phd id: 10711527 jjtu, department of pharmaceu page...

PhD ID: 10711527

PhD Thesis- PhD ID: 10711527

7 JJTU, DEPARTMENT OF PHARMACEU

UTICAL SCIENCES Page 54


PhD ID: 10711527 JJTU, DEPARTMENT OF PHARMACEUTICAL SCIENCES Page 55

3.0 LITERATURE REVIEW

3.1 AIR SUSPENSION COATING

Wurster technology was invented by Dr. Dale Wurster in 1959 when he was at

university of Wisconsin, and was labelled as Wurster System [Wurster et. al, 1959].

This machine was originally designed to coat tablet, now this process is commonly

being used for substrates as small as 100 microns. The technique is principally

enumerated in below Fig.04 [David M Jones et.al 1988] enumerates the major

components of the Wurster technology.

Fig. 4 Wurster bottom spry technique [David M Jones et al 1988]

Jones et.al 1988 enumerates in his article that in pharmaceutical dosage form

development, many products require coating to provide the desired release

characteristic. For coating to happen the particle has to travel numerous times through

coating zone, this consistent passage of particle from coating zone ensures proper

coverage for the particle. Multiple activities which happen simultaneously are droplet

formation, contact, spreading, coalescence, and evaporation as shown below in Fig.05

Fig.5 Deposition mechanism of droplets on substrate [David M Jones et al 1988]



Jones et al 1988 have identified critical factors in fluid bed processing as size, shape,

porosity, & friability of the particles. He also exemplified critical factors as friability,

bulk density, and moisture content of starting core being critical. He enumerates that

in Wurster nozzle is immersed in the air flow in order to spray concurrently into

fluidised particles, the solution droplets travel only a small distance before they

contact substrate. Spray rate and required fluidising air volume is critical to consider

for scale up. Mehta et al 1986 enumerates those process variables which can be

optimised during manufacturing process. The manufacturing process points include

the spray rate, atomisation air, inlet air, air volume, batch size, type of equipment

because these parameters can easily alter the end product performance. In addition to

method of spraying almost 20 other variable are involved in the manufacturing of

controlled release products

Hall et al 2004 indicate in his article various manufacturing process than were

invented way back in 1953 with various techniques such as microencapsulation

Christensen & Bertelsen et.al 1997 Exemplifies that the fluid bed coating process

consists of pre heating, spraying, drying or curing as major steps. The key factors for

coating are core or substrate, the coating solution or suspension, air volume, spray rate

& atomisation. Wurster has well defined product movement in the coating zone.

Each FBP has one product container & expansion chamber. The spray rate should be

modified based on drying capacity, product movement, droplet size in the sprayed

mist in such a way that efficient coating of the polymer is being done on the substrate

3.2 BASIC OF PELLETISATION:

Most of the time when pellets dosage offer important therapeutic advantages over a

single unit dosage forms [Ghebre-Sellassie, et al 1994]. Because pellets due to their

small number and more surface area have tendency to get widely distributed over

large surface area. The pellet dosage form is less prone to dose dumping than the

conventional formulations when they are formulated as modified release formulations.

Two different active pellets can be combined with diversified therapeutic benefit with

different release mechanisms & can be delivered to different sites within the

gastrointestinal tract.

3.3 PELLETISATION TECHNIQUES

PhD ID: 10711527

Palletisation is a process

manufacturing of pellets

referred to as pellets

manufacturing process s

porosity etc [Lecomte et

Technologies:

Bottom

Fig 6 Broad overview of

3.3.1 EXTRUSION - SPHERON

This process involves m

celluloses, granulation of

like extrudates, then tran

speed to convert dry pellets

pellets & screening to obt

3.3.2 SOLUTION/SUSPENSIO


JJTU, DEPARTMENT OF PHARMACEU

cess by which small bead like materials can be de

s can be from starter core of sucrose, granu

[Ghebre-Sellassie, et al 1989a]. The type

strongly affects the film formation, mechanica

t al., 2004]. A broad overview of the fluid b

m Spray Top Spray Tangential Spray

Fluid bed processors

SPHERONIZATION

mixing of the any active with probable excip

f mass with water followed by extrusion of the

ransfer of the mass to Spheronizer which will hav

dry pellets to rounded pellets, followed by drying o

tain required particle size.

Fig 7 Extrusion Spheronization

PENSION LAYERING BY WURSTER

UTICAL SCIENCES Page 57

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PhD ID: 10711527 JJTU, DEPARTMENT OF PHARMACEUTICAL SCIENCES 8

In Wurster technology for deposition of active on the starter core generally a

solution/suspension can be layered on the starter core which require spraying of

solution and/or suspension of drug substance, binders on substrate, The quality of

pellets manufactured depend on the process followed and type of the equipment used

[Ghebre-Sellassie and Knoch, et al 2002]. As a starter core could be sugar based or

microcrystalline cellulose based, generally the bottom spray coating is known as the

Wurster & Hüettlin. In this system solution/suspension layering on neutral pellets has

been conducted by using different type of distribution plates and air fluidization

mechanism (see Figure 08). The Hüettlin Palletisation system allows movement of

particles in centrifugal direction with Disk jet gas distribution plate which has an air

gap of 45 angles. [Bauer et al., 1998]. Following design provides an overview to the

fluid bed processing.

Fig 8 Schematic of a fluidised bed apparatus a] bottom spray with Wurster column

insert b] Top spray technique c] Tangential spray technique [Felton et al 2007]

3.3.3 POWDER LAYERING

Powder layering is a technique generally used for high dose drug loading wherein it

uses multiple deposition, on the cores with the help of a binder solution [Ghebre-

Sellassie and Knoch, et al 2002]. Powder layering is achieved by tangential spray or

centrifugal spray technique. In this technology powder is layered from top over the

circulating beads & binder solution is sprayed from tangential angle to hold the

powder on the surface



Fig 12 Principle of the powder layering process [www.glatt.com]

Powder layering process can be chosen instead of the solution/suspension layering

process in cases when the solution or suspension is too thick, or has a low potency,

but the high pellets potency is required, when the process is too long, when the drug is

not stable in the solution or comparatively low pellets density is desired (for rapid

disintegration) [Jones, et al 2005a].

3.3.4 DIRECT PELLETIZATION

Direct Palletisation process leads to formation of homogeneous pellets which have

microscopically uniform structure and no core can be detected. The Palletisation of

powdered starting materials is facilitated by the addition of binder liquid and a

suitable movement of wetted powders. The agglomerates in this process are result of

the formation impact and acceleration forces, which become rounded out into uniform

and dense pellets. [Kleinebudde and Knop, et al 2007]

Fig 13 Pellets prepared by direct Palletisation



The use of DOE studies, generally provide a useful tool for identification and

correlation of significant factors that affect the process [Korakianiti et. al.2000].

Properties of pellets obtained using direct Pelletization in rotary tangential processor

have been found to depend on process parameters like spray rate, rotor speed, type of

rotor plate used (smooth and rough), amount of liquid added, atomization pressure,

inlet air temperature, etc.

3.3.5 CONVENTIONAL FLUIDIZED BED GRANULATOR

First powder, later granules or pellets are fluidized in the cylindrical product container

by an air stream. The inlet air passes a screen or a perforated plate, fluidizes the

particles and leaves the product container through a filter. This exhaust air filter

prevents product losses and air pollution. The fluidizing air can be heated to the

desired temperature to dry or melt the fluidized product. The position of the nozzle is

above the fluidized product in most cases [Kleinebudde and Knop, et al 2007].

Fig 14 Mechanism of Film formation in Wurster [FBP]

SPRAY AGGLOMERATION: [Top Spray granulation]

Granulation is nothing but agglomeration & is achieved by wetting of granules in

presence of air. To achieve granules of desired size fraction, process involves

spraying of binder solution on the powder bed which leads to agglomeration,



Fig 15 Top Spray Agglomeration

3.3.6 ROTARY FLUIDIZED BED PROCESSOR

Since conventional fluidized bed granulator was not the method of choice for

production of pellets, there was a need to modify the equipment in order to achieve

highly spherical pellets. This type of system in which the whole cycle of liquid

addition, agglomeration, spheronization, and process can be performed is a rotary

fluidized bed processor [Gu et al., 2004].

Fig 16 Roto processor [Gu et al., 2004]

If the movement does not occur in the spheronization phase, no spherical pellets will

be obtained. In this particular design the nozzle or the nozzles in the rotary processor

are generally located tangentially in the wall of the container in the height of the

fluidized product [Kleinebudde and Knop, et al 2007].

3.3.7 FLUIDIZED BED CONCEPT: A mathematical approach

Generally in typical fluidized-bed processor or FBP attached with Wurster product

container, the fluidizing air enters the bed through an air distributor plate at the

bottom of processor. These bottom plates have different aperture sizes, each plate is

labelled as C, D or A, the selection of bottom plate is based on size of the starting core

and amount of drug loading. The air passes up through the bed of pellets or core on



which loading is expected, setting pellets to move in upward direction providing

fountain like appearance. In the upper part of FBD processor, an expansion chamber

slows down the particle velocity [Parikh, et al 2006]. As the speed of air velocity of

input air is further increased. At a particular velocity of fluidizing air particle start

fluidisation.

3.3.8 THEORY OF PELLET FORMATION BY SUSPENSION LAYERING

[WRUSTER COATING]

This process involves spraying of liquid in solution or suspension form on the surface

of substrate with desire to get quality product. Where the quality is based on

efficiency, yield, assay etc. In this process fines are produced as a result of attrition or

spray drying, especially when the process is not optimized. Hence concentration of

binder is critical in this type of system.

3.4 ASPECTS OF COATING OF PELLETS

Film coating is mainly done by using solutions or dispersion in which other excipients

are dissolved consists mainly of polymers, antitacking, plasticizer etc which are

applied to the cores. Film formation from solutions or dispersions occurs by different

mechanism [Bauer et al., 1998]. First functional polymers have been used to coat

pharmaceutical solid dosage forms for protective, decorative and functional purposes.

3.4.1 MECHANISM OF FILM FORMATION

A film forming polymer in polymeric dispersion is atomized and deposited from the

nozzle onto the surface of pellets intended for coating. Polymeric dispersion contains

submicron-size spheres and each sphere consists of hundreds of polymer chains.

Deposited on the surface, they coalesce into a continuous film as the aqueous phase

evaporates, since interfacial tension between water and polymer pushes particles into

contact point in a close-packed arrangement (Figure 22). Frankel’s mathematical

model:



This equation illustrates the inverse relationship between internal viscosity (N) of the

spheres and the driving forces (Ȗ) necessary to fuse or coalesce discrete particles. It is

evident that smaller radius polymer spheres require less driving force (capillarity) to

completely fuse or coalesce. Water is evaporated from the coating system as a result

polymeric solid remain on the surface of substrate. These residual solid composed of

discrete particle, become a homogenous film. Fusion and film formation of polymeric

particles can be explained by following theories:

Fig 17 Schematic representation of the film formation process for and aqueous

polymeric dispersion: (A) atomization of polymeric dispersion; (B) deposition of the

polymeric dispersion on the substrate surface; (C) packing of the polymer spheres

with water filling the void spaces; (D) formation of continuous polymeric film

[Felton, et al 2007]

3.4.2 Tg MELTING TEMPERATURE FOR POLYMER]

Film formation of polymer dispersions is correlated to the glass transition temperature

of the polymer itself, because the flexibility of the polymer chains changes as the

temperature decreases or increases. “The glass transition temperature” (Tg) is the

temperature at which the viscosity of a melted polymer increases considerably on



cooling, or decreases noticeably on heating. In molecular terms, it is the temperature

at which the flexibility of polymer chains changes by several orders of magnitude

3.4.3 MINIMUM FILM - FORMING TEMPERATURE

The term “minimum film formation temperature” (MFT) is the temperature in degrees

Celsius above which a continuous film is formed under distinct drying conditions

[Lehman, et al 1997]. This temperature determines the temperature at which a film

can form; hence it is an important parameter to determine appropriate bed temperature

required for film formation [Frohoff-Huelsmann et al., 1999]. The coated dosage

forms are than cured, namely treated at high temperatures for short time. This

procedure completes the film formation, especially in the case of dispersions with

high MFT (over 40°C) [Dashevsky et al., 2005]. Polymer is deformable above Ts

which is necessary for film formation. The Tg of the polymer generally determines

the softening films and is directly related to sharp increase in polymer chain mobility

[A. O. Okhamafe et al (1988)] this glass transition and softening temperature is

determined by DSC and by penetration test in thermo mechanical analysis

respectively. Thus film formation varies with coating condition and ranges between

the Ts and MFT.

Table 1:- effect of process parameters on quality of film formation by the Wurster

process Amer et al 1988

Tg ஈC)

Bed temperature (ஈC)

Quality 35 53 60

38 41 40

Excellent Fair Poor

4.0 FORMULATION AND PROCESSING FACTORS

4.1 FORMULATION FACTORS

4.1.1 POLYMERIC PARTICLE SIZE:-

Smaller particle size ensures strong film formation compared to higher size of

polymer. Latexes and pseudo latexes are easier for film formation due to its

submicron size. Nakagami et al 1991 studied effect of size of particles on film

formation of methacrylic acid copolymer suspension. They also investigated and



compared EC latex having (particle size 171µm) with micronized EC (4.5µm particle

size).

Table 2:- Effect of different % of plasticizer and processing temperature on film

formation from ethyl cellulose dispersions Nakagami et al 1991

Temperature(ஈC)

Plasticizer level Aquacoat EC N-10F 0% 10% 25% 40%

0% 10% 25% 40%

25 30 40 50 60

- + ++ ++ + ++ ++ + ++ ++ ++ ++ ++ ++ ++ ++

- - + ++ - - + ++ - - + ++ - - ++ ++ - - ++ ++

4.1.2 PLASTICIZER:-

The main function of any plasticizers is to decrease Ts and Tg values. The degrees of

decrease in Ts depend on the plasticizer concentration and physiochemical properties

of plasticizer. They help to improve polymer mobility and flexibility. The plasticizer

must be compatible with the polymer. Toyoshima et al investigated cloud point where

polymer & plasticizer molecules force to break bond was investigated, Nakagami et al

1991 worked in his research with polymer and plasticizer which depends on DT and

CP values and concluded the plasticizer having lower dew point [DP] and CP values

are compatible with polymer.

Table 3:- The Effect of temperature and cloud point on ethyl cellulose dispersion at

various concentration of plasticizer and compatibility Nakagami et al 1991

Plasticizer DT (ஈC) CP (ஈC) Compatibility PG PEG 400 Triacetin Polysorbate 80 TEC Diethyl d-Tartrate

174 RT 133 139 50 RT

- - - - - <0

× + × × + ++



4.1.3 BLENDING OF POLYMERS:-

Blending of polymer is done to adjust the softening temperature of the polymer. For

example: - Eudragit NE30D has low Ts at 18ஈC and is blended with RS30D. Up

to

40% of NE30D there is slight decrease in temperature but above 40% of NE30D there

is drastic change in temperature. The blend of RS30D /NE30D is in the ratio of 2:3

with Ts of 53ஈC. Release profile of this blend was very fast indicating poor

film formation. Coating only with NE30D resulted in stickiness due to low Ts.

But sustained release profile was noticed for blend of RS30D /NE30D is in the ratio of

2:3 further heated at 60ஈC for 12 hours during the coating process. Thus, it

can be concluded in the RS30D dispersion hard polymeric particles can be

incorporated at certain % [Protzman et al 1960)]

4.1.4 HYDRATION OF POLYMER:-

For excellent film formation, hydration of polymer is important apart from polymer

particle size. For example:- Eudragit L30D shows excellent film forming ability due

to its small size , Lehmann et al 1989 . The hydrogen bond between the polymer and

pendent ester can be broken by water molecules and hydration causes lowering of

mechanical strength of particle and polymer particle to deform. Hydrogen bond

between water and carboxyl groups act as driving force for film formation. Nakagami

et al 1991 showed glass transition temperature of plain L30D can be altered by

wetting which is achieved by processing them at 30ஈC, 90% RH in coating chamber

it changed from 91ஈC to 48ஈC. Such type of coating under wet condition resulted

in to more permeable membrane Nakagami et al 1991.

5. PROPERTIES OF THE CORE SURFACE:-

Core used must be porous granules. Protzman and Brown et al 1960 in their research

work studied permeable surface of film resulting into higher film forming

temperature. Yang and Ghebre-Sellassie et al 1990 reported this problem resulted in

poor film former. Migration of drug can be avoided by slow coating at initial stage or

seal coating of cores.



5.1.1 ADDITIVES:-

Pigments (TiO2, food dyes) which are insoluble in nature are used as additives in

water are used in colouring the coating, membrane diluents to thicken the membrane,

example: talc or magnesium stearate Goodhart et al 1984 and they can also be used as

anti-tacking to separate interactive polymeric particle and avoid coagulation. Waldie

et al 1981 & Ghebre-Sellassie et al 1989 explained (Myuacet 9-40) in aquatic

formulation act as anti-adherent and anticoagulant respectively. Bodmeir and

Paeratakul et al 1989 reported that coalescence can be avoided by replacing anionic

surfactant with non-ionic surfactant like Pluronic P103 in Aquacoat or surelease

particles.

5.1.2 COATING OF MULTI-PARTICULATES USING POLYMERIC

SOLUTIONS

Multiparticulate dosage forms comprising of pellets formulation was introduced

around 1950. Organic solvents as well as aqueous solvents were used as media for

coating of these particles

5.1.3 SOLUTION OF POLYMER IN ORGANIC SOLVENT:-

Organic solvents are used to make polymeric solutions which then can be used to coat

substrate in more effective way as they can be evaporated from the system

5.1.4 SOLUBILITY OF POLYMERS IN ORGANIC SOLVENTS:

There are various solvents that can be used for development of polymeric films:

Mehta et al 1989 indicated that most of the solvents have a high affinity towards

polymer molecules and have tendency to lower their intermolecular forces

5.1.5 PREPARATION OF POLYMER SOLUTIONS:

While preparation of the polymer solution polymer swell in the solvent the viscosity

of solution gets increased therefore the polymer should be added during vigorous

stirring it prevents sticky polymer particles to sediment.

Few of the cellulose derivatives show the solubility at higher temperature. Such

derivatives give good dispersion at higher temperature and faster dissolution when

temperature is reduced. For polymers capable of forming the hydrogen bond, water is

good co solvent.



5.1.6 ASPECTS OF SOLVENTS:

5.1.6.1 WATER:

Cellulose derivatives (i.e. MC, HPMC) are water soluble, they can be used to prepare

water soluble film coating. It can effectively be used in colouring layer, taste masking.

The application of water as film formation is preferred mainly on tablets and not on

pellets

5.1.6.2 ORGANIC SOLVENTS:

Mostly preferred organic solvents are ethanol, methanol, IPA, Acetone,

Dichloromethane,

Table 4 Physical Data of selected solvents

Solvent Boiling point (oC) at 1013 mbar

Heat of evaporation (J/g)

Vapor Pressure at 200c (mbar)

MAK/TLV ppm (ml/m3)

Minimum odor detection (mg/m3)

Ignition temperature (oC)

Ethanol 78.3 855 60 1000 93 425 Methanol 64.7 1102 128 200 7800 508 IPA 82.3 667 40 400 90 634 Acetone 56.2 520 240 1000 770 540 Dichloromethane 40.2 321 475 100 550 605 Tri- chloromethane

61.2 247 210 10 1000 -

Water 100 2264 17.5 NO Very high

Very high

Table 5 polymeric solubility in different solvents

Solvents MC HPMC CAP HPMCP EC Water + + >pH6 >pH5-6 - Methanol + - Sw + Ethanol - + - Sw + IPA - Sw + Acetone + + + + Dichloromethane - - Sw + Ethyl acetate - +



Table 6 Solubility of Polymethacrylate in organic solvents and water

Solvents Poly-amino- methacrylate E100

Methacrylic acid

copolymers

Ammonio methacrylate copolymers

L100-55 S100 RL 100 RS 100 Water <pH 5 >pH5.5

7 >pH6- sw sw

Methanol + + + + + Ethanol + + + (+) (+) IPA + + + (+) (+) Acetone + + + + + Dichloromethane + - - + + Ethyl acetate + - - +

5.1.6.3 SOLVENT MIXTURES:

When water is added in small quantity (3-5%) it normally improve the solubility of

polymers,. The solvent mixtures are more preferred when multiple polymers are

required to be dissolved or dispersed in common spraying system, this is usually done

with

5.1.6.4 RESIDUAL SOLVENTS:

When the film is very thin and entire surface is not covered with the film at this level

the residual solvent evaporation is very easy. To avoid solvent trapping in the

Multiparticulate system spay should be done at slow speed at beginning and stopped

for intermediate drying. The process should be controlled in such a manner that the

thin layer of coating is applied with regular interval of drying step.

6.0 FACTORS THAT AFFECT PROCESS VARIABLE

The factors which affects the process are generally core, polymeric composition such

as Substrate size , Size distribution , Surface roughness , Insoluble additives &

Soluble additives in the coating system,

7.0 BIOPHARMACEUTICS OVERVIEW: GI Transit time and pH profile



Table No. 09 GI transit pH profile

Region Time pH profile Stomach 60 - 90 min 1.0 to 1.5 (empty)

3.0 to 5.0 (Chyme) duodenum 30 - 40 min 5.5 to 6.5 Jejunum 1.5 - 2 hours 6.0 to 7.0 ileum 5 - 7 hours 6.5 to 7.0 colon 35 - 36 hours 6.0 to 7.5

8. TARGET AREA SELECTED:

There are numerous formulation are available to achieve a Zero order pH independent

drug release systems,

Table No. 10

GIT Segment pH Stomach 1-3 Small Intestine 5-7.5 Large intestine 6.8-7.8 Rectum 7.8-8

9.0 POLYMER THRESHOLD:

There are numerous polymers available as enumerated below which can be used to

target the release in a pH required. As these polymers have pH dependent solubility it

becomes a critical task in developing a modified release formulation using these

polymers.

Table No.11

Polymer Threshold pH E L 100 6.0 E S100 7.0 E L30D 5.6 E FS30D 6.8 E L100-55 5.5 Polyvinyl acetate Phthalate 5.0 HPMC Phthalate 50 5.2 HPMCP55 5.4 Cellulose acetate trimellitate 4.8



[E: Eudragit]

Hence it is expected design the drug delivery where upon a active which has pH

dependent solubility will be chosen, and its extended release formulation will be

developed using some of the modified release polymers as enumerated above.

It was also hypothesized to use some of the solubliser or pH modulators in the

formulation in such a way that then it helps in solubising the active in the non-

favourable pH region.

10. REVIEW OF SCIENTIFIC LITERATURE

A comprehensive literature search was carried out to capture information about

dosage form, work done on similar type of systems, scientific journals, research

papers, books; patent data base was evaluated as enumerated below for drug of

cardiovascular category such as Dipyridamole. Similarly a feasibility of this design

would be investigated on another drug molecule from cardiovascular category such as

Carvedilol phosphate. This would help to create a platform drug delivery technology

for drugs having pH dependant solubility.

From design perspective, the development of this concept involves as exemplified in

introduction, a drug layering process using Wurster technology, followed by coating

with modified release polymeric mixture coating to achieve the desired drug release,

as the proposed concept defines control of release of acid from drug delivery system

which is critical for in-situ solubilisation of active in the formulation.

Singh; et al. [2007] explained various modified release formulation drug delivery

systems where solid formulations are targeted for specific drug delivery such as

lower gastrointestinal (GI) tract and are effective for many site specific diseases.

These formulations are developed to avoid systemic drug absorption from the target

area.

H. Kranz, Brun & Wagner; et al. [2005] have studied a compound which can be

used for immunity related diseases. The solubility of the compound is pH dependant,

these researchers developed a matrix tablet & evaluated for drug release, tablet with

specific pH has direct impact on the release from matrix tablets. The objective of their

research was to develop a formulation which has pH independent release. A



controlled release tablets can be manufactured by various techniques such as

compression of drug along with gel or swell forming polymer such as (polyvinyl

acetate/polyvinyl pyrrolidone; and excipients such as soluble diluents. A pH-

independent release profile was obtained.

S Siepe, Lueckel, Kramer, Ries & Gurny; et al. [2006] have studied many pH

modifiers such as weak acids to enhance the release of basic actives. The study was

focused on: (a) The effect of micro environmental pH within the formulation, pH

modifier, and drug release from the formulation and (b) release of drug and acid.

These researchers investigated active and acid release. Fumaric acid has low aqueous

solubility & high strength, Fumaric acid was retained for sufficiently log period of

time this can help to maintain the pH within the formulation

Siepmann, Lecomte, & Bodmeier; et al. [1999] have studied the effect of the

composition of diffusion-controlled release devices. The compositional variables such

as amount of plasticizer, type of rate controlling polymer may have significant effect

on the drug diffusion. Drugs like theophylline and Diltiazem hydrochloride were

studied using various dispersions. In the investigated systems the drug diffusivity had

direct relationship with the type and amount of plasticizer, whereas a minor role was

played by chain length of the polymer.

Frenning, Tuno & Alderborn; et al. [2003] explained a various drug release

patterns from different dosage forms coated pellets having a granular core. According

to these researchers this model has been validated

A.Gursoy, D. Karakus, I. Okar; et al. [1999] have studied the various formulations

of Dipyridamole using microsphere technology.

Naonori Kohri & others; et al. [1992] investigated that the solubility of

Dipyridamole. The dissolution of these sustained-release granules was controlled by

various polymers was explained.

Ulrich Heigoldt and other; et al. [2010] have studied vitro dissolution testing to

understand drug release pattern and its in vivo performance of a drug product.



D. Beten, Amighi & Moes; et al. [1995] studied controlled-release drug-polymer co

evaporates using Dipyridamole as a model drug on an industrial scale, omitting the

recovery problems and the milling and sieving processes encountered when co

evaporates are prepared by the conventional solvent-evaporation technique

Pallavi Bassi 2010 et al, in her research review indicated that drugs with pH

dependant solubility will provide pH-dependent drug release rather than the much

more desirable pH independent release profile if formulated as such without any pH

modifiers. Solubility data and pKa values of a few drugs that demonstrate pH-

dependent solubility

Table No. 12

The solubility of weak base can be increased by decreasing pH of the

microenvironment by the use of organic acids Fumaric, tartaric and succinic acid and

that of weak acid can be increased by increasing pH of the microenvironment by the

use of basic excipients such as dicalcium phosphate (DCP), magnesium oxide (MgO)

and magnesium hydroxide. Varma et al. 2005 demonstrated pH-independent release

from Oxybutynin hydrochloride tablets containing Fumaric acid (FA) as pH modifier.



Table No. 13

The relative effectiveness of pH modifiers can be evaluated by three different

parameters: i) measurement of residence time of organic acid in the formulation; ii)

measurement of micro-environmental pH; and iii) measurement of percentage release

of organic acid from the formulation

Measurement of micro-environmental pH in the vicinity can be measured by various

methods. Indicator dyes that change colour with a change in pH play a special role in

micro-environmental pH measurement. These dyes can be incorporated into the

formulation. for measuring the acidity of Oxybutynin matrix tablets containing

Fumaric acid [FA]. It was observed that the tablet core remained red for 8 h,

demonstrating pH < 2.8 when FA (10% w/v) was used. Other indicator dyes that have

been used include methyl red and bromophenol blue Measuring percentage release of

organic acid. The amount of organic acid released in the dissolution media can be

correlated to the relative efficacy of organic acid. The greater the amount of organic

acid released the lesser would be the amount of acid that would be available within

the matrix to control pH and the lower would be the efficacy of the pH modifier. Also,

the release of organic acid is directly proportional to its solubility. For example, Siepe

et al 2006 studied the release of Dipyridamole from matrices containing organic acids

(Fumaric acid [FA], citric acid [CA], SA and adipic acid [AA]) (20% w/w).), whereas

a significant amount of the initial amount of FA (28.4%) was still present. The drug

release values correlated with the order of organic acid released. The presence of

either CA or FA in the formulation created an acidic and favourable environment

All the above studies demonstrated that FA is most effective in modulating the micro-

environmental pH as it has higher acid strength (low pKa) and lower solubility, as a

result of which it remains in the formulation system for a longer time and is able to



replenish the lost acid from the matrix and decrease micro-environmental pH over

period of time. The rank order of efficacy of other organic acids in terms of

maintaining micro-environmental pH was found to be FA > CA > SA > AA. Different

studies have also elucidated the concentration of FA that must be used in order to

obtain pH-independent drug release.

Phuong Ha-Lien Tran 2010, et al enumerated another critical factor involved in the

dissolution process, which reflects the corresponding drug release and follows the

same laws as the active substance. Thus, evaluation of pH modifier release behaviours

is crucial for thoroughly understanding the drug release mechanism from such pH

modulating systems.

Literature from excipient hand book

Table No. 14

However, this study suggested that the enhanced dissolution effect was mainly due to

the formation of a porous matrix structure by citric acid. This explanation contrasted

with that of Siepe, who claimed that pH modulation in system is the main contributor

to enhanced drug release.

Different acids have different solubility and they may impact solubility of active

accordingly. There are couple of actives which have pH dependant solubility e.g

Dipyridamole, this drug is basic in nature and has best solubility in acidic pH. This

could provide a very good indication for impact of acid on solubility of such basic

drugs as enumerated below

Table No. 15



Fig 23 Solubility of Dipyridamole as a function of pH

Fig 24 Effect of different pH on release of active

Based on this it can be observed that acid strength has impact on drug release



Fig 25 Effect of pH modifiers on Dipyridamole release rate

(Phosphate buffer pH 6.8, SDS 0.1%)

Most of the pH modifiers appear to show good solubility and could be effectively

solubilised in the matrix system & were rapidly diffused out. While Fumaric acid has

low saturation solubility, hence it is possible that when Fumaric acid is added in the

tablet will remain there for sufficiently long time to allow the drug to get solubilised

followed by diffusion from the system. Siepe et al 2006 explained that a soluble acids

tend to lower the pH environment & can diffuse out from the system in faster way

Fig 26 Effect of different acid on pH

A formulation strategy to improve active release in the intestine is to incorporate

organic acids as pH modifiers into the formulation. These pH modifiers decrease the

micro-environmental pH inside the solid dosage form. With decreasing micro-

environmental pH, drug solubility increases and drug release is enhanced. If an

organic acid is used as pH modifier, the pH-modifying effect strongly depend on the

aqueous solubility, acidic strength and buffer capacity of the incorporated acid, and

the solubility of the salt formed with the drug. The ratio of the amount of incorporated

acid and that of the drug can influence drug release enhancement. It is expected to

have some quantity of the pH modifier inside the dosage form over the entire time

period of drug release to maintain the pH-modifying effect. To prevent rapid diffusion

of the soluble organic acid out of the pellet, a coating barrier is recommended. The

desired drug release is only maintained if the acidic compound does not diffuse

through this coating membrane or out of the pellets faster than the drug itself. As acid

modifiers differ with regard to their solubility and their pKa value, the selection of a

suitable organic acid is crucial in the development of any such drug delivery where



acid and base is involved. The effect of the pH modifiers adipic acid, Fumaric acid,

succinic acid, and tartaric acid on the release of dipyridamole from extruded and

Spheronized pellets was investigated by Warren et al. However, differences in drug

release were found depending on the type of acid used another approach is based on

coated tartaric acid crystals as starter cores. A blend of sustained release and enteric

polymers was used as coating material for the tartaric acid crystals. The weakly basic

drug was layered onto these coated cores. Subsequently, an overcoat consisting of

sustained release and enteric polymers was applied. The use of polymer blends in both

coating layers resulted in a significant retardation of tartaric acid release. From these

results, it was concluded that regulators of pH such as succinic or Fumaric acid with a

rather low aqueous solubility are required for maintaining the acidic micro-

environmental pH within the dosage form. In two patents, citric and tartaric acid were

used in the form of coated starter cores for manufacture of drug delivery systems

containing weakly basic drugs. These readily soluble acids form a slowly depleting

reservoir. Due to the enteric coating on the starter cores, a gradual increase in the

organic acid release can be obtained. The suitability of this strategy has been

demonstrated with diffusion pellets, consisting of coated citric acid cores and the drug

di-hydro ergotamine methane sulfonate. This study deals with the development of a

propiverine ER pellet formulation containing coated citric acid pellets as starter cores.

A blend of enteric polymers was used as coating material for the citric acid starter

cores. Pellets, comprising several coating layers, are manufactured by a fluid bed

coating procedure. The formulation principle, based on membrane-coated multiple

units,

All these literature search indicated use of Fumaric acid to improve drug solubility

due to its high retention property in the formulation, it was also indicated that faster

release of soluble acid will deplete the reservoir and leading to low dissolution of

active, in our research we targeted a highly soluble acid such as Tartaric acid and

investigated different drugs such as dipyridamole & Carvedilol phosphate to modulate

the release of active from the formulation in such a way that it ensured a profile

similar to reference product, a commercial friendly manufacturing composition and

process was established , in this way this research work will result into development



of generic cost effective formulations for patients in need, thus fulfilling the social

cause.

Aspirin is a crystalline, white odourless material with following structural formula

.

Fig 27 Acetyl salicylic acid

Our search through the published papers and patents shows that there is ongoing

research to develop new techniques, methods to formulate stable Aspirin dosage

forms which resulted in to either tablet or granules formulation, Our search through

the published papers and patents shows that there is ongoing research to develop new

techniques, methods to formulate stable Aspirin dosage forms which resulted in to

either tablet or granules formulation,

Researchers of the PCT Patent Publication No WO2010036975 indicated that

acetylsalicylic acid pellets were prepared by an extrusion and spheronization

technique comprising at least one of the following steps: (1) wet granulation of

acetylsalicylic acid and at least one pharmaceutically acceptable excipient to form a

wet mass; (2) extrusion of the wet mass to form rod-shaped particles, preferably of

uniform size; (3) spheronizing the rod-shaped particles to form spherical particles; (4)

drying the spherical particles; and (5) separating the particles of the desired particle

size range by sieving.

According researchers of the PCT Patent Publication No WO 2012081905, J. Y. Choi

and his research colleagues, aspirin (Spectrum Chemical, USA),

hydroxypropylmethyl cellulose (HPMC) (Shinetsu, Japan), citric acid, polyethylene

glycol and talc were dissolved in a mixture of water and acetone to obtain a coating

solution containing aspirin. The coating solution thus obtained was sprayed to

microcrystalline spherical beads (Pharmatrans Sanaq, Switzerland) in a fluidized bed

coating machine (NQ-125, Fujipaudal, Japan) to obtain pellets containing aspirin.

Aspirin pellets thus prepared were coated with an enteric coating layer.



Hydroxypropylmethyl cellulose phthalate (HPMCP) (Shinetsu, Japan), Myvacet, talc

and TiO2 were dissolved and dispersed in a mixture of ethanol and acetone, to prepare

an enteric coating solution. The enteric coating solution was sprayed to the aspirin

pellets in a fluidized bed coating machine (NQ-125, Fujipaudal, Japan). The resultant

was then dried to obtain pellets having the enteric coating layer. Once enteric coat is

provided as ingress of the moisture is minimized & stable pellets can be prepared,

however use of water, acid, PEG in the drug coating solution will have negative effect

as concluded in our studies and hence this technique may not provide commercially

viable stable pellets.

According to Deasy P.B et al 1996, this article did not give information on stability

of the product.

PCT Patent Publication WO2011096665A2 Patent reveals two manufacturing

process, pellet preparation by extrusion spheronisation and other by Wruster

technique, in both the technique MCC [Microcrystalline cellulose] was used, our

study indicate that Aspirin when layered on MCC beads led to higher impurities

compared to sugar beads. This patent also exemplifies use of acidic excipient such as

citric acid, our investigation indicate that aspirin although stable at acidic pH tend to

become unstable on stability when exposed to heat and moisture and hence acidic

excipients cannot be used in the formulation this can be supported by research work

carried out by Mina et al 2006,

Fig.29 Normal degradation pathway for Aspirin hydrolysis

Despite many progress there are still some potential problems associated with the use

of Aspirin. The major objective was to investigate the possibility of using an

alternative, cost effective commercially viable manufacturing process and

composition which can provide stable aspirin formulation

This provide a great challenge in developing a stable commercially viable pellet

dosage form, Literature search also reveals Aspirin pellet formulation with extrusion



spheronisation and use of powder layering techniques for preparation of pellets, The

major problem in Wruster technology is stability and manufacturing issue as Aspirin

is highly susceptible to heat, moisture. Importantly all researchers have coated these

pellets with either enteric coat or hydrophobic coat which prevent ingression of

moisture in the product and thus prevent hydrolysis, we could not identify a detail

manufacturing process to provide immediate release aspirin pellets using Wruster

Technology. Hence In our research work we tried to address the major limitations of

Aspirin stability & manufacturability & also proposed to combine these pellets

synergistically with cardiovascular drugs such as dipyridamole, Carvedilol phosphate,

etc.

11. REVIEW OF PATENT

A comprehensive patent search was carried out on the selected drug molecule to

understand patent limitations and develop an out of scope formulation strategy

following list enumerates critical active and inactive patents on the selected molecule ,

this is being used as a reference to initiate development in this direction.

Yang Wang Huailin Liu; et al. [2010]; CN102210693 studied method for preparing

aspirin and Dipyridamole multilayer tablets, The invention provides a method for

preparing aspirin and Dipyridamole multilayer tablets, which is characterized by

comprising: preparing Dipyridamole sustained-release tablet cores by tableting; and

coating a stomach soluble insulation layer, an aspirin quick-release layer and a

stomach soluble protective layer in turn. The method has the advantage that aspirin

common release and Dipyridamole sustained-release compound preparations are

prepared by using conventional pharmaceutical equipment.

Pasahn Manohar; et al. [2010]; EP2361615 (A1) discussed and

proposed Dipyridamole prolonged-release tablet which essentially claims Intra gastric

floating tablet, comprising a) in the Intragranular phase: a pharmaceutically active

ingredient and a water-swellable polymer, and b) in the extra granular phase:

hydroxypropyl methyl cellulose (HPMC), wherein the tablet contains a gas generating

agent.



Zhang Jun; et al. [2011]; CN102178671 (A) discussed and proposed in his

patent Aspirin and Dipyridamole gastric floating tablets and preparation method

thereof

Ben-menachem avshalom; et al. [2010] WO2010036975 (A2) & US

2010/0080846 A1 have developed and discussed - Dipyridamole and acetyl

salicylic acid formulations and process for preparing the same & broadly claims a

pharmaceutical formulation comprising: (i) pellets comprising Dipyridamole, and (ii)

pellets comprising acetylsalicylic acid, wherein components (i) and (ii) are physically

separated.

Ahmed Salah U; et al. [2009] WO2009097156 (A1) & US2009196935 (A1) have

exemplified & enumerated pharmaceutical capsules comprising extended release

Dipyridamole pellets and broadly claims A pharmaceutical capsule comprising: a

Dipyridamole extended release pellet.

Guangyan Wu; et al. [2008] CN201299813 (Y) - have exemplified tablet capsule

containing aspirin tablet and Dipyridamole tablet, he also discusses various methods

for making tablet formulation of Dipyridamole and aspirin

Rongsheng Ma; et al. [2008] CN101259132 (A) have discussed aspirin

Dipyridamole sustained-release capsules and production method, The invention

discloses Aspirin-Dipyridamole Sustained-Release Capsules and a production method

thereof, the capsule contains an Aspirin film coated tablet and Dipyridamole

Sustained-Release pellets, with each Aspirin film coated tablet contains 12.5mg of

Aspirin, and the content of Dipyridamole Sustained-Release pellets in each capsule

reach 0.1g.

Gilbert James C; et al. [2008] US2008188497 (A1) studied combination of -

Angiotensin II Antagonist, Acetylsalicylic Acid, and Dipyridamole Pharmaceutical

Compositions and broadly it claims.

Ming Zhang; et al. [2008] CN201157559 (Y) have studied & enumerated - Aspirin

Dipyridamole dual-release capsule fine tablet & The utility model relates to an

aspirin Dipyridamole two-release capsules slow-release micro tablet, which comprises

a capsule body 1, an aspirin immediate-release micro tablet 2 filled in the intra-cavity

of the capsule body 1 and a Dipyridamole slow-release micro tablet 3. The micro



tablet has simple preparation technology and does not need to be compressed for

several times

Minutza Leibovici; et al. [2008] HK1104791 (A1) & US20070184110A1 have

studied and exemplified Dipyridamole extended-release formulations and process for

preparing same the invention is directed to a Dipyridamole formulation comprising an

extended release formulation of Dipyridamole and a pharmaceutically acceptable acid

such as carboxylic acid, wherein the dosage form is solid tablet having a diameter of

1.5 mm to 3 mm. Optionally, the formulation may further comprise an immediate

release acetylsalicylic acid formulation.

BAIZHONG XUE; et al. [2009] CN101428030 (A) have studied and claimed

Compound Dipyridamole/aspirin sustained-release capsule and preparation thereof &

the invention relates to compound Dipyridamole/aspirin sustained-release capsules

and a preparation technique thereof. The invention is characterized in that sustained-

release micro pill technique is applied to prepare two components: sustained-release

Dipyridamole and quick acting aspirin into compound preparation which is used for

treating cardiovascular and cerebrovascular diseases.

Patil Atul et al [2008] EP1894561 (A1) - have studied on Dipyridamole

pharmaceutical compositions Pharmaceutical compositions which comprise a

pharmaceutically inert core coated with an seal coating, followed by Dipyridamole

coating, and followed by coating comprising a drug release modifier.

Leibovici; Minutza; et al. [2007]; US 2007/0184110 A1 have incorporated in its

patent application a Dipyridamole formulation comprising: an extended release

formulation of Dipyridamole and a pharmaceutically acceptable carboxylic acid,

wherein the formulation is in a mini-tablet solid form having a diameter of around 1.5

mm to around 3 mm.

Eisert, et al. [1995]; US6015577 claims A formulation comprising: first part as

Dipyridamole as a rounded pellets, with core as acid excipient, a first coating around

the core consisting active and binder, and a final coating, on drug layered pellets, the

final coating comprising enteric polymers; second part as a sugar coated

acetylsalicylic acid tablet and all being incorporated in capsule.



Gruber; et al. [1980]; US 4,367,217 disclosed a composition where

Dipyridamole and carboxylic acid are combined together into spheroid

particles which are surrounded with a dialysis membrane consisting

essentially of acid-insoluble lacquers soluble in intestinal juices.

Weithmann, et al. [1985] US4,694,024 disclosed that "surprisingly" it was

found that administration, of Dipyridamole and O-acetylsalicylic acid

successively with a time interval

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