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Pharmaceutical Development and Technology, 2010; 15(2): 139153

R E S E A R C H A R T I C L E

Design and in vitro evaluation of novel sustained-releasematrix tablets for lornoxicam based on the combinationof hydrophilic matrix formers and basic pH-modifiers

Yassin El-Said Hamza, and Mona Hassan Aburahma

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt

Address for Correspondence: Mona Hassan Aburahma, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University,Kasr El-Aini Street, Cairo 11562, Egypt. el: +20 1046 13747. E-mail: [email protected]

(Received 17 March 2009; revised 20 May 2009; accepted 20 May 2009)

Introduction

Te goal of sustained-release (SR) delivery systems is toprovide desirable drug delivery profile that can achievepredictable plasma levels. However, physiological varia-bles in gastrointestinal (GI) tract including GI pH, gastricresidence time, intestinal motility, and GI contents mayalter the in vivo drug release performance from peroral SR

systems.[1]Moreover, weakly acidic or basic drugs dem-onstrate pH-dependent release profiles based on theirionizable groups. Depending on the pH of the releasemedium or intestinal fluid, these drugs exist in eithertheir dissociated or non-dissociated form.[2]Tus, drugsrelease from SR delivery systems, especially for weakly

acidic or basic drugs, may vary as a function of theirmovement into various segments of GI tract that are char-acterized by different pH values. Tis leads to inefficientdrug delivery accompanied by high intra/inter-subjectvariability.[3]Consequently, building greater control intoa dosage form, such as providing pH-independent drugrelease, is desirable to assure reliable drug therapy.[4]Tisapproach has been addressed by incorporating different

pH-modifiers into SR delivery systems to keep the micro-environmental pH within and in the close vicinity of thedosage form constant throughout the drug release phase,hence producing medium independent drug release.owards this purpose, several attempts were reported inliterature based on the presence of acidic excipients such

ISSN 1083-7450 print/ISSN 1097-9867 online 2010 Informa UK Ltd

DOI: 10.3109/10837450903059371

AbstractThe short half-life of lornoxicam, a potent non-steroidal anti-inflammatory drug, makes the developmentof sustained-release (SR) forms extremely advantageous. However, due to its weak acidic nature, its releasefrom SR delivery systems is limited to the lower gastrointestinal tract which consequently leads to a delayedonset of its analgesic action. Accordingly, the aim of this study was to develop lornoxicam SR matrix tabletsthat provide complete drug release that starts in the stomach to rapidly alleviate the painful symptomsand continues in the intestine to maintain protracted analgesic effect as well as meets the reported SRspecifications. The proposed strategy was based on preparing directly compressed hydroxypropylmeth-ylcellulose matrix tablets to sustain lornoxicam release. Basic pH-modifiers, either sodium bicarbonate ormagnesium oxide, were incorporated into these matrix tablets to create basic micro-environmental pHinside the tablets favorable to drug release in acidic conditions. All the prepared matrix tablets contain-ing basic pH-modifiers showed acceptable physical properties before and after storage. Release studies,performed in simulated gastric and intestinal fluids used in sequence to mimic the GI transit, demonstratethe possibility of sustaining lornoxicam release by combining hydrophilic matrix formers and basic pH-Modifiers to prepare tablets that meet the reported sustained-release specifications.

Keywords: Lornoxicam; sustained-release; compatibility; basic pH-modifiers; matrix tablets

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140 Y. El-Said Hamza and M.H. Aburahma

as organic acids within the SR delivery systems to over-come pH-dependent release of weakly basic drugs.[3,58]Tese acidic excipients tend to keep the pH within thedelivery systems in the intestinal pH-range low andthus increase drug solubility and release. However,fewer studies have been carried out in order to achieve

pH-independent release of weakly acidic drugs fromSR delivery systems.[2,9]Added to that, it is reported thatan initial burst of drug release from SR delivery systemsfollowed by prolonged drug release phase that extendsover a defined period of time is required for successfultreatments using non-steroidal anti-inflammatory drugs(NSAIDs). Tis release pattern assures the attainmentof maximum pain relief as quickly as possible as well asavoids repeated drug administration due to its extendedrelease phase.[10]

Lornoxicam is an extremely potent member of theoxicam group of NSAIDs[11]that is widely used in man-

agement of peri/postoperative pain associated withdifferent surgeries.[12] Moreover, lornoxicam shows bet-ter GI tolerability compared to other NSAIDs which isextremely advantageous in terms of fewer side effects.[13]However, due to its rapid elimination rate, repeated dailyadministration of lornoxicam is required to achievelong lasting and constant pain relief.[14,15]Added to that,lornoxicam shows a distinct pH-dependent solubilitycharacterized by poor solubility in low pH conditionspresent in the stomach[15]which consequently leads todelay in its analgesic effect.

One of the most common methods used for devel-oping SR formulations for different therapeutic agents

is to include them in matrix tablets as they are easilymanufactured, cost effective, and has broad regulatoryacceptance.[16]From the wide choice of possible matrixforming materials, hydroxypropylmethylcellulose(HPMC) was employed in the current study due to itsnon-toxicity, capacity to accommodate high levels ofdrug loading, good compressibility, as well as its supe-rior matrix building abilities.[17]

Surprisingly, to date, no literature has been publishedconcerning SR formulations for lornoxicam althoughthis is highly desirable from therapeutic view point. [10]Accordingly, the current study was undertaken to prepareSR matrix tablets containing lornoxicam that are able to

promptly release lornoxicam in the stomach with the aimof reaching high serum concentration in a short period oftime, ensuring rapid palliative effect for the painful symp-toms. Tis action is then pursued by an extended-releasephase of lornoxicam to maintain its effective plasma levelfor prolonged period of time. Tree different viscositygrades of HPMC, namely HPMC K4M, HPMC K15M,and HPMC K100M were used as matrix-forming materi-als. After verification of the compatibility of lornoxicamamong different excipients visually and by using differen-tial scanning calorimetry (DSC) and Fourier-transformed

infrared spectroscopy (FIR), matrix tablets were pre-pared by direct compression. In order to reach the pre-fixed goal, the effect of two basic pH-modifiers, sodiumbicarbonate and magnesium oxide, on the release char-acteristics of lornoxicam from the prepared hydrophilicmatrices was investigated. Finally, the effect of storage

on physical characteristics and in vitro drug release fromselected tablets formulations was studied.

Materials and methods

Materials

Lornoxicam was kindly provided by Delta Pharma, 10thof Ramadan City, Egypt. Different viscosity grades ofHPMC (HPMC K4M, HPMC K15M, and HPMC K100M)were generously donated by Colorcon, Midland, USA.Avicel PH 102 (microcrystalline cellulose) was purchased

from FMC Corp., Pennsylvania, USA. Magnesium stear-ate was provided by Prolabo, Paris, France. Magnesiumoxide (MgO) was obtained from Dr Paul LohmannGmbh KG Chemische Fabric, Weserbergland, Germany.Sodium bicarbonate (NaHCO

3) was purchased from

El-Nasr pharmaceutical chemicals company, Cairo,Egypt. All other chemicals and solvents were of analyti-cal grade and were used as received.

Determination of the saturated solubility oflornoxicam in 0.1N HCl, in deionized water, and inphosphate buffer of pH 6.8

Te saturated solubility of lornoxicam in 0.1N HCl ofpH 1.2, in deionized water of pH 5.1, and in phosphatebuffer of pH 6.8 was determined. Excess amounts of lor-noxicam were added to 20 mL of the above-mentionedmedia in screw capped glass vials. Next, these vials weresonicated in an ultrasonic water bath (Model 275 ,Crest Ultrasonics Corp., renton, USA) for 1 h then wereshaken for seven days at 25 0.5C using a thermostati-cally controlled shaking water bath (Model 1083, GLFCorp., Burgwedel, Germany) maintained at a speed of 50strokes per min. Following that, the suspension in eachvial was withdrawn through 0.45m Millipore filter and

the amount of lornoxicam dissolved in each mediumwas determined spectrophotometrically by means ofUV spectroscopy (1601-PC Double beam spectrometer,Shimadzu, Kyoto, Japan) with reference to its calibrationcurve. Each experiment was carried out in triplicate.

Compatibility of lornoxicam with different tabletsexcipients

Physical mixtures of lornoxicam with various tabletsexcipients namely; HPMC K4M, HPMC K15M, HPMC


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Lornoxicam matrix tablets containing basic pH-modifiers 141

K100M, Avicel PH 102, magnesium oxide, sodium bicar-bonate, and magnesium stearate were prepared by mix-ing in weight ratio of 1:1. Te prepared mixtures wereevaluated for possible interactions via the following tests:(a) visual inspection, (b) differential scanning calorim-etry and (c) Fourier-transform infrared spectroscopy.

Visual inspection

Samples of the prepared physical mixtures of lornoxi-cam with the previously mentioned excipients were sub-jected to weekly visual examination during their storageperiod that extended for twelve weeks at 40C/75% rela-tive humidity (RH).

Differential Scanning Calorimetry (DSC)

DSC analysis was performed using Shimadzu differen-

tial scanning calorimeter (DSC-60, Shimadzu, Kyoto,Japan). Te apparatus was calibrated with purifiedindium (99.9%). Samples (34 mg) were placed in flat-bottomed aluminium pan and heated at a constant rateof 10C/min in an atmosphere of nitrogen in a tempera-ture range of 20400C. Te DSC studies were performedfor pure drug, pure excipients, and for the drug-excipientpowder mixtures.

Fourier-Transform Infrared Spectroscopy (FTIR)

Te FIR spectra of pure drug, pure excipients, anddrug-excipient powder mixtures stored for 12 weeks at

40C/75% RH were recorded using FIR spectrophotom-eter (Model 22, Bruker, UK) according to the KBr disctechnique. Te smoothing of the spectra and the baseline correlation procedures were applied. Te spectrawere saved using a Lotus 123 computer program. TeFIR measurements were performed in the scanningrange of 4000 400 cm1at ambient temperature.

Preparation of HPMC matrix tablets containinglornoxicam

Matrix tablets with theoretical weight of 100 mg con-taining lornoxicam together with other excipients were

prepared by direct compression. Te concentration oflornoxicam was kept constant in all the prepared tabletsat 8% by weight (8 mg/tablet). Different viscosity gradesof HPMC were chosen as polymeric matrix materials:namely HPMC K4M, HPMC K15M, and HPMC K100M,with reported nominal viscosity values of 4000, 15000,and 100000 cP, respectively, when present in concentra-tion of 2% in water at 20C.[18]Avicel PH 102 was selectedas tablets diluent to increasing the compressibility andflowability of the ingredients as well as to maintainthe tablets weight constant at 100 mg.[19] Magnesium

stearate was used as a lubricant at concentration of 1%by weight.[20]

o make powder mixtures; the drug, polymer, andAvicel PH 102 were thoroughly mixed for 30 min by meansof a pestle in a glass mortar. Tereafter, the powder blendwas mixed with magnesium stearate for another 30 min.

Te resultant powder mixtures of exactly 100 mg weredirectly compressed into tablets using a single-punchtablet machine (Rotary abletting Machine, CMB3-16,Cadmach, Ahmedabad, India) equipped with 7 mmround, flat, and plain punches. Te force of compressionwas adjusted so that hardness of all the prepared tabletsranged from 5.56.5 kg. Te detailed compositions of theprepared matrix tablets formulations are given in able 1.

In vitro drug release studies

Te release of lornoxicam from the prepared HPMCmatrix tablets was performed in a USP Dissolutionester (VK 7000 Dissolution esting Station, VankelIndustries Inc., NJ, USA), Apparatus II (Rotating paddle)at a rotation of 100 rpm.[21]Te release studies were ini-tially carried out in 400 mL of 0.1 N HCl maintained at37 0.5C for a period of 2 h followed by release in phos-phate buffer of pH 6.8 achieved by adding 200 mL of0.2 M tri-sodium ortho-phosphate solution, preheatedto 37 0.5C, to the release medium for the subsequent6 h.[22,23]At predetermined time intervals, aliquots fromthe release medium were withdrawn through Milliporemembrane filter of 0.45m pore size. Concentrations oflornoxicam in the withdrawn samples were determined

Table 1. Composition of the prepared HPMC matrix tablets containing

lornoxicam.

Formulation

code

Composition

Lornoxicam

(mg ) HPMC grade (% w/w)

Magnesium

stearate

Avicel

PH 102

up to

F 1 8 HPMC K4M 5 1% 100 mg

F 2 8 10 1% 100 mg

F 3 8 15 1% 100 mg

F 4 8 20 1% 100 mg

F 5 8 25 1% 100 mg

F 6 8 30 1% 100 mg

F 7 8 HPMC K15M 5 1% 100 mg

F 8 8 10 1% 100 mg

F 9 8 15 1% 100 mg

F 10 8 20 1% 100 mg

F 11 8 25 1% 100 mg

F 12 8 30 1% 100 mg

F 13 8 HPMC K100M 5 1% 100 mg

F 14 8 10 1% 100 mg

F 15 8 15 1% 100 mg

F 16 8 20 1% 100 mg

F 17 8 25 1% 100 mg

F 18 8 30 1% 100 mg


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spectrophotometrically by measuring their absorb-ances using a UV spectroscopy (1601-PC Double beamspectrometer, Shimadzu, Kyoto, Japan) at

maxvalues of

372 nm and 376.8 nm when 0.1 N HCl and phosphatebuffer of pH 6.8 were used as release medium, respec-tively. All the withdrawn samples were replenished with

equal volumes of same release medium to keep therelease volume constant throughout the experiment.Release studies were carried out in triplicate and themean values were plotted versus time. Based on theresultant release data, further modifications, by incor-porating different classes of basic pH-modifiers, wereperformed on selected matrix tablets in order to complywith the release specifications reported for SR products.

Preparation of lornoxicam matrix tablets containingbasic pH-modifiers

In order to prepare lornoxicam matrix tablets withmicro-environmental pH-control; two different classesof basic pH-modifiers,[2]water-soluble, namely sodiumbicarbonate versus water-insoluble, namely magne-sium oxide, were incorporated into matrix tablets atconcentrations of either 5% or 10% by weight. Eachmodifier was cogrounded with lornoxicam for 30 min ina glass mortar using a pestle, then the resultant blendwas incorporated into the matrix tablets using the sameprocedures utilized for preparing HPMC matrix tablets.Te detailed compositions of the matrix tablets formu-lations containing basic pH-modifiers are presented inable 2. In vitro drug release studies for these tablets

were performed using the same procedures presentedformerly for HPMC matrix tablets.

Physical tests for the prepared matrix tabletscontaining basic pH-modifiers

Tablet weight variationwenty tablets were randomly selected and accuratelyweighed using an electronic balance (Sartorius GmbH,Gottingen, Germany). Te results are expressed as meanvalues of 20 determinations.

Drug content uniformityen tablets were weighed individually, crushed, and thedrug was extracted in phosphate buffer of pH 6.8. Tesolution was filtered through a 0.45 m millipore filterand the drug content was determined by UV spectros-copy (1601-PC Double beam spectrometer, Shimadzu,

Kyoto, Japan) after a suitable dilution with reference tothe calibration curve.

Tablet friabilityAccording to the BP specifications,[24] a sample of 20tablets was placed in the drum of a tablet friability testapparatus (FAB-2, Logan Instruments Corp., NJ, USA).Te drum was adjusted to rotate 100 times in 4 min thenthe tablets were removed from the drum, dedusted andaccurately weighed. Tis process was repeated for alltablets formulations and the percentage weight loss wascalculated.

Morphological examination of matrix tabletscontaining basic pH-modifierSelected tablets were withdrawn from the dissolutionvessels after 2 h from the release run and their pho-tographs were recorded using an optical computermicroscope (Intel Corp., Santa Clara, USA) in order toexamine their morphological appearance after exposureto release medium in comparison to dry tablets. Aimingto visualize the micro-environmental pH in close vicin-ity of the tablets; selected tablets were carefully placed ina dish containing 5 mL of 0.1 N HCl to which one drop ofthymol-blue, a pH-indicator, was added. Te change in

the colour of the solution present in the dish and in closevicinity of the tablets was carefully monitored.[25]

Stability study for matrix tablets containing basicpH-modifierStability study for selected tablets was carried under accel-erated temperature and RH conditions, 40C 2C/75% 5% RH, maintained using saturated solution of NaCl, [26]in stability chambers for a period of 12 weeks.[27,28] Testored tablets were visual inspection for any changes incolor and/or appearance every week. Evaluation of the

Table 2. Composition of the prepared HPMC matrix tablets containing lornoxicam and basic pH-modifiers.

Formulation

code

Composition

Lornoxicam (mg )

HPMC grade

(% w/w)

Basic pH- modifier

Magnesiumstearate Avicel PH 102up toype (%w/w)

F I 8 20% HPMCK4M NaHCo3

5 1 % 100 mg

F II 8 NaHCo3

10 1 % 100 mg

F III 8 MgO 5 1 % 100 mg

F IV 8 MgO 10 1 % 100 mg

F V 8 15% HPMCK15M NaHCo3

5 1 % 100 mg

F VI 8 NaHCo3

10 1 % 100 mg

F VII 8 MgO 5 1 % 100 mg

F VIII 8 MgO 10 1 % 100 mg


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tablets drug content, friability, and in vitro release wasrepeated at the end of the storage period using the sameprocedures utilized for the fresh ones. Release profilesof the fresh and stored tablets were compared accordingto the model independent mathematical approach ofMoore and Flanner.[29]Te similarity factor (

2) was cal-

culated according to the Equation:

f n Rt Tt22

t=1

n 0 550 log{[1+(1/ ) 100}( ) ]

.=

(1)

where nis the number of sampling points, Rtand T

t

are the mean percent released from reference (fresh)and from test (stored) at time t.f

2represents a logarith-

mic transformation of the sum of squared error of differ-ences between the reference and test products over alltime points.

A value of 100% for the similarity factor (2) suggests

that the test and reference profiles are identical. Valuesbetween 50 and 100 indicate that the release profiles aresimilar, whereas smaller values imply an increase in dis-similarity between release profiles.[29]

Results and discussion

Saturated solubility of lornoxicam in 0.1N HCl, indeionized water, and in phosphate buffer of pH 6.8

Te saturated solubility of lornoxicam in media withdifferent pH-values is compiled in able 3. Lornoxicam

is a weak acid with pKa value of 5.5.

[15]

It is present as azwitterion in the pH range of 25 and in an anionic format pH > 6.[12]It is clearly evident from able 3 that lornoxi-cam is poorly soluble in aqueous media, particularly inmedia with pH value lower than its pKa value and showshigher solubility in media with pH value above its pkavalue, i.e. pH 6.8. Tis pH-dependent solubility is prob-ably attributed to the presence of lornoxicam moleculesuncharged at lower pH-values, whereas at higher pHvalues lornoxicam molecules are negatively charged.

Compatibility of lornoxicam with different tablet

excipientsVisual inspectionTe stored powder mixtures of lornoxicam with differenttablets excipients did not show any change in color orappearance (e.g. discoloration, caking, liquefaction, for-mation of clumps). Tis represents a good preliminaryindication of physical stability.

Differential Scanning Calorimetry (DSC)Te compatibility of lornoxicam with the afore-mentioned excipients was investigated using DSC

analysis,[3032]since it is considered as a rapid method forevaluating any possible incompatibilities between drugand excipients.[33,34]Te 1:1 weight ratio of drug to excipi-ent was chosen because it maximizes the likelihoodof observing any possible interactions.[32,34] Te DSCthermograms of pure lornoxicam, pure excipients, and

their 1:1 physical mixtures are shown in Figure 1. TeDSC thermogram of lornoxicam (Figure 1a) exhibiteda sharp exothermic peak at 232.5C which correspondsto its melting and decomposition.[11]Regarding the DSCscans of pure excipients; the thermograms of all gradesof HPMC, namely K4M, K15M, and K100M, showed afaintly endothermic effect ranging from 50120C thatmight be ascribed to their dehydration and an exother-mic effect above 300C that might be attributed to theirdecomposition (Figure 1b, 1c and 1d). Avicel PH 102showed a slightly exothermic effect above 300C thatmight be attributed to its decomposition (Figures 1e). A

broad shallow endothermic peak was observed in caseof magnesium stearate at 119.36C due to its dehydra-tion (Figure 1f). Concerning the DSC of the utilizedbasic pH modifiers; a characteristic endothermic effectbelow 100C was observed in the thermogram of sodiumbicarbonate (Figure 1g), however the thermogram of

Table 3. Saturated solubility of lornoxicam in different media at

25 0.5C (mean SD, n = 3).

Media tested Mean drug solubility (mg/mL) SD

0.1N HCl (pH 1.2) 0.006 0.002

Deionized water (pH 5.1) 0.021 0.009

Phosphate buffer (pH 6.8) 0.305 0.083

0 100 200 300 400

Temprature C

0 100 200 300 400

Temprature C

(a) (a)

(i)

(j)

(k)

(l)

(m)

(n)

(o)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 1. DSC Termograms of (a) lornoxicam; (b) HPMC K4M; (c)

HPMC K15M; (d) HPMC K100M; (e) Avicel PH 102; (f) magnesium

stearate; (g) sodium bicarbonate; (h) magnesium oxide (i) physical

mixture of lornoxicam and HPMC K4M; (j) physical mixture of lor-

noxicam and HPMC K15M; (k) physical mixture of lornoxicam and

HPMC K100M; (l) physical mixture of lornoxicam and Avicel PH

102; (m) physical mixture of lornoxicam and magnesium stearate;

(n) physical mixture of lornoxicam and sodium bicarbonate; and

(o) physical mixture of lornoxicam and magnesium oxide.


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magnesium oxide show a slight endothermic effectabove 300C (Figure 1h). Similar findings have beenreported by other authors.[35,36] Basically, lornoxicamexothermic peak was evident in all the thermogramsof its physical mixtures with the mentioned excipientswhich might indicate compatibility. However, noticeable

broadening in lornoxicam peak intensity was observedin some thermograms. Tis is probably attributed to dif-ferences in geometry of the mixture samples as reportedby other authors.[37,38] In conclusion, the observed DSCresults ruled out the incidence of any incompatibilitybetween lornoxicam and the investigated excipients.Nevertheless, it is stated that DSC analysis, being a ther-mal method of analysis, should not be used individu-ally to detect any inherent incompatibility. It has to besupported by other non-thermal techniques, such asFIR.[3032] Terefore, the latter was considered in con-junction with DSC to reach a definite conclusion.

Fourier-Transform Infrared Spectroscopy (FTIR)Te FIR spectrum of pure lornoxicam, pure excipi-ents, and their 1:1 physical mixtures are shown inFigure 2. Te FIR spectrum of lornoxicam showed acharacteristic peak at 3090 cm1corresponding to NHstretching vibration. Intense absorption peak was found

at 1642 cm1due to the stretching vibration of the C = Ogroup in the primary amide. Other peaks were observedat 1597 cm1 and at 1559 cm1 and were assigned tobending vibrations of NH group in the secondary amide.Te stretching vibrations of the O = S = O group appearedat 1157 cm1, 1387 cm1, and at 1336 cm1. Other promi-nent peaks appeared at 827. 94 cm1 corresponding toCH aromatic ring bending and heteroaromatics andat 766. 8 cm1 due CCl bending vibration (Figure 2a).It is clear evident that the FIR spectra of the physicalmixtures of lornoxicam with different excipients showedthe presence of lornoxicam characteristic bands at their

4000 3000 2000 1000 400 4000 3000 2000 1000 400

Wavenumbers Wavenumbers

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h) (o)

(n)

(m)

(l)

(k)

(j)

(i)

(a)

(%)Transmittance

Figure 2. FIR Spectra of (a) lornoxicam; (b) HPMC K4M; (c) HPMC K15M; (d) HPMC K100M; (e) Avicel PH 102; (f) magnesium stearate; (g)

sodium bicarbonate; (h) magnesium oxide (i) physical mixture of lornoxicam and HPMC K4M; (j) physical mixture of lornoxicam and HPMC

K15M; (k) physical mixture of lornoxicam and HPMC K100M; (l) physical mixture of lornoxicam and Avicel PH 102; (m) physical mixture of

lornoxicam and magnesium stearate; (n) physical mixture of lornoxicam and sodium bicarbonate; and (o) physical mixture of lornoxicam and

magnesium oxide.


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same positions. Moreover, these spectra can be simplyregarded as the superposition lornoxicam and the inves-tigated excipients. Tis could indicate the absence ofchemical interaction between the drug and the excipi-ents confirming the DSC results presented formerly.

In vitro drug release studiesFigure 3 illustrates the in vitro release profiles of lornoxi-cam from the prepared HPMC matrix tablets containingdifferent concentrations and viscosity grades of HPMC.o simulate the conditions that exist as tablets transit inhumans GI tract, the release studies were performed in0.1 N HCl of pH 1.2 for 2 h followed by phosphate bufferof pH 6.8 for the sequential 6 h.[39]Moreover, the releasesampling duration lasted 8 h as the total GI transittime for oral dosage forms in humans is reported to beapproximately 8 h.[40]

Due to its distinct pH-dependent solubility, lornoxi-

cam showed an extremely slow dissolution in acidicconditions, in fact, less than 10% of the drug was dis-solved after 2 h. However, complete drug dissolutionwas displayed when the pH of the release mediumwas converted to 6.8. It is clearly evident that all matrixtablets prepared using HPMC K4M, HPMC K15M, andHPMC K100M employed at concentrations of 5% and10% failed to sustain lornoxicam release. Tis is prob-ably attributed to the extensive disintegration of thesetablets at the beginning of the release study whichprevented the formation of a continuous gel layer ontheir surfaces that is responsible for modulation ofdrug release process.[16] In these cases, complete drug

release took place after changing the pH of the releasemedium from 1.26.8. On the other hand, matrix tabletscontaining 15% and 20% of different viscosity grades ofHPMC were able to keep their integrity and thereforethey showed control on lornoxicam release depend-ing on both the viscosity grade and concentration ofHPMC used. In these cases, it was remarkable that atsame polymer concentration, tablets prepared usingthe highest viscosity grade polymer, HPMC K100M,showed more extended-release profiles when com-pared to the corresponding tablets prepared usinglower viscosity grades polymers, HPMC K4M or HPMCK15M. Tis observation is in concordance with that

reported in literature by several research groups. [4446]Te observed discrepancy in drug release patternswhen employing different cellulose grades in the tabletscan be explained by the fact that the hydrated gel layerof HPMC K100M is more viscous and less erodible thanthat of the lower viscosity grades, HPMC K4M or HPMCK15M, thus provides a stronger barrier for drug diffu-sion which consequently causes slower drug release.[45]Added to that, it is reported that the average molecularweights of HPMC K4M, K15M, and K100M polymers areequal to 96, 134, and 267 kDa, respectively.[46]Actually,

the increase in polymer molecular weight is coupledwith an increase in the entanglement of the polymermacromolecules. Tis leads to decrease in water anddrug diffusion coefficients and therefore decrease indrug release. Furthermore, the polymer dissolutionrate decrease with increasing molecular weight, i.e.

the dissolution rate decrease in the rank order HPMCK4M > K15M > K100M.[47] Surprisingly, all the matri-ces prepared using different viscosity grades of HPMCemployed at concentrations of 25% and 30% showedcomparable release profiles. Tis result suggests that,in these conditions, the drug release is no longer influ-enced by the viscosity grade of HPMC and implies thatviscosities of the hydrated matrices may be identicalwhen different viscosity grades of HPMC are present inhigh concentrations.[48]A similar trend was reported byNellore et al.[41]who observed minor changes in meto-prolol release rates when high concentrations of differ-

ent viscosity grades of HPMC were employed in matrixtablets.Te target release profile parameters for SR products

were reported as follows; after 2 h, 2050% of the drugis released, 4575% of the drug is released after 4 h, andfinally 75105% of the drug is release after 8 h.[49]Addedto that, it is stated that successful SR formulationsmust also show pH-independent drug release thatstart in upper GI tract and continue for nearly 68 hin the lower GI tract.[43]Consequently, for assessmentand comparison with these release specifications; thepercent of drug released from the prepared matrix tab-lets after 2, 4, and 8 h were extracted directly from the

release data and were graphically depicted in Figure 4.It is quite evident that none of the prepared matricesfulfilled the target release profile parameters for SRproducts. However, only matrix tablets belonging toformulations F 4 and F 9, that contained 20% HPMCK4M and 15% HPMC K15M, respectively, compliedwith the SR requirements concerning the percentageof drug release after 4 and 8 h, though they showed aninitial delay in drug release during the first 2 h of therelease study performed in acidic medium. Terefore,further optimization was attempted for these tabletsformulations aiming to achieve the target in vitro SRprofile. Tis was attempted by incorporation of differ-

ent basic pH-modifiers, namely sodium bicarbonateand magnesium oxide, to these tablets formulations inconcentration of 5% and 10%. Tese modifiers presum-ably increase the micro-environmental pH within, andin the close vicinity of the swollen gel layer of the matrixtablets and thus increase the solubility and release ofthe drug in acidic pH.[3]

Te release profiles of the prepared HPMC matrixtablets containing basic pH-modifiers are graphicallypresented in Figure 5. It is clearly evident that all theprepared tablets formulations containing magnesium


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oxide, present in either 5% or 10% concentrations,showed a marked decrease in the extent of lornoxicamrelease in phosphate buffer of pH 6.8 compared to the

corresponding tablets formulations prepared withoutmagnesium oxide. Being practically water-insoluble,magnesium oxide presence in the tablets hinders drug

0

20

40

60

80

100

PercentLornoxicam

Released

Time (hours)

Lornoxicam Powder F 1 (5 % HPMC K4M) F 2 (10 % HPMC K4M)

F 3 (15 % HPMC K4M) F 4 (20% HPMC K4M) F 5 (25 % HPMC K4M)F 6 (30% HPMC K4M)

pH=6.8pH=1.2(a)

0

20

40

60

80

100

PercentLornoxicam

Released

Time (hours)

Lornoxicam Powder F 7 (5 % HPMC K15M) F 8 (10% HPMC K15M)

F 9 (15 % HPMC K15M) F 10 (20 % HPMC K15M) F 11 (25 % HPMC K15M)

F 12 (30 % HPMC K15M)

pH=6.8pH=1.2(b)

0

20

40

60

80

100

PercentLornoxicam

Released

Time (hours)

Lornoxicam Powder F 13 (5 % HPMC K100M) F 14 (10% HPMC K100M)

F 15 (15 % HPMC K100M) F 16 (20 % HPMC K100M) F 17 (25 % HPMC K100M)

F 18 (30% HPMC K100M)

pH=6.8pH=1.2(c)

0 1 2 3 4 5 6 7 8

0 1 2 3 4 5 6 7 8

0 1 2 3 4 5 6 7 8

Figure 3. In vitro release profiles of lornoxicam from HPMC matrix tablets performed in 0.1 N HCl of pH 1.2 for 2 hours and in phosphate buffer

of pH 6.8 for the subsequent 6 hours at 37 0.5C. (a) HPMC K4M (b) HPMC K15M (c) HPMC K100M.


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diffusion and/or medium infiltration into the tablets.On the other hand, the incorporation of sodium bicar-bonate into HPMC matrix tablets increased lornoxicamrelease during the early stages of the release study, i.e. in0.1N HCl, compared to the corresponding formulation

prepared without sodium bicarbonate. It was alsoobserved that matrix tablets belonging to formulationsF I and F II, which contained 20% HPMC K4M in pres-ence of 5% and 10% sodium bicarbonate respectively,disintegrated when exposed to the release medium.

0

20

40

60

80

100

F 6(30% HPMC K4M)

PercentLornoxicam

Released

(a)

0

20

40

60

80

100

F 12

(30% HPMC K15M)

PercentLornoxicam

Released

(b)

0

20

40

60

80

100

F 18(30% HPMC K100M)

% released after 2 hours % released after 4 hours % released after 8 hours

Percen

tLornoxicam

R

eleased

(c)

F 1(5% HPMC K4M)

F 2(10% HPMC K4M)

F 3(15% HPMC K4M)

F 4(20% HPMC K4M)

F 5(25% HPMC K4M)

F 7

(5% HPMC K15M)F 8

(1% HPMC K15M)

F 9

(15% HPMC K15M)

F 10

(20% HPMC K15M)

F 11

(25% HPMC K15M)

F 13(5% HPMC K100M)

F 1410% HPMC K100M)

F 15(15% HPMC K100M)

F 16(20% HPMC K100M)

F 17(25% HPMC K100M)

Figure 4. Te percentages of lornoxicam released after 2, 4, and 8 hours from HPMC matrix tablets. (a) HPMC K4M (b) HPMC K15M (c) HPMC

K100M.


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It is well known that HPMC can modify drug releaserate by forming of a gelatinous layer on the surface of thetablets. However, the presence of sodium bicarbonate inthese matrix tablets caused the formation a structurallydifferent gel layer on the tablets surface upon hydra-tion. Tis gel layer is characterized by less entangled

polymeric chains due to formation of a porous poly-meric network that resulted from the rapid dissolutionof sodium bicarbonate upon contact with the acidicrelease medium. Tis consequently led to lowering ofthe gel resistance and weakening in tablets structureswhich accordingly disintegrated in the release medium.Similar observations were reported by Amaral et al.[50]On the contrary to that, matrix tablets belonging toformulation F V and F VI, that contained 15% HPMCK15M in presence of 5% or 10% sodium bicarbonate,were able to maintain their integrity throughout thewhole release study. Tis may be due to the higher

degree of polymeric entanglement when using thehigher viscosity grade of HPMC, HPMC K15M, was

used. As expected, in tablets belonging to formulationsF V and F VI, increasing the concentration of sodiumbicarbonate from 510%, led to a marked accelerationin the extent of lornoxicam release. Sodium bicarbo-nate leaches out of the tablets thereby create pores inthe matrix structure. At high sodium bicarbonate con-

centration, the porosity and segregation of the gel layerpresent on the tablets surfaces increase allowing betterdiffusion and release of lornoxicam. Conclusively, thepresence of magnesium oxide or sodium bicarbonatehad opposite effects on lornoxicam release from HPMCtablets: Te former displayed a negative influence dueto its relative inability to elevate the tablets micro-environmental pH; besides, its poor solubility reducedthe matrix erosion process and consequently hindereddrug diffusion and release, whereas the latter had apositive effect due to its capability to elevate the tabletsmicro-environmental pH as well as its rapid dissolu-

tion in the release medium that allowed a decrease intortuosity and/or an increase in the matrix porosity. For

0

20

40

60

80

100

PercentLornoxicam

Released

Time (hours)

Lornoxicam Powder F 4 F I (5% NaHCo3)F II (10% NaHCo3) F III (5% MgO) F IV (10% MgO)

pH=6.8pH=1.2(a)

0

20

40

60

80

100

PercentLornoxicam

Released

Time (hours)

Lornoxicam Powder F 9 F V(5% NaHCo3)F VI(10% NaHCo3) F VII(5% MgO) F VIII(10% MgO)

pH=6.8pH=1.2(b)

0 1 2 3 4 5 6 7 8

0 1 2 3 4 5 6 7 8

Figure 5. Effect of incorporating different basic pH-modifiers on lornoxicam release from HPMC matrix tablets performed in 0.1 N HCl of pH 1.2

for 2 hours and in phosphate buffer of pH 6.8 for the subsequent 6 hours at 37 0.5C. (a) ablets contain 20% of HPMC K4M (b) ablets contain

15% of HPMC K15M.


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assessment and comparison with the release require-ments of SR products, the percentage of drug releasedafter 2, 4, and 8 h were extracted from the release dataand were graphically depicted in Figure 6. It is clearlyevident that only tablets belonging to formulationF VI complied with the reported release specifications

concerning SR products. Te percentages of lornoxi-cam released from these tablets were 34.45% after 2 h,and 68.15% and 85.19% after 4 and 8 h, respectively.Moreover, these tablets also illustrated a burst releaseof nearly 30% their drug content during the first 30 minof the release study, so they are expected to overcomethe disadvantages associated with the delayed dissolu-tion of lornoxicam in acidic conditions.

Physical tests for the prepared matrix tablets containingbasic pH-modifiersTe comparison of physical properties of the prepared

matrix tablets are shown in able 4. Te weight of tabletsformulations ranged from 100.23102.70 mg. All tabletsformulations prepared in this study met the pharmaco-peial requirements for weight variation tolerance. Drug

uniformity results were found to be good among dif-ferent tablets formulations, and the percentage of drugcontent was more than 97%. ablets hardness is not anabsolute indicator of strength. Another measure of atablets strength is friability.[51]In the present study, thepercentage friability for all the formulations was below

1% indicating that the friability is within the compendiallimits. Terefore, all the tablet formulations showedacceptable physical properties and complied with the

0

20

40

60

80

100

F IV (10% MgO)

PercentLornoxicamR

eleased

(a)

0

20

40

60

80

100

FVIII (10% MgO)

% released after 2 hours % released after 4 hours % released after 8 hours

PercentLornoxic

amR

eleased

(b)

F I (5% NaHCo3)F 4 F II (10% NaHCo3) F III (5% MgO)

F 9 F V (5% NaHCo3) F VI (10% NaHCo3) F VII (5% MgO)

Figure 6. Te percentages of lornoxicam released after 2, 4, and 8 hours from HPMC matrix tablets containing basic pH-modifiers. (a) ablets

contain 20% of HPMC K4M (b) ablets contain 15% of HPMC K15M.

Table 4. Characterization of the prepared HPMC matrix tablets

containing basic pH-modifiers.

Formulation

code

Average weight

(mg) SD

Average drug content

(%) SD Friability (%)

F I 101.40 1.51 100.65 1.20 0.39

F II 102.63 2.49 101.00 2.12 0.48

F III 101.60 2.03 98.50 1.56 0.33

F IV 102.70 1.23 99.50 4.38 0.34

F V 100.23 2.00 99.45 0.92 0.38F VI 102.20 1.47 99.65 1.48 0.30

F VII 100.80 2.41 98.70 1.70 0.45

F VIII 102.27 1.40 97.25 2.05 0.35


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reported pharmacopoeial specifications. Finally, it isworth noting that lornoxicam matrix tablets belong-ing to formulation F VI, composed of 15% of HPMCK15M and 10% sodium bicarbonate, complied with therelease specifications for SR products and also exhibitedacceptable weight variation, drug content, and friabil-

ity. Hence, these matrix tablets were chosen for furtherinvestigations.

Morphological examination of matrix tabletscontaining basic pH-modifierTe photographs of tablets belonging to formulation FVI before and after dissolution for two hours in 0.1NHCl are depicted in Figure 7. Upon contact with therelease medium, these tablets swell as the solvent mol-ecules penetrate into the matrix system along the poresformed due to the rapid leaching of sodium bicarbo-nate into the release medium causing polymeric chains

relaxation.

[3]

Moreover, it is obvious that these tabletsshowed anisotropic swelling phenomenon with pref-erential expansion in the axial direction due to relaxa-tion of the compression forces imposed on the tabletsduring tableting process. A similar phenomenon wasobserved in previously published studies by Contiet al.[52]and by Papadimitriou et al.[53]who related thepredominantly axial relaxation of HPMC compacts tothe relief of stress induced during their compaction.Furthermore, the changes in micro-environmental pHof the selected tablets matrices were visualized withthe aid of thymol-blue as a pH indicator. [3]Tymol-bluecolour transits from red to yellow at pH range of 1.22.8

and changes from yellow to blue at pH higher than 7.As clearly shown in Figure 8, the red solution (formedas a result of adding one drop of thymol-blue to 0.1NHCl) that surrounds the tablet gradually faded and wasconverted to yellow colour which indicates that pHof this solution progressively increases from 1.22.8.Furthermore, after one hour, a blue ring surroundingthe tablet boarders became visible which indicate thepresence of a region with high pH value near the tab-lets boarders. Concisely, these observations are attrib-uted to the leaching of NaHCO

3from the tablets when

exposed to the dissolution medium creating a basicmicro-environment pH in the vicinity surrounding the

tablets.

Stability study for matrix tablets containing basicpH-modifierA drug product may undergo changes in its physi-cochemical characteristics during storage and thesechanges can affect the bioavailability of drug from dos-age forms. A unit of solid oral dosage form such as atablet has to meet pharmacopeial specifications, suchas drug content, friability, and release during its shelflife.[54] Accordingly, the effect of storage at 40C/75%

RH for 12 weeks on the physical properties and invitro release of tablets belonging to formulation F VIwas investigated. All the stored tablets didnt showany change in their colour or appearance throughoutthe storage period. Te physical characteristics of thestored tablets in comparison to fresh ones are com-piled in able 5. It is evident that the drug content oftablets belonging to formulation F VI remained withinthe acceptable limits.[21] A slight increase in tablets

friability was observed compared to the fresh ones.Figure 9 presents the release profiles of the fresh andstored tablets belonging to formulation F VI. Evidently,a slight decrease in drug release was observed on com-paring the fresh tablets to the stored tablets. However,even with this decrement, the stored tablets compliedwith the reported specifications of sustained-releaseproducts. In order to assess the effect of storage on therelease characteristics objectively, the mean releasedata of fresh and stored tablets were analyzed using themodel independent mathematical approach of Moore

(a) (b)

Figure 7. Photographs of directly compressed HPMC matrix tablets

containing basic pH-modifier before and after dissolution for 2 hour

in 0.1 N HCl. (a) top view (b) side view.

(a) (b)

Figure 8. Photographs of directly compressed HPMC matrix tablets

containing basic pH-modifier. (a) Immediately after the tablet was

immersed in 0.1N HCl containing one drop of thymol blue; (b) After

one hour showing a blue region of high pH region around the tablet

due to leaching of sodium bicarbonate from the tablet into the indi-

cators solution.

Table 5. Effect of storage on the physical properties of tablets

belonging to formulation F VI.

Physical properties

investigated

Fresh tablets Stored tablets

Average drug content(%) SD

99.65 1.48 97.84 0.803

Friability (%) 0.30 0.61


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and Flanner.[29]Te computedf2value was 63.58% indi-

cating that the release profiles of fresh and stored tab-

lets belonging to formulation F VI could be consideredsimilar and that the storage at the specified conditionshad no marked effect on the release of the drug from itstablets formulation. Similar results were reported in theliterature by several research groups when they studiedthe effect of storage under accelerated conditions onthe physical properties and the release characteristicsof HPMC tablet matrices.[27,44,55,56]

Based on the results presented in the current study,further in vivo studies for matrix tablets belonging toformulation F VI are ongoing and will be published laterto assess their therapeutic effectiveness in comparisonwith immediate release formulations.

Conclusion

In the current study, HPMC matrix tablets that provideinitial burst drug release in acidic medium followedby an extended-release phase for 8 h was successfullydesigned for lornoxicam. Tis was attempted by incor-porating water soluble basic pH-modifier exemplifiedby sodium bicarbonate into selected matrix tabletsformulations.

Results obtained demonstrated that tablets belongingto formulation FVI, composed of 15% of HPMC K15Mand 10% sodium bicarbonate, possessed acceptablephysical properties and elicited the required in vitrorelease pattern, before and after storage, that coincideswith the purpose set for this study.

In conclusion, HPMC swellable tablets can provide auseful tool for retarding drug release. Besides, the drugsrelease profiles of these tablets can be further modifiedand tailored, according to their pharmacokinetics andtherapeutic needs, by manipulating the tablets micro-environmental pH. Tis can be achieved through theincorporation of pH-modifiers in an inexpensive and

easy to scale-up process that does not require specialproduction equipments.

Acknowledgements

Te authors are deeply grateful to Colorcon Corp.,(Midland, USA) for providing gift samples of differentviscosity grades of HPMC.

Declaration of interest: Te authors report no conflictsof interest. Te authors alone are responsible for thecontent and writing of the paper.

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ntLornoxicam

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