COMPARATIVE EVALUATION OF TASTE MASKING METHODS OF ONDANSETRON HCl

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Bhalekar et al. SJIF Impact Factor 2.786 Volume 3, Issue 8, 982-995. Research Article ISSN 2278 4357 COMPARATIVE EVALUATION OF TASTE MASKING METHODS OF ONDANSETRON HCl Mangesh.R. Bhalekar*, Ashwini R. Madgulkar, Rahul R. Padalkar, Dipul. B.Manwar Department of Pharmaceutics, AISSMS college of Pharmacy, Kennedy Road, near R.T.O, Pune -411001, India Article Received on 09 May 2014, Revised on 19 June 2014, Accepted on 05 July 2014 *Correspondence for Author Dr.Mangesh. R. Bhalekar Department of Pharmaceutics, AISSMS college of Pharmacy, Kennedy Road, near R.T.O Pune -411001, India ABSTRACT The present work was aimed to mask the bitter taste of ondansetron HCl using different methods including ion exchange complexation and liquid matrix of xyloglucan polymer. Ondansetron HCl is 5HT3 receptor antagonist used for treatment of emesis. The drug has bitter taste therefore faces problem in oral administration. Indion 234 was used for ion exchange complex formation. The process was optimized for maximum drug loading. It was observed that drug and resin when used in 1:1 ratio gave optimum outcomes. Complexes were evaluated for drug loading, taste evaluation and drug release. Characterization of complex was carried out with the help of IR spectroscopy. Taste masked suspension of this drug resin complex was formulated and evaluated for taste, drug content, viscosity, sedimentation volume, drug release. Evaluation of suspension shows satisfactory result with 73.3 % drug release within 20 min. In another method a liquid matrix of xyloglucan in syrup base was formulated and evaluated for taste, drug content, ph viscosity and drug release. Polymer concentration 5 % and sugar concentration 10 % showed satisfactory result. Comparative In vitro taste evaluation of drug resin complex suspension and syrup with xyloglucan polymer shows that suspension with drug resin complex was more beneficial in taste masking. Keywords OndansetronHCl, Indion234, xyloglucan, taste masking. INTRODUCTION Any medication which imparts an unpleasant taste is likely to result in poor patient compliance to a drug regimen especially for the children and elderly. Different taste masking technologies have been used to address the problem of patient compliance. Conventional www.wjpps.com Vol 3, Issue 8, 2014. 982

taste masking techniques such as the use of sweeteners, amino acids and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs 1. Ion exchange resin (IER) provides alternative method for taste masking. In which weak cation exchange or weak anion exchange resins are used for taste masking, depending on the nature of drug 2. The nature of the drug resin -complex formed is such that the average ph of 6.7 and cation concentration of about 40meq/L in the saliva are not able to break the drug resin complex but it is weak enough to break down by hydrochloric acid present in the stomach. 3, 4 Thus the drug resin complex is absolutely tasteless with no after taste, and at the same time, its bioavailability is not affected. Ondansetron HCl is 5HT3 antagonist commonly used as antiemetic but having problem of bitter taste, while prescribing the drug to pediatric and geriatric patient the tablet and capsule dosage form have to face difficulty in swallowing, so liquid formulations are good alternative for that. Here is one attempt to form tasteless resinate of ondansetron with Indion 234 and incorporate it into suspension with suitable suspending agent like xanthan gum. Another method used for taste masking involve forming of paste of xyloglucan polymer containing drug so the drug get incorporate in it and dilute the paste to required volume with addition of sweetener, and flavor to form oral liquid(syrup) with pleasant taste. MATERIALS AND METHODS 1 Materials Ondansetron HCl (Pranami drugs pvt. Ltd., Ankleshwar, India), Indion234 (Ion Exchange Ltd., Mumbai, India), Xyloglucan(Encore polymer pvt.ltd) were obtained as a gift sample. All other Chemicals used were of Analytical Reagent grade and procured from the local suppliers. 2.Methodology 2.1Method of analysis The drug was estimated spectrophotometrically at 248 nm using UV VIS spectrophotometer. In this research work Following two taste masking products of ondansetron HCl was prepared. 1) Suspension of taste masked drug: resin complex. 2) Taste masked Syrup using xyloglucan. www.wjpps.com Vol 3, Issue 8, 2014. 983

2.2Suspension of taste masked drug: resin complex Taste masked resinate (drug: resin complex) was prepared using suitable ion exchange resin. Indion 235 resin was selected for taste masking. After characterization these resinate was incorporate into suspending medium to formulate suspension. 2.2.1 Preparation of taste masked resinate Drug resin complexes were prepared by batch method, 100 mg of drug added into 100 ml deionised water. Required amount of resin was added into drug solution to form various drug resin ratios like 1: 0.5, 1: 1, 1:1.5 and stirred for 3 hour. The amount of drug adsorbed was determined by the difference between amount of drug present in stock solution and amount remaining in filtrate at the end of equilibrium. The drug resin ratio with highest drug loading was further checked for effect of ph and stirring time to find optimum conditions for drug loading. 2.2.2Evaluation of Resinate Drug content 100 mg Resinate was stirred with 100ml of 0.1 N HCL for 3 h, till the entire drug leached out, and then the solution was filtered through a Whatman filter paper. Further dilutions were made with 0.1 N HCl and the drug content was determined spectrophotometrically at 248 nm using 0.1 N HCl as blank. Taste evaluation It was done in 2 parts A) Threshold bitterness concentration of Ondansetron HCl A panel of ten healthy human volunteers (age 20-25) was selected. A series of solutions of OndansetronHCl of concentrations 10, 20, 30, 40 and 50 μg/ml was prepared. Ten healthy human volunteers (age 20-25) were asked to taste and rate the taste. Based on the opinion of the volunteers, threshold bitterness concentration of drug was judged. B) In vitro taste evaluation A quantity of DRC equivalent to dose of Ondansetron HCl was added to each of the 3 volumetric flasks containing 10 ml of phosphate buffer of ph 6.8. The mixtures were vortexed for 20, 40 and 60 seconds and filtered. Content of Ondansetron HCl in each filtrate www.wjpps.com Vol 3, Issue 8, 2014. 984

was determined. For satisfactory taste masking, the amount of drug dissolved at the end of 60 seconds should not be more than the threshold bitterness concentration of the drug. Micromeritic properties Compressibility, angle of repose, and bulk density were determined using the methods described in the literature. FTIR diffraction The Infrared spectra of ondansetron HCl, Indion 234 and resinate were obtained using Fourier Transform Infrared (FTIR) spectroscopy (Jasco 460 plus, Tokyo, Japan). Differential scanning calorimetry study (DSC) A Mettler Toledo Differential Scanning Calorimeter (DSC) 821 (Mettler Toledo, Greifensee, Switzerland) equipped with an intracooler and a refrigerated cooling system was used to analyze the thermal behavior of ondansetron HCl, xyloglucan and ondansetron HCl loaded beads, in hermetically sealed flat aluminium crucibles, with temperature range from 30 to 300ºC. Indium standard was used to calibrate the DSC temperature. Nitrogen was purged at 40 ml/min and 100 ml/min through cooling unit. In vitro release of on dansetron HCl from resinate Weighed quantity of resinate equivalent to normal dose of drug was subjected to dissolution studies using USP Type II dissolution test apparatus at 50 rpm with temperature of 37 ± 0.5 C and 900 ml 0.1 N HCl used as the dissolution medium. An aliquot equal to 5 ml was withdrawn at specific time interval, and it was filtered through Whatman filter paper. Absorption of the filtered solution was checked by UV spectroscopy at 248 nm and quantity of drug released was determined periodically 2.2.3.Formulation of Oral Suspension of Taste masked resinate of Ondansetron HCl Suspending medium plays an important role in suspension stability and acceptability of suspension as oral drug delivery system. Syrup based suspending medium were developed for suspending the taste masked product previously prepared. 5, 6, 7 (Table 1) www.wjpps.com Vol 3, Issue 8, 2014. 985

Table 1- Formula for Suspension Ingredients F1 F2 F3 F4 DRC 113.6 mg 113.6 mg 113.6 mg 113.6 mg Sucrose 15 gm 15 gm 15 gm 15 gm Sorbitol 4 ml 4 ml 4 ml 4 ml Xanthan 20 mg 30 mg 40 mg 50 mg Glycerine 4 ml 4 ml 4 ml 4 ml Tween 80 0.02 ml 0.02 ml 0.02 ml 0.02 ml M.Paraben 80 mg 80 mg 80 mg 80 mg P.Paraben 16 mg 16 mg 16 mg 16 mg Raspberry flavour 10 mg 10 mg 10 mg 10 mg Deionised water Up to 50 ml Up to 50 ml Up to 50 ml Up to 50 ml These media were evaluated for their pourability, redispersibility and height of sedimentation from these suspending medium. One medium was chosen for the final formulation. Procedure for preparation of suspension A) Preparation of syrup base A weighed quantity of sugar (15 gm) was dissolved in 25 ml of boiled water and filtered. Weighed quantities of sorbitol (4 ml), glycerin (4 ml), varying amount of xanthan gum (20, 30, 40, 50mg), Tween-80(0.02ml), methyl paraben (80 mg), propyl paraben (16 mg) were added in sugar solution under stirring. B) Mixing of DR complex with Syrup The drug resin complex obtained was added in to sugar solution under stirring. Weighed quantity of flavoring agent was added in above solution & stirred for 10 min. The volume of suspension was made up to required quantity by using purified water. 2.3. Taste masked syrup using xyloglucan syrup Taste masked syrup was prepared using natural polymer xyloglucan; drug and polymer were mix homogenously to form stiff paste and dilute with water to required volume. Table 2 Formula of Taste masked syrup Ingredients F1 F2 F3 F4 Drug 50mg 50mg 50mg 50mg Xyloglucan 1.0 gm 1.5 gm 2.0 gm 2.5 gm Sucrose 5.0 gm 5.0 gm 5.0 gm 5.0gm Flavour 10 mg 10 mg 10 mg 10mg Distilled H 2 O Upto 50 ml Upto 50 ml Upto 50 ml Upto 50 ml www.wjpps.com Vol 3, Issue 8, 2014. 986

1. Preparation of Taste masked syrup 50 mg of Ondansetron HCl was mix with varying concentration of xyloglucan (2, 3, 4, &5% w/v) polymer to form stiff paste so drug was homogeneously mixed with polymer and the paste was diluted using distilled water with mild stirring to required volume (50 ml). 10 % sucrose was added in liquid along with sufficient quantity of flavor. (Table 2) 2.4.Evaluation of taste masked products 1) Taste masked suspensions Viscosity: The viscosity of suspensions was determined at ambient condition using Brookfield viscometer. In adapter 15ml of suspension was taken and the adapter is set over the viscometer by a stand such a way that spindle is completely immersed in the suspension. Spindle no. S 62 was used to measure the viscosity of suspension. Sedimentation characteristic: The formulated suspensions were evaluated for physical stability by determining the Sedimentation ratio. 25 ml each of suspension was taken in 25 ml stopped graduated measuring cylinder. The suspension was dispersed thoroughly by moving upside down for three times. Later, the suspension was allowed to settle for three minutes and the volume of sediment was noted. This is the original volume of sediment (Ho). The cylinder was kept undisturbed for 14 days. The volume of sediment read on the 14th day was considered as final volume of sediment (Hu). Separation ratio = Hs/Ho Where Hs= Height of upper clear layer in mm and Ho= Original height of sample column in mm. Resuspendability: Resuspendability of suspension was expressed in terms of number of shakes required to redispersed the settled layer resulting after one month storage period at room temperature. The redispersibility of the suspensions was checked by tilting the stoppered cylinder upside down until there was no sediment at the bottom of the cylinder. Number of tilts required for suspension was shown in table. ph: ph of the suspension was determined by the use of ph meter. Drug content of suspension: 5 ml of suspension was diluted suitably using 0.1 N HCL and drug content was estimated spectrophotometrically. www.wjpps.com Vol 3, Issue 8, 2014. 987

In vitro Taste Evaluation: Suspension equal to normal dose of drug was added to each of the 3 volumetric flasks containing 10 ml of phosphate buffer of ph 6.8. The mixtures were vortexes for 20, 40 and 60 seconds and filtered. Content of Ondansetron in each filtrate was determined. For satisfactory taste masking, the amount of drug dissolved at the end of 60 seconds should not be more than the threshold bitterness concentration of the drug. In-vitro drug release profile: The dissolution studies were carried out in USP Dissolution Test Apparatus Type II. 900ml of 0.1 N HCl was used as dissolution medium maintained at 37 C ± 0.5 C. Paddles were rotated at 100rpm. 5ml samples were collected at interval of 5 min for 30min. The collected samples were analyzed for drug release by spectrophotometric analysis. 2) Evaluation of Taste masked Syrup Viscosity The viscosity of syrup was determined at ambient condition using Brookfield viscometer. In adapter 15ml of syrup was taken and the adapter is set over the viscometer by a stand such a way that spindle is completely immersed in the syrup. Spindle no. S 62 was used to measure the viscosity of suspension. ph: ph of the solution was determined by the use of ph meter. Drug content of Syrup: 5 ml of solution was diluted suitably using 0.1 N HCl and drug content was estimated spectrophotometrically. In vitro Taste Evaluation: Syrup equal to normal dose of drug was added to each of the 3 volumetric flasks containing 10 ml of phosphate buffer of ph 6.8. The mixtures were vortexes for 20, 40 and 60 seconds and filtered. Content of Ondansetron in each filtrate was determined. For satisfactory taste masking, the amount of drug dissolved at the end of 60 seconds should not be more than the threshold bitterness concentration of the drug. In-vitro drug release profile: The dissolution studies were carried out in USP Dissolution Apparatus Type II. 900ml of 0.1 N HCl was used as dissolution medium maintained at 37 C ± 0.5 C. Paddles were rotated at 100rpm. 5ml samples were collected at interval of 5 min for 30min. The collected samples were analyzed for drug release by spectrophotometric analysis. www.wjpps.com Vol 3, Issue 8, 2014. 988

RESULT AND DISCUSSION 1) Taste masked suspension using ion exchange resin 1.1 Preparation of taste masked resinate Attempt was made to optimize drug loading by carrying out drug loading at different drug: resin concentrations. Resinate was prepared using different drug: resin ratio. Table 3 show that drug : resin ratio 1:1 shows maximum drug loading and entrapment, ph 3.5 show maximum drug loading this can be attributed that cationic drug is ionized at lower ph value hence demonstrates high binding capacity. Drug loading also affected by stirring time. Drug loading increases with increasing Time up to 4 hours after that there was no significant increase in drug loading. Thus resinate prepared by batch method using Indion 234 with a drug resin ratio 1:1 at ph 3.4 and stirred for 4 hours gives optimum drug loading. So it was selected for further study. Table 3 % Drug Loading (n = 3) Drug : resin ratio % Drug loading 1: 0.5 83.95 ± 0.84 1: 1 88.01 ± 0.42 1 : 1.5 75.55 ± 0.24 Drug content When DRC was prepared using all of the optimized parameters for drug loading, the percent drug loading was found to be 88.01 and hence, the drug content was 44.00 % wt/wt. Taste evaluation Threshold bitterness of ondansetron HCl Most volunteers reported Threshold bitterness at 30µg/ml (table 4). Table 4 -Threshold bitterness of ondansetron HCl Volunteer No. Rating on the scale of bitterness 10µg/ml 20µg/ml 30µg/ml 40µg/ml 50µg/ml 1 0 0 1 2 2 2 0 0 1 2 3 3 0 0 1 1 2 4 0 0 1 2 3 www.wjpps.com Vol 3, Issue 8, 2014. 989

5 0 0 1 2 3 6 0 0 1 2 2 7 0 0 1 3 3 8 0 1 3 3 3 9 0 1 2 2 3 10 0 0 2 3 3 0 =No bitterness, 1=Threshold bitterness, 2=bitter, 3=Moderate bitter, 4=Strong bitter In vitro taste evaluation Resinate with drug: resin concentration 1:1 show satisfactory result with 11.1µg/ml in vitro drug release in SSF within 60 sec lower than threshold bitterness concentration of ondansetron (Table 5). Table 5- In vitro taste evaluation of resinate Sr.no Time ( sec) Concentration( μg/ml) 1 20 5.59 ± 0.22 2 40 8.8 ± 0.03 3 60 11.09 ± 0.33 Micromeritic properties of resinate Micromeritic properties of Drug resin complex were evaluated such as bulk density, angle of repose and compressibility (Table 6).It was found that the flow and compressibility of resinate were satisfactory. Table 6 Micromeritic properties of resinate FTIR study Sr. No. Property DRC 1 Bulk density( g/ml ) 0.617 2 Tap density( g/ml ) 0.758 3 Angle of repose ( º ) 28.49 4 Carr s index ( % ) 18.16 5 Hausner ratio 1.22 From IR data (Figure 26), pure drug shows band of bonded O-H from 3477.03 to 3376.19 cm -1. Indion 234 shows Charecteristics peak at 1674 cm -1 corresponding to C=O stretching of aryl acid. The absence of peak at 3477.03 to 3376.19 cm -1 in spectra of DRC confirms Complexation of secondary amine group in the drug to with resin. (Fig 1) www.wjpps.com Vol 3, Issue 8, 2014. 990

Differential scanning calorimetry study (DSC) The thermogram of Ondansetron HCl shows a sharp endothermic peak at 183.96 C which is melting point of pure drug. The endothermic peak of Ondansetron HCl was absent in the thermogram of DRC therefore it was confirmed that drug was completely dispersed in matrix structure of Indion234 resin shown in Figure 2. Fig 1 FTIR spectrum A) Ondansetron, B) Indion 234, C) DRC Fig 2- DSC Thermogram of 1) Ondansetron HCl 2) DRC www.wjpps.com Vol 3, Issue 8, 2014. 991

% RELEASE Bhalekar et al. In vitro drug release In vitro release profile of DRC234 shows drug release of 80.15 % within 20 min (Figure 3). Indion 234 is a weak cationic resin and has high affinity for H + ions. So, in acidic environment, it readily loses the adsorbed drug species hence drug release is observed at a faster rate. 120 100 80 60 40 20 0 % Release 0 10 20 30 40 TIME (min) % Release Fig 3 - In vitro drug release profile from resinate 1.2 Evaluation of suspension Physiological characteristics of suspension: Sedimentation studies showed that the sedimentation ratio of all formulations is in the range of 0.98 to 1, which indicates that the formulations were acceptable. Table 7 Evaluation of Suspension Evaluation parameters F1 F2 F3 F4 Viscosity (cps) 46 47 50 50.4 ph 6.0 5.8 6.2 6.2 Sedimentation ratio 0.98 0.98 1 1 Resuspendability (no. of tilts) 7 6 4 4 Assay % 99.15 99.23 99.15 98.8 The viscosity of the formulations was such that it would be easily pourable from the container. The percentage drug content of the prepared suspension was within the limits. Results of the evaluation of Ondansetron HCl suspension formulations are shown in above Table 7. www.wjpps.com Vol 3, Issue 8, 2014. 992

% RELEASE Bhalekar et al. In vitro taste evaluation of Suspension The in-vitro taste evaluation of suspension in the buffer of salivary ph 6.8 showed that the drug does not get released in saliva to attain threshold bitterness concentrations indicates satisfactory Tate masking was done. Table 8 In vitro taste evaluation of Suspension Formulation Code Drug release in Phosphate buffer of ph 6.8 20 sec 40 sec 60 sec F1 4.90 ug/ml 5.90 μg/ml 10.94 μg/ml F2 4.20 μg/ml 6.02μg/ml 10.14 μg/ml F3 4.40μg/ml 6.12 μg/ml 10.38 μg/ml F4 4.12 μg/ml 6.52 μg/ml 10.12 μg/ml Dissolution studies: The Study was carried out in 0.1 N HCL using USP paddle apparatus at 100 rpm. The formulation showed 73.3 % drug release within 20 min (Fig 4). 120 100 80 60 40 20 0 % RELEASE 0 10 20 30 40 % RELEASE TIME (min) Fig 4 In vitro drug release profile of suspension 1 2. Evaluation of taste masked syrup Taste masked Syrup was evaluated for different Parameters like ph, viscosity and drug content. All tests show satisfactory result. (Table9) Table 9 Evaluation of Taste masked Syrup. Evaluation parameters F1 F2 F3 F4 Viscosity (cps) 46 48 53 56 ph 6.2 6.0 6.2 6.2 Assay % 98.3 98.2 98.3 98.5 www.wjpps.com Vol 3, Issue 8, 2014. 993

% RELEASE Bhalekar et al. In vitro taste evaluation of Syrup The in vitro taste evaluation of syrup in buffer of salivary ph 6.8was done for all 4 formulations,.among them formulation F4 (5% polymer concentration) shows satisfactory result with drug release lower than the threshold bitterness concentration of the drug. While remaining 3 formulations shows drug release more than threshold bitterness concentration of drug. So formulation F4 was selected for further study. Table 10-In vitro taste evaluation of Syrup Formulation Code Drug release in Phosphate buffer of ph 6.8 20 sec 40 sec 60 sec F1 65.3 ug/ml 74.34 μg/ml 88.98 μg/ml F2 46.56 μg/ml 52.94μg/ml 56.23 μg/ml F3 18.67 μg/ml 26.87 μg/ml 40.12 μg/ml F4 12.1 μg/ml 22.5 μg/ml 28.52 μg/ml Dissolution study 120 100 80 60 40 20 0 % RELEASE 0 10 20 30 40 TIME (sec) % RELEASE Fig 5 - In vitro drug release profile of syrup Dissolution study of syrup was carried out in 0.1 N HCl using USP paddle apparatus at 100 rpm. The formulation shows93.65 % drug release within 20 min. (Fig 5) 4. CONCLUSION The present work was based on comparative evaluation of taste masking methods for ondansetron HCl. Initially taste masking was carried out by ion exchange complexation using Indion 234 and liquid polymer matrix of xyloglucan in syrup base. In both cases the processes were optimized for various physical parameters and satisfactory taste masking. www.wjpps.com Vol 3, Issue 8, 2014. 994

When comparative evaluation of both methods was done it was observed that ion exchange complexation using weak cation exchange resins like Indion 234 is more suitable method for taste masking on ondansetron HCl. REFERENCES 1. Sohi H, Sultana Y, Khar R, Taste masking technologies in oral pharmaceuticals: Recent developments and approaches, Drug Dev. Ind. Pharm., 2004, 30(5), 429-448. 2. Avari J.G, Bhalekar M.R., Cation exchange resin for taste masking and rapid dissolution of sparfloxacin, IndianDrugs 41 (2004) 19-23. 3. Madgulkar A., Bhalekar M., Padalkar R., Formulation Design and Optimization of Novel Taste Masked Mouth-Dissolving Tablets of Tramadol Having Adequate Mechanical Strength, AAPS PharmSciTech. 2009; 10(2): 574 581. 4. Anand V, Kandarapu R, Garg S, Ion-exchange resins: carrying drug delivery forward, DDT, 2001, 6, 905 914. Vol 1: 2 (2011)IJPI s Journal of Pharmaceutics and Cosmetology. 5. Holl W, Sontheimer H, Ion exchange kinetics of the protonation of weak acid ion exchange resins, Chem. Eng. Sci., 1977, 32, 755 762. 6. Borodkin S, Sundberg DP, Polycarboxylic acid ion-exchange resin adsorbates for taste coverage in chewable tablets, J. Pharm. Sci., 1971, 60, 1523 1527. 7) Patel NK, Lloyd K, Saul L. Pharmaceutical suspensions. In: Lachman L Liberman, HA Kanig JL, editors. The Theory and Practice of Industrial Pharmacy, Bombay Varghese Publishing House 1991; 479-501. 7. Blase CM, Shah M, inventors. Taste masked pharmaceutical suspensions containing xanthum gum and microcrystalline cellulose. European Patent 0556057. 18 th August. 1993. 8. Sayed UG, Bajaj AN. Oral control release bromhexine ion exchange resinates suspension formulation. Indian Drugs 2000; 37:185-189. www.wjpps.com Vol 3, Issue 8, 2014. 995