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Drug Development and Industrial Pharmacy

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Sustained release of diltiazem HCl tableted afterco-spray drying and physical mixing with PVAc andPVP

Nizar Al-Zoubi, Ghada Al-obaidi, Bassam Tashtoush & Stavros Malamataris

To cite this article: Nizar Al-Zoubi, Ghada Al-obaidi, Bassam Tashtoush & Stavros Malamataris(2016) Sustained release of diltiazem HCl tableted after co-spray drying and physicalmixing with PVAc and PVP, Drug Development and Industrial Pharmacy, 42:2, 270-279, DOI:10.3109/03639045.2015.1047848

To link to this article: http://dx.doi.org/10.3109/03639045.2015.1047848

Published online: 02 Jun 2015.

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Drug Dev Ind Pharm, 2016; 42(2): 270–279! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2015.1047848

RESEARCH ARTICLE

Sustained release of diltiazem HCl tableted after co-spray drying andphysical mixing with PVAc and PVP

Nizar Al-Zoubi1, Ghada Al-obaidi2, Bassam Tashtoush3y, and Stavros Malamataris4

1Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, Jordan, 2Faculty of Pharmacy, Applied Science University, Amman, Jordan,3Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan, and4Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece

Abstract

In this work, aqueous diltiazem HCl and polyvinyl-pyrrolidone (PVP) solutions were mixed withKollicoat SR 30D and spray dried to microparticles of different drug:excipient ratio and PVPcontent. Co-spray dried products and physical mixtures of drug, Kollidon SR and PVP weretableted. Spray drying process, co-spray dried products and compressibility/compactability ofco-spray dried and physical mixtures, as well as drug release and water uptake of matrix-tabletswas evaluated. Simple power equation fitted drug release and water uptake (R240.909 and0.938, respectively) and correlations between them were examined. Co-spray dried productswith PVP content lower than in physical mixtures result in slower release, while at equal PVPcontent (19 and 29% w/w of excipient) in similar release (f2450). Increase of PVP contentincreases release rate and co-spray drying might be an alternative, when physical mixing isinadequate. Co-spray dried products show better compressibility/compatibility but higherstickiness to the die-wall compared to physical mixtures. SEM observations and comparison ofrelease and swelling showed that distribution of tableted component affects only the swelling,while PVP content for both co-spray dried and physical mixes is major reason for releasealterations and an aid for drug release control.

Keywords

Kollicoat SR 30D, Kollidon SR, microparticles,spray drying, tabletability

History

Received 2 October 2014Revised 6 March 2015Accepted 25 April 2015Published online 2 June 2015

Introduction

Excipients based on polyvinyl-acetate and polyvinyl-pyrrolidone(PVAc and PVP) combination, commonly known by the tradenames Kollicoat� SR 30D and Kollidon� SR, are gainingincreasing interest as drug release controlling agents.

Kollicoat SR 30D is an aqueous dispersion containing 27%PVAc, 2.7% PVP and 0.3% w/w sodium lauryl sulfate (SLS). Itsmajor application is in membrane-controlled drug deliverysystems1–7, but however, it has been successfully employed inmatrix tablet preparation via fluidized-bed granulation8 and spraydrying9.

Kollidon SR is a co-spray-dried powder composed of 80%PVAc, 19% PVP, 0.8% SLS and 0.2% w/w silica. It has good flow,compression and compaction properties7,10 and is suitable androbust as a matrix former for sustaining drug release by direct-compression tableting11–15 since the release was found to behighly independent to compression force16,17. Nevertheless, foractive pharmaceutical ingredients of poor flow and compressionproperties the preparation of matrix tablets by direct compression

might be unattainable, particularly at high drug loading. Attemptsto overcome such difficulties were based on the preparation ofsolid dispersions of drugs in Kollidon SR with solvent-evaporation18 and the wet granulation. Tableting of wet granulatesresulted in remarkably faster release compared to that obtained bydirect compression of corresponding physical mixtures, which hasbeen explained by the localization of PVP during drying of wetgranulations as separate small masses between polyvinyl-acetateparticles, leading to a faster channeling action16,19.

For overcoming the problems of quick release due to wetgranulation, the expected retrogression of flow, compression andcompaction and the difficulty in scaling up associated with thesolid dispersion by solvent-evaporation when Kollidon SR is used,the co-spray drying of water soluble drugs with Kollicoat SR 30Dand then subsequent compression of the co-spray dried productsseems an interesting alternative. This approach might be particu-larly useful for release modification in cases of extremelycohesive and poorly flowing powdered drugs that cannot beefficiently mixed with Kollidon SR. In addition, it has potentialadvantage for formulating low-dose drugs (due to the expectedbetter distribution in the release-controlling excipient and matrixtablets simultaneously) and for high-dose drugs as well (due topossible improvement of compressibility and compactability).However, until now there is limited information regardingcomparative evaluation of tableted co-spray dried pharmaceuticalKollicoat SR 30D products and directly compressed physicalmixtures of Kollidon SR and drugs. Furthermore, the improved

yDeceased

Address for correspondence: Nizar Al-Zoubi, Faculty of PharmaceuticalSciences, Hashemite University, Zarqa 13115, Jordan. Tel: +962 53903333. Fax: +962 5 3903368. E-mail: nzoubi@hu.edu.jo

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distribution of the components in the matrix tablet and thepossibility of solid-state changes (commonly encountered in spraydrying) might lead to drug release alteration comparatively tosimple physical mixing. Also, co-spray drying with Kollicoat SR30D permits the release modification by incorporation of PVPexcess, since the PVP content in the solid fraction of Kollicoat SR30D is less than that in Kollidon SR (9 versus 19% w/w) and theincrease of PVP content has been reported to increase drugrelease rate from matrix tablets prepared with simple physicalmixing of powdered PVP and PVAc20.

The aim of this work is to evaluate the co-spray dried productof a representative water soluble drug (diltiazem HCl) andKollicoat SR 30D dispersion as an alternative to powder physicalmixing with Kollidon SR for the preparation of controlled releasematrix tablets when physical mixing is inadequate. Furthermore,to examine the release modification by altering PVP content inboth the co-spray dried product and the physical mixture asformulators help in drug release programming.

Materials and methods

Materials

Diltiazem HCl (lot: 12004), kindly donated by UPM, Amman,Jordan, was used as a highly soluble model drug. Kollicoat� SR30D liquid dispersion (lot: 58523916K0), Kollidon� SR (lot:03016024U0) and PVP (Kollidon� K30, lot: 41527656P0)powders were kindly donated by BASF (Ludwigshafen,Germany). Absolute ethanol of analytical grade (lot:460152MS) was obtained from Panreac (Barcelona, Spain).

Spray drying

In 100 ml of distilled water or aqueous PVP solutions, appropriateamounts of diltiazem HCl was dissolved and Kollicoat SR 30Ddispersion was added. Three different drug:excipient (D:E) ratios(1:1, 1:2 and 1:3) and increasing PVP content (expressedhereinafter in this paper as a percentage of total excipients, 9, 14,19 and 29% w/w) were applied. After mixing the volume wascompleted with distilled water to 200 ml, before spray drying,keeping constant the total volume and the solid concentration (20%w/v) in all the runs. Spray drying was performed in a mini-spraydrier (Pulvis GA 32 ,Yamato Scientific, Tokyo, Japan) and thespray drying conditions were as follows: inlet air temperature135 �C, outlet air temperature 58–62 �C, air pressure 1 kg/cm2, feedrate 10 ml/min, spray nozzle 406mm. The collected amount ofspray dried products was accurately weighed and production yieldwas calculated as percentage of the total initial solid content (40 g)in the spray dried liquid and is summarized in Table 1, togetherwith the nominal composition of the co-spray dried products.

Physical mixing

Physical mixtures were obtained by hand mixing for 15 min usinga mortar and a spatula. Diltiazem HCl was sieved and the fractionof 5180 lm was used. The powders of Kollidon� SR and PVP(Kollidon� K30) were used as received. The composition of thephysical mixtures is summarized together with the nominalcomposition of the co-spray dried products in Table 2.

Characterization of co-spray dried products andphysical mixtures

Encapsulation efficiency

The encapsulation efficiency of the co-spray dried products wasdetermined by dissolving 50 mg samples of each batch in10 ml absolute ethanol and completing the volume to 100 mlwith distilled water. The concentration of diltiazem HCl wasdetermined, with a UV spectrophotometer (Spectronic 601,Milton Roy, PA) at 235 nm, after filtration through 0.45 mmcellulose acetate filter and suitable further dilution with 10% (v/v)ethanol/water mixture. The results were expressed as percentageof the diltiazem HCl amount added initially. The determinationwas repeated three times and mean value and standard deviationwas calculated.

Differential scanning calorimetry

Thermal behavior of co-spray dried products and of physicalmixture composed of diltiazem HCl and Kollidon SR (at 1:2 ratio)was examined using a differential scanning calorimeter(Shimadzu DSC 50, Kyoto, Japan). Samples (�3 mg) placed incrimped aluminum pan were accurately weighed and heated fromambient temperature to 300 �C, at a heating rate of 10 �C/min,in nitrogen atmosphere.

Particle size analysis

Median particle size and particle size distribution (expressed byX90/X10) were determined using a laser diffraction particle sizeanalyzer (Microtrac Inc., North Largo, FL) equipped with the drypowder accessory (Turbotrac, Frisco, TX). About 1.0 g samples ofeach co-spray dried product were used and the mean value andstandard deviation of three determinations was calculated.

Field emission gun scanning electron microscopy

Micrographs of the co-spray dried products and the powdered rawmaterials of Kollidon SR and diltiazem HCl were obtained byusing a field emission gun scanning electron microscope (FEICompany – Inspect F50 / FEG, Eindhoven, Netherlands). Sampleswere mounted on aluminum stubs with double-sided sticky discs

Table 1. Nominal composition of the co-spray dried products together with the production yield, encapsulation efficiency and particle size results.

Particle size

Batch no. D:E* ratioPVP in Ey(% w/w)

Productionyield (%)

Encapsulationefficiency (%)z Median� (mm) X90/X10

SD1 1:1 9 31.7 98.6 9.68 4.33SD2 1:2 9 31.5 99.1 11.47 3.25SD3 1:2 14 35.0 99.8 10.46 4.79SD4 1:2 19 33.5 98.1 10.31 5.91SD5 1:2 29 32.3 98.4 9.79 5.75SD6 1:3 9 30.4 102.2 23.14 6.56

*Drug:excipient weight ratio.yPVP percentage in total of contained excipients.zCV� 1.3%, n¼ 3.�CV� 16%, n¼ 3.

DOI: 10.3109/03639045.2015.1047848 Sustained release diltiazem HCl matrix tablets 271

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of conductive carbon and then coated with approximately 15 nmof platinum in a sputter coater (Emitech Ltd., Ashford, Kent, UK).

Compressibility and compactability

Compressibility of the co-spray dried products and physicalmixtures was evaluated on the basis of the work of compression,Wc, and the elastic recovery, ER, using a bench top computer-controlled instrumented press (Model GTP-1, Gamlen TabletingLtd, Nottingham, UK) and compression at a maximum force of350 kg (3.43 kN) with punch speed during loading and unloading60 mm/s. The load cell (5 kN) was calibrated by using a provingring (No: ES013) of 500 kg capacity equipped with dial testindicator of 0.002 mm resolution, while the punch displacementtransducer was calibrated with stainless steel cylinders (1, 2 and3 mm thick) under loading, for correction of the punch andcompression frame distortion. Fixed amount (60 mg) of powderwas placed in the die cavity of 6 mm diameter and force versusdisplacement data during compression, decompression and ejec-tion were recorded at a frequency of 200 Hz for four replicatesof each powdered sample. The work of compression, Wc, wasestimated from the area under the curve (force versus displace-ment) during compression and decompression stages21 and theelastic recovery (%) of the compacts was calculated from theirminimum thickness under load, in the die, and the thicknessmeasured one week after the compression.

Compactability of the co-spray dried products and physicalmixtures was evaluated on the basis of the tensile strength, Ts,of the compacts determined by loading until diametral breakingin an Erweka TBH 325 hardness tester (Erweka GmbH,Heusenstamm, Germany) and calculated by applying the Felland Newton equation22:

Ts ¼ 2F=�DT ð1Þ

where, F is the breaking force, D and T are the diameter andthickness of the compacts, respectively. The sticking of thecompacted powders to the die wall was estimated on the basis ofthe maximum ejection force (Fej)

23,24.

Preparation of matrix tablets

Matrix-tablets were prepared by compressing amounts of co-spraydried products (SD matrix-tablets) and corresponding physicalmixtures (PM matrix-tablets) containing 180 mg of diltiazem HClby using a 13-mm diameter die and flat-faced punches set, in amanually operated hydraulic press (Riken Seiki, Japan), at 14 kN

force for 5 s, resulting in saturated compacts (packing fractionabove 0.9).

Characterization of matrix tablets

Drug release

Release of diltiazem HCl from the matrix tablets was determinedin a USP Apparatus II (paddle) dissolution system (Pharma TestPTW 2, Hainburg, Germany), at 100 rpm, using 900 ml ofdistilled water (pH 6.5) as dissolution medium, at a temperature of37 ± 0.5 �C. At predetermined time intervals up to 24 h, sampleswere withdrawn, filtered and the concentration of dissolved drugwas determined, after suitable dilution, by UV spectroscopy atwave length corresponding to maximum absorption (235 nm). Alltests were performed in triplicate and from the mean concentra-tion results the drug released (%) was determined.

In order to characterize the release mechanism, the power lawmodel of Peppas was fitted to the first 60% release data25:

Mt=M1 ¼ Kp � tn ð2Þ

where, Mt/M1 represents the fractional release of drug, Kp isconstant depending on the tablet composition, and n is the releaseexponent indicating the drug release mechanism. In the case ofcylindrical tablet, a value of n� 0.45 indicates Fickian diffusion,while 0.45� n� 0.89 indicates non-Fickian (anomalous) diffu-sion and n¼ 0.89 indicates erosion controlled and zero-orderkinetics26.

The dissolution efficiency considered as an extent parameter ofdrug release was calculated by the following equation27:

D:E: ¼R t

0y� dt

y100 � t� 100% ð3Þ

where, y is the drug percent dissolved at time t.

Water uptake

Hydration of matrix tablets was evaluated as water uptake (%)under conditions identical to those described above for releasetesting. At certain time intervals up to 12 h, tablets were gentlywithdrawn from the dissolution media and weighed after carefulblotting of excess water from around them. Water uptake wasdetermined taking into account the amount of drug released byapplying the following equation:

Water uptake ð%Þ ¼WW � ðWi � RtÞðWi � RtÞ

� 100 ð4Þ

Table 2. Compressibility (work of compression, Wc, and elastic recovery, ER) and compactability (tensile strength, Ts, and maximum ejection force,Fej) parameters of the co-spray dried products and physical mixtures.

Formula Preparation method D:E ratio PVP in E (% w/w) Wc (mJ) ER (%) Ts (MPa) Fej (N)

Effect of component distribution1 SD 1:1 9 2016 18.7 6.8 2082 SD 1:2 9 2072 19.5 10.9 1653 SD 1:3 9 2108 20.2 7.6 1384 PM 1:1 19 1613 19.7 3.4 1855 PM 1:2 19 1742 21.2 4.4 1386 PM 1:3 19 1899 22.4 5.7 116

Effect of PVP content2 SD 1:2 9 2072 19.5 10.9 1657 SD 1:2 14 2115 19.9 7.7 1668 SD 1:2 19 2054 19.2 6.3 1689 SD 1:2 29 2111 18.4 9.5 1825 PM 1:2 19 1742 21.2 4.4 138

10 PM 1:2 29 1638 20.7 5.2 154

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where, Ww the weight of wet matrix tablet at time t, Wi the initialweight of the tablet before hydration, and Rt is the amount of drugreleased from the tablet at time t. Morphological examination ofthe swollen tablets was also carried out after 24 h hydration byremoving from the medium and taking pictures with a digitalcamera before and after drying.

Surface roughness and pore formation

Surfaces of matrix tablets were qualitatively characterized bytaking scanning electron micrographs before hydration, to visu-alize pores which may affect the water uptake behavior, and after24 h of hydration and vacuum drying to constant weight at roomtemperature, to visualize surface erosion and pore formation. Forthis purpose, field emission gun scanning electron microscope(FEI Company – FEI Quanta 450 FEG, Eindhoven, TheNetherlands) was used applying the already described preparationprocedure for the powder samples.

Results and discussion

Characterization of co-spray dried products andphysical mixtures

The results of co-spray drying yield, encapsulation efficiencyand particle size of co-spray dried products are given in Table 1,and show the following: The co-spray drying yield is relativelylow (between 30 and 35%) and should be associated with highadhesion of the sprayed droplets to the internal surfaces of thedrying chamber and cyclone28,29. The encapsulation efficiency isaround 100%, i.e. the drug is found in the co-spray driedproducts at ratios similar to those expected theoretically, andthat indicates equal extent of loss for the drug and excipients aswell during the spray drying. The median particle size increasesremarkably with the increase of excipient content in the spraydried dispersions but decreases slightly with the increase of PVPcontent. The size distribution, in general, becomes wider (higherX90/X10) with increasing excipient content (except case SD2)and with higher PVP content at certain (1:2) D:E ratio (exceptcase SD5).

The increased viscosity of feed liquid dispersion, which isexpected due to the increasing excipient content, is normallyassociated with increased size of sprayed droplets and thusincreased particle size of final product. Therefore, the slight sizedecrease with the increased PVP content observed might beattributed to comparatively lower viscosity of polyvinyl-pyrrolidone solution than that of equivalent polyvinyl acetatecolloidal dispersion. However, in small scale spray driers, higherviscosity might be also associated with increased stickiness to theinternal surfaces of the drying chamber, particularly in the case oflarge droplets due to insufficient drying capacity. Furthermore,stickiness of co-spray dried products might be associated with theformation of amorphous diltiazem HCl30. In view of that, theincrease in particle size for the co-spray dried products preparedat low (1:3) D:E ratio might be explained by reduced stickingextent of large droplets, resulting due to faster drying and/ordue to decreased content of drug, which seems to be inamorphous form.

Scanning electron micrographs of the co-spray dried productsand powdered raw materials (Kollidon SR and diltiazem HCI) aregiven in Figure 1 and show that the particles of the co-spray driedproducts are less spherical, with some shriveled particles, andremarkably smaller than those of commercial Kollidon SR. Thesedifferences might be related to the different type of spray-drierused during their production. Regarding the particles of drug theyare also relatively large compared to the co-spray dried productsand columnar in shape.

The results of DSC analysis for all the co-spray dried productsand one representative physical mixture containing drug andKollidon SR at the medium (1:2) weight ratio (PM formula 5,Table 2) are shown in Figure 2. The physical mixture shows threeendothermic peaks; a small at 39.3 �C, corresponding to glasstransition (Tg) of Kollidon SR31–33; a relatively sharp at 211.5 �C,corresponding to melting of diltiazem HCl, and a wide peakappearing after melting, corresponding to degradation of thedrug34. For the co-spray dried products, in addition to the abovedescribed three endothermic peaks, an exothermic peak corres-ponding to crystallization is seen (at about 130 �C) confirming theexistence of amorphous diltiazem HCl.

Furthermore, the DSC results show that Tg is lower in thephysical mixture (PM formula 5, Table 2) than in the corres-ponding co-spray dried product (SD4 batch, Table 1). Also, theyshow that Tg is decreasing with the increase of excipients contentand is slightly increasing with the PVP content increase. Theseresults are in agreement with higher Tg values for amorphousdiltiazem HCl (100 �C35) and for PVP (175 �C36). In other words,the Tg in the case of co-spray dried products is indicative ofamorphous drug existence and of the polymer mixturecomposition.

In Table 2, the results of the compressibility (work ofcompression, Wc, and elastic recovery, ER) and compactability(tensile strength, Ts, and maximum ejection force, Fej) parametersof the co-spray dried products and physical mixtures are given.They show that the work of compression is slightly higher for theco-spray dried products than for the physical mixtures and that itincreases slightly with the increase of excipients content for bothco-spray dried products and physical mixtures. This can beexplained by the compressibility decrease of the components inthe following order: excipients 4 amorphous drug 4 crystallinedrug. In consistence with Wc, the % elastic recovery is slightlyhigher and the tensile strength lower for the physical mixturesthan for the co-spray dried products. No effect of PVP content isobserved although PVP is an efficient binder, probably becausethe other main component of the excipients (PVAc) is also highlycompressible and compactable. The maximum ejection force (Fej)is slightly higher for the co-spray dried products than for thephysical mixtures; it decreases with excipient content and doesnot change remarkably with the PVP content, indicating thatincreased sticking might be due to reduced elastic recoverybesides to the extended contact of polymeric excipients with thedie wall.

Characterization of matrix tablets

Table 3 summarizes the results of dissolution efficiency percent-age together with the parameters of the power equation describingdrug release and water uptake. The effect of drug:excipient (D:E)ratio on drug release is shown in Figure 3, for tablets preparedfrom physical mixtures of drug and Kollidon SR (containing 19%PVP) and from co-spray dried products obtained with KollicoatSR 30D (containing 9% PVP), without extra addition of PVP.Figure 4 shows the effect of PVP content on drug release fortablets of constant (1:2) D:E ratio prepared from co-spray driedproducts obtained with Kollicoat SR 30D and additional(increased) PVP content (9, 14, 19 and 29%) and from physicalmixtures of drug, Kollidon SR and PVP (containing 19 and29% PVP).

From Figure 3 and the dissolution efficiency results(Table 3), it can be seen that the release rate is slower anddissolution efficiency is smaller for matrix-tablets preparedfrom co-spray dried products with drug and Kollicoat SR 30Donly (containing 9% PVP) than for those prepared fromphysical mixtures with drug and Kollidon SR only (containing

DOI: 10.3109/03639045.2015.1047848 Sustained release diltiazem HCl matrix tablets 273

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19% PVP). The values of similarity factor (f2) comparing theprofiles for each one of the three D:E ratios (1:3, 1:2 and 1:1)were less than 40 confirming the differences. Furthermore,from Figure 4 and Table 3, it can be seen that increasing PVPpercentage from 9 to 29% causes a remarkable increase inrelease rate and in dissolution efficiency (from 27.5 to 76.7%)

for matrix-tablets prepared from co-spray dried products.Therefore, these results are in agreement with those reportedby Novoa et al.20, although the exponent n (Table 3) is notexceeding the value 0.45, which corresponds to Fickiandiffusion, and show the possibility of reducing release ratewithout alteration of the release mechanism for matrix tablets

Figure 1. SEM images of all the co-spraydried products (SD1–SD6, Table 1), andphysical mixture components (Kollidon SR,A and diltiazem HCl, B).

274 N. Al-Zoubi et al. Drug Dev Ind Pharm, 2016; 42(2): 270–279

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Figure 2. DSC thermograms for all theco-spray dried products (SD1–SD6, Table 1)and one physical mixture containing drug andKollidon SR at 1:2 weight ratio (PMformula 5, Table 2).

Table 3. Dissolution efficiency % together with the parameters of power equation describing drug release (Mt/M1¼Kp� tn) and water uptake(Wup ¼ K

0

p � tn0 ) for the investigated matrix tablets (up to 60% release, number of pair values n¼ 3–10).

Formula Preparation D:E PVP in E DissolutionRelease parameters Water uptake parameters

no. method ratio (%) efficiency (%) n Kp (min�n) R2 n0 K0

p (min�n) R2

Effect of component distribution1 SD 1:1 9 80.1 0.321 0.1141 0.970 0.404 0.0502 0.9382 SD 1:2 9 27.5 0.193 0.0813 0.930 0.396 0.0253 0.9733 SD 1:3 9 18.4 0.126 0.0840 0.909 0.341 0.0278 0.9674 PM 1:1 19 93.4 0.441 0.0898 0.991 0.614 0.0604 0.9855 PM 1:2 19 59.9 0.396 0.0524 0.997 0.477 0.0470 0.9916 PM 1:3 19 35.4 0.369 0.0337 0.970 0.457 0.0297 0.992

Effect of PVP content2 SD 1:2 9 27.5 0.193 0.0813 0.930 0.396 0.0253 0.9737 SD 1:2 14 44.1 0.328 0.0546 0.992 0.377 0.0288 0.9918 SD 1:2 19 63.9 0.419 0.0469 0.996 0.337 0.0382 0.9809 SD 1:2 29 76.7 0.452 0.0475 0.996 0.402 0.0304 0.9805 PM 1:2 19 59.9 0.396 0.0524 0.997 0.477 0.0470 0.991

10 PM 1:2 29 66.9 0.456 0.0434 0.993 0.476 0.0336 0.994

Figure 3. Release profiles of diltiazem HCl from matrix tablets of different drug:excipient (D:E) ratio prepared: (A) from physical mixtures of drug andKollidon SR (containing 19% PVP), and (B) from co-spray dried products (containing 9% PVP). Error bars represent standard deviation (n¼ 3).

DOI: 10.3109/03639045.2015.1047848 Sustained release diltiazem HCl matrix tablets 275

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prepared from co-spray dried products by changing D:E ratioand/or PVP content in order to optimize release profile.

From Figure 4, it can also be seen that for PVP content 19 and29%, the release profiles for matrix tablets prepared fromco-spray-dried and from physical mixture are similar in the firstperiod of release (up to the time of six and two hours for 19 and29% PVP content, respectively) and then show slight differences.Nevertheless, the calculated similarity factors were higher than 50(f2¼ 70 and 53, respectively). This indicates that the differentdistribution of tablet components and particularly the particle sizeand the crystal form of diltiazem HCl as well as the larger particlesize of Kollidon SR compared to that of co-spray dried productsdo not have some significant effect on drug release, while thedifference in PVP content of both co-spray dried and physical

mixes is the major reason for all the observed alterations inrelease rate and can become an aid for drug release control.

The results of water uptake are shown in Figures 5 and 6, formatrix tablets of the same composition as those for drug release inFigures 3 and 4, respectively. From Figure 5, it can be seen thatwater uptake is remarkably higher for the matrix tablets preparedfrom physical mixtures than those from co-spray dried productsand increases by increasing D:E ratio for both. In other words,water uptake changes in Figure 5 show similarity to those of drugrelease shown in Figure 3. On the contrary, Figure 6 showsdifferent trend of changes in water uptake profiles than thecorresponding release profiles (Figure 4). More specifically, wateruptake is remarkably higher for tablets prepared from physicalmixtures containing 19 and 29% PVP in the excipients than for

Figure 5. Water uptake (%) for matrix tablets of different drug:excipient (D:E) ratio prepared: (A) from physical mixtures (containing 19% PVP), and(B) from co-spray dried products (containing 9% PVP). Error bars represent standard deviation (n¼ 3).

Figure 4. Release profiles of diltiazem HCl from matrix tablets ofconstant (1:2) drug:excipient (D:E) ratio prepared from co-spray driedproducts of increased PVP content (9, 14, 19 and 29%, solid lines) andphysical mixtures (containing 19 and 29% PVP, dotted line). Error barsrepresent standard deviation (n¼ 3).

Figure 6. Water uptake (%) from matrix tablets of constant (1:2)drug:excipient ratio prepared from co-spray dried (SD) products ofincreasing PVP content (9, 14, 19 and 29%, solid lines) and physicalmixtures containing 19 and 29% PVP, dotted line). Error bars representstandard deviation (n¼ 3).

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corresponding co-spray dried products and the effect of PVPcontent of tablets is unclear and negligible.

Photographs after 24 h swelling of tablets obtained fromco-spray dried products (SD) and physical mixtures (PM),corresponding to 1:2 D:E ratio and increasing PVP content, aregiven in Figure 7, and show that the diameter of swollen andsubsequently dried SD and PM tablets decreases with PVPcontent, probably due to PVP dissolution. Also, Figure 7 showsthat the diameter of swollen PM tablets is remarkably greatercompared to those of co-spray dried products and of physicalmixtures after drying. Therefore, the difference in water uptakeseen in Figure 5 with D:E change cannot be attributed to thedifference in PVP content between Kollidon SR and Kollicoat SR30D, like the case of drug release but to the amount of diltiazemand to the larger particle size of Kollidon SR (Figure 1), tochannel formation, and possibly to relaxation differences betweenKollidon SR and co-spray dried particles. More specifically,regaining of the initial spherical shape by the deformed polymerparticles upon wetting and the consequent increase in intra-particulate and inter-particulate voids seem to be much less forco-spray dried particles, probably due to leaching of diltiazemHCl and PVP from their interior, while from the exterior ofKollidon SR particles in the tableted physical mixtures.

For elucidation of relations between drug release and wateruptake mechanisms the experimental water uptake data, as in thecase of release, were fitted to the simple power equation: Wateruptake %¼K

0

p � tn0 , where K0

p is a constant which should berelated to the particular matrix tablet construction and n0 exponentrelated to the swelling mechanism. Table 3 summarizes theparameters for water uptake and release up to the 60%, showinghigh correlation (R240.939 and 0.909, respectively, for numberof time points between 3 and 10). Also Table 3 shows thatexponent n0 is higher than n while the coefficient K

0

ps is lowerthan Kp. Comparison of trends in the changes of the correspond-ing parameters shows that for the change of D:E ratio, Kp and K

0

p,as well as n and n0 follow similar trend in both matrix tabletsystems (SD and PM), but for the change in PVP content the trendof change for swelling is different from that for release. Therefore,while the incorporation of the water soluble drug affects similarlyboth release and swelling for both tablet systems the incorporationof PVP does not.

In order to confirm the effects of formulation variables onswelling and release, scanning electron microscopic images havebeen obtained for surface of representative tablets before and afterswelling and drying (Figure 8). Before swelling, the interparticlevoids were more but smaller for the tableted co-spray driedproduct than for corresponding physical mixture. This is asexpected due to: (i) the difference in size between particles of co-spray dried product, Kollidon SR and diltiazem HCl, (ii) the factthat bigger particles result in larger interparticle voids and (iii) thepredominance of plastic deformation during Kollidon SR tablet-ing20. After swelling and drying, tablets of physical mixture (at 19and 29 PVP content) show the existence of larger voids betweenspherical particles, probably due to dissolution of diltiazem HCland PVP and shape recovery of the Kollidon SR particles. Incontrast, swollen and dried tablets of co-spray dried product (at 9and 19% PVP content) show relatively rougher surface than thatbefore swelling but with fewer and smaller pores compared tophysical mixtures. This is attributed to the incorporation of PVPand diltiazem HCl in the interior of the small co-spray driedparticles and their absence as large particles like the case oftableted physical mixtures, in the exterior of Kollidon SRparticles. The above described distribution of tablet componentsseems to be responsible for the difference between SD andPM tablets. Changes in surface porosity due to the effect ofPVP content is not clear, for both co-spray dried and physicalmixtures, which is in agreement with the results of water uptake(Figure 6).

Conclusion

From all the above it can be concluded that co-spray drying withKollicoat SR 30D gives slower release than that obtained byphysical mixing with Kollidon SR, and therefore it may be a goodalternative in cases where the application of direct compressionencounters difficulties. Drug release, matrix tablet swelling andSEM observations implied that although swelling depends on thedistribution of tableted component, the PVP content in bothco-spray dried products and physical mixes is the major reason forall the observed alterations in release rate and therefore an aid fordrug release control.

Figure 7. Photographs after 24 h swelling and subsequent drying to constant weight, for tablets obtained from co-spray dried and physical mixtures ofconstant (1:2) drug:excipient ratio and increasing PVP content (in parenthesis).

DOI: 10.3109/03639045.2015.1047848 Sustained release diltiazem HCl matrix tablets 277

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Figure 8. SEM images for surface of representative matrix tablets with constant (1:2) drug:excipient ratio and different PVP content prepared fromco-spray dried, SD, and physical mixtures, PM, before and after hydration and drying.

278 N. Al-Zoubi et al. Drug Dev Ind Pharm, 2016; 42(2): 270–279

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Acknowledgements

The authors would like to thank Dr. Iyad Rashid and Dr. Adnan Badwan(Jordanian Pharmaceutical Manufacturing Company, Amman, Jordan) forthe facilitation and help with the use of Gamlen bench top press. Theauthors dedicate this paper to Professor Bassam Tashtoush who prema-turely passed away during revision of the manuscript.

Declaration of interest

The authors report no conflicts of interest.

References

1. Kolter K, Dashevsky A, Irfan M, Bodmeier R. Polyvinyl acetate-based film coatings. Int J Pharm 2013;457:470–9.

2. Dashevsky A, Ahmed AR, Mota J, et al. Effect of water-solublepolymers on the physical stability of aqueous polymeric dispersionsand their implications on the drug release from coated pellets. DrugDev Ind Pharm 2010;36:152–60.

3. Guthmann C, Lipp R, Wagner T, Kranz H. Development of amultiple unit pellet formulation for a weakly basic drug. Drug DevInd Pharm 2007;33:341–9.

4. Dashevsky A, Wagner K, Kolter K, Bodmeier R. Physicochemicaland release properties of pellets coated with Kollicoat� SR 30 D,a new aqueous colloidal polyvinyl acetate dispersion for extendedrelease. Int J Pharm 2005;290:15–23.

5. Shao ZJ, Morales L, Diaz S, Muhammad NA. Drug release fromKollicoat SR 30D-coated nonpareil beads: evaluation of coatinglevel, plasticizer type, and curing condition. AAPS PharmSciTech2002;3:87–96.

6. Wei H, Li-Fang F, Min B, et al. Chitosan/Kollicoat� SR 30 D film-coated pellets of aminosalicylates for colonic drug delivery. J PharmSci 2010;99:186–95.

7. Strubing S, Abboud T, Contri RV, et al. New insights on poly (vinylacetate)-based coated floating tablets: characterisation of hydrationand CO2 generation by benchtop MRI and its relation to drug releaseand floating strength. Eur J Pharm Biopharm 2008;69:708–17.

8. Bordaweka M, Zia H, Quadir A. Evaluation of polyvinyl acetatedispersion as a sustained release polymer for tablets. Drug Deliv2006;13:121–31.

9. Al-Zoubi N, AlKhatib H, Bustanji Y, et al. Sustained-release ofbuspirone HCl by co spray-drying with aqueous polymeric disper-sions. Eur J Pharm Biopharm 2008;69:735–42.

10. Strubing S, Metz H, Mader K. Characterization of poly(vinylacetate) based floating matrix tablets, J Control Release 2008;126:149–55.

11. Shao ZJ, Farooqi MI, Diaz S, et al. Effects of formulation variablesand post-compression curing on drug release from new sustained-release matrix material: polyvinylacetate–povidone. Pharm DevTechnol 2001;6:247–54.

12. Reza MS, Quadir MA, Haider SS. Comparative evaluation ofplastic, hydrophobic and hydrophilic polymers as matrices forcontrolled-release drug delivery. J Pharm Pharm Sci 2003;6:282–91.

13. Kranz H, Le Brun V, Wagner T. Development of a multi particulateextended release formulation for ZK 811 752, a weakly basic drug.Int J Pharm 2005;299:84–91.

14. Sahoo J, Murthy P, Biswal S, et al. Comparative study ofpropranolol hydrochloride release from matrix tablets withKollidon� SR or hydroxypropyl methyl cellulose. AAPSPharmSciTech 2008;9:577–82.

15. Sakr W, Alanazi F, Sakr A. Effect of Kollidon� SR on the release ofalbuterol sulphate from matrix tablets. Saudi Pharm J 2011;19:19–27.

16. Kranz H, Wagner T. Effects of formulation and process variables onthe release of a weakly basic drug from single unit extended releaseformulation. Eur J Pharm Biopharm 2006;62:70–6.

17. Siepmann F, Eckart K, Maschke A, et al. Modeling drug releasefrom PVAc/PVP matrix tablets. J Control Release 2010;141:216–22.

18. Sahoo J, Murthy P, Biswal S. Formulation of sustained-releasedosage form of verapamil hydrochloride by solid dispersion tech-nique using Eudragit RLPO or kollidon�SR. AAPS PharmSciTech2009;10:27–33.

19. Draganoiu E, Andheria M. Sakr A. Evaluation of new polyvinyla-cetate/povidone excipient for matrix sustained release dosage forms.Pharm Ind 2002;63:624–9.

20. Novoa GAG, Heinamaki J, Mirza S, et al. Physical solid-stateproperties and dissolution of sustained-release matrices of poly-vinylacetate. Eur J Pharm Biopharm 2005;59:343–50.

21. Gamlen MJD, Martini LG, Al Obaidy KG. Effect of repeatedcompaction of tablets on tablet properties and work of compactionusing an instrumented laboratory tablet press. Drug Dev Ind Pharm2015;41:163–9.

22. Fell JT, Newton JM. Determination of tablet strength by thediametral compression test. J Pharm Sci 1970;59:688–91.

23. Shibata Y, Fujii M, Noda S, et al. Fluidity and tableting character-istics of a powder solid dispersion of the low melting drugsketoprofen and ibuprofen with crospovidone. Drug Dev Ind Pharm2006;32:449–56.

24. Wang J, Wen H, Desai D. Lubrication in tablet formulations. Eur JPharm Biopharm 2010;75:1–15.

25. Peppas N. Analysis of Fickian and non-Fickian drug release frompolymers. Pharm Acta Helv 1985;60:110–11.

26. Ritger P, Peppas N. A simple equation for description of soluterelease. II. Fickian and anomalous release from swellable devices.J Control Release 1987;5:37–42.

27. Khan K. The concept of dissolution efficiency. J Pharm Pharmacol1975;27:48–49.

28. Bowey K, Swift BE, Flynn LE, Neufeld RJ. Characterization ofbiologically active insulin-loaded alginate microparticles preparedby spray drying. Drug Dev Ind Pharm 2013;39:457–65.

29. Fouad EA, EL-Badry M, Mahrous GM, et al. The use of spray-drying to enhance celecoxib solubility. Drug Dev Ind Pharm 2011;37:1463–72.

30. Ambike A, Mahadik K, Paradkar A. Spray-dried amorphous soliddispersions of simvastatin, a low Tg drug: in vitro and in vivoevaluations. Pharm Res 2005;22:990–8.

31. Hauschild K, Picker-Freyer KM. Evaluation of tableting and tabletproperties of Kollidon SR: the influence of moisture and mixtureswith theophylline monohydrate. Pharm Dev Technol 2006;11:125–40.

32. Ozguney I, Shuwisitkul D, Bodmeier R. Development andcharacterization of extended release Kollidon� SR mini-matricesprepared by hot-melt extrusion. Eur J Pharm Biopharm 2009;73:140–5.

33. Wiranidchapong C, Ruangpayungsak N, Suwattanasuk P, et al.Plasticizing effect of ibuprofen induced an alteration of drugreleased from Kollidon SR matrices produced by direct compres-sion. Drug Dev Ind Pharm 2014. [Epub ahead of print]. doi:10.3109/03639045.2014.925917.

34. Mazzo D, Obetz C, Shuster J. Diltiazem hydrochloride, In: BrittainHG, ed. Analytical profiles of drug substances and excipients.Vol. 23. California: Academic Press; 1994:53–98.

35. Nikowitz K, Pintye-Hodi K, Regdon Jr G. Study of the recrystal-lization in coated pellets – effect of coating on API crystallinity.Eur J Pharm Sci 2013;48:563–71.

36. Giron D. Thermal analysis in pharmaceutical routine analysis. ActaPharm Jugosl 1990;40:95–175.

DOI: 10.3109/03639045.2015.1047848 Sustained release diltiazem HCl matrix tablets 279

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