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Drug Development and Industrial Pharmacy

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Comparative study of different approaches forpreparation of chlorzoxazone orodispersibletablets

Helal Abdo Moqbel, Aliaa Nabil ElMeshad & Mohamed Ahmed El-Nabarawi

To cite this article: Helal Abdo Moqbel, Aliaa Nabil ElMeshad & Mohamed Ahmed El-Nabarawi (2017) Comparative study of different approaches for preparation of chlorzoxazoneorodispersible tablets, Drug Development and Industrial Pharmacy, 43:5, 742-750, DOI:10.1080/03639045.2016.1225753

To link to this article: http://dx.doi.org/10.1080/03639045.2016.1225753

Accepted author version posted online: 18Aug 2016.Published online: 02 Sep 2016.

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RESEARCH ARTICLE

Comparative study of different approaches for preparation of chlorzoxazoneorodispersible tablets

Helal Abdo Moqbel, Aliaa Nabil ElMeshad and Mohamed Ahmed El-Nabarawi

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

ABSTRACTContext: Muscle spasm is a painful involuntary contraction of muscles, which causes involuntary move-ment and distortion. Chlorzoxazone is a centrally acting muscle-relaxant with sedative properties, butgiven orally, it is hepatically metabolized leading to decreased bioavailability.Objective: Orodispersible tablets (ODTs) of chlorzoxazone were formulated using two differentapproaches; by coprocessed excipients (CE) or by liquisolid (LS) technique.Materials and methods: PharmaburstVR 500, StarlacVR , Pearlitol flashVR , ProsolvVR odt and F-meltVR were usedas coprocessed superdisintegrants, whereas in LS, AvicelVR PH101, MicrocelacVR 100 and CellactoseVR 80 wereused as carriers, while AerosilVR 200 was the coating material. ODTs were evaluated in terms of weight andthickness variations, drug content, hardness, friability, wetting time, dissolution, disintegration time (DT)and palatability.Results: In vitro DT of CE-ODTs ranged from 26.43±1.693 s to >180 s, whereas it was between25.42±0.203 s to >180 s in LS-ODTs. Complete drug release within 15min was attained by CE1 preparedwith 92.5mg PharmaburstVR 500. In vivo DT of CE1 and LS3 were 19.779±0.810 and 18.105±0.423 s,respectively, using six volunteers. Volunteers found that CE1 had more acceptable taste and was more pal-atable than LS3.Conclusion: It was concluded that chlorzoxazone ODTs could be successfully formulated using either CEor LS techniques and be used as novel dosage forms for pediatrics and geriatrics showing improved drugrelease. Moreover, CE technique was superior to LS technique in terms of palatability.

ARTICLE HISTORYReceived 29 March 2016Revised 3 July 2016Accepted 3 August 2016Published online 2 Septem-ber 2016

KEYWORDSOrodispersible tablet;chlorzoxazone; coprocessedsuperdisintegrant; liquisolidtechnique; disintegrationtime; dissolution

Introduction

Orodispersible tablets (ODTs) are solid dosage forms that areplaced in the mouth and rapidly disintegrate/dissolve when incontact with the saliva without the need for water1. ODTs, alsocommonly known as fast melt, quick melt, orally disintegratingtablets and orodispersible systems, have the unique property ofdisintegrating in the mouth in seconds2. ODTs provide practicalsolution for wide range of people who experience difficulty inswallowing (dysphasia) including pediatric and geriatric patients,as well as hospitalized or bedridden patients suffering from a var-iety of disorders like stroke, thyroid disorders, Parkinson’s diseaseand other neurological disorders like multiple sclerosis and cere-bral palsy3. The convenience and ease of using ODTs is alsoimportant with normal consumers, as it offers convenient andpractical dosage all the time especially in case of no access towater. In addition to improving patient compliance, ODTs havebeen investigated for their potential in increasing the bioavailabil-ity of poorly water-soluble drug, through enhancing the dissol-ution profile of the drug4 and providing rapid onset of action, byavoiding the need for gastric disintegration and facilitating pregas-tric absorption (through the buccal and esophageal mucosa)5.Moreover, pharmaceutical companies also have commercial rea-sons for formulating ODTs. As a drug reaches the end of itspatent, the development and formulation of the drug into newdosage forms allows pharmaceutical companies to extend thepatent life and market exclusivity6. Manufacturing of ODTs using

conventional tableting and packaging equipment is the simplestand most cost-effective among other available techniques. Directcompression was based on using appropriate combinations ofcarefully selected excipients as the main components, without theneed of further processing.

The poor solubility of drugs (BCS Class II) in gastrointestinalfluid gives rise to variations in dissolution rate and incomplete bio-availability7. An improvement of the dissolution rates of water-insoluble drugs is one of the most challenging and importanttasks of drug development, as it can increase drug bioavailability8.Chemically, chlorzoxazone (CLZ) is 5-chloro-3H-benzooxazol-2-one,with poor solubility in water (0.2–0.3mg/mL)9. After oral adminis-tration, CLZ is completely absorbed and is rapidly metabolized inthe liver to pharmacologically inactive 6-hydroxychlorzoxazone.CLZ belongs to skeletal muscle relaxant (centrally acting) class. Ithas half-life of 1.1 h and the usual initial oral dose is 500mg threeor four times daily; though the dose can often be reduced subse-quently to 250mg three or four times daily10. It is necessary toimprove the dissolution rate of CLZ to enhance the bioavailability.There are different chemical or formulation approaches to improvedrug dissolution and bioavailability. Various strategies were usingcoprocessed excipients (CEs)11 and liquisolid (LS) technique12. Theselected excipients provide rapid disintegration profile, pleasantmouth feel and adequate physical strength. The direct compres-sion process is highly influenced by the powder characteristicssuch flowability, compressibility and dilution potential.

CONTACT Helal Abdo Moqbel helalmaster2012@yahoo.com Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, KasrEl Aini St., Cairo, 11562, Egypt� 2016 Informa UK Limited, trading as Taylor & Francis Group

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2017VOL. 43, NO. 5, 742–750http://dx.doi.org/10.1080/03639045.2016.1225753

Coprocessing is one of the most widely studied options in thefield of direct compression in order to obtain functionality addedbenefits. CEs are a mixture of two or more existing excipients atsubparticle level. LS technique has been identified as a promisingapproach to improve the dissolution rate of poorly water-solubledrugs13. When properly formulated, LS powder blends possessacceptable flowability and compressibility properties. They are pre-pared by simple blending with selected powder excipients referredto as the carrier and the coating materials.

In this study, directly compressed ODTs of CLZ were developedusing two different approaches: compression with CEs and com-pression after LS development. The aim of formulation of CLZODTs was to provide rapid drug release. The study involves com-paring the two techniques used to prepare CLZ ODTs by charac-terization of the prepared tablets to reach the best method ofpreparation.

Experimental

Materials

Chlorzoxazone powder was received as a kind gift from EVAPharmaceutical Industries, (Cairo, Egypt). PharmaburstVR 500,LubripharmVR (Sodium stearyl fumarate, SSF) were supplied by SPIPharma, Wilmington, (DE, USA). StarlacVR and Perlitol flashVR wereobtained from Roquette, Lestrem, (France). ProsolvVR odt and F-meltVR were obtained from JRS Pharma GmbH& Co. KG, Rosenberg,(Germany) and Fuji Chemical Industry Ltd., (Japan), respectively. Inaddition, the following materials were obtained: monoammoniumglycyrrhizinate (MAG), from Indena S.P.A, Milan, Italy; polyethyleneglycol 400 (PEG 400), from Merck, Schuchardt, (Germany); propyl-ene glycol (PG), from Adwic Co., Cairo, (Egypt); Tween 80, fromAtlas Chemical Industries, Inc., Wilmington (USA); microcrystallinecellulose (AvicelVR PH 101), from FMC Corporation, Philadelphia,(USA); AerosilVR 200, from Degussa AG, (Germany); CellactoseVR 80and MicrocelacVR 100, from Meggle Pharma, Wasserburg,(Germany); and finally sodium starch glycolate (SSG), was obtainedfrom Maruti Chemicals, Ahmadabad, India.

Method

Preparation of orodispersible tablets of chlorzoxazoneDifferent ODTs of CLZ were formulated: 15 of which were preparedby direct compression method using CEs (CE-ODTs, compositionreported in our previous work and summarized in Table 1)10 and11 of which were prepared by direct compression after LS develop-ment (LS-ODTs, Table 2(a,b)). In case of LS-ODTs, the solubility ofCLZ was first screened in three nonvolatile solvents (Tween 80, PG

and PEG 400). Three different ratios of the drug to the liquidvehicle (1:1, 1:2 and 1:3) and three different ratios (R) of carrier tocoating materials (10, 15 and 20) were employed. Three differentcarriers (AvicelVR PH101, MicrocelacVR 100 and CellactoseVR 80) wereused, whereas AerosilVR 200 was utilized as the coating material.

To prepare the powder for LS-ODTs, calculated quantities ofCLZ (50mg/tablet) were dissolved in the nonvolatile solvent, usingheat to dissolve the drug. The selected weights of liquid medica-tion were added to the carrier first and mixed well in the mortar,and then, the coating material was added and mixed properly.The mixing process was carried out on three steps as described bySpireas et al.14. The system was blended in a mortar at a rate ofone rotation/s for approximately one min in order to distributethe liquid medication onto the powder. The liquid/powder admix-ture was evenly spread over the mortar surface and left standingfor 5min to allow the drug solution to be absorbed in the interiorof the powder particles. Then, the powder was scraped off andblended with the other excipients (disintegrant and lubricant),according to Table 2(b), for another 30 s. Finally, LS tablets werecompressed with a single punch press machine (Royal Artist,Bombay, India) equipped with flat-faced 12 and 15mm punch anddie sets according to the tablet final weight.

Evaluation of the prepared tablets

Saturated solubilitySaturated solubility study of drug was carried out in distilled waterand three different nonvolatile solvents: PG, PEG 400 and Tween80 to choose the best solvent for CLZ.

Saturated solutions of the drug were prepared by dissolvingexcess amount of CLZ (500mg) in a solvent (3mL) and kept inshaker (Shaking water bath, Julabo Sw-20c, Germany) for 48 h at25 �C under vibration of 100 rpm. After this period, the solutionswere centrifuged, filtered, diluted and concentration of drug wasdetermined spectrophotometrically at kmax 281 nm. Three determi-nations were carried out for each sample to calculate the solubilityof CLZ in each solvent.

Weight variationTwenty tablets were selected randomly from each formulation andweighed individually. The individual weights were compared tothe mean weight and the standard deviation (SD) was calculated.

Thickness variationTen tablets from each formulation were taken randomly and theirthickness was measured using micrometer (Starrett, Athol, MA,India), and then, the mean thickness and SD were calculated.

Table 1. Composition of different ODTs prepared by direct compression using different coprocessed excipients.

Ratio of drug: excipients

0.5:1 1:1 2:1

Formula

Ingredients (mg) CE1 CE2 CE3 CE4 CE5 CE6 CE7 CE8 CE9 CE10 CE11 CE12 CE13 CE14 CE15

Chlorzoxazone 50 50 50 50 50 75 75 75 75 75 100 100 100 100 100PharmaburstVR 500 92.5 67.5 42.5Pearlitol flashVR 92.5 67.5 42.5StarlacVR 92.5 67.5 42.5ProsolvVR odt 92.5 67.5 42.5F-meltVR 92.5 67.5 42.5LubripharmVR (Ssf) 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5MAG 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3Total (mg) 150 150 150 150 150 150 150 150 150 150 150 150 150 150 150

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 743

Friability testFive tablets of each formula were weighed and placed in aFriabilator (Mumbai, India) and rotated at 25 rpm for 4min. Thetablets were reweighed and the percent friability was then calcu-lated according to the following equation:

% Friability ¼ Loss in weight=Initial weightð Þ � 100 (1)

Hardness testThe hardness of three tablets from each formulation was testedusing Monsanto hardness tester (Creve Coeur, MO) and the meanand SD values were calculated.

Drug contentA tablet containing the drug was dissolved in simulated salivasolution (SSS, pH 6.8) [sodium chloride (0.8% w/v), sodium phos-phate dibasic (0.238% w/v) and potassium phosphate monobasic(0.019% w/v)], filtered through 0.22-mm membrane filter and ana-lyzed spectrophotometrically at 281 nm. The concentration of CLZin the tablet was deduced from a preconstructed calibration curve(R2¼0.998, n¼ 3). Drug content was determined in triplicate foreach formulation and the results were expressed as mean± SD.

Wetting time (WT)A piece of tissue paper folded twice was placed in a small petridish (4.5 cm diameter) containing 6mL of dye solution (methyleneblue aqueous solution). A tablet was carefully placed on the sur-face of the paper and the time required for the dye solution toreach the upper surface of the tablet was noted as the WT11.Values exceeding 3min were considered slow WT. The WT foreach formulation was carried out in triplicate and the results wereexpressed as mean± SD.

In vitro disintegration time (DT)One tablet was placed in a beaker containing 5mL SSS (pH 6.8) at37 ± 0.5 �C and the time required for complete disintegration ofthe tablet was determined. In vitro DT for each formulation was

carried out in triplicate and the results were expressed asmean± SD.

In vitro dissolution studyIn vitro dissolution studies were performed using type-II (paddle)dissolution apparatus at 50 rpm and 37 ± 0.5 �C using 900mL ofSSS (pH 6.8) as a dissolution medium. Aliquots of the dissolutionmedium (5mL) were withdrawn at specific time intervals (2, 4, 6,10, 15, 20, 25, 30, 45 and 60min) and were replaced immediatelywith equal volume of fresh medium kept at the same temperature.The samples were filtered through 0.22-mm membrane filter,diluted suitability and analyzed spectrophotometrically at 281 nm.Drug concentration was expressed as cumulative percent drug dis-solved. The dissolution study for each formulation was carried outin triplicate and the results were expressed as mean± SD.

Differential scanning calorimetry (DSC)The compatibility of CLZ with the different excipients used in ODTformulations was studied using a differential scanning calorimeter(model TA-50 WSI, Shimadzu, Japan) calibrated with indium.Samples were placed in flat-bottomed aluminum pan and heatedat constant rate of 10 �C/min in an inert nitrogen atmosphere at atemperature range of 10–300 �C. The DSC thermograms were per-formed for pure CLZ, different excipients and the selected CE1and LS3.

Morphology and internal matrixThe surface morphology and the internal matrices of selected CE1and LS3 were examined by scanning electron microscope (SEM).The tablet was placed on the SEM sample holder and was coatedwith gold using a sputter coater (Edwards S-105A, England) toachieve a film of 150 Ao thickness. The tablets were then exam-ined using SEM (Jeol, JXA-840A, Tokyo, Japan).

In vivo disintegration time (DT) and palatabilitySix healthy human volunteers (age 25–40) (4 males and 2 females)evaluated the in vivo disintegration time and overall acceptability

Table 2b. Composition of different ODTs prepared by direct compression using liquisolid technique.

Ratio of drug:liquid vehicle

1:1 1:2 1:3 1:1

Formula

Ingredients (mg) LS1 LS2 LS3 LS4 LS5 LS6 LS7 LS8 LS9 LS10 LS11

Chlorzoxazone 50 50 50 50 50 50 50 50 50 50 50AvicelVR PH101 (MCC) 302 450.5 595 453 676 893 604 901 1190MicrocelacVR 100 595CellactoseVR 80 595AerosilVR 200 30.21 30 29.76 45.3 45 44.64 60.42 60 59.5 29.76 29.76SSG 5% 22.69 29.31 38 34 45.72 57 45.38 60.90 76 38 38Lubripharm (SSF) 1% 4.58 6.15 7.69 6.88 6.26 11.56 9 12.34 15.41 7.69 7.69Total weight (mg) 459.5 616 770.5 689 923 1157 919 1234 1541 770.5 770.5

Table 2a. Carrier: coating ratio (R) and liquid load factor (Lf) of different ODTs prepared by direct compression using liquisolid technique.

Ratio of drug: liquid vehicle 1:1 1:2 1:3 1:1

Formula LS1 LS2 LS3 LS4 LS5 LS6 LS7 LS8 LS9 LS10 LS11

Carrier:coating ratio (R) 10 15 20 10 15 20 10 15 20 20 20Liquid load factor (Lf) 0.331 0.222 0.168 0.331 0.222 0.168 0.331 0.222 0.168 0.168 0.168

744 H. A. MOQBEL ET AL.

of the selected CE1 and LS3 formulations. The study protocol wasapproved by the Ethics Committee of Faculty of Pharmacy, CairoUniversity, Egypt and complied with the principles of theDeclaration of Helsinki. All volunteers were informed with the pur-pose and the conditions of the study and the possible side effectsof the drug were explained to them. The volunteers signed a writ-ten consent form before beginning the study. No food or waterwas allowed during conducting the study except what was givenby the conductor of the study. The volunteers were divided ran-domly into two equal groups, each group assessing one type ofODT. A cross-over design experiment was followed. CE1 formulawas given to volunteers of group A, and LS3 formula was given tothe volunteers of group B. The volunteers were instructed to putthe ODTs on their tongues and not to swallow them; and theywere free to move their tongue while conducting the experiment.The time required for the total disintegration of each ODT in theoral cavity was recorded. Moreover, the subjects were asked togive an evaluation of the overall acceptability of the tablets using5-point score scale where score 1 represented very good palatabil-ity, two good palatability, three acceptable palatability and fourpoor palatability and five corresponded to highest dissatisfactionpalatability15. After 15min, the volunteers washed their mouthcavity with water and were given a slice of bread. After that, LS3formula was given to volunteers of group A and CE1 formula wasgiven to volunteers of group B and the experiment was repeatedfollowing the same procedures.

Statistical analysis

Analysis of the factorial design was performed using SocialPackage for Statistical Study software (SPSSVR 17, SPSS Inc.,Chicago, IL) using a significance of p < .05.

Results

Solubility studies

The saturated solubility of CLZ in distilled water, PG, PEG 400 andTween 80 was presented as bar chart in Figure (1). It was foundthat the drug was practically insoluble in distilled water(0.061 ± 1.392mg/mL) which increased significantly when the threenonvolatile solvents were used. PEG 400 attained the highest solv-ation power for CLZ reaching 128.408 ± 2.230mg/mL, followed byTween 80 (50.834 ± 0.515mg/mL) and PG (44.509 ± 0.546mg/mL)which were non-significantly different from each other (p> 0.05).

Weight variation

The mean weight of all the ODT formulations (Tables 3 and 4)were found to be in the range of 145.023 ± 0.002mg (CE4) to151.221 ± 0.034 (CE5) for CE-ODTs and from 456.6 ± 5.358 (LS1) to1526.2 ± 4.391mg (LS9) for LS-ODTs, which fell within the

acceptable weight variation range, according to the EuropeanPharmacopeia16 .

Thickness variation

Tablet thickness was found to be almost uniform in all the formu-lations, where the mean thickness was found to range from3.416 ± 0.057mm (CE3) to 0.915± 0.007 cm (LS9) (Tables 3 and 4).

Friability

Friability was determined to evaluate the ability of the tablets towithstand abrasion in packing, handling and transporting. AllODTs showed acceptable friability according to the BritishPharmacopeia 17, except CE7, CE8, CE12, LS6 and LS9 which hadfriability >1% (Tables 3 and 4). Results showed that the friabilityof CE-ODTs was higher than those of LS-ODTs, where CE13, CE14and CE15 formulations broke and showed capping during the test,while all LS-ODTs remained intact during friability test.

Hardness

The hardness values for all tested tablets were within2.532 ± 0.213 kg (CE15) to 5.724 ± 0.340 kg (CE1) (Tables 3 and 4).In case of LS-ODTs, it was found that there was an inverse rela-tionship between R-value and the hardness of the tablets, that is,when the R-value increased from 10 to 15 and to 20, the hardnessof the tablets decreased from 4.48 ± 0.213 kg (LS1) to3.613 ± 0.213 kg (LS2) and 3.36 ± 0.213 kg (LS3) in case of 1:1 drugratio to liquid vehicle. But in case of CE-ODTs, it was found thatincreasing the drug/excipients ratio led to a decrease in the ODTshardness.

Drug content

Results in Tables 3 and 4 showed that the percentage of drugcontent was found to be between 89.213 ± 1.452% (LS8) and102.120 ± 1.883% (LS6) for LS-ODTs, while that of CE-ODTs wasfound to be between 92.654 ± 3.776% (CE9) to 104.54 ± 1.506%(CE2).

Wetting time (WT)

The mean WT of all ODTs are listed in Tables 3 and 4. LS-ODTsexhibited WT between 10.302 ± 0.072 s (LS6) to 157.240 ± 0.201 s(LS7), whereas WT of CE-ODTs ranged from 18.83 ± 0.340 s (CE1) to>180 s (CE4, CE8, CE9, CE12, CE13 and CE14) which failed to bewetted in the predetermined time of ODTs. By statistically analyz-ing the results, it was found that the WT of LS6 was significantlyshorter than that of CE1. Results showed that all ProsolvVR ODT-based formulations (CE4, CE9 and CE14) showed prolonged WT.Replacing AvicelVR PH101 (LS3) with MicrocelacVR 100 (LS10) andCellactoseVR 80 (LS11) increased the WT of ODTs significantly from16.572 ± 0.386 s to 75.653± 0.282 and 91.146 ± 0.109 s, respectively.

In vitro disintegration time (DT)

The mean DT of all ODTs is listed in Tables 3 and 4. LS-ODTs hadDT ranging from 25.42 ± 0.203 s (LS3) to >180 s (LS10 and LS11),whereas DT of CE-ODTs ranged from 26.43 ±1.693 s (CE1) to>180 s (CE4, CE9, CE12, CE13 and CE14). Results showed that theoverall DT of LS-ODTs was found to be shorter than that ofFigure 1. Solubility of CLZ in different nonvolatile solvents.

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 745

CE-ODTs. In case of liquisolid technique, results showed thatdecreasing the liquid load factor (Lf) led to shorter DT of tablets.For MicrocelacVR 100 (LS10) and CellactoseVR 80 (LS11)-based formu-lations, the DT was delayed compared to AvicelVR PH101 (LS3). Butin case of CEs, PharmaburstVR 500 in all ratios with the drug,proved to be the best excipient exhibiting the shortest DT(26.43 ± 1.693, 28.00 ± 3.464 and 43.33 ± 1.527 s for CE1, CE6 andCE11, respectively).

In vitro dissolution studies

The amount of CLZ dissolved after 15min (Q15) and after 2min(Q2) were used as parameters to compare different ODTs (Tables 5and 6, respectively). The data showed that CE1 (prepared usingPharmaburstVR 500) attained the highest (Q15) value(100.633 ± 0.172%), whereas CE9 (prepared using ProsolvVR odt)exhibited the lowest (Q15) value (20.179 ± 1.474%). In case of LS-ODTs, we noticed that the rate of dissolution of drug from LS-ODTs was better when R value was 20 in all ratios of drug in PEG400 (Figure 2(a–d)). In case of R value 20 for all ratios of drug inliquid vehicle, the results of dissolution rate showed that therewas no significant difference between LS-ODTs (LS3, LS6 and LS9),where the mean percent CLZ dissolved after 15min from theseformulations were 88.151 ± 0.484%, 87.552 ± 2.009% and84.744 ± 0.217%, respectively, even if the liquid vehicle amount intheses formulations was different. But in case of coprocessedsuperdisintegrants, it was found that ODTs prepared usingPharmaburstVR 500 were the best as Q15 of CE1, CE6 and CE11were the highest (100.633 ± 0.172%, 97.408 ± 0.118% and79.388 ± 3.393%, respectively) compared to the ODT containingthe same drug/excipients ratio. The fastest release of CLZ fromdifferent ODTs after 2min was attained by LS3 (75.343 ± 1.017%),

whereas the slowest was from CE14 (1.497 ± 0.093%). Generally,LS-ODTs attained faster dissolution rate of CLZ after 2min com-pared to CE-ODTs.

Table 3. Physical evaluation of ODT formulations prepared by coprocessed excipients.

FormulaParameter

Mean weight(mg) ± (SD)

Mean thickness(mm) ± (SD)

Mean friability(%) ± (SD)

Mean hardness(kg) ± (SD)

Mean drug content(%) ± (SD) Mean WT (s) ± (SD) Mean DT (s) ± (SD)

CE1 146.659 ± 0.001 3.641 ± 0.054 0.230 ± 0.034 5.724 ± 0.340 101.07 ± 2.896 18.83 ± 0.340 26.43 ± 1.693CE2 147.352 ± 0.001 3.424 ± 0.044 0.393 ± 0.023 3.954 ± 0.349 104.54 ± 1.506 79.236 ± 0.931 35.00 ± 1.0CE3 146.410 ± 0.008 3.416 ± 0.057 0.382 ± 0.310 3.742 ± 0.545 97.735 ± 4.994 115.163 ± 1.671 50.00 ± 2.530CE4 145.023 ± 0.002 3.423 ± 0.044 0.150 ± 0.005 5.280 ± 0.513 102.201 ± 3.20 >180 >180CE5 151.221 ± 0.034 3.895 ± 0.006 0.432 ± 0.173 4.865 ± 0.351 101.562 ± 0.32 56.75 ± 1.241 64.10 ± 0.986CE6 147.150 ± 0.003 3.750 ± 0.064 0.175 ± 0.062 4.343 ± 0.149 97.752 ± 3.692 40.48 ± 0.6390 28.00 ± 3.464CE7 147.023 ± 0.0158 3.551 ± 0.017 1.338 ± 0.031 3.221 ± 0.594 95.701 ± 2.818 171.72 ± 3.124 67.66 ± 8.082CE8 148.221 ± 0.005 3.483 ± 0.028 2.559 ± 0.102 3.167 ± 0.130 97.600 ± 3.236 >180 84.00 ± 3.605CE9 148.712 ± 0.025 3.632 ± 0.072 0.210 ± 0.304 4.536 ± 0.362 92.654 ± 3.776 >180 >180CE10 149.532 ± 0.021 3.942 ± 0.004 0.867 ± 0.037 3.685 ± 0.045 98.625 ± 0.405 86.312 ± 0.041 105.73 ± 0.061CE11 146.915 ± 1.003 3.841 ± 0.034 0.275 ± 0.125 3.951 ± 0.229 93.118 ± 2.921 45.326 ± 0.938 43.333 ± 1.527CE12 149.326 ± 0.063 3.654 ± 0.018 1.523 ± 0.253 2.833 ± 0.235 93.860 ± 4.117 >180 >180CE13 145.713 ± 0.004 3.504 ± 0.056 Broken 2.569 ± 0.662 97.291 ± 8.427 >180 >180CE14 148.230 ± 0.072 3.766 ± 0.120 Broken 3.945 ± 0.535 92.863 ± 6.862 >180 >180CE15 150.642 ± 0.354 3.846 ± 0.005 Broken 2.532 ± 0.213 101.231 ± 0.46 162.823 ± 0.015 176.43 ± 0.23

Table 4. Physical evaluation of ODT formulations prepared by liquisolid technique.

FormulaParameter

Mean weight(mg) ± (SD)

Thickness(cm) ± (SD)

Mean friability(%) ± (SD)

Mean hardness(kg) ± (SD)

Mean drug content(%) ± (SD) Mean WT (s) ± (SD) Mean DT (s) ± (SD)

LS1 456.6 ± 5.358 0.357 ± 0.004 0.468 ± 0.132 4.48 ± 0.049 97.652 ± 1.230 23.731 ± 0.043 67.43 ± 0.031LS2 609.3 ± 2.790 0.540 ± 0.001 0.178 ± 0.188 3.613 ± 0.056 101.115 ± 1.902 15.343 ± 0.124 29.20 ± 0.413LS3 765.4 ± 5.103 0.645 ± 0.001 0.797 ± 0.011 3.36 ± 0.056 97.845 ± 3.372 16.572 ± 0.386 25.42 ± 0.203LS4 681.3 ± 4.083 0.525 ± 0.001 0.226 ± 0.082 3.86 ± 0.084 95.365 ± 3.174 21.814 ± 0.059 115.16 ± 1.213LS5 914.1 ± 6.261 0.615 ± 0.001 0.625 ± 0.086 3.451 ± 0.007 100.942 ± 2.136 18.461 ± 0.751 32.13 ± 0.096LS6 1151.2 ± 3.705 0.829 ± 0.001 1.328 ± 0.290 3.205 ± 0.127 102.120 ± 1.883 10.302 ± 0.072 29.96 ± 0.041LS7 901.3 ± 3.241 0.554 ± 0.008 0.574 ± 0.223 3.541 ± 0.141 99.743 ± 2.058 157.240 ± 0.201 172.50 ± 0.130LS8 1224.4 ± 2.547 0.675 ± 0.007 0.702 ± 0.461 4.024 ± 0.042 89.213 ± 1.452 64.221 ± 0.314 80.10 ± 0.035LS9 1526.2 ± 4.391 0.915 ± 0.007 2.197 ± 0.649 3.76 ± 0.155 100.00 ± 0.484 43.292 ± 0.045 50.14 ± 0.110LS10 769.2 ± 0.143 0.570 ± 0.002 0.671 ± 0.013 3.42 ± 0.104 97.234 ± 1.431 75.653 ± 0.282 >180LS11 766.4 ± 0.357 0.491 ± 0.001 0.443 ± 0.246 2.59 ± 0.325 99.762 ± 0.590 91.146 ± 0.109 >180

Table 5. Percent of CLZ dissolved after15min (Q15) of different ODTs.

Formula Mean Q15 (%)±SD

CE1 100.633 ± 0.172CE2 96.026 ± 2.363CE3 88.684 ± 1.417CE4 48.010 ± 0.426CE5 71.428 ± 1.264CE6 97.408 ± 0.118CE7 61.558 ± 0.357CE8 35.941 ± 0.668CE9 20.179 ± 1.474CE10 47.308 ± 1.772CE11 79.388 ± 3.393CE12 45.503 ± 0.716CE13 37.139 ± 0.394CE14 23.837 ± 0.258CE15 49.961 ± 1.983LS1 82.672 ± 0.290LS2 92.227 ± 0.290LS3 88.151 ± 0.484LS4 84.162 ± 1.380LS5 84.521 ± 0.145LS6 87.552 ± 2.009LS7 85.461 ± 3.103LS8 88.812 ± 2.290LS9 84.744 ± 0.217LS10 88.442 ± 0.267LS11 85.148 ± 1.787

746 H. A. MOQBEL ET AL.

From the results obtained, it was concluded that CE1 and LS3were the best ODT formulations. Both formulations exhibited fastWT, DT and dissolution rate of CLZ. Thus, CE1 and LS3 were sub-jected to further investigations.

Differential scanning calorimetry (DSC)

The components of LS3 and CE1 were scanned by DSC to detectany interaction between the drug and any excipient used. As men-tioned in our previous research10, the thermogram of CLZ showedan endothermic peak with onset at 188.12 �C and an end set at196.27 �C with peak at 191.4 �C corresponding to its melting point(Figure 3(a,b)). DSC thermogram of AvicelVR PH101 showed smallendothermic peak at 86.73 �C18 (Figure 3(a)), while that of AerosilVR

200 did not show any sharp peaks, proving its presence in anamorphous state19 (Figure 3(a)). The DSC of LS3 (Figure 3(a))showed complete disappearance of the characteristic peak of CLZ.The thermogram of PharmaburstVR 500 showed an endothermicpeak at 166.59 �C due to the mannitol content of the coprocessedexcipient (the melting point of pure mannitol ranges from 166 to168 �C) (Figure 3(b)). The thermogram of the chosen CE1 did notshow the appearance of new peaks, though there was a slightshift in the existing peaks (Figure 3(b)).

Morphology and internal matrix

Intact and longitudinally sectioned ODTs of the selected formula-tions CE1 and LS3 were examined for their surfaces and internalmatrices using SEM (Figure 4). The micrographs of the surface ofCE1 (Figure 4(a,b)) revealed the porous structure of the preparedODT, showing pores of sizes ranging from 1.490 to 4.627 mm.Figure (4(c,d)) demonstrated that the surface of LS3 had pores oflarger size (ranging from 5.008 to 21.32 mm). SEM micrographs ofinternal matrices of CE1 (Figure 4(e)) and LS3 (Figure 4(f)) con-firmed the porous structure of the internal matrices of both tab-lets. Comparing the micrographs of the surfaces of the two ODTs

Figure 2. In vitro dissolution profile of chlorzoxazone from different LS-ODTs at (a) 1:1 ratio of drug: PEG 400; (b) 1:2 ratio of drug: PEG 400; (c) 1:3 ratio of drug: PEG400; (d) at 1:1 ratio of drug: PEG 400 by using MicrocelacVR 100 (LS10) and CellactoseVR 80 (LS11) as carriers.

Table 6. Percent of CLZ dissolved after 2min (Q2) ofdifferent ODTs.

Formula Mean Q2 (%)±SD

CE1 31.653 ± 1.552CE2 24.376 ± 1.382CE3 26.740 ± 2.710CE4 4.403 ± 0.123CE5 5.917 ± 2.092CE6 41.767 ± 0.445CE7 6.421 ± 0.744CE8 6.226 ± 0.546CE9 2.372 ± 0.344CE10 6.616 ± 0.348CE11 18.419 ± 1.521CE12 5.658 ± 0.201CE13 3.459 ± 0.042CE14 1.497 ± 0.093CE15 3.482 ± 0.435LS1 46.781 ± 0.096LS2 57.723 ± 0.169LS3 75.343 ± 1.017LS4 55.154 ± 0.508LS5 54.949 ± 0.411LS6 71.117 ± 1.017LS7 45.236 ± 2.031LS8 56.234 ± 8.088LS9 75.189 ± 1.283LS10 39.161 ± 0.324LS11 20.342 ± 2.266

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 747

(CE1 and LS3) obtained clearly showed that CE1 tablets containedmore number of pores, that is, having higher pore density thanLS3 tablets. In fact, CE1 acquired a sponge-like surface. In addition,the matrix of CE1 showed relatively smaller sized (ranging from7.84 to 8.40 mm) and shallower pores, whereas the matrix of LS3showed larger sized (range 9.06–22.69mm) and deeper pores. Thissupported the relatively faster WT of LS3 (16.572± 0.386 s) com-pared to that of CE1 (18.83 ± 0.340 s), which led to significantlyfaster dissolution rate of CLZ after 2min (Q2) (75.343± 1.017%from LS3) compared to (31.653 ± 1.552% from CE1) (Table 6).

This also verified the higher friability of CE ODTs compared tothat of LS ODTs owing to the sponge-like surface of the formertablets.

In vivo disintegration time (DT) and palatability

The in vivo DT of CE1 and LS3 were evaluated by the six volun-teers participating in the study. The DT was estimated from thetime placing the ODT on the tongues of volunteers to completelydisintegrating in the mouth cavity. Results showed that the meanin vivo DT of CE1 was 19.78 ± 0.810 s and that of LS3 was18.11 ± 0.423 s. Furthermore, the overall acceptability of the twoODTs was evaluated by the volunteers according to a 5-point scor-ing scale. Volunteers found that CE1 dissolved rapidly withoutleaving any gritty particles in the mouth cavity. In addition, itstaste was sweet and the volunteers gave it a mean score of 3. ForLS3, the tablets dissolved fast, but left some powder on thetongue of the volunteers. The taste of LS3 was not as sweet asCE1 and the mean score given by the volunteers was 4.

Discussion

Since PEG 400 had more solubility power for CLZ, it was used asthe solvent vehicle in preparation of different liquisolidformulations.

The reason for the higher friability of CE-ODTs compared tothat of LS-ODTs might be due to the porous nature of ODTs pre-pared using coprocessed excipients that made it more friable.Incase of LS-ODTs, the reason for the inverse relationship between Rvalue and the hardness of the tablets can be explained as follows:increasing the R value leads to an increase in the amount of car-rier powder (AvicelVR PH101) used which is a highly porous mater-ial and a decrease in the amount of coating powder (AerosilVR 200)and this subsequently leads to a decrease in the hardness of thetablets20. But in case of CE-ODTs, the coexcipients had better com-pression properties compared with CLZ powder. So, increasing thedrug to excipients ratio, might have affected the internal structureof the tablet leading to the formation of more fragile tablets10.

The drug content of all tablet formulations was acceptableaccording the pharmacopeial limits21.

The significantly faster WT of LS6 compared with CE1 might bedue to the highly porous nature of the tablet matrix produced byliquisolid technique allowing water to penetrate into the core oftablets and wet their internal matrix rapidly. ProsolvVR odt-basedformulations showed prolonged WT because ProsolvVR odt is com-posed of microcrystalline cellulose and fructose that might lead toan increase in WT depending on the applied compression forceduring tablet manufacture, so increasing compression force led toan increase in WT22. CE12 contained Pearlitol flashVR (composed ofmaize starch and mannitol) in a drug/excipient ratio 2:1. Previousresearchers showed that crospovidone has higher force equivalentparameter values than maize starch23. Therefore, the rate of wateruptake of crospovidone would be higher, so having faster WT. Thereason for the prolonged WT of CE12 was that the ratio ofPearlitol flashVR in the tablet was less than CE2 and CE7, which ledto an increase in the WT of this formula. Both CE8 and CE13 wereformed of StarlacVR (composed of maize starch and lactose). Theformer component was the reason for delaying of WT, in additionto the latter component which was known to form slowly disinte-grating tablets because of slow wetting of tablets caused by theless porosity of the prepared tablets24. Moreover, the ratio ofStarlacVR in these formulations was less compared to that in CE3tablets. In case of LS7, the delay of WT for this formulation might

Figure 3. (a) DSC thermograms of CLZ, AvicelVR

PH101, AerosilVR

200, LubripharmVR

as well as selected ODT (LS3); (b) DSC thermograms of CLZ, PharmaburstVR 500,MAG, LubripharmVR as well as selected ODT (CE1).

Figure 4. SEM micrographs of the selected ODTs: (a) surface of CE1(bar¼ 200lm); (b) surface of CE1 (bar¼ 50lm); (c) surface of LS3(bar¼ 100lm); (d) surface of LS3 (bar¼ 50lm); (e) internal matrix of CE1(bar¼ 50lm); and (f) internal matrix of LS3 (bar¼ 50lm).

748 H. A. MOQBEL ET AL.

be due to decreasing R value meaning a decreased amount of thecarrier powder (AvicelVR PH101), a highly porous material, and anincreased amount of the coating material (AerosilVR 200), of hydro-phobic nature, and this subsequently led to increasing WT of thetablet. In case of ODTs prepared by MicrocelacVR 100 (LS10) andCellactoseVR 80 (LS11) which are coprocess excipients containinglactose, previous researchers showed that lactose-containing tab-lets showed lower percentage of pores when measured using mer-cury porosimetry, so this would lead to a delayed WT of ODTscontaining these two coexcipients24. This explained the prolongedWT of LS10 and LS11.

The most important parameter that needs to be optimized inthe development of ODTs is the disintegration time of the tablet.Generally, the faster DT of LS-ODTs compared to CE-ODTs mightbe due to the porous nature of the ODTs formulated by liquisolidtechnique, as a result of inclusion of both MCC and SSG, highlyporous materials, creating a higher permeable tablet matrix. Incase of liquisolid technique, it was clear that decreasing the liquidload factor (Lf) led to increasing the amount of carrier powder(AvicelVR PH101) used which is a highly porous material thus facili-tating the disintegration of tablets. For MicrocelacVR 100 (LS10) andCellactoseVR 80 (LS11) based formulations, the delayed DT was aresult of presence of lactose25. In case of CEs, PharmaburstVR 500 inall ratios with the drug, proved to be the best excipient exhibitingthe fastest DT owing to the higher capacity of crospovidone assuperdisintegrant (component of coexcipient PharmaburstVR 500),as it had rapid capillary-forming activity and pronounced hydra-tion with little tendency to gel formation. These factors suggestedthat the DT could be decreased by using wicking type disinte-grants as crospovidone26.

As tablet disintegration is necessary for the release of thedrug from ODTs, so the drug dissolution from the tablet beingthe most important parameter for drug absorption27. A previousstudy confirmed that the R value is an important parameter forLS systems and must reach at least 20 to obtain enhanced drugrelease28. An increase in the R value resulted in an enhanceddrug release rate because LS-ODTs with high R values containedhigh amounts of AvicelVR PH101, low quantities of AerosilVR 200and low liquid-to-powder ratios. This was associated withenhanced wicking, disintegration and thus, enhanced drugrelease. In contrast, if high amounts of AerosilVR 200 are used,which means that the R value is low, the LS-ODTs is overloadedwith liquid formulation due to a high Lf. In such cases, eventhough drug diffusion out of the primary particles could berapid, oversaturation might occur resulting in local precipitationor recrystallization of the drug and thus decreased releaserates29. Since the drug particles in LS-ODTs are in state ofmolecular dispersion, then, its saturated solubility might beincreased. The small amount of liquid vehicle in LS-ODTs mightnot be adequate to increase the overall saturation solubility ofdrug particles in the dissolution medium. Nevertheless, in the dif-fusion layer (the solid/liquid interface between primary liquisolidparticles and dissolution medium), in such a microenvironment, itis possible that infinite amount of liquid vehicle diffuse with thedrug particles away from the primary liquisolid particles. In thiscase, small amount of liquid vehicle might be sufficient toimprove the solubility of drug particles by acting as cosolventwith the dissolution medium of the diffusion layer. As a conse-quence of increase in saturated solubility (Cs), the concentrationgradient (Cs-C) of the drug will be increased, and hence, thedrug dissolution rate would be increased12,19,28–31. The faster dis-solution rate of CLZ from LS-ODTs after 2min compared toCE-ODTs could be attributed to results obtained by WT and DTstudies.

The complete disappearance of the characteristic peak of CLZin DSC thermogram of LS3 (Figure 3(a)) proved the formation ofdrug solution in the liquisolid-powdered system (the drug wasmolecularly dispersed within the liquisolid matrix32. The thermo-gram of the chosen CE1 did not show the appearance of newpeaks, thus indicating no interaction between the drug and theused excipients (Figure 3(b)). However, the slight shift in the peakswas produced by virtue of mixing of components which reducedthe purity of the components.

The SEM micrographs of the porous surfaces of CE1 (Figure4(a,b)) and LS3 (Figure 4(c,d)) supported previous results obtainedby WT and DT where the porous surfaces of the two ODTsincreased the hydration capacity (wetting) and consequently thefast disintegration of the tablets.

The in vivo DT of both tablets did not differ significantly fromeach other. So, it could not be used as a parameter to comparethe two approaches used to prepare the tablets. The sweet tasteof CE1 was due to the mannitol content of PharmaburstVR 500. LS3suffered from powdery taste that was due to the high powdercontent in the tablet. Moreover, the tablet weight of LS3 is morethan 5 times that of CE1, which makes it also much less palatable.

Thus, it was concluded that CE1 was more acceptable and itstaste was more palatable than that of LS3.

Conclusion

In this study, orodispersible tablets of chlorzoxazone were success-fully prepared by direct compression method using different cop-rocessed superdisintegrants or liquisolid technique. Bothapproaches were capable of producing orodispersible tablets withease and low cost of manufacture. Both tablets attained short invivo disintegration time (CE1, 19.78 and LS3, 18.11 s), which werenonsignificantly different from each other (p> .05). Orodispersibletablets prepared by compression with PharmaburstVR 500 in thehighest concentration (CE1) showed the highest Q15min and hadacceptable palatability. Thus, the use of coprocessed superdisinte-grant could be effective in formulating orodispersible tablets ofchlorzoxazone beneficial for pediatrics, geriatrics and psychiatricpatients and will also help to improve patient compliance. Futurestudies involving comparative bioavailability studies of theselected formulations prepared by both techniques in human vol-unteers is required to help choosing the optimum approach informulation.

Disclosure statement

The authors report no conflicts of interest. The authors alone areresponsible for the content and writing of this article.

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