoto K:Physicochemical properties of amorphous clarithromycin obtained by grinding and spraydrying. Eur J Pharm Sci 7: 331-338, 1999a

137

Yonemochi E, Inoue Y, Buckton G, Moffat A, Oguchi T, Yamamoto K: Differences incrystallization behavior between quenched and ground amorphous ursodeoxycholic acid.Pharm Res 16: 835-840, 1999b

Yoshioka M, Hancock BC, Zografi G: Inhibition of indomethacin crystallization inpoly(vinylpyrrolidone) coprecipitates. J Pharm Sci 84: 983-986, 1995

Yu L: Amorphous pharmaceutical solids: preparation, characterization and stabilization.Adv Drug Deliv Rev 48: 27-42, 2001

Zeng XM, Martin GP, Marriott C: Particulate interactions in dry powder aerosols. In:Particulate Interactions in Dry Powder Formulations for Inhalation, p. 139. Eds. XMZeng, GP Martin, C Marriott, CRC Press LLC, New York, NY, USA, 2000a

Zeng XM, Martin GP, Marriott C: Interparticulate forces in pharmaceutical powders. In:Particulate Interactions in Dry Powder Formulations for Inhalation, pp. 30-63. Eds. XMZeng, GP Martin, C Marriott, CRC Press LLC, New York, NY, USA, 2000b

Zerbe HG, Krumme M: Smartrix system: Design characteristics and release properties ofa novel erosion-controlled oral delivery system. In: Modified-Release Drug DeliveryTechnology, pp. 59-76. Ed. M Rathbone, Marcel Dekker Inc., New York, NY, USA,2002

Zhang GGZ, Law D, Scmitt EA, Qiu Y: Phase transformation considerations duringprocess development and manufacture of solid oral dosage forms. Adv Drug Deliv Rev56: 371-390, 2004

Zuleger S, Lippold BC: Polymer particle erosion controlling drug release. I. Factorsinfluencing drug release and characterization of the release mechanism. Int J Pharm 217:139-152, 2001

138

ORIGINAL PUBLICATIONS

I Mäki R, Suihko E, Korhonen O, Pitkänen H, Niemi R, Lehtonen M, Ketolainen J:

Controlled release of saccharides from matrix tablets. Eur J Pharm Biopharm 62:

163-170, 2006.

II Mäki R, Suihko E, Rost S, Heiskanen M, Murtomaa M, Lehto VP, Ketolainen J:

Modifying drug release and tablet properties of starch acetate tablets by dry

powder agglomeration. J Pharm Sci 96: 438-447, 2007.

III Laitinen R, Suihko E, Toukola K, Björkqvist M, Riikonen J, Lehto VP, Järvinen

K, Ketolainen J: Intraorally fast dissolving particles of a poorly soluble drug:

preparation and in vitro characterization. Eur J Pharm Biopharm 71: 271-281,

2009

IV Laitinen R, Suihko E, Björkqvist M, Riikonen J, Lehto VP, Järvinen K,

Ketolainen J: Perphenazine solid dispersions for orally fast disintegrating tablets:

physical stability and formulation. Drug Dev Ind Pharm, submitted

Kuopio University Publications A. Pharmaceutical Sciences A 100. Toropainen, Elisa. Corneal epithelial cell culture model for pharmaceutical studies. 2007. 81 p. Acad. Diss. A 101. Mannila, Janne. Cyclodextrins in intraoral delivery of delta-9-tetrahydrocannabinol and cannabidiol. 2007. 90 p. Acad. Diss. A 102. Männistö, Marjo. Polymeric carriers in non-viral gene delivery: a study of physicochemical properties and biological activity in human RPE cell line. 2007. 65 p. Acad. Diss. A 103. Mauriala, Timo. Development of LC-MS methods for quantitative and qualitative analyses of endogenous compounds, drugs, and their metabolities to support drug discovery programs. 2007. 126 p. Acad. Diss. A 104. Kumpulainen, Hanna. Novel prodrug structures for improved drug delivery. 2007. 129 p. Acad. Diss. A 105. Korjamo, Timo. Improvement of the Caco-2 permeability model by genetic and hydrodynamic modifications. 2008. 134 p. Acad. Diss. A 106. Pappinen, Sari. The organotypic culture of rat epidermal keratinocytes (ROC) in pharmaceutical and chemical testing. 2008. 83 p. Acad. Diss. A 107. Mönkkönen, Kati. Gαі₂ in ciliated tissues: physiological role in regulation of ependymal ciliary function and characteristics in human female reproductive tissues. 2008. 85 p. Acad. Diss. A 108. Matilainen, Laura. Cyclodextrins in peptide deliverty: in vitro studies for injectable and inhaled formulations. 2008. 144 p. Acad. Diss. A 109. Lääkepäivät : lääkkeitä myös terveille? 25.-26.4.2008, Kuopio. 2008. 120 p. Abstracts. A 110. Myöhänen, Timo. Distribution of prolyl oligopeptidase and its colocalizations with neurotransmitters and substrates in mammalian tissues. 2008. 101 p. Acad. Diss. A 111. Toropainen, Tarja. Cyclodextrins and their solid-state complexes: studies for pulmonary drug delivery. 2008. 136 p. Acad. Diss. A 112. Määttä, Juha. Cytokine, chemokine, and chemokine receptor expression in RAW 264.7 mouse macrophages and in the lungs of mice after exposure to wood dust. 2008. 69 p. Acad. Diss. A 113. Kääriäinen, Tiina. Interaction of the dopaminergic and serotonergic systems in rat brain: studies in parkinsonian models and brain microdialysis. 2008. 128 p. Acad. Diss. A 114. Kiviranta, Päivi H. Design and synthesis of silent information regulator human type 2 (SIRT2) inhibitors. 2008. 148 p. Acad. Diss.

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