ghent university faculty of pharmaceutical...

GHENT UNIVERSITY

FACULTY OF PHARMACEUTICAL SCIENCES

Department of Pharmaceutics

Laboratory of Pharmaceutical Technology

Academic year 2008‐2009

TABLET FORMULATION OF POROUS SILICON

MICROPARTICLES FOR IMPROVED DISSOLUTION

OF POORLY SOLUBLE DRUG MATERIALS

Liesbeth VANDERHAEGEN

First Master in Drug Development

Promoters Prof. Dr. C.Vervaet Prof. Dr. J. Yliruusi

Commissioners

Prof. Dr. S. De Smedt Dr. E. Mehuys

“The author and the promoters give the authorization to consult and to copy parts of this thesis

for personal use only. Any other use is limited by the laws of copyright, especially concerning

the obligation to refer to the source whenever results from this thesis are cited.”

June 2nd , 2009

Promotor Author

Prof. dr. C. Vervaet Liesbeth Vanderhaegen

ACKNOWLEDGEMENTS

First of all I would like to thank Prof. C. Vervaet and

the Faculty of Pharmaceutical Sciences for creating the opportunity

to write my master’s thesis abroad.

I am also grateful to Dr. J. Heinämäki, for his guidance during this period.

I would like to express my gratitude to Tanja Rotko for

all her help and patience during the experiments

and for her help with the analysis of our results.

I would also like to thank Leena Peltonen for her help with the results.

My thanks also go to Helder Santos for his assistance with the dissolution tests

and Timo Laaksonen for his help with the TEM pictures.

Without all these researcher my work would have been impossible.

A special thank goes to Simon who always stood me by in the laboratory and during our four

months in Helsinki.

I am also grateful to all the staff from the Division of Pharmaceutical Technology for their great

welcoming and for creating a very nice atmosphere.

They were always ready to help.

I especially want to thank Kati(Germany) and Jordane(France) for creating a nice ambience in

the lab.

My deepest thanks goes to my mother who gave me the chance to study in Helsinki.

TABLE OF CONTENT

LIST OF USED ABBRIVIATIONS

1 INTRODUCTION ...................................................................................................... 1

1.1 THE USE OF MESOPOROUS SILICON PARTICLES .................................................... 1 1.2 SILICON PARTICLES FOR ORAL DRUG DELIVERY .................................................... 3 1.2.1 Fabrication of mesoporous silicon particles ............................................. 3

1.2.2 Drug loading into the mesoporous silicon particles .................................. 6

1.3 TABLETING ............................................................................................................ 7 1.3.1 Compaction .............................................................................................. 7

1.3.2 Tablet excipients .................................................................................... 10

1.4 TABLETING OF POROUS MATERIALS ................................................................... 10 1.4.1 Porous Calcium Silicate .......................................................................... 10

1.4.2 Mesoporous silicon particles .................................................................. 13

2 THE AIMS OF THE STUDY ...................................................................................... 16

3 MATERIALS AND METHODS ................................................................................. 17

3.1 MATERIALS .......................................................................................................... 17 3.2 METHODS ........................................................................................................... 18 3.2.1 Tableting ................................................................................................ 18

3.2.2 HPLC analyses ........................................................................................ 19

3.2.3 Characterization of Tablets .................................................................... 19

3.2.3.1 Crushing strenght ................................................................................. 19 3.2.3.2 Thickness .............................................................................................. 20 3.2.3.3 Friability ............................................................................................... 20 3.2.3.4 Disintegration test ............................................................................... 20 3.2.3.5 Dissolution test .................................................................................... 20

3.2.4 Transmission electron microscope (TEM) ............................................... 23

4 RESULTS AND DISCUSSION ................................................................................... 24

4.1 TOPSI –IBUPROFEN TABLETS ............................................................................... 24 4.2 TOPSI – INDOMETHACIN TABLETS ...................................................................... 34 4.2.1 Dissolution profile of TOPSi – Indomethacin tablets compared with TOPSi – Indomethacin particles and pure Indomethacin powder. ..................................... 37

5 CONCLUSIONS ...................................................................................................... 43

6 REFERENCES ......................................................................................................... 44

LIST OF USED ABBREVIATIONS

GI: gastrointestinal

IUPAC: International Union of Pure and Applied Chemistry

HF: hydrofluoric

PSi: porous silicon

TOPSi: thermal oxidized porous silicon particles

TCPSi: thermal carbonized porous silicon particles

THCPSi: thermal hydrocarbonized mesoporous silicon

MCC: microcrystalline cellulose

PVP: polyvinylpyrrolidone

TEM: transmission electron microscope

1 INTRODUCTION

1.1 THE USE OF MESOPOROUS SILICON PARTICLES

Oral dosage forms, especially tablets, are one of the most convenient formulation

forms, as well in fabrication and administration. The production costs are very low

compared to other dosage forms. Tablets have lots of advantages such as such as ease

of transportation, easier delivery especially in elderly and patients with low vision,

patient compliance and accurate dosing (Takeuchi et al., 2005).

The tablet formulation of lot of potential hydrophobic and/or lipophilic drug

molecules can be very problematic due to their poor pharmacokinetics/ADME

parameters. These include a low solubility in the stability range of temperature and/or a

low dissolution rate of the drug in the intestinal lumen, low permeation properties

through the gastrointestinal (GI) wall and rapid intestinal wall metabolism or high

hepatic first pass effect. The oral bioavailability of these molecules can be very low

because the rate of absorption of the drug is restricted by the poor dissolution

throughout the GI tract (Salonen et al., 2008; Hirvonen et al. ,2008)

Recently the slowing down of the therapeutic effect has become mandatory in order

to down regulate the frequency of the administration and reduce the side ‐ effects in

the cases of immediate or rapid drug release (Salonen et al., 2008)

New focuses for oral drug delivery systems are the inorganic drug carries,

especially the porous carriers, “these are low density solids with open or closed pore

structure and they provide large exposed surface area for drug loading”. Examples of

porous drug carriers are:

‐ porous silicon dioxide (Sylysia)

‐ polypropylene foam powder (Accurel)

‐ porous calcium silicate (Florite)

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‐ magnesium aluminimeta silicate (Neusilin)

‐ porous ceramic

‐ Mesoporous silicon particles (Sharma et al., 2005).

In this study we will focus on the use of mesoporous silicon particles for oral use in

tablets. The mesoporous silicon particles show a lot of interesting properties considering

drug delivery applications. The International Union of Pure and Applied Chemistry

(IUPAC) defines mesoporous particles as inorganic drug carrier molecules with pore size

between 2 and 50 nanometres. These small pores “engage the effects of the surface

interactions of the drug molecules and the pore wall” (Salonen et al., 2008).

The pores of the silicon particles are just a few times larger than a drug molecule.

Due to the confined space inside the pores of the silicon particles, the drug molecules

cannot align themselves into crystals. Thus the mesoporous carriers confine the drug

molecules in their amorphous, noncrystalline form. The drug leaves the pore in its

amorphous form, which is far more soluble because the often high crystal energy has

not to be overcome. The drug release out of the particles is not hampered by the

electrostatic interactions nor chemical bonds between the particles and the drug, as

these forces are very weak in silicon. The dissolution rate is also improved by the better

wetting properties of the silicon particles and the greatly expanded surface area (up to

several hundreds of m²/g).

These mesoporous carriers can be used as well to produce formulations with

controlled or sustained release. The carrier molecule helps to release a steady flow of

the drug into the circulation and it can be used as a magic bullet as it directs the drug

into a specified target (e.g. cancer cells) (Hirvonen et al., 2008).

2

The pore size and surface chemistry of the pore walls can be modified quite

easily. (Salonen et al., 2008). The surface properties will influence the affinity of the

compound drug towards the particle and the release of drug and increase drug stability.

(Salonen et al., 2005a).

The mesoporous materials can, besides improving the dissolution, also enhance

the permeability of large hydrophobic molecules in addition to the classical oral

permeation enhancers (Hirvonen et al., 2008).

1.2 SILICON PARTICLES FOR ORAL DRUG DELIVERY

1.2.1 Fabrication of mesoporous silicon particles

During the fabrication of the particles for oral use, it must be ensured that they

can resist the acid environment of the stomach and the harsh conditions of the GI

lumen. They have to preserve their physicochemical properties and their function as

non‐erosive drug carrier (Salonen et al., 2008).

The first production of PSi was actually about 40 years ago by Uhlir. He

discovered that during electropolishing of silicon in an aqueous hydrofluoric acid (HF)

medium, the surface of the silicon became black, brown or red (Uhlir, 1956). But the

porous nature of the silicon was not yet recognized. The porous nature was first

discovered in the early seventies. (Watanbe et al., 1971)

Usually, porous silicon (PSi) particles are manufactured by cavitation during

electrochemical anodization of silicium wafers in hydrofluoric (HF) acid solutions

(Salonen et al., 2005a). During this process, the pores are etched into the material. The

process is mostly regulated by an anodic current because this method gives a better

control of the porosity and thickness and the fabrication is more reproducible. The

production process can also be controlled by voltage. Figure 1.1. shows a schematic

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setup of this process. A strip of Si is dipped into the HF acid solution and the etching

current is laid on between the two electrodes. As the process continues the porous

layers are formed on the surface of the positive Si anode. Usually the cathode is made of

platinum and the fabrication cell must be made of an HF resistant material, like Teflon

for example. The used electrolyte can also be an ethanolic HF solution. The ethanol is

added to lower the surface tension and to absorb hydrogen, thus to reduce the

formation of hydrogen bubbles (insulators) but also to improve the permeability of the

electrolyte in the pores, which results in a more uniform PSi layer. When the fabrication

is completed, freestanding porous films can be obtained by abruptly increasing the

current density. Porous powder with specific particle size can be obtained by ball milling

and sieving of the films (Hirvonen et al., 2008). In our study the production of powder is

very important, as we want to make tablets out of the loaded particles samples.

FIG 1.1.: SCHEMATIC PRESENTATION OF THE ANODIZATION OF SILICON IN A TEFLON

CELL, FILLED WITH A HF ACID – EHANOL SOLUTION (Hirvonen et al., 2008)

As seen previously, the surface chemistry of the porous particles is very

important concerning their properties. The as‐anodized hydrogen terminated (Si‐H, Si‐

H2, Si‐H3) PSi surface is hydrophobic and very susceptible for oxidation, even at room

temperature. This leads to changes in its properties and structure.

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The simplest modification of the surface is thermal oxidation. The oxidation is

usually performed in quite mild conditions (300°C), this causes back‐bond oxidation of

the PSi. Instead of replacing the hydrogen atoms, oxygen – bridges are formed between

different layers of the PSi (Figure 1.2.). The structure modification does not only

improve the stability of the particles, but also turns the surface from hydrophobic to

hydrophilic. A slight decrease in pore diameter is noticed after the oxidation. This type

of silica particle is not applicable for every drug delivery system because the surface is

still partially chemically unstable. These particles are called thermal oxidized porous

silicon particles (TOPSi) (Hirvonen et al., 2008).

FIG 1.2.: OXYGEN BRIDGES BETWEENS LAYERS OF SILICA (Anglin et al., 2008)

Particles produced by thermal carbonization are chemically more stable. Two

different types of surfaces can be obtained, depending on the used technique. Both

particles are produced by the adsorption of acetylene to the PSi surface. Gaseous

acetylene is used because of its small size and due to its ability to diffuse quite fast into

the pores. After the adsorption at room temperature, the temperature is increased. This

causes desorption of the hydrogen atoms while the acetylene atoms bind to the Si

atoms. This results in a carbonized surface. When the temperature is kept below 700°C

and there is a continuous flow of acetylene, a partially carbonized surface is obtained.

The surface of these particles still consist hydrogen atoms, these particles are called

thermally hydrocarbonized PSi (THCPSi). When the temperature is raised above 700°C,

thermally carbonized PSi’s are formed. During this process the acetylene flow has to be

stopped before the temperature is raised. The high temperature treatment removes all

the hydrogen atoms, so the surface is completely carbonized. Before the modification

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the PSi particles are first dipped in an aqueous HF – solution to ensure that the surface is

hydrogen determinate (Salonen et al., 2005b), because the surface was oxidized during

the milling procedure (Salonen et al., 2005a). This procedure is not necessary before the

thermal oxidation modification.

TOPSi and TCPSi both show hydrophilic behaviour, with low contact angle

towards water. This explains why the porous silicon particles have better wetting

properties. The particles with this kind of surface are applicable for oral drug

formulations (Salonen et al., 2005a)

This fabrication process determines the pore architecture while the surface

modifications are important for interactions with the PSi particles (Hirvonen et al.,

2008).

1.2.2 Drug loading into the mesoporous silicon particles

The particles are immersed into a drug solution to get them drug loaded. The

choice of a solvent depends on the solubility characteristics of the drug (Salonen et al.,

2008).. Afterwards the particles are filtered out of the loading solution, rinsed with the

drug‐free solvent and dried to powder (Salonen et al., 2005a).

An alternative drug loading method is impregnation. Here a controlled amount

of drug solution is added to the silicon particles. Capillary forces infuse the drug into the

pores. Both methods can be performed at room temperature and do not expose the

drug to any harsh chemical conditions. The first method can be better dose‐controlled.

The capillary infusion method is more usable in case of expensive drugs, small amounts

of drugs or when the porous particles are still attached on the Si wafer (Salonen et al.,

2008).

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1.3 TABLETING

Powders, granules, pellets or film coated multiple pellets can be used for the

direct production of tablets. This is only possible when the materials show good

compressibility properties to form a tablet, which means that a material is able to

undergo a stable reduction in volume as a result of the applied pressure. The

compressibility can be presented as a plot of the tablet porosity towards the

compaction pressure.

The simplest method to produce tablets is by direct compression. The active

ingredient and the suitable excipients are dry mixed and then compacted. Although it is

a simple procedure, the powder must have specific properties to have a successful

compaction. These properties include high flowability, low segregation tendency and

high compactibility. The compactibility is defined by Patel et al. (2006) as the ability of a

material to produce tablets with a sufficient strength under the effect of densification

and is represented by a plot of tablet tensile strength against tablet porosity. In general

particle modification is necessary prior to the direct compaction because a lot of

pharmaceutical powders do not have these properties. The most common procedure for

particle modification is the production of granules, the particles are agglomerated to

form larger secondary particles. These are more porous than the primary particles (Patel

et al., 2006).

1.3.1 Compaction

Compaction is one of the most important steps in the formulation of tablets

because during this process the following properties of a tablet are determined:

‐ Mechanical properties

• Friability Tablet integrity • Hardness

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‐ Physicochemical properties

• Disintegration in watery environment Bio availability

• Solubility

The reliability of the compaction depends on the physicochemical properties of

the drug and the excipients. Especially their deformation behaviour contributes to

successful tableting. Besides the components of the tablets, also the settings of the

tableting instrument are important to get a standardized compaction.

The compaction process can be divided into 2 main stages, a compression and

consolidation step. During the initial compression there is a reduction in the bulk

volume due to an expulsion of trapped air. Further volume reduction is accomplished by

a tighter packing of the powder particles, as the smaller particles nestle themselves

between the larger ones. This results in a less porous structure. When the compaction

force is further increased, the subsequent volume reduction is accomplished by particle

deformation.

The consolidation step involves particle‐particle interactions, these

interparticulate bond formations are made possible as the powder particles became

closer to each other during the volume reduction. Consolidation is very important in the

fabrication of tablet as it gives them the mandatory mechanical strength.

The actual compaction cycle consist of 5 stages:

1. Precompression: loading of the compressive device

2. Initial compression: expulsion of trapped air

3. Particle deformation

‐ Reversible compression: elastic deformation of the particles

‐ Exceeding critical pressure: plastic deformation (irreversible)

‐ Irreversible compression: fragmentation of particles

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4. Removing the compression: partial elastic recoil or decompression

5. Ejection of the tablet: avoid adhesion

The kind of particle deformation is based on the mechanical properties of the

powder but is as well dependent on the rate and magnitude of the applied force and of

the duration of the induced pressure. Elastic deformation is a reversible process, while

the shape of the particles only changes temporarily, and occurs when the applied stress

does not reach the critical deformation value. Plastic deformation is irreversible as the

original shape of the particles changes permanently. This kind of deformation takes

place when a critical stress is exceeded. Further fragmentation of particles into smaller

ones is called brittle fraction, it starts while exceeding a threshold called crushing

compression. These smaller particles reallocate which results in minute further volume

reduction, by particle deformation, in part elastic and in part plastic. A single particle

can undergo this circle of deformation for several times (Patel et al., 2006; Alderborn,

2002)

When the applied force is removed, the tablet is put under a new kind of stress,

the elastic recovery. To accommodate to this stress the tablets must be mechanically

strong enough or otherwise structural failure will take place. Types of structural failure

are capping and lamination (figure 1.2). This happens when the degree and rate of

elastic recovery are high. Structural failure can be prevented or at least reduced by

adding excipients which deform plastically, like microcrystalline cellulose (MCC) and

polyvinylpyrrolidone (PVP).

FIG 1.3.: LAMINATION AND CAPPING OF A TABLET (Alderborn, 2002)

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The next and last step in the compression cycle is the ejection phase. In this

stage the tablets are removed from the die. There is a force needed to break the

adhesion between the die and the formed tablet. To reduce this stress a lubricant can

be used (Patel et al., 2006).

1.3.2 Tablet excipients

Excipients are essential in the formulation of tablets, the most commonly used

are a filler or diluents, a binder, a disintegration accelerator and a lubricant. Less used

are antiadherents, sorbents, flavouring components and colorants (Alderborn, 2002)

The diluents are the most important of all the excipients listed above as they are

present in amounts higher than all the other excipients (Patel et al., 2006). They are

used to increase the bulk volume of the powder, as tablets have a minimum weight

(commercially available tablets 50mg). A disintegration accelerator is used to facilitate

the formation of smaller particles when the tablet comes in contact with liquids. The

formation of these smaller particles increases the dissolution rate, as the total surface

area enlarges. The binders are added to the tablet blend to ensure that tablets are

formed with the right mechanical force. These are mostly added in a very low

concentration, only 2‐10 % of the tablet weight. Lubricants lower the disintegration and

dissolution rate as most of them are hydrophobic. This negative effect is strongly related

to the amount of lubricant used, normally the concentration is 1% or even lower

(Alderborn, 2002).

1.4 TABLETING OF POROUS MATERIALS

1.4.1 Porous Calcium Silicate

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Calcium Silicate is a porous structure (figure 1.4) of which the formulation of

drug loaded microparticles into tablets has already been studied. The microparticles

were first characterized and afterwards formulated into tablets (Sharma et al., 2005).

Thanks to the interparticle and intraparticle pores it was used before as a medicinal

additive to absorb oily drugs and to improve the dissolution and compression properties

of drugs (Asano et al., 1997).

.

FIG 1.4.: SCANNING ELECTRON MICROSCOPE PICTURE OF CALCIUM SILICATE (Florite RE®

or FLR). SCALE: 4100X

[2CaO.3SiO2.mSiO2.nH2O (1<m<2; 2<n<3)] at 4100X (Sharma et al., 2005)

Tableting studies of unloaded porous calcium silicate show actually really good

results. FLR has high plasticity and a low elastic recovery during the compression cycle.

On top of that most of the energy during the process is consumed by plastic

deformation and brittle fracture of the particles. Because of these properties FLR tablets

show high hardness, which is very important parameter in tablet formulation. The

reason for the good compressibility of this material can be found in its porous structure

(Asano et al., 1997).

To formulate the tablets, the loaded microparticles were directly compressed

with lactose IP, primogel, PVP‐K30 and magnesium stearate IP as excipients. The tablets

were evaluated by measuring their thickness, hardness, disintegration time and

friability. These results were compared with a commercial available tablet (Figure 1.5.).

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The tablets of the loaded microparticles show good mechanical properties and

disintegration time and friability are according to pharmacopeia standards.

FIG 1.5. PHYSICAL PROPERTIES OF FLR‐MELOXICAM TABLET AND COMMERCIAL TABLETS

(Sharma et al., 2005)

MSD1 (1:1 MIXTURE FLR AND MELOXICAM)

MSD3 (1:3 MIXTURE FLR AND MELOXICAM)

Dissolution tests were performed both in acid and basic medium and compared

to the commercial available tablet of meloxicam, in both media the FLR tablets gives

faster drug release (Figure 1.6. and 1.7.).

FIG 1.6. DISSOLUTION TEST OF FLR TABLETS COMPARED TO COMMERCIAL TABLETS IN

PH 7.4 (Sharma et al., 2005)

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FIG 1.7.: DISSOLUTION TEST OF FLR TABLETS COMPARED TO COMMERCIAL TABLETS

ACCORDING TO METHOD A OF USP XXIV FOR DISSOLUTION OF ENTERIC COATED

(DELAYED RELEASE) TABLETS (Sharma et al., 2005)

1.4.2 Mesoporous silicon particles

In the earlier studies, tablet production of mesoporous silicon particles has

mainly been focused on tableting of unloaded samples to see how the particles behave

during and after the compression. Tablets of 50 mg have been directly compressed with

silicified microcrystalline cellulose (as needed), PVP (4,5 w/w %) as a binder and as a

disintegration accelerator, a sodium salt of cross – linked carboxymethylcellulose (0,5

w/w %). Three kinds of PSi particles were used in this study. Tablets with variable

concentration of PSi particles were formulated and it seems that the highest amount in

the tablets could be obtained by the TOPSi particles (Table 1.1.)

During tableting procedure, segregation of the tablet blend was noticed and so

there is a possibility of forming inhomogeneous tablets. A few tablets also showed

capping after their removal from the tableting machine.

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Thickness, crushing strength and disintegration time of the tablets were

examined after the compression. According to the measurement of the crushing

strength (n=3), the TCPSi tablets were the hardest ones (Table 1.2.). The disintegration

time showed a lot of variation for the different samples, it could either take a few

minutes or several hours. Optical microscope pictures of the filtrated disintegrated

samples show that the disintegrated particles are bigger than the original PSi particles

(Figure 1.8.)

TABLE 1.1. USED AMOUNTS OF PSI PARTICLES IN THE STUDY (Presentation Rotko T.,

2009)

Used particles Weight percent used (%)

TCPSi 40‐50

TOPSi 50‐75

THCPSi 40‐50

TABLE 1.2. CRUSHINGS STRENGHT DATA IN THE STUDY (Presentation T.Rotko, 2009)

Used

particles

Sample 1 Sample 2 Sample 3 Mean Standard

deviation

TOPSi 108 N 96 N 114 N 106 N 9 N

TCPSi 144 N 159 N 154 N 152 N 8 N

THCPSi 94 N 70 N 73 N 79 N 13 N

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FIG 1.8.: OPTICAL MICROSCOPE PICTURE (5X MAGNIFICATION)

LEFT: ORIGINAL TOPSI PARTICLES (BATCH 2 15.09.2008)

RIGHT: DISINTEGRATED 65% TOPSI TABLET (Presentation T.Rotko, 2009)

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2 THE AIMS OF THE STUDY

The main purpose of this Master’s thesis was to formulate drug loaded silica micro ‐

particles into a tablet form, as it is of great importance to create an oral applicable

dosage form for this drug delivery system.

Before my participation in the study, only the compression of unloaded particles

was studied. The actual compression was not the main focus in this study, but the

compression data were important to characterize the tablets, so at first the thickness

and crushing strength of the tablets were measured. During the compression the forces

upon the powder bed were monitored.

To examine if the surface of the tablets was damaged and/or if they showed

evidence of lamination or capping a friability test was performed, as well to investigate

if the tablets were mechanically strong enough.

The most important part of this study was to evaluate the drug release from the

mesoporous particle tablets. For this purpose, disintegration and dissolution tests were

performed. The dissolution tests were actually the most essential element of this study.

The drug release profile of the tablets should resemble the profile of the pure

mesoporous particles. The dissolution behaviour from the particles could eventually be

improved by the addition of certain excipients in the tablets. There were thought that

the particles could eventually break during the compression or that the excipients could

block the pores, which both could give a negative effect on the dissolution behaviour.

After dissolution and disintegration tests, the filtrated samples were investigated

with optical and electron microscopes. These images were compared to the pure

particles to discover eventual modifications formed during these experiments or during

the compression.

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3 MATERIALS AND METHODS

3.1 MATERIALS

The mesoporous silicon particles were fabricated and loaded at the University of

Turku, Finland. The thermally oxidized type was always used based on the preliminary

studies with the empty PSi particles since the TOPSi tablets could have the highest

concentration of PSi particles. This is quite important for the further research as the

purpose is to increase the amount of TOPSi particles in the tablets.

The particles were either loaded with Ibuprofen or Indomethacin. They were

kept in storage in desiccators and used as received. The particles loaded with

Indomethacin were protected from light since it is sensitive to breakdown under the

influence of light.

FIG 3.1.: OPTICAL MICROSCOPE PICTURE TOPSI PARTICLES (MAGNIFICATION 5X)

LEFT: TOPSi PARTICLES LOADED WITH IBUPROFEN BEFORE COMPRESSION

RIGHT: TOPSi PARTICLES LOADED WITH INDOMETHACIN BEFORE

COMPRESSION

Lactose monohydrate (Pharmatose DMV international, The Netherlands) and

microcrystalline cellulose (Avicel PH102, FMC Biopolymer, Ireland) were used as filling

agents. AcDiSol (FMC Biopolymer, Ireland), a sodium salt of carboxymethylcellulose, was

17

used as a disintegration accelerator. As a binder PVP was used (Kolidon 30, Bast

Corporation, Germany). All the excipients were used as received.

The tablet composition was the same for the Ibuprofen and the Indomethacin

series:

‐ 20% (w/w) of drug loaded TOPSi particles

‐ 1.5% (w/w) of disintegration accelerator

‐ 4.5% (w/w) of PVP

‐ 30% (w/w) of MCC

‐ 44% (w/w) of lactose monohydrate

3.2 METHODS

3.2.1 Tableting

The PSi particles were dry mixed together with the excipients, this was done

manually with a spoon and by shaking.

Tablets were directly compressed using a manual single ‐ punch eccentric tablet

machine (Korsch EKO, Berlin, Germany) with 5 mm diameter circular punches with flat

faces. The powder for the tablet (50 mg or 30 mg) was weighed before every

compression and poured manually into the die. The tablet mold was lubricated with a

5% (w/w) magnesium‐stearate (Yliopiston Apteekki, Helsinki, Finland) in acetone (Fluka

Aceton) solution before every compression. The upper and lower compression forces

were monitored during tableting (Single Station DAAS measure). The tableting

procedure was performed in a relative humidity controlled room.

After the compression the tablets were kept in a storage room, the TOPSi –

indomethacin tablets were protected from light.

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3.2.2 HPLC analyses

HPLC (Agilent Technologies 1100 series) analyses were fulfilled on the TOPSi‐

Indomethacin particles to evaluate the drug release in different media. The used media

were pH 1.2 (0.2M HCl –KCl), pH 7.4(phosphate buffer) and ethanol. The buffer solutions

were prepared according to the USP. About 1 mg of particles were dissolved in ten

millilitres of pH 7.4 and ethanol. As the solubility (Table 3.1.) of Indomethacin is lower in

pH 1.2, only 150 µg – 250 µg particles were dissolved in 50 millilitres. The samples were

stirred overnight, protected from light.

TABLE 3.1. SOLUBILITY OF INDOMETHACIN IN DIFFERENT MEDIA, DETERMINED IN THE

DIFFERENT pH VALUES USING A FLASK DISSOLUTION METHOD AT 37°C (Personal

communication with Helder Santos, University of Helsinki, Division of Pharmaceutical

Technology, Solubility in ethanol: Martindale 28th edition)

pH 1.2 (µg/mL)

pH 5.5 (µg/mL)

pH 7.4 (µg/mL)

Ethanol (g/mL)

Indomethacin solubility 1 3.9 70 0.02

The used chromatographic system consisted of a DAD absorbance detector (λ =

320nm, retention time of Indomethacin between 3.9 and 4.4 minutes). The mobile

phase consisted of 60% of acetonnitrille and 40% of 0.2% phosphate acid, the flow rate

was 1.5 mL/min. A Luma C18 column, size 250 x 4.60 mm was used. The pore size of the

column was 100 Å.

3.2.3 Characterization of Tablets

3.2.3.1 Crushing strength

Tablet crushing strength (n = 6) was measured according to the method of the

European Pharmacopeia and was calculated as the force (N) needed to break the tablet

diametrically. The used apparatus was a Schleuniger‐2E 8003, Mod 2E/205

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(Switzerland). Samples were measured in a relative humidity controlled room, at least

one day after the fabrication. The crushing strength was also monitored during tableting

to obtain tablets with the acceptable crushing strengths.

3.2.3.2 Thickness

Tablet thickness (Sony Magnescale Inc, serial number 100774, Japan) was

measured directly after the compression in a relative humidity controlled room.

3.2.3.3 Friability

Tablet friability was measured according to the method of the European

Pharmacopeia for uncoated tablets (for tablets up to 0.65g rotate the drum 100 times

with 20 tablets). The test was performed in a Sotax Friabilator USP (Basel, Switzerland)

3.2.3.4 Disintegration test

The disintegration time (n=3) of the tablets was determined using the method

and apparatus (Sotax DT3, Basel, Switzerland) according to the European Pharmacopeia.

The used medium was purified water at a temperature of 37°C ± 0.5°C. Afterwards

samples were filtrated and kept in storage. Optical microscope (Leica DMLB,

Germany)/TEM analysis was performed on the residue.

3.2.3.5 Dissolution test

All dissolution tests were performed using a paddle type dissolution apparatus

(Erweka DT‐D6, Heusenstamm, Germany). 1000 mL of a buffer solution was used as a

dissolution medium, for Ibuprofen pH 1.2 (0.2M HCl‐KCl) was used, while the tests for

Indomethacin were performed in pH 5.5 (Neutralized Phthalate Buffer). All buffer

solutions were prepared according to the USP. The medium was heated at 37°C ± 0.5˚C

20

and kept at this temperature during the experiment. The paddle speed was 100 rpm.

Samples (5mL) were taken every 20 seconds during the first minute, afterwards every

minute until 15 minutes time. To follow the drug release after longer period, samples

were taken after 30 minutes and 1 hour time. After taking each sample, the volume was

replaced by the same volume of the equilibrated buffer solution at 37°C ± 0.5˚C. The

samples were always manually taken from the same place and height in the vessel.

Tests with Indomethacin powder and TOPSi – Indomethacin were performed by

weighing an amount into capsule number 0. A metal wire was girdled around the

capsule to ensure that the capsule settled down in the vessel.

The samples were analyzed with a UV spectrophotometer (Pharmacia LKB

Ultrospec III, Sweden). In case of experiments with tablets or TOPSi particles, the

samples were filtrated trough a filter with pore size 0.45µm (Sartorius biotech GmbH,

Goettingen, Germany) before the UV ‐ measurement. The wavelength for the Ibuprofen

samples was 221 nm (USP, monograph for Ibuprofen tablets), the wavelength for the

Indomethacin samples was 318 nm (USP, monograph of Indomethacin).

The exact amount of drug release was calculated using a calibration curve (figure

3.2. and figure 3.3.). To compose these curves, exact known amounts of Ibuprofen

(Boots Pharmaceuticals, batch 165004, Nottingham, England) and Indomethacin

(Indomethacin USP, Hawkins, lot number pH05113013) were dissolved in 96% of

ethanol (Etax A12, Altia, Rajamäki, Finland), as the drugs show better solubility in this

solvent (Ibuprofen: 0.57 g/ml, Salonen et al., 2005b, Indomethacin: see table 4.1.). The

calibration solutions were also measured at 221nm for Ibuprofen and at 318nm for

Indomethacin.

21

y = R²

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

0 0,005 0,01 0,015 0,02

Absorba

nce at 221nm

Concentration of Ibuprofen in EtOH (mg/mL)

Calibration curve of Ibuprofen in e

40,369x + 0,001 = 0,9998

0,025

thanol

FIG 3.2.: CALIBRATION CURVE OF PURE IBUPROFEN IN 96% OF ETHANOL

y =

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

0 0,01 0,02 0,03 0,04

Absorba

nce at 318nm

Concentration of Indomethacine in EtOH

Calibration curve of indomethacine ethanol

16,653x ‐ 0,0024R² = 0,9999

0,05 0,06

(mg/mL)

in

FIG 3.3.: CALIBRATION CURVE OF PURE INDOMETHACINE IN 96% OF ETHANOL

22

To calculate the recovery after the dissolution test, the medium was filtrated.

The filters (Whatman Schleicher & Schuell, number 5) were dried overnight and

afterward the powder residue was dissolved in 25mL of 96% ethanol (Etax A12, Altia,

Rajamäki, Finland). The samples were stirred, and afterwards measured with the

spectrophotometer at the same wavelengths as described above. Before the UV

measurement the samples were again filtrated.

3.2.4 Transmission electron microscope (TEM)

The samples were made by dispersing (4‐6 µL water) powder of pure TOPSi

particles and disintegrated tablets on a cupper, small plate, coated with a carbon layer.

Images (FEI Tecnia F12, Philips Electron Optics, The Netherlands) were taken the next

day, as the samples need to dry for at least one night. The used camera was a Gatan

Multiscan 794 1k x 1k CCD (Gatan Inc., USA).

(http://www.biocenter.helsinki.fi/bi/EM/f12.htm)

23

4 RESULTS AND DISCUSSION

The tablet blends were made a day before (kept in a storage room) or the same

date as when the compressions were performed. As they were mixed manually, it is

possible that the blends were not completely homogeneous. For all tablet blends, both

for the Indomethacin as the Ibuprofen tablets, segregation of the components was

noticed, which might lead to an inhomogeneous blend and inhomogeneous tablets. In

the preliminary studies, no lubricants were used, which in part might have increased the

segregation.

4.1 TOPSi –IBUPROFEN TABLETS

Four different series of TOPSi – Ibuprofen tablets were compressed. The first

series (Table 4.1.) was a test compression, as the used batch of loaded TOPSi – particles

was quite old (batch from year 2007). Nine tablets were made in total. The punch

settings were adjusted by changing the distance of the upper punch until acceptable

crushing strengths (Table 4.2.) were obtained. The lower punch was set upon 10.8 mm,

the upper one was set a bit lower than 8.2 mm.

Only a disintegration test was performed for this series of tablets, as we were

not sure if the quality of the particles was still good. Tablet 5, 6 and 8 were randomly

chosen and all three tablets had a disintegration time of about 2 minutes which falls

within the limits stated by the European pharmacopeia for immediate release tablets.

The average thickness of the tablets measured during compression was 2.012 ± 0.145

cm. It is hard to interpret the result of the crushing strengths as the compression forces

of tablet 3 could not be written down as the tableting machine got stuck due to the too

high adjustment of the upper punch (9mm). For tablet 4 the lower force is missing as

the program used for monitoring the forces doesn’t save the data and forces needed to

be written down very quickly after the compression. This also happened with the other

24

series but these tablets were not selected to study their crushing strengths. Tablet 2 was

mechanical so weak that it broke when the thickness was measured.

TABLE 4.1. COMPRESSION DATA OF TOPSi IBUPROFEN FROM SERIES 1

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(cm)

AverageMax Min

49.9 ± 0.2 50.2 49.6

49 ± 1.9 52.5 46.5

13611 ± 8001 19949 413

11647 ± 7705 18446 230

2.012 ± 0.145 2.239 1.814

TABLE 4.2.: DATA OF TOPSi TABLETS SERIES 1, CRUSHING STRENGHT MEASURED

DURING COMPRESSION

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2 3 4

49.6 50.1 50.1 49.6

52.5 47 49.7 48.8

1150 413 ‐

18245

829 230 ‐ ‐

2.239 Tablet broke

1.926 2.123

0 ‐ 41 66

As no significant problems were noticed during the test compression, a second

small series of 19 tablets (Table 4.3.) was made, as soon as new particle material was

available. The same punch setting as for series one were used, while still observing the

crushing strengths during the first compressions. At least one day after the compression

six tablets were randomly chosen, based on their compression forces during tableting,

for measuring their crushing strength. Tablets with high, intermediate and low forces

were picked out (tablet 7, 8, 12, 16, 18, 19). The average crushing strength for this series

was 32 ± 8N.

25

TABLE 4.3. COMPRESSION DATA OF TOPSi ‐ IBUPROFEN TABLETS FROM SERIES 2

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

AverageMax Min

50 ± 0.4 50.6 49.2

48.7 ± 1.6 51.8 45.5

6233 ± 2166 10296 2572

5390 ± 1968 9409 2386

2.004 ± 0.100 2.195 1.853

TABLE 4.4. DATA OF INVESTIGATED TOPSi – IBUPROFEN TABLETS SERIES 2

TABLETS 1 – 4: CRUSHING STRENGHT MEASURED DURING COMPRESSION

TABLETS 7 – 19: CRUSHING STRENGHT MEASURED AT LEAST AFTER ONE DAY OF

STORAGE

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2 3 4

49.6 49.6 50.5 49.5

49.3 49 51.8 46.9

2742 6250 9423 6060

2386 5975 8564 5284

2.125 1.955 2.195 failure

0 26 0 5

7 8 12 16 18 19

49.9 50.1 49.2 50.2 49.5 49.4

45.5 49.3 47.8 48.1 49.3 48.9

4392 10296 8413 4872 2572 5897

3676 9409 6718 5164 2688 4651

1.928 2.052 1.853 1.927 2.051 2.050

17 33 37 32 41 32

As the tablets showed acceptable mechanical properties, a disintegration test

was performed. Three tablets were randomly chosen (5, 10, 15). The disintegration

started immediately, no aggregates were formed and the time was about 30 seconds for

each tablet. The fast disintegration is very encouraging towards the drug release from

the tablets but we have to take into account that the tablets contain a lot of excipients

in the used composition. A filtrated sample was investigated with a transmission

electron microscope (TEM) (figure 4.1.) and compared to the uncompressed TOPSi –

Ibuprofen particles. The surface still looks porous, thus the mesoporous structure is

26

maintained after the compression according to these TEM images. According to these

TEM images it seems that the particles have split into smaller ones but this decrease in

particles size was not noticed with the optical microscope (figure 4.2). The actual

particle size can be measured using laser diffraction, the only problem is that cellulose

might interfere as it doesn’t dissolve in water and is left in the residue together with the

particles. The laser diffraction experiment will be performed at the University of Turku,

as they have more experience with measuring the particles size of the pores, since they

fulfill it as well after the synthesis of the particles.

FIGURE 4.1. TEM IMAGES OF DRUG (IBUPROFEN) LOADED TOPSi

LEFT: PURE TOPSI – IBUPROFEN PARTICLES (UNCOMPRESSED) PORES

RIGHT: COMPRESSED TOPSi PARTICLES AFTER DISINTEGRATION TEST

FIGURE 4.2.: OPTICAL MICROSCOPE IMAGES OF TOPSi –IBUPROFEN(5X MAGNIFICATION)

LEFT: PURE TOPSI – IBUPROFEN PARTICLES (UNCOMPRESSED)

RIGHT: COMPRESSED TOPSi PARTICLES AFTER DISINTEGRATION TEST

27

As series two showed very promising results concerning the disintegration and

because the porous structure remained after the compression according to the TEM

images, it was decided to make a larger series of tablets, as more tablets are needed to

measure the friability. The series were as well made to set up the dissolution profile of

the tablets. In fact two tablet series were made from the same tablet blend, but with

different crushing strengths. Tablets with crushing strengths between 30 and 40N (Table

4.5.) and a series with crushing strengths of 50 – 60N were made (Table 4.7.). The

settings of the upper punch were again adjusted until the right crushing strengths were

achieved. Tablet thickness was only measured as from the right settings.

For the series with crushing strengths between 30 and 40N (Table 4.5.), the

distance of the lower punch was again 10.8 mm, while the upper punch distance was 8.1

mm. The average thickness was 1.923 ± 0.118 mm. It seems that the tablets (10, 24, 30,

33, 42, 50) got stronger during storage, as the crushing strengths (Table 4.6.) were

higher than the range we had set. The average crushing strength for the series was 52 ±

4.5 N.

During the production of the tablets (Table 4.7.) with crushing strengths 50 –

60N, the lower punch was set upon 10.8 mm and the upper was a bit lower than 8.2 mm

because when the punch was set upon 8.2 mm the compression forces were too high

which blocked the tableting machine. The average crushing strength (tablet 11, 14, 28,

37, 46, 49) after at least one day of storage was 65.5 ± 3 N (Table 4.8.). We can conclude

that for both series, the tablets got stronger during storage. The samples for the

crushing strengths were for both series again chosen by the compression forces, namely

with low, high and intermediate forces. The average thickness for this series was 1.881

± 0.075 mm.

28

TABLE 4.5. COMPRESSION DATA TOPSi ‐ IBUPROFEN TABLETS WITH C.S. 30 – 40N (50

TABLETS)

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

AverageMax Min

50.1 ± 0.3 50.5 49.5

48.5 ± 7 51.6 46

8350 ± 3989 14363 975

7679 ± 3749 13315 820

1.923 ± 0.118 2.502 1.798

TABLE 4.6. DATA OF INVESTIGATED TOPSi – IBUPROFEN TABLETS WITH C.S. 30 – 40N


TABLETS 10 – 50: CRUSHING STRENGHT MEASURED AFTER AT LEAST ONE DAY OF

STORAGE

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2 3 4

50.2 50.3 50 49.8

47.5 49.9 ‐

48.9

3895 1381 4320 8719

3442 1162 3850 7283

‐ ‐ ‐ ‐

19 18 44 38

10 24 30 33 42 50

50.5 50 50 49.8 49.8 50

48.6 48.3 48.8 46.5 48.6 48.7

12285 10938 12030 5084 975 4760

10571 9843 11090 4366 820 5228

1.834 1.890 1.965 1.938 1.983 1.847

56,5 54 50,5 46 47 56

TABLE 4.7.: COMPRESSION DATA TOPSi ‐ IBUPROFEN TABLETS WITH C.S. 50 – 60N (54

TABLETS)

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

AverageMax Min

50 ± 0.3 50.7 49.5

49.1 ± 1.1 51.7 46.8

16551 ± 3370 22927 4001

15185 ± 2852 22400 3474

1.881 ± 0.075 2.069 1.766

29

TABLE 4.8.: DATA OF INVESTIGATED TOPSi – IBUPROFEN TABLETS WITH C.S. 50 – 60N



STORAGE

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2 3 4 5 6 7

50.2 49.9 50.6 50 50.1 50.1 49.7

47.8 49.6 ‐ ‐

49.9 49.3 46.8

8246 716

Too high Too high 7859 12336 15816

7155 556

Too high Too high 7460 10663 14101

‐ ‐ ‐ ‐ ‐ ‐ ‐

37 27 80 80 38 45 59

11 14 28 37 46 49

49.9 49.7 50 50 49.5 50.1

51.6 49.3 47.7 47.5 49 51.4

21104 12419 12416 16425 4001 22927

20011 10754 13206 14333 3474 22400

1.901 1.854 1.913 1.788 1.828 1.986

66 63 68 68 68 60

To evaluate if the tablets were mechanically strong enough, a friability test was

performed for each series (the 30 – 40N and 50 – 60N tablets). According to the

European Pharmacopeia the mass loss should be less than 1% after the rotation. The

mass loss for the series with crushing strengths between 30N and 40N was 0.699%, for

the series with higher crushing strengths it was 0.750% and the tablets were not

damaged during the process. According to these values the tablets satisfy to the limit of

the European Pharmacopoeia. But due to the small size of the tablets, some of them got

stuck in the friability drum during the experiment, which can give a biased

representation of the results as not all tablets were turned 100 times. As we compare

these results to the friability of the porous calcium silicate tablets, the friability of TOPSi

‐ Ibuprofen tablets is much higher. The porous calcium silicate tablets were

automatically compressed and our tablets were manually produced. The manual

30

production can give more variation in the mechanical properties of the tablets. The

other values cannot be compared, as the porous Calcium Silicate tablets weighed 175mg

so the height of the tablets was higher. The crushing strengths were measured in a

different unit.

As the tablets showed good mechanical properties (crushing strengths just a bit

higher than we wanted), disintegration and dissolution tests were performed.

Disintegration time for 30 – 40N tablet series (tablet 7, 21, 37) was around 1min for

each tablet, while for the mechanically stronger tablets (26, 36, 45) it was almost 3

minutes. Samples were again randomly chosen. The disintegration for both series

started immediately from the whole tablet and aggregation was not noticed. These

results are quite similar to the other tablet series and are logical, as stronger tablets

need more time to disintegrate.

Drug release from the tablets was determined in 1000mL of buffer solution, as

we wanted to work using sink conditions, which means that the buffer volume doesn’t

restrict the dissolution of the drug. To work in these conditions, the maximum amount

of drug that can dissolve from the tablet in the buffer volume is preferably lower than

30% of the maximum solubility. The solubility of Ibuprofen in pH 1.2 is 8.9 µg/mL

(Personal communication with Helder Santos, University of Helsinki, Division of

Pharmaceutical Technology)

For both crushing strength series, it seems that almost all Ibuprofen is released

from the tablet after 20 seconds. The recovery for the 30 ‐ 40N was 6 .3% (n=1, tablet

31) and for the other series the average recovery was 7.0 ± 1.8 % (n=2, tablet 38 and

41). Since the recovery is low, the results of the dissolution test can be trusted, which is

very promising as the solubility of Ibuprofen is very low in this pH. As the pKa of

Ibuprofen is 4.9 (Salonen et al., 2005), it adopts the anionic form in this acid medium.

31

The anionic form has a lower solubility than its ionic form, the latter being formed at

higher pH values.

Compared to the TOPSi particles and the Ibuprofen powder the dissolution of

the TOPSi – Ibuprofen tablets is much faster. For the TOPSi particles and the Ibuprofen

powder there is a lag phase in the profile, as the time for the dissolution of the

gelatinous capsule needs to be taken into account (Figure 4.3.). But we must remind

that the results for the tablets can only give an estimation as the production is still on a

very low scale and done manually which gives a high inter – batch variation. This

variation influences all the stages of the process, as the compression, as the dissolution,

as the disintegration.

As the dissolution is enhanced by the tablet form, we can conclude that the

excipients do not block the pores of the TOPSi particles and that the particles are not

fully destroyed during the compression. It is possible that the TOPSi particles are

partially damaged but they do not loosen their capacity to improve dissolution of poorly

soluble drugs. They maintain their porous structure, no damaged particles were noticed

in the sample by TEM.

During the dissolution tests of both series, we noticed that some tablet did not

disintegrate completely and that aggregates were formed. This TOPSi – Ibuprofen blend

already had aggregated during tableting.

32

HPLC results

0

20

40

60

80

100

120

0 10 20 30 40 50 60Time (min)

% ib

u re

leas

ed TOPSi+ibuPure ibu

FIG 4.3.: DISSOLUTION PROFILE OF TOPSi – IBUPROFEN (AMORPHOUS) PARTICLES

SPEED 300 RPM

(SINK CONDITIONS, VERY LOW AMOUNT OF

(Helder of Helsinki, Division of Pharmaceutical Technology)

For all the TOPSi – ibuprofen tablet series no correlations were found between

compression

a

COMPARED TO PURE IBUPROFEN POWDER (CRYSTALINNE), MEASURED WITH HPLC

USED CONDITIONS:

MAGNETIC STIRRING

UV MEASUREMENT AT 264 NM

USED BUFFER VOLUME: 50 ML

PARTICLES USED)

Santos, University

the force and the thickness and the crushing strength because there was

too much deviation in compression force and the tablet height. It is possible that

tablets, which contain more porous material, are higher, bec use the tablet blend could

be inhomogeneous as a result of the segregation. The differences in compression forces

are mainly due to human factor in manual compression. Probably the composition of

the powder loaded into the die was not always homogenous due to the segregation of

33

the blend, which might also cause these fluctuations. To improve reproducibility, further

trials should add lubricants to reduce the amount of segregation and aggregation.

But for the crushing strength values for the series between 30 – 40N and 50 –

60N, we can conclude that the compression forces during tableting did not affect the

values of the crushing strengths as we get acceptable crushing strengths for high,

intermediate and low forces.

4.2 TOPSi – INDOMETHACIN TABLETS

Two seizes of TOPSi – Indomethacin tablets were made, tablets of 50 mg and of

30 mg. The series of 30 mg were especially made to determine the dissolution profile of

Indomethacin as it has a very low solubility and it was too expensive to work in sink

condition with the 50 mg 20% TOPSi tablets (too high volumes of buffer needed).

The setting of the punches for the 50 mg series were again adjusted until

acceptable crushing strengths were obtained. The settings were 10.3 mm for the lower

punch and between 8.1 and 8.2 mm for the upper one. Tablet thickness was measured

during tableting (as from the right settings) (Table 4.9.), the average was 1.910 ± 0.056

mm. Crushing strengths (Table 4.10.) and disintegration time were measured again at

least one day after the production. The mean value for the crushing strength was 53 ±

5N. Samples for the crushing strengths were chosen in the same way as for the other

tablet series and for this 50 mg tablet series we can as well conclude that the

compression forces during tableting do not affect the mechanical strengths of the

tablets, as acceptable crushing strengths are obtained for low, high and intermediate

tableting forces.

The disintegration time (tablets) was once more under the 15 minutes limit of

the European Pharmacopoeia and was about 1 min 30 seconds. The disintegration

34

started immediately and no aggregates were formed as the tablets disintegrated

completely into powder. Drug release from the 50 mg tablets was not investigated as

the needed volume, in order to work under sink conditions, was too large for the

dissolution apparatus.

TABLE 4.9. COMPRESSION DATA TOPSi – IMDOMETHACINE 50 MG TABLETS (19

TABLETS)

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

AverageMax Min

50.1 ± 0.3 50.5 49.6

48.8 ± 1.4 52.2 46.2

3090 ± 2837 10125 205

2881 ± 2655 9935 269

1.910 ± 0.056 1.998 1.826

TABLE 4.10.: DATA OF INVESTIGATED TOPSi – INDOMETHACIN 50 MG TABLETS



STORAGE

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2

50.3 50.5

48.3 48.8

Too low 2425

Too low 2719

‐ ‐

0 64

5 6 7 10 15 16

50.5 49.9 50.3 50 50.2 49.9

50.4 47.9 49.8 48.4 52.2 47.4

985 1711 8147 4671 10125 205

971 1306 7294 4020 9935 269

1.906 1.948 1.988 1.967 1.948 1.979

58 50 49 58 56 48

As the tablets (Table 4.11.) from the second series only weighed 30 mg, the

punches needed to be adjusted again. The lower punch was not changed, the upper

punch was set upon 9 mm to get tablets with a good mechanical strength (Table 4.12.).

35

The average thickness measured directly after the compression was 1.171 ± 0.100 mm.

The crushing strength (Table 4.12.) measured at least one day after the compression had

a mean value of 37± 11 N. For this series, there were lower crushing strengths observed

than usual. When the compression forces during tableting are compared, the tablets

with lower crushing strengths seem to have lower compression forces, especially tablet

35. But on the other hand, tablet 16 had even lower compression forces but showed

acceptable mechanical properties. These fluctuations are most likely due to the manual

compression and because the amount of powder poured into the die did vary due to

segregation of the blend.

As the TOPSi Ibuprofen tablets got stuck in the friability drum, the friability test

was not repeated for the TOPSi – Indomethacin tablets.

TABLE 4.11. COMPRESSION DATA TOPSi – INDOMETHACINE 30 MG TABLETS (38

TABLETS)

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

AverageMax Min

30.1 ± 0.4 30.7 29.5

29.2 ± 0.7 30.6 27.1

4378 ± 3141 9937 41

4064 ± 2864 8945 48

1.171 ± 0.1 1.319 1.110

TABLE 4.8.: DATA OF INVESTIGATED TOPSi – INDOMETHACIN 30MG TABLETS



STORAGE

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 1 2 3

30.4 29.5 29.6

‐ ‐ ‐

41 342 2648

48 176 2198

‐ ‐ ‐

0 0 45

36

Continuation:

Tablet number

m (blend)

(mg)

m(tablet)

(mg)

Upper compression

force (N)

Lower compression

force (N)

Thickness

(mm)

Crushing strength

(N) 7 9 16 25 27 35

30.1 30.1 30.1 30.1 30.3 30.6

30.1 29.6 30.4 29.4 29.4 29.4

9937 401 69 2717 6084 533

8410 364 51 2441 5486 442

1.136 1.193 1.143 1.157 1.149 1.240

40 46 45 26 42 21

Poor correlation of the compression data of these TOPSi – Indomethacin tablets

because there is too much variation in the manual fabrication process as with the TOPSi

– Ibuprofen tablets.

4.2.1 Dissolution profile of TOPSi – Indomethacin tablets compared with TOPSi – Indomethacin particles and pure Indomethacin powder.

Before dissolution tests were performed on the TOPSi – Indomethacin particles

and tablets, the drug release out of the pure particles was investigated by HPLC analysis.

The main purpose of this experiment was to determine which medium best fitted for

the dissolution test.

In pH 1.2, no Indomethacin was released from the particles, as no peak was

shown on the chromatogram (figure 4.4.). The same was noticed with silicon oxide

particles loaded with Indomethacin during the dissolution experiments. The

Indomethacin did not leave the particles in a very acid environment but the recovery in

ethanol was very high (unpublished data, University of Helsinki, Division of

Pharmaceutical Technology). The tendency of staying into the pores could be due to the

poor solubility of Indomethacin in acid media (1µg/mL) which may increase the

interactions between the mesoporous structure and the Indomethacin molecules.

37

In ethanol and pH 7.4, there was a clear peak of Indomethacin (figure 4.5. and

4.6.). The samples were stirred overnight but still the concentration (Table 4.13.) in the

media never reached the maximum possible concentration, calculated from the loading

degree (measured by thermogravimetry). Most likely there was no 100% drug release as

the experiment was not performed using sink conditions. The solubility was restricted by

the volume of the buffer or ethanol.

The HPLC analysis showed that the dissolution tests for Indomethacin were

better performed in another medium than buffer pH 1.2, as Indomethacin isn’t released

from the particles in low pH values. For Indomethacin we worked with a buffer solution

with a pH of 5.5, as the solubility is almost 4 times higher than in pH 1.2 (3.8 µg/mL) The

solubility is increased as in pH 5.5 Indomethacin (pKa = 4.5, Merck Index 10th edition) is

no longer in its anionic form but has adopted its ionic form, which is known for its better

solubility.

TABLE 4.13.: CALCULCULATIONS OF CONCENTRATION OF CONCENTRATIONS

INDOMETHACINE IN TOPSi PARTICLES (LOADING DEGREE OF THE USED TOPSi PARTICLES

WAS 17%)

Weighed and dissolved in

10 mL

Concentration

(µg/mL)

Concentration Indomethacin

(µg/mL)

Concentration with HPLC

%

pH 7.4 Ethanol

0.9 mg 0.9 mg

90 90

15.3 15.3

9.373779 7.42728

61.27 48.54

38

IG 4.4.: HPLC CHROMATOGRAM OF TOPSi – INDOMETHACIN PARTICLES DISSOLVED IN

H 1.2

FIG 4.5.: HPLC CHROMATOGRAM OF TOPSi – INDOMETHACIN PARTICLES DISSOLVED IN

pH 7.4

F

p

39

FIG 4.6: HPLC CHROMATOGRAM OF TOPSi – INDOMETHACIN PARTICLES DISSOLVED IN

The dissolution experiment for TOPSi – Indomethacin tablets, TOPSi –

particles and the pure Indomethacin was also performed using sink

as Indomethacin has an even lower solubility than Ibuprofen.

The drug release from the TOPSi ‐ Indomethacin tablets resembles (standard

are overlapping) the release from the pure particles (figure 4.7.) and shows

accelerated release opposite to the pure Indomethacin powder. In figure 4.7. there is

clear lag phase in the dissolution from the TOPSi – Indomethacin particles, as the

capsule needs to dissolve before the drug can be released from the TOPSi

can start. The average recovery for the TOPSi – Indomethacin tablets was 1.175

0.418 % (n=3, tablet 10, 22, 38), this low value ensures that the dissolution data can be

ETHANOL.

Indomethacin

conditions,

deviations

an

a

gelatinous

particles

±

trusted.

40

41

FIG 4.7. DISSOLUTION PROFILE OF TOPSi ‐ INDOMETHACIN COMPARED TO PURE

PARTICLES AND INDOMETHACIN POWDER.

If the Indomethacin curve is compared to the one of Ibuprofen, it shows a lot

ore fluctuations, but the TOPSi – Ibuprofen dissolution tests were performed in

maller scale apparatus and the working conditions were different. As the paddle

tirring is not that efficient as magnetic, it was possible that different concentration

yers were formed. We tried to take the sample from the same height and place but it

possible that this manual action can have an influence on these results.

As the profile looks similar we can conclude that the dissolution from the TOPSi

blets is not restricted by the tablet excipients, as we were afraid that they could block

e pores and hamper the drug release.

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Concen

tration (%

) to maxim

um

time (min)

Pure indomethacin powderTOPSi ‐ Indomethacin tabletTOPSi ‐ Indometacin particles

m

s

s

la

is

ta

th

The dried filtrated residue of the dissolution experiment was only investigated

ter the dissolution test.

ST

with the optical microscope (figure 4.8.). The shape of the particles looks the same

before or af

FIGURE 4.8. OPTICAL MICROSCOPE IMAGES OF DRUG (INDOMETHACIN) LOADED TOPSi

(5X MAGNIFICATION)

LEFT: PURE TOPSI – INDOMETHACIN PARTICLES (UNCOMPRESSED)

RIGHT: COMPRESSED TOPSi – INDOMETHACIN PARTICLES AFTER DISSOLUTION

TE

42

5 CONCLUSIONS

According to this very preliminary study, it seems that drug release from the tablets

with Ibuprofen is improved comparing to the pure TOPSi particles. For the Indomethacin

it resembles the profile of the TOPSi ‐ particles, so the dissolution from the particles is

not restricted by the tablet excipients. Because there were thoughts that the excipients

could block the pores and leave a negative influence on the dissolution. Compression

does not fully destroy the particles or their porous structure. It is possible that the

structure is partially broken but no evidence was found with TEM or optical microscope.

We must consider that these results can only give an estimation as there was a lot

of variation in the tablet composition due to the manual preparation of the blend and

the tablets. Automatical compression was not possible as the tablet weight was too low

and there was not enough particle material.

m Stearate and/or Silicon dioxide should be

dded to the tablet blend, to reduce the segregation and aggregation of the tablet

blend.

In the future, lubricants as Magnesiu

a

43

6 RE

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Livingstone, Edinburgh, UK, Chapter 27.

Anglin, E. J.; Cheng, L.; Freeman, W. R.; Sailor, M. J. (2008). Porous silicon in drug

delivery devices and materials. Advanced Drug Delivery Reviews, 60

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