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International Journal of Drug Development & Research | April-June 2012 | Vol. 4 | Issue 2 | ISSN 0975-9344 | Available online http://www.ijddr.in Covered in Official Product of Elsevier, The Netherlands SJR Impact Value 0.03,& H index 2 ©2012 IJDDR Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide Shaikh Sanaa, Athawale Rajania*, Nadkar Sumedhab and Bharati Maheshb a FULL Length Research Paper Covered in Index Copernicus with IC Value 4.68 for 2010 C.
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    Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide   Shaikh Sana a , Athawale Rajani a* , Nadkar Sumedha b  and Bharati Mahesh b   a C.U. Shah College of Pharmacy, S.N.D.T Women’s University, Sir Vithaldas Vidya Vihar, Juhu Road, Santacruz (West), Mumbai-400 049, India. b Novartis Healthcare Pvt. Ltd., OTC Buisness Unit, R&D Lab, Tiffany, 6 th  Floor, Hiranandani Business Park, Off Ghodbunder Road, Patlipada, Thane (W)- 400 607, India.  Key words : Resin, Dextromethorphan Hydrobromide, taste masking, pediatric, redispersibility, optimization.  How to Cite this Paper  : Shaikh Sana, Athawale Rajani * , Nadkar Sumedha and Bharati Mahesh  “Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide”, Int. J. Drug Dev. & Res., April-June 2012, 4(2): 159-172 Copyright © 2012 IJDDR, Shaikh Sana et al . This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal  work is properly cited.   1. INTRODUCTION  A wide variety of active pharmaceutical agents exhibit the undesirable characteristic of bitter taste either during or immediately after oral administration. Among these are included such    International Journal of Drug Development & Research |  April-June 2012 |   Vol. 4 |    Issue 2 |  ISSN 0975-9344 |   Available online http://www.ijddr.in Covered in Official Product of Elsevier, The Netherlands SJR Impact Value 0.03,& H index 2 ©2012 IJDDR    Abstract Taste is an important factor in the development of dosage form. The problem of bitter and obnoxious taste of drug in pediatric and geriatric formulations is a challenge to the pharmacist in the present scenario. In order to ensure patient compliance bitterness masking becomes essential. The purpose of this research was to mask the intensely bitter taste of Dextromethorphan Hydrobromide using ion exchange resin and to formulate oral suspension of the taste masked drug. When suspension is swallowed bitter taste may not be felt because ion exchange resin complex does not release drug at salivary pH. When it comes in contact with acidic environment of stomach, the complex will be broken down releasing the drug which may then absorbed. Batch method was used for formation of drug resin complex. Various ion exchange resins such as Ionex QM 1011, Ionex WC 23 and Kyron T- 114 were tried to obtained taste masked drug resin complex (DRC). Optimization of drug loading was carried out. With Ionex QM 1011, the drug-resin proportion of 1:6 achieved equilibrium in 6 hours. 96% w/w of drug loading was possible by this method. Complex formation was confirmed by DSC and IR studies. Oral taste masked suspension was prepared using xanthum gum and tween 80 and  was evaluated with respect to parameters such as Colour, pH,  Viscosity, Sedimentation volume, Redispersibility, Assay, drug release. Taste masking was evaluated with the help of panel of human volunteers and Rat Behavioral Avoidance Taste Model. Taste masked suspension showed easy redispersibility and more than 99.6 % of the drug release within 45 minutes at pH 1.2. Thus, results conclusively demonstrated successful taste masking and formulation of suspension with taste masked drug especially for pediatric, geriatric, bedridden, and non cooperative patients. *Corresponding author, Mailing address:  Athawale Rajani E-mail: rajani.athawale@gmail.com  Article History:------------------------  Date of Submission: 27-03-2012  Date of Acceptance: 11-04-2012 Conflict of Interest: NIL  Source of Support  :  NONE    F  UL L L  en g t h R e s e ar ch P a p er C o v er e d i  nI n d  ex C o p erni   c u s wi   t h I  C V al   u e 4 . 6  8 f   or2 01  0   Int. J. Drug Dev. & Res., April-June 2012, 4 (2): 159-172 Covered in Scopus & Embase, Elsevier 159  diverse medicinal agents as acetaminophen, ampicillin, azithromycin, chlorpheniramine, cimetidine, dextromethorphan, diphenhydramine, erythromycin, ibuprofen, penicillin, phenylbutazone, psuedoephedrine, ranitidine, spironolactone and theophylline. [1]   Various techniques have been identified for taste masking which include polymer coating, inclusion complex formation with β-cyclodextrin, use of ion exchange resins, solubility limiting methods, etc 2 Conventional taste masking techniques such as the use of sweeteners and flavoring agents alone are often inadequate in masking the taste of highly bitter drugs. Coating is more efficient technology for aggressively bitter drugs even though coating imperfections, if present, reduce the efficiency of the technique. [3]   With respect to OTC preparations, such as cough and cold syrups, the bitterness of the preparation leads to lack of patient compliance. There are numerous pharmaceutical and OTC preparations that contain Dextromethorphan Hydrobromide as active which is  bitter in taste. [2]  Dextromethorphan Hydrobromide is an antitussive used in much over-the-counter cold medication. It has an opioid like structure but, being a d-isomer it does not possess the analgesic or addictive properties of opioids. It is active against dry cough and does not exhibit significant expectorant properties for productive cough. [4]  Dextromethorphan Hydrobromide has amine as a functional group, which is the cause of their obnoxious taste. If this functional group is blocked by complex formation the bitterness of the drug reduces drastically. [4]  Ion exchange resins have been increasingly used as taste masking agents. Desired properties of pharmaceutical grade Ion Exchange Resins are: 5  a) Fine, free flowing powders  b) Particle size of 25 - 150 microns c) Contain functional group that capable of exchanging ions and/or ionic groups d) Insoluble in all solvents & all pH conditions. e) Not absorbed by body Ion exchange resins are water insoluble, cross-linked polymers containing salt forming groups in repeating position on the polymer chain. Drug can be bound to the ion exchange resin by either repeated exposure of the resin to the drug in a chromatographic column (column method) or by prolonged contact of resin  with the drug solution (batch method). Drugs are attached to the oppositively charged resin substrates or resinates through weak ionic bonding so that dissociation of the drug-resin complex does not occur under salivary pH conditions. This suitably masks the unpleasant taste and odour of drugs [5] . Thus the aim of present research work was to formulate & evaluate oral taste masked suspension of antitussive drug. 2. MATERIAL AND METHODS 2.1 Materials Dextromethorphan Hydrobromide was procured from Divi’s Laboratories Ltd., (Hyderabad, India). Ionex WC 23 and Ionex QM 1011 were obtained as gift sample from Phaex Polymers (Mumbai, India)  whereas Kyron T-114 was obtained as gift sample from Corel Pharma Chem. (Ahmedabad, India). Sucrose, Sorbitol, Xanthum gum, Sucralose, Methyl paraben, Propyl paraben, Cherry and Pineapple flavour were purchased from S. D. Fine chemicals (Mumbai, India). All other chemicals/solvents of analytical grade were used. 2.2 Methodology 2.2.1 Formation of Drug Complex Using Suitable Ion Exchange Resin 2.2.1.1 Preparation of drug resin complex (DRC): Drug and resin were accurately weighed in required ratio. Then slurry of resin was made in demineralised F  UL L L  en g t h R e s e ar ch P a p er C o v er e d i  nI n d  ex C o p erni   c u s wi   t h I  C V al   u e 4 . 6  8 f   or2 01  0  Athawale Rajani et al: Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide   Int. J. Drug Dev. & Res., April-June 2012, 4 (2): 159-172 Covered in Scopus & Embase, Elsevier 160   water and stirred for half an hour at 900 rpm in order to allow polymer structure to swell uniformly. Drug was added slowly under stirred condition. The drug resin mixture was continuously stirred for 6 to 8 hours. 2.2.1.2 Preparation of drug- resinate granules:   After drug-resin mixtures were stirred for required time, the drug-resinates were thoroughly washed  with demineralized water for several times then filtered by using 0.45󰂵 filter paper and dried. The powdered drug-resinate particles were form into damp mass, then passed through sieve no-22 and dried at 50°C for 30 minutes. The dried granules  were again passed through sieve no-22 over sieve no-44 to obtained uniform granules. Quantities of drug and resin taken for different drug to resin ratios were as shown in Table 1. Table 1:  Quantities of drug and resin taken for different drug to resin ratios. Drug to resin ratio  Amount of Dextromethorphan Hydrobromide taken(grams)  Amount of resin taken (in grams)  Volume of water taken to disperse (in ml) 1:1 1 1 100 1:2 1 2 100 1:3 1 3 100 1:4 1 4 100 1:5 1 5 100 1:6 1 6 100 2.2.1.3 Selection of Optimum Resins and Drug to Resin Ratio Several trials were carried out for preparation of resinate using different resins in different drug to resin ratio   as shown in table 2. For the selection of the proper drug resin ratio, the concentration of resin was varied, keeping concentration of drug constant. The pH of the solution was maintained at 8. Solution of complex  with pH below 8 was adjusted with 10 % KOH solution. 2.2.1.4 Optimization of Process of Preparing Drug Resin Complex The process of preparing drug-resinate was optimized with respect to: ã   Time of adsorption. ã   Drug resin proportion Loading was carried out by batch method with weak cation exchange resin Ionex QM 1011. The percentage of drug loading on the resin is shown in the table 3.3. Further batches (T18-1 to T18-5) were prepared by keeping 1:6 ratio constant and varying stirring time from 4 to 8 hrs. Then next batches (T18-6 to T18-8)  were prepared by keeping stirring time constant as 6 hrs and varying ratio from 1:5 to 1:7. 2.2.1.4.1 Evaluation of drug loading by UV analytical method:  The mixtures of drug resin complex to be evaluated  were kept aside to allow the particles to sediment and then filtered. From this filtrate 5 ml was diluted to 100 ml using distilled water and absorbances were noted at 278 nm, from which amount of uncomplexed drug was calculated. Results are shown in table 3. 2.2.2 Characterization of Dextromethorphan Hydrobromide-Ionex QM 1011 Complex a) pH of complex The pH of drug resin complex was checked using Metler Toledo pH meter. Result is shown in table 4.  b) Differential scanning calorimetry (DSC) [ 6] The molecular state of the drug in the resinate was evaluated by performing DSC analyses of pure drug, resin, physical mixture and resinate. DSC curves of the samples were obtained with a differential scanning calorimeter (TA, Model Q200). Each sample was placed in an aluminum pan and then crimped with an aluminum cover. Heating rate was F  UL L L  en g t h R e s e ar ch P a p er C o v er e d i  nI n d  ex C o p erni   c u s wi   t h I  C V al   u e 4 . 6  8 f   or2 01  0  Athawale Rajani  et al: Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide   Int. J. Drug Dev. & Res., April-June 2012, 4 (2): 159-172 Covered in Scopus & Embase, Elsevier 161  10°C min–1. All measurements were performed over 0–500 °C under a nitrogen purge at 50 mL min–1. The onsets of the melting points and enthalpies of fusion were calculated by the thermal advantage software. The cell and sample were held isothermally at −79ºC for 30 min to purge the headspace and sample with nitrogen before heating. Results are shown in Fig. 3. c) FTIR spectroscopy [6, 7] Chemical interaction between the drug and resin was studied by FTIR spectroscopy. The IR spectra of the samples were obtained using a Fourier transform infrared spectrometer (Perkin Elmer, USA). Measurements were carried out according to the KBr disk method, the scanning range was 4000 to 450 cm–1. Result is shown in Fig.4. d) Drug loading Percentage complexation was calculated using procedure given under  Evaluation of drug loading by UV analytical method  . Result is shown in table 4. e) Drug content [8]  Resinate so prepared by the batch process, was evaluated for the drug content. Resinate equivalent to 300 mg of drug was magnetically stirred with about 70ml of buffer (pH 1.2 and 6.8) in 100 ml volumetric flask and then diluted to volume with buffer. Then the Suspension was filtered and further 5ml was diluted to 100 ml. The drug content was noted spectrometrically at 278nm using gastric simulated fluid (pH 1.2) or simulated salivary fluid (pH 6.8) as  blank. The readings were taken in triplicate. Results are given in table 5. f) Taste Evaluation of Resinate   [9]  i) Assessment of the bitter taste of the Dextromethorphan Hydrobromide (bitterness threshold) The bitter taste threshold value of Dextromethorphan Hydrobromide was determined based on the bitter taste recognized by six volunteers. A series of Dextromethorphan Hydrobromide   aqueous solutions  were prepared at different concentrations as standard solutions, i.e. 5, 10, 15, 20, 25, 30, 35, 40 and 45µg/ml, respectively. The test was performed as follows: 1 ml of each standard solution was placed on the center of the tongue, it was retained in the mouth for 30 s, and then the mouth was thoroughly rinsed  with distilled water. The threshold value was correspondingly selected from the different Dextromethorphan Hydrobromide concentrations as the lowest concentration that had a bitter taste.  ii) Evaluation of Taste of Resinate Taste of resinate was checked by time intensity method. For this purpose 6 human volunteers were selected. In this method a sample equivalent to a normal dose 15 mg was held in mouth for 60 seconds and volunteers were asked to evaluate the resinate for taste. Bitterness levels were recorded at 2, 10 and 60 sec. The bitterness level was recorded against pure drug (15 mg) using a numerical scale (3– Strong Bitter, 2 – Moderate Bitter, 1 –Slight Bitter, X – Threshold Bitter, 0 – No Bitter). These volunteers  were instructed not to swallow the granules, which  were placed on the tongue. They were instructed to thoroughly gargle their mouth with distilled water after the completion of test. Results are revealed in table 6 and fig. 5. 2.2.3 Formulation of Oral Taste Masked Suspension  A series of formulations were prepared as given in table 7 with various concentrations of suspending and wetting agents and were evaluated for sedimentation volume and redispersibility. DXM 4  was formulated using plain drug without resin, to provide clear distinction between actual taste of drug  before masking and taste after masking by making complex with Ion Exchange Resin. F  UL L L  en g t h R e s e ar ch P a p er C o v er e d i  nI n d  ex C o p erni   c u s wi   t h I  C V al   u e 4 . 6  8 f   or2 01  0  Athawale Rajani et al: Formulation and Evaluation of taste masked oral suspension of Dextromethorphan Hydrobromide   Int. J. Drug Dev. & Res., April-June 2012, 4 (2): 159-172 Covered in Scopus & Embase, Elsevier 162
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