International Journal of Pharmaceutics 469 (2014) 94–101

The effect of polymer properties on direct compression and drugrelease from water-insoluble controlled release matrix tablets

Julia Grund, Martin Koerber *, Mathias Walther, Roland BodmeierCollege of Pharmacy, Freie Universität Berlin, Kelchstr. 31, Berlin 12169, Germany

A R T I C L E I N F O

Article history:Received 17 January 2014Received in revised form 8 April 2014Accepted 12 April 2014Available online 16 April 2014

PubChem classification:Ethocel1 Std. (PubChem CID: 24832091)Eudragit1 RS (PubChem CID: 104931)Polyvinyl pyrrolidone (PubChem CID: 6917)Diprophylline (PubChem CID: 3182)Fumed silica (PubChem CID: 24261)Magnesium stearate (PubChem CID: 11177)

Keywords:Controlled releaseDirect compressionGlass transition temperatureMatrix tabletPercolation thresholdWater-insoluble polymers

A B S T R A C T

The objective of this study was to identify and evaluate key polymer properties affecting directcompression and drug release from water-insoluble matrices. Commonly used polymers, such asKollidon1 SR, Eudragit1 RS and ethyl cellulose, were characterized, formulated into tablets andcompared with regard to their properties in dry and wet state. A similar site percolation threshold of 65%v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were thesurface properties and the glass transition temperature (Tg), affecting polymer elasticity and particlesize-dependent binding. The important properties observed in dry state also governed matrixcharacteristics and therefore drug release in wet state. A low Tg (Kollidon1 SR < Eudragit1 RS)decreased the percolation threshold, particle size effect and tortuosity, but increased permeability andsensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of ahigh-Tg polymer (ethyl cellulose). However, release retardation was observed in the same order as matrixintegrity (Eudragit1 RS < ethyl cellulose < Kollidon1 SR), as the high permeability was counteracted byPVP in case of Kollidon1 SR. Therefore, the Tg and composition of a polymer need to be considered inpolymer design and formulation of controlled-release matrix systems.

ã 2014 Elsevier B.V. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journa l home page : www.e l sev ier .com/ loca te / i jpharm

1. Introduction

Formulation and manufacturing of oral controlled releasematrix tablets are well known and established processes thatresult in highly reproducible controlled drug delivery. Thedevelopment of innovative functional excipients (entirely newsubstances as well as derivative synthesis, grafting or coprocessingof existing materials) and the evaluation of the drug deliverypotential of these systems make matrix tablets an extremelyinteresting field of research (Colombo et al., 2009).

The release-controlling excipients for matrix preparation can bedivided into water-soluble and -insoluble carriers. Tablets pre-pared with the former dissolve or erode with time, depening ontheir molecular weight and solution viscosity (Viridén et al., 2009),whereas tablets made with the latter stay intact during drugrelease and are excreted as an empty scaffold (Barra et al., 2000).Polymer properties affecting the integrity and drug release from

* Corresponding author. Tel.: +49 30 838 50708; fax: +49 30 838 50707.E-mail address: koerberm@zedat.fu-berlin.de (M. Koerber).

http://dx.doi.org/10.1016/j.ijpharm.2014.04.0330378-5173/ã 2014 Elsevier B.V. All rights reserved.

insoluble matrices have not been fully evaluated, yet. Typicalexamples of insoluble carriers are Kollidon1 SR (co-processedpolyvinyl acetate and polyvinyl pyrrolidone, ratio 8:2), Eudragit1

RS (ammonium methacrylate copolymer) and ethyl cellulose,which allow matrix preparation by direct compression, thesimplest and most cost effective method for tablet manufacturing(Caraballo et al., 1996; Kranz et al., 2005; Leuenberger et al., 1995;Neau et al., 1999).

The concepts of percolation theory were evaluated for suchmatrices with regard to tabletting and drug release (Bonny andLeuenberger, 1993; Leuenberger et al., 1987). The percolationthreshold of a component is the critical concentration necessary toform a coherent network and to dominate the properties of thewhole system. In case of insoluble matrices important features aredrug release retardation combined with matrix integrity, whichcan only be obtained if the percolation threshold of the polymer isexceeded. A bond percolation threshold, where particles of thesame species are connected via weak interparticular bonds, and asite percolation threshold, discernible by measurable cohesion, canbe distinguished (Leu and Leuenberger, 1993). Below the percola-tion threshold, matrix tablets would erode (below site percolation)

J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101 95

or even disintegrate (below bond percolation), resulting in fastliberation of the drug. Drug percolation thresholds have beenestimated by the break of slope of the "tablet property b", the slopeof the Higuchi equation, vs. total porosity plot (Bonny andLeuenberger, 1991; Higuchi, 1963), but this approach could notpredict the polymer percolation (Caraballo et al., 1999). Significantmatrix characteristics can be derived from the Higuchi equation,such as tablet dimensions and porosity, but it fails to describepolymer properties affecting drug release.

The objective of this study was the determination of thepolymer percolation threshold and the identification and evalua-tion of polymer properties affecting processing and drug release.The results will enable knowledge-based formulation of insolublematrix tablets and may contribute to the development offunctional excipients.

2. Materials and methods

2.1. Materials

Ethocel1 10 cp (ethyl cellulose) in granular and fine powdergrade (The Dow Chemical Company, Midland, MI, USA), Kollidon1

SR, Kollidon1 30 and diprophylline, micronized (BASF SE,Ludwigshafen, Germany), Aerosil1 200 and Eudragit1 RS (EvonikIndustries AG, Darmstadt, Germany), magnesium stearate(Baerlocher GmbH, Unterschleissheim, Germany).

2.2. Methods

2.2.1. Characterization of polymer particlesThe particle size distributions of the polymer powders were

measured using laser diffractometry (LS 230, Beckman CoulterGmbH, Krefeld, Germany). Particle shape was analyzedmicroscopically (Zeiss Axioscope, Carl Zeiss Jena GmbH, Jena,Germany; magnification 10�). Flow properties were assessed byutilizing a tap densiometer (Erweka GmbH, Heusenstamm,Germany) and calculating the Hausner ratio. The flow energywas determined with the PT4 Powder rheometer (FreemanTechnology, Tewkesbury, UK) at similar conditions reported byLindberg et al. (2004), but for a tip speed of 30 mm/s.

2.2.2. Blends for tablettingDifferent polymer powder fractions were prepared by sieve

classification (100 mm, 125 mm, 250 mm, 315 mm, 425 mm and500 mm; Analysette 3 PRO, Fritsch GmbH, Idar-Oberstein,Germany). To obtain different size fractions of the micronizedmodel drug, it was granulated with PVP-solution (1% w/w), driedovernight and classified.

Polymer and drug powders were physically mixed in a 6:4 ratiow/w to obtain 10 g of blend. In case of wet granulation thesemixtures were wetted with isopropanol/water (88/12 w/w) toform granules and dried overnight at room temperature.

1% w/w of each, Aerosil1 and Mg stearate were added todrug/polymer formulations prior to compression.

2.2.3. CompactionCompaction behavior was evaluated by compressing the blends

into 7 mm flat faceted tablets with an instrumented single punchtabletting machine (EK0, Korsch AG, Berlin, Germany) at acompression speed of 10 rpm. Compression force and upper andlower punch displacement were recorded during the compactionprocess (MGCplus, catman, HBM, Darmstadt, Germany). The network of compaction, as well as elastic and plastic work wasobtained by calculating the areas under the curve of the force-displacement diagrams of the upper punch (List, 1985).

2.2.4. Tablet characterizationThe tablets were characterized regarding their dimensions and

hardness (Multicheck, Erweka GmbH, Heusenstamm, Germany)allowing the comparison of different sized tablets by calculatingthe tensile strength of the tablets, s0, according to Fell and Newton(1970).

s0 ¼ 2PpDt

P is the force applied to form the tablet and D is the diameter and tthe thickness of the tablet.

The porosity of the compacts was derived from the ratio ofapparent and true density.

To investigate the impact of thermal treatment, tabletscontaining Kollidon SR and Eudragit RS as matrix former weresubjected to dry heat at 25 �C above glass transition temperature ofthe polymer, whereas tablets of all matrix polymers weresubjected to heat/humidity treatment at 60 �C/75 % RH for 24 hrespectively (oven Heraeus T6060, Thermo Fischer ScientificGmbH, Dreieich, Germany).

Dissolution tests were performed using USP II paddle apparatus(VK 7200, Agilent Technologies Deutschland GmbH, Böblingen,Germany), 900 ml phosphate buffer pH 6.8, 50 rpm and 37 �C.Samples were taken at predetermined time points and analyzedspectrophotometrically at 272 nm.

Water uptake and weight loss were determined gravimetricallyby weighing tablets in the dry, wet and dried state (dried at 105 �Covernight, Heraeus T6000, Hanau, Germany) and swelling oftablets was measured macroscopically (IQ easy measure, INTEQInformationstechnik GmbH, Berlin, Germany).

All measurements were performed in triplicate.Scanning electron microscopy (gold sputtering, Hitachi S2700,

Hitachi Kabushiki-gaisha, Tokyo, Japan) was used to investigate thebreaking surfaces of polymeric tablets after diametrical hardnesstesting.

3. Results and discussion

3.1. Characterization of polymer particles

Direct compression into tablets requires good flowability andcompactibility of the excipients to guarantee reproducibility of theprocess and product quality.

The flowability of a powder depends on material properties likethe particle surface, size and shape (Lindberg et al., 2004). Table 1summarizes the properties of the polymers used in this study.Kollidon1 SR particles were spherical in shape, while the otherpolymers exhibited irregular shaped particles (Fig. 1). Onlymarginal differences could be seen between Kollidon1 SR andEudragit1 RS regarding particle size, whereas ethyl celluloseparticles of the standard grade were larger. The ethyl cellulose finepowder grade consisted of very small particles of approximately10 mm according to the manufacturer but tended to agglomerate toclusters of up to 1 mm in diameter hindering accurate measure-ment by laser diffractometry.

Hence, highest flowability was expected for Kollidon1 SR amidthe investigated polymers and confirmed by the lowest Hausnerratio and flow energy. Eudragit1 RS and ethyl cellulose exhibitedmoderately higher Hausner ratios and flow energies, indicatinghigher surface roughness of the particles. Therefore, powder flowthrough a vibrating funnel was determined, to ensure processibili-ty. A differentiation of the materials was not obtained by thismethod, because all polymers showed comparable flow ofapproximately 5 g/s with the exception of the fine powder gradeof ethyl cellulose. For Ethocel1 10 cP FP, powder flow wascompletely prevented by arching due to the higher surface area

Table 1Surface properties and particle size of the matrix polymers.

Polymer Glass transition temperaturea Particle shape Particle size (mm) Hausner ratio Flow energy (mJ)

<10% <50% <90% Mean SD Mean SD

Kollidon SR 35 �C Spherical 29.3 86.5 156.0 1.19 0.03 4.6 0.4Eudragit RS 58 �C Irregular 28.8 94.4 175.8 1.33 0.02 11.0 0.4EC 10 cP 133 �C Irregular 60.4 277.4 522.0 1.25 0.00 21.1 4.1EC 10 cP FP Irregular agglomerates 6–10a 1.33 0.05 n.d

a Product brochures of the manufacturers (Bühler, 2008; Eudragit – Evonik 2012; Ethocel – Dow 2005).

96 J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101

and subsequently higher cohesive forces and friction betweenparticles. Hence, this material cannot be used without addition ofany glidants.

The literature states that all investigated polymers areamorphous (Draganoiu, 2003; Upadrashta et al., 1994; Wu andMcGinity, 2003) but differ widely in glass transition temperatures(Table 1). The impact of this difference is subject of the followingstudies.

The compactibility of the polymers followed the order:Eudragit1 RS < ethyl cellulose < Kollidon1 SR (Fig. 2A). Frompunch force–displacement curves the proportion of plastic andelastic work in total work of compaction was determined (Fig. 3).With increasing compression forces the proportion of plastic workdecreased and of elastic work increased. The dominant densifica-tion mechanism was plastic deformation, confirming previousresults obtained for Kollidon1 SR and ethyl cellulose (Katikaneniet al., 1995; Reza et al., 2003). The plasticity was almost similar forall polymers (slightly lower for ethyl cellulose) but the degree ofelastic deformation differed, following the glass transitiontemperature of the polymers (Fig. 3, Table 1). The deformationbehavior should generate a different compactibility order than theone observed, but diverse binding mechanisms need to be takeninto account. The contribution of mechanical interlocking of thepolymer particles is more likely for irregular particles and strongerwith rougher surfaces. This could explain the higher compactibilityof ethyl cellulose particles, which exhibited the highest surfaceroughness (Table 1).

The impact of particle size on compaction was analyzed bycompressing different polymer size fractions into tablets (Fig. 4).No effect was seen for Kollidon1 SR, but the other polymers weresensitive to size effects (confirming previous results for ethyl

Fig. 1. Macroscopic pictures of (A) Kollidon1 SR, (B)

cellulose by Katikaneni et al.,1995). Generally, the polymer particlesize affected the hardness of a tablet but not the requiredcompaction force except for very large particles (ethyl cellulose>500 mm). The size dependence of compactibility followed theorder of Kollidon1 SR < Eudragit1 RS < ethyl cellulose, which wasconsistent with the flow energy and the glass transition tempera-ture of the materials (Table 1). When comparing the particle sizefractions to the bulk materials, the overall compactibility could beconsidered as the mean value of the individual compactibilities, sothat the particle size could be used as formulation tool if poormatrix hardness and integrity is an issue.

Differences in matrix integrity could also be seen in SEMpictures of the surfaces of diametrically broken polymer tabletscompressed with 20 kN (Fig. 5). Kollidon1 SR matrices appeared asa continuous dense mass with a clean break, whereas individualparticles and pores could be clearly distinguished for Eudragit1 RS.Ethyl cellulose tablets had a rough breaking surface where cracksseparated the aggregates formed during compaction. The picturesalso stressed that tablets have to be considered as binary systemsof solids and air, often referred to as tablet porosity.

3.2. Tablets – binary systems (polymer and air)

The analysis of the compaction data regarding air content of thecompacts revealed that a porosity of more than approximately 35%,or a volume fraction of less than 65% polymer, did not result in firmcompacts similar for all polymers (Fig. 2B,C). At this porosity level,the inter-particle bonding was insufficient to maintain the matrixform and as a result disintegration into smaller aggregatesoccurred. This critical concentration can be regarded as the sitepercolation threshold of the polymer (Leu and Leuenberger, 1993).

Eudragit1 RS, (C) EC 10 cP and (D) EC 10 cP FP.

0

2

4

6

8

10

0 10 20 30compre ssion force, kN

tens

ile s

treng

th, N

/mm

²

0

2

4

6

8

10

0 10 20 30 40porosit y, %

tens

ile s

treng

th, N

/mm

²

Kollidon SR

Ethocel Std. 10Eudrag it RS

0

10

20

30

40

0 10 20 30compre ssion force, kN

poro

sity

, %

A B C

Fig. 2. Compactibility of matrix polymers (A) tensile strength in dependence of compression force; (B) tensile strength in dependence of tablet porosity; (C) tablet porosity independence of applied compression force.

0

10

20

30

40

50

60

0 10 20 30comp ression fo rce, kN

plas

tic w

ork,

%

Kollid on SREthocel Std. 10Eudragit RS

0

2

4

6

8

10

0 10 20 30compression force, kN

elas

tic w

ork,

%

Kollidon SREthocel Std. 10

Eudrag it RS

A B

Fig. 3. Plastic and elastic work relative to the total work of compaction of matrix polymers in dependence of compression force.

J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101 97

As expected, a lower porosity resulted in stronger tablets(Fig. 2B). The tensile strength–porosity plot also confirmed thesuperior compactibility of Kollidon1 SR and revealed that ethylcellulose and Eudragit1 RS tablets had a similar hardness at thesame porosity level. They only differed in the smallest achievableporosity, which was �8% and 15% for ethyl cellulose andEudragit1 RS, respectively. Application of higher compressionforces did not result in denser tablets due to increasing elasticrecovery (Fig. 3B).

3.3. Tablets – ternary systems (polymer, drug and air)

The drug used in this study, diprophylline, was micronized andthus exhibited poor flowability, but still acceptable compactibility.

Drug-containing matrices were formulated with a polymervolume fraction of approximately 56%, which was close to the site

0

2

4

6

8

10

0 10 20 30comp res sion forc e, kN

tens

ile s

treng

th, N

/mm

²

Kollid on SR

Ethocel Std. 10 FP

Ethocel Std. 10

Eudragit RS

Fig. 4. Effect of particle size on the compactibility of polymers <125 mm (&), 125–250 mm (^), 250–315 mm (4), 315–500 mm (�), >500 m (-). Tablet porosity of 16%.

percolation threshold of the polymer described above. The surfacearea of the tablets was controlled and the porosity was set to 16%(84% solids fraction) so that matrix integrity after compaction wasgiven. The particle size effect on matrix hardness was verified forternary systems of drug, polymer and air (data not shown),confirming the size-dependent percolation of the polymerparticles (Barra et al., 1999).

During drug release experiments, the drug would dissolve anddiffuse from the matrix leaving a polymer scaffold with water-filled pores. At the adjusted polymer volume fraction, surfaceerosion was expected and every parameter changing the percola-tion threshold would have a recognizable impact on matrixintegrity, resulting in either tablet disintegration or coherence.Hence, the matrix system was very sensitive and identification ofcritical properties was facilitated.

3.3.1. Drug release – polymer typeDrug release of tablets prepared with identical particle size

ratio, dimensions and porosity was plotted in Fig. 6. The fastestrelease profile was obtained for Eudragit1 RS, followed by ethylcellulose and Kollidon1 SR. Percolation of the polymer could beassumed as no pronounced matrix erosion occurred.

In previous studies, a lower glass transition temperature atelevated humidity was reported for PVP and Kollidon1 SR(Hauschild and Picker-Freyer, 2006; Oksanen and Zografi, 1990).Therefore, the conversion of Kollidon1 SR from glassy to rubberystate was possible in the wet state at 37 �C during dissolutionstudies. The interaction between aqueous medium and thepolymers was investigated by studying water uptake and weightloss for drug-free films and tablets (Fig. 7). Both Kollidon1 SR andEudragit1 RS films and tablets showed high water uptakeexceeding the pore volume calculated from their total porosities.Thus, the polymers had to swell to keep these amounts of water,

Fig. 5. SEM photographs of polymer compact surfaces after diametrical breaking. Kollidon1 SR, Eudragit1 RS and ethyl cellulose (left to right), scale bars (500 mm in the topline and 100 mm in the bottom line) in the bottom right corner of each picture.

98 J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101

indicating polymer mobility for both materials. Ethyl cellulosefilms took up negligible amounts of water confirming its suitabilityas moisture barrier, whereas the extent of water uptake in tabletswas consistent with the filling of all pores.

Weight loss after drying of Kollidon1 SR tablets was highcompared to the insignificant weight loss of the other polymers.Part of the povidone therefore leached from the matricesconfirming previous results of Shao et al., 2001. The diffusion ofpolymers is considerably slow compared to small drug molecules(Wesselingh, 1993), so that supposedly more povidone dissolvedthan what diffused out. This is significantly changing themicroenvironment inside the tablet. A povidone solution exhibitsan increased viscosity compared to aqueous buffer solution(Bühler, 2008), which will decrease general diffusivity. Waterpenetration into the matrix, as well as drug diffusion out of thetablets, could be decreased.

The differences seen in drug release can be explained by thesefindings: when immersed in dissolution medium, Kollidon1 SRand Eudragit1 RS matrices swelled, increasing the surface areafrom which drug release occurred compared to ethyl cellulosematrices. But in the case of Kollidon1 SR matrices the diffusion ofdrug out of the matrix was slowed by the dissolution of povidoneinside the matrix resulting in retarded release. This hypothesis

0

20

40

60

80

100

0 5 10 15tim e, h

drug

rele

ased

, %

Eudrag it RS

Ethocel Std. 10

Kollidon SR

Fig. 6. Effect of polymer type on drug release from matrix tablets (drug particlesize/polymer particle size ratio 425 mm/<125 mm).

could be confirmed with Eudragit1 RS matrices containing PVP in asimilar ratio as Kollidon1 SR (i.e., water-insoluble polymer: PVP8:2). Almost equally retarded drug release was obtained (data notshown).

Recently, a mathematical description of drug diffusivity inKollidon1 SR matrices was published (Grund et al., 2013),extending the predictability of drug release from Fick’s secondlaw of diffusion to tablets containing drugs of different solubilitiesand varying amounts of drug and polymer.

3.3.2. Drug release – particle size of drug and polymerThe particle size dependence of compactibility found for binary

systems was reflected in drug release studies from ternarystructures (Fig. 8) and was governed by the glass transitiontemperature. On one hand, for Kollidon1 SR only marginaldifferences could be seen. All matrices stayed intact during drugrelease, implying polymer fusion during the release and percola-tion. Diprophylline liberation was retarded over 15 h independentof the particle sizes (Fig. 8A). On the other hand, the polymersEudragit1 RS and ethyl cellulose showed particle size-dependentprofiles. For better comparison the drug/polymer size ratio wasemployed. At ratios <1 the matrices disintegrated, whereas atratios �1 integrity of the tablets was maintained (Fig. 8B,C). In caseof Eudragit1 RS, overall drug release was very fast and differencesbetween matrices that stayed intact during drug release wereinsignificant. With ethyl cellulose, a higher drug/polymer size ratiocaused further retarded drug release. Consequently, strongesttablets and retention of drug could be achieved with the finepowder grade of the polymer, but manufacturing was challengingbecause of flow and segregation issues.

The effect of drug and polymer particle size could be explainedby a shift in the percolation threshold of each of the constituentswith smaller particles percolating at lower concentrations (Barraet al., 2000; Caraballo et al., 1996; Millán et al., 1998). Moreover, atsimilar porosities, the pore size and distribution differed accordingto the drug/polymer size ratio, changing the path length(tortuosity) for the diffusing molecules (Crowley et al., 2004).The tortuosity was used as fitting parameter for the Higuchi model(Higuchi, 1963), but with the knowledge of the size effect it can bereplaced by a measurable feature.

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

micronized / 125 -250 µm

125-250 µm / 12 5-250 µm

micronized / <125 µm

>425 µm / <1 25 µm0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

micronized / 250-500 µmmicronized / bulk materia l125 -250 µm / 100 -250 µmmicronized / <100 µm>425 µm / <100 µm

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

micronized / 250 -315 µm250-425 µm / 25 0-315 µmmicronized / <125 µm>425 µm / <125 µmmicronized / FP>425 µm / FP

A B C

Fig. 8. Effect of drug particle size/polymer particle size ratio for different matrix polymers (A) Kollidon1 SR; (B) Eudragit1 RS; (C) EC 10 cP.

0

20

40

60

80

100

120

0 5 10 15 20time, h

wat

er u

ptak

e, m

g

Kollido n SR

Eudrag it RS

Ethocel Std. 10

0

20

40

60

80

100

120

0 5 10 15 20time, h

wat

er u

ptak

e, m

g

Kollidon SR

Eudragit RS

Ethocel Std. 10

A B

Fig. 7. Water uptake of (A) polymer films and (B) matrix tablets (16% porosity).

J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101 99

3.3.3. Percolation threshold – wet stateFrom the drug release experiments differences in polymer

percolation thresholds for the matrix carriers can be concluded. Acritical concentration less than 55% v/v polymer was observed forKollidon1 SR, because fusion of the polymer in wet state causedcoincidence of bond and site percolation, contributed to matrixintegrity and diminished the particle size effect. The other twopolymers differed only slightly in cohesion. The size dependent sitepolymer threshold of close to 65% volume fraction observed for drymatrices could be confirmed.

3.3.4. Preparation methodGranules were formulated by wet granulation with an IPA/

water mixture, which is known to affect the flowability as well asthe distribution of the polymer in the tablet blend. Therefore, bondas well as site percolation thresholds of the polymer might bereduced. The physical mixture of drug and polymer was wetted

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

Kollidon SR (WG)

Eudrag it RS (DC)

Eudrag it RS (W G)Kollidon SR (DC )

A

Fig. 9. Effect of preparation method on

with organic solution to dissolve the polymer particles and formsolid bridges after drying.

In case of Kollidon1 SR no difference between directlycompressed (DC) and wet granulated (WG) matrices was expecteddue to fusion of the polymer during dissolution. But wet granulatedmatrices exhibited faster drug release than those prepared bydirect compression (Fig. 9). Riis et al., 2007 observed similar resultsfor wet granulation with aqueous media, which was attributed to aloss in polymer structure. Segregation of theco-processed polymers polyvinyl acetate and PVP is likely dueto different solubility in the granulation fluid. Clusters of PVP formthat result in increased pore radii and therefore, decreasedtortuosity after dissolution.

Only little or no effects were seen for Eudragit1 RS and ethylcellulose matrices, respectively. In contrast to literature (e.g., Khanand Meidan, 2007), the porosity of the tablets after compactionwas kept constant. Furthermore, these polymers are known to

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

EC <125µm (DC )

EC <1 25µm (W G)

EC FP (DC)

EC FP (WG)

B

drug release from matrix tablets.

Table 2Effect of preparation method and thermal treatment on tablet hardness.

Polymer Hardness of tablets, N

Direct compression Wet granulation

After compaction Thermally treated After compaction Thermally treated

Kollidon1 SR 110 160 (44 �C)192 (64 �C)

110 160 (64 �C)

Eudragit1 RS 70 140 (63 �C)155 (83 �C)

70 110 (83 �C)

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

ambient

24h / 44°C

24h / 64°C

0

20

40

60

80

100

0 5 10 15tim e, hdr

ug re

leas

ed, %

DC ambient

DC 24h / 63°C

DC 24h / 83°C

WG ambient

WG 2 4h / 83°C

A B

Fig. 10. Effect of thermal treatment on drug release from (A) Kollidon1 SR and (B) Eudragit1 RS matrix tablets.

100 J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101

form rather brittle films (Abbaspour et al., 2007; Rekhi andJambhekar, 1995), thus the bondages that occurred due todissolution and precipitation of the polymer particles in wetgranulation might be broken by the compaction forces duringtabletting.

Consequently, above the percolation threshold of the polymer,wet granulation alone cannot provide further drug releaseretardation for the formulations under investigation.

3.3.5. Thermal/humidity treatmentImproved contact between the polymer particles, decreased

porosity, and increased tortuosity of the matrices due to thermaltreatment of tablets after compaction was reported in theliterature (Azarmi et al., 2005; Shao et al., 2001). Because of thehigh Tg of ethyl cellulose, the required temperature exceeded150 �C. Hence, tablets with this carrier were not treated. The effectof thermal treatment (curing) of Kollidon1 SR and Eudragit1 RStablets on tablet hardness is shown in Table 2. Breaking strength ofthe tablets was considerably higher after thermal treatment,promoting polymer fusion due to increased mobility. A change indimensions and therefore porosity of the tablets was not observed,

0

20

40

60

80

100

0 5 10 15time, h

drug

rele

ased

, %

Etho cel Std. 10 FP

Kollidon SR

Eudragit RS

Fig. 11. Effect of heat and humidity on drug release from matrix tablets: ambient(&), 24 h at 60 �C/75% RH (^).

but redistribution of the pores is possible. Drug release fromthermally treated tablets was not affected in case of Kollidon1 SRtablets, suggesting that polymer mobility is higher in the wet state(during dissolution testing) than in the dry state (during thermaltreatment, Fig. 10A). However, Eudragit1 RS matrices showedslightly decreased release after thermal treatment of directlycompressed tablets and an even stronger effect on wet granulatedtablets, which can be explained by regeneration of the solid bridgesobtained during wet granulation (Fig. 10B).

Matrix tablets of all polymers were subjected to a combinationcuring of heat and humidity treatment (60 �C/75% RH) for 24 h(Fig. 11). Kollidon1 SR matrices showed the strongest retardationof drug release after heat/humidity treatment. The elevatedtemperature, as described above does not primarily cause theretention. It results from the sensitivity to humidity, due to areduced Tg of the polymer as concluded previously (AlKhatib et al.,2010). The effect, however, is insufficient to separate the PVP fromthe matrix as seen in wet granulation. Theoretically, this can beutilized as formulation tool but special moisture protectionsshould then be considered for storage of Kollidon1 SR matrixtablets. In contrast, only a small decrease of drug release could beobserved for Eudragit1 RS matrices, which was attributed tofurther fusion of the polymer particles. Drug release was onlymarginally affected with ethyl cellulose. Its low affinity to waterand its high Tg result in no curing effect at the tested conditions.However, release from ethylcellulose matrices may be lesssensitive to humidity and thus be more stable during regularstability studies than Kollidon1 SR and Eudragit1 RS matrices.

4. Conclusions

Insoluble matrix polymers were evaluated with regard to drugrelease-affecting properties. The key parameter was the glasstransition temperature of the polymers. It governed othercharacteristics such as compactibility, matrix integrity duringprocessing and drug release (polymer percolation threshold),permeability of the matrix for medium and drug, the particle sizeeffect on drug release and sensitivity against influences from

J. Grund et al. / International Journal of Pharmaceutics 469 (2014) 94–101 101

temperature and humidity. For the polymers investigated, a low Tg(Kollidon1 SR) came along with low elasticity, a low percolationthreshold and high matrix integrity, but also with sensitivity tohumidity. Correspondingly, a high Tg (ethyl cellulose) wasassociated by high elasticity, a high and particle size-dependentpercolation threshold but also high stability against temperatureand humidity influences. Hence, its effect on drug release iscomplex.

Incorporation of drug release affecting polymer properties intomathematical models would be another step to comprehensiveprediction of drug release from insoluble matrix tablets.

References

Abbaspour, M.R., Sadeghi, F., Afrasiabi Garekani, H., 2007. Thermal treating as a toolto produce plastic pellets based on Eudragit RS PO and RL PO aimed fortabletting. European Journal of Pharmaceutics and Biopharmaceutics 67,260–267.

AlKhatib, H., Hamed, S., Mohammad, M., Bustanji, Y., AlKhalidi, B., Aiedeh, K.,Najjar, S., 2010. Effects of thermal curing conditions on drug release frompolyvinyl acetate–polyvinyl pyrrolidone matrices. AAPS PharmSciTech 11, 253–266.

Azarmi, S., Ghaffari, F., Löbenberg, R., Nokhodchi, A., 2005. Mechanistic evaluation ofthe effect of thermal-treating on Eudragit RS matrices. Il Farmaco 60, 925–930.

Barra, J., Falson-Rieg, F., Doelker, E., 1999. Influences of the organization of binarymixes on their compactibility. Pharmaceutical Research 16, 1449–1455.

Barra, J., Falson-Rieg, F., Doelker, E., 2000. Modified drug release from inert matrixtablets prepared from formulations of identical composition but differentorganization. Journal of Controlled Release 65, 419–428.

Bonny, J.D., Leuenberger, H., 1991. Matrix-type controlled release systems: I. Effectof percolation on drug dissolution kinetics. Pharmaceutica Acta Helvetiae 66,160–164.

Bonny, J.D., Leuenberger, H., 1993. Matrix-type controlled release systems: II.Percolation effects in nonswellable matrices. Pharmaceutica Acta Helvetiae 68,25–33.

Bühler, V., 2008. Kollidon1 – Polyvinylpyrrolidone Excipients or the PharmaceuticalIndustry. BASF, Ludwigshafen.

Caraballo, I., Millán, M., Rabasco, A.M., 1996. Relationship between drug percolationthreshold and particle size in matrix tablets. Pharmaceutical Research 13,387–390.

Caraballo, I., Melgoza, L.M., Alvarez-Fuentes, J., Soriano, M.C., Rabasco, A.M., 1999.Design of controlled release inert matrices of naltrexone hydrochloride basedon percolation concepts. International Journal of Pharmaceutics 181, 23–30.

Colombo, P., Sonvico, F., Colombo, G., Bettini, R., 2009. Novel platforms for oral drugdelivery. Pharmaceutical Research 26, 601–611.

Crowley, M.M., Schroeder, B., Fredersdorf, A., Obara, S., Talarico, M., Kucera, S.,McGinity, J.W., 2004. Physicochemical properties and mechanism of drugrelease from ethyl cellulose matrix tablets prepared by direct compression andhot-melt extrusion. International Journal of Pharmaceutics 269, 509–522.

Draganoiu, S.E., 2003. Evaluation of Kollidon SR for pH-independent extendedrelease matrix system, PhD thesis. University of Cincinnati, Cincinnati.

Ethocel Ethylcellulose Polymer Technical Handbook, 2005. Dow cellulosics.Eudragit1 Application Guidelines, twelfth ed. Evonik Industries AG, Darmstadt.Fell, J.T., Newton, J.M., 1970. Determination of tablet strength by the diametral-

compression test. Journal of Pharmaceutical Sciences 59, 688–691.Grund, J., Koerber, M., Bodmeier, R., 2013. Predictability of drug release from water-

insoluble polymeric matrix tablets. European Journal of Pharmaceutics andBiopharmaceutics 85, 650–655.

Hauschild, K., Picker-Freyer, K.M., 2006. Evaluation of tableting and tabletproperties of Kollidon SR: the influence of moisture and mixtures withtheophylline monohydrate. Pharmaceutical Development and Technology 11,125–140.

Higuchi, T., 1963. Mechanism of sustained-action medication. Journal of Pharma-ceutical Sciences 52, 145–149.

Katikaneni, P.R., Upadrashta, S.M., Rowlings, C.E., Neau, S.H., Hileman, G.A., 1995.Consolidation of ethylcellulose: effect of particle size, press speed, andlubricants. International Journal of Pharmaceutics 117, 13–21.

Khan, G.M., Meidan, V.M., 2007. Drug release kinetics from tablet matrices basedupon ethylcellulose ether-derivatives: a comparison between differentformulations. Drug Development and Industrial Pharmacy 33, 627–639.

Kranz, H., Le Brun, V., Wagner, T., 2005. Development of a multi particulate extendedrelease formulation for ZK 811752, a weakly basic drug. International Journal ofPharmaceutics 299, 84–91.

Leu, R., Leuenberger, H., 1993. The application of percolation theory to thecompaction of pharmaceutical powders. International Journal of Pharmaceutics90, 213–219.

Leuenberger, H., Rohera, B.D., Haas, C., 1987. Percolation theory – a novel approachto solid dosage form design. International Journal of Pharmaceutics 38,109–115.

Leuenberger, H., Bonny, J.D., Kolb, M., 1995. Percolation effects in matrix-typecontrolled drug release systems. International Journal of Pharmaceutics 115,217–224.

Lindberg, N.O., Palsson, M., Pihl, A.C., Freeman, R., Freeman, T., Zetzener, H., Enstad,G., 2004. Flowability measurements of pharmaceutical powder mixtures withpoor flow using five different techniques. Drug Development and IndustrialPharmacy 30, 785–791.

List, P.H., 1985. Arzneiformenlehre. Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart.

Millán, M., Caraballo, I., Rabasco, A.M., 1998. The role of the drug/excipient particlesize ratio in the percolation model for tablets. Pharmaceutical Research 15,216–220.

Neau, S.H., Howard, M.A., Claudius, J.S., Howard, D.R.,1999. The effect of the aqueoussolubility of xanthine derivatives on the release mechanism from ethylcellulosematrix tablets. International Journal of Pharmaceutics 179, 97–105.

Oksanen, C.A., Zografi, G., 1990. The relationship between the glass transitiontemperature and water vapour absorption by poly(vinylpyrrolidone). Pharma-ceutical Research 7, 654–657.

Rekhi, G.S., Jambhekar, S.S., 1995. Ethylcellulose – a polymer review. DrugDevelopment and Industrial Pharmacy 21, 61–77.

Reza, M.S., Quadir, M.A., Haider, S.S., 2003. Comparative evaluation of plastic,hydrophobic and hydrophilic polymers as matrices for controlled-release drugdelivery. Journal of Pharmacy and Pharmaceutical Sciences 6, 282–291.

Riis, T., Bauer-Brandl, A., Wagner, T., Kranz, H., 2007. pH-independent drug release ofan extremely poorly soluble weakly acidic drug from multiparticulate extendedrelease formulations. European Journal of Pharmaceutics and Biopharmaceutics65, 78–84.

Shao, Z.J., Farooqi, M.I., Diaz, S., Krishna, A.K., Muhammad, N.A., 2001. Effects offormulation variables and post-compression curing on drug release from a newsustained-release matrix material: polyvinylacetate–povidone. PharmaceuticalDevelopment and Technology 6, 247–254.

Upadrashta, S.M., Katikaneni, P.R., Hileman, G.A., Neau, S.H., Rowlings, C.E., 1994.Compressibility and compactibility properties of ethylcellulose. InternationalJournal of Pharmaceutics 112, 173–179.

Viridén, A., Wittgren, B., Larsson, A., 2009. Investigation of critical polymerproperties for polymer release and swelling of HPMC matrix tablets. EuropeanJournal of Pharmaceutical Sciences 36, 297–309.

Wesselingh, J.A., 1993. Controlling diffusion. Journal of Controlled Release 24,47–60.

Wu, C., McGinity, J.W., 2003. Influence of methylparaben as a solid-state plasticizeron the physicochemical properties of Eudragit1 RS PO hot-melt extrudates.European Journal of Pharmaceutics and Biopharmaceutics 56, 95–100.