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1 Impact factor: /ICV: Pharma Science Monitor 6(1), Jan-Mar 2015 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES Journal home page: TASTE MASKING OF ONDANSETRON HYDROCHLORIDE BY NEUTRALIZATION METHOD AND FORMULATION OF ORODISPERSIBLE TABLETS Gayatri C. Patel 1, Shruti V. Patel 2, Ankita U. Patel* 3, Dinesh R. Shah 3 1 Associate Professor, Ramanbhai Patel College of Pharmacy, Charotar University of Science & Technology (CHARUSAT), CHARUSAT Campus, Changa , Gujarat, India 2 Research Associate, Baxter Healthcare, Round Lake, Illinois Maliba Pharmacy College, Maliba Campus, Gopal Vidyanagar, Uka Tarsadia University, Bardoli-Mahuva Road, Tarsadi, Surat , Gujarat, India. ABSTRACT Ondansetron Hydrochloride is a potent antiemetic drug indicated for the treatment and/or prophylaxis of postoperative or chemotherapy- or radiotherapy-induced emesis. It is extremely bitter in taste. The purpose of this research was to mask the bitter taste of Ondansetron Hydrochloride with carbopol by neutralization method. The effect of variables like type of alkali, concentration of alkali, grades of carbopol and concentration of carbopol on bitterness level was studied. Results showed that neutralization of drug with equimolar sodium hydroxide and subsequent complexation with 0.6% carbopol 971G gave effective taste masking. The drug polymer complex was used to formulate orodispersible tablets by direct compression method using three different superdisintegrants like croscarmellose sodium, crospovidone and Kyron T The prepared tablets were evaluated for the parameters like general appearance, thickness, hardness, weight variation, friability, wetting time, water absorption ratio, in vitro and in vivo disintegration time. The disintegration tests showed rapid disintegration within seconds. In vitro dissolution studies showed 100% drug release in 10 minutes. The formulations were subjected to stability testing for three months at 25⁰C/60%RH and 40⁰C/75%RH. Results revealed no appreciable change in any of the formulations. It is concluded that the method attempted here for formulation of orodispersible tablets of taste masked Ondansetron Hydrochloride being simple and cost effective. KEYWORDS: Taste masking, Ondansetron Hydrochloride, Orodispersible tablet, Carbopol, Complexation. INTRODUCTION Ondansetron hydrochloride (ODH) is a potent antiemetic drug [1] indicated for the treatment and/or prophylaxis of postoperative or chemotherapy- or radiotherapy-induced emesis and also used in the early onset of alcoholism [2, 3]. In general, emesis is preceded with nausea and in such condition it is difficult to administer drug with a glass of water; hence it is beneficial to administer such drugs as orodispersible tablets (ODT) [4].

2 Impact factor: /ICV: Among the various dosage forms developed to facilitate ease of medication, orodispersible tablet is one of the most widely employed commercial products [5]. The orodispersible tablet has remarkable disintegration properties; it can rapidly disintegrate without water in the mouth within a few seconds. When an orodispersible tablet is placed in the oral cavity, saliva quickly penetrates into the pores causing rapid disintegration. ODTs are useful in patients, such as pediatric, geriatric, bedridden, or developmentally disabled, who may face difficulty in swallowing conventional tablets or capsules and liquid orals or syrup, leading to ineffective therapy, with persistent nausea, sudden episodes of allergic attacks, or coughing for those who have an active lifestyle. ODTs are also applicable when local action in the mouth is desirable, such as a local anesthetic for toothaches, oral ulcers, cold sores, or teething, and to deliver sustained release multiparticulate system for those who cannot swallow intact sustained action tablets/capsules [6]. Ondansetron HCl is an intensely bitter drug; hence, if it is incorporated directly into an orodispersible the main objective behind the formulation of such a dosage form will definitely get futile. Thus, in the present study an attempt has been made to mask the taste of ondansetron HCl and to formulate orodispersible with good mouth feel so as to prepare a patient friendly dosage form [4]. The present investigation is aimed at the use of Carbopol as taste masking agent [7, 8]. Carbopol are polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. Carbopol contains numerous carboxylic acid groups [9]. Due to the unavailability of free nitrogen in ODH, simple complexation with carbopol aqueous dispersion did not yield desired taste masking. Hence neutralization method is used. MATERIALS AND METHODS Materials Ondansetron hydrochloride was obtained as a gift sample from Sun Pharmaceuticals; grades of Carbopol as well as Kyron T- 314 were gifted by Corel Pharmachem, Ahmedabad; Mannitol, talc and magnesium stearate were obtained from S.D. Fine chem. Ltd., Mumbai; Crosscarmellose (Ac-Di-Sol), crospovidone (Polyplasdone XL), Starch 1500 and microcrystalline cellulose were gifted by Welable Pharmaceuticals; Other chemicals used were of analytical grade. Preparation of drug polymer complex ODH and Carbopol complex was prepared by neutralization method. ODH was accurately weighed and dispersed in equimolar alkali solution. Carbopol aqueous dispersion was prepared

3 Impact factor: /ICV: and added drop by drop until phase separation occurred while maintaining constant stirring with the help of magnetic stirrer. The mixture was then filtered and washed with deionized water. It was then dried in oven at 50⁰C. The resulting complex was then used for further study. Optimization of DPC For optimization of DPC different variables like type of alkali (sodium hydroxide, potassium hydroxide), concentration of alkali (bimolar, equimolar, half molar), grades of Carbopol (Carbopol 934P,Carbopol 941, Carbopol 971G, Carbopol 974) and concentration of Carbopol ( 0.4%, 0.5%, 0.6%) were selected. The formed complexes were then evaluated for bitterness level. Characterization of DPC Molecular properties on complexation were studied by Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). Infrared spectra of ODH, carbopol 971G and DPC were obtained using FTIR 8300 model, Shimadzu. The pellets were prepared on KBr press, and the spectra were recorded over the wave number 4000 to 400 cm -1. The X-ray powder diffractograms of ODH, Carbopol 971G and DPC were recorded using Phillips PW 3710 scanner, IW 1830 generator with a CuK anode at 40 kv and 30 ma and at a scan rate of 1 min -1 from 2 range from 0 to 90. Evaluations of DPC Taste evaluation Taste evaluation of DPC was done by a panel of 6 volunteers in the age group of 20 to 25 years using time intensity method. DPC equivalent to 10 mg ODH was held in the mouth by each volunteer and bitterness levels were recorded at the end of 10 seconds, 30 seconds, 1 minute and 2 minutes against pure drug. Drug content in the complex DPC equivalent to 100 mg of drug was dissolved in 0.1 N Hydrochloric acid in 100 ml volumetric flask. The mixture was sonicated for 15 min and filtered using Whatman filter paper. The above solution was suitably diluted to get solution of 10µg/ml drug content was estimated using UV spectrophotometer at 310 nm, taking 404 as specific absorbance [10]. The drug content was measured using following equation, %Assay = 100 (1) Theoretical concentration of ODH = 1000μg/ml Physical properties of DPC

4 Impact factor: /ICV: Physical properties of DPC such as angle of repose, bulk density, tapped density, compressibility index and Hausner s ratio were determined. In vitro drug release from DPC In vitro drug release study from DPC (equivalent to 10mg ODH) was performed using USP XXIV type II dissolution apparatus in 500ml of 0.1N HCl [10, 11]. The volume withdrawn at each time interval was replaced with a fresh quantity of dissolution medium. Drug content in the filtrate of the sample was analyzed spectrophotometrically at λ max 310 nm. In vitro drug release from the DPC was also performed in deionized water and simulated salivary fluid ph 6.8 by repeating the same procedure. Selection of Superdisintegrants and formulation of orodispersible tablet Orodispersible tablets of the prepared DPC were formulated using three different superdisintegrants croscarmellose sodium (Ac Di Sol), crospovidone (Polyplasdone XL) and Polacriline potassium (Kyron T-314). Direct compression technique was used to formulate fast dispersible tablet of ODH. Formulation compositions of orodispersible tablets are given in Table 1. All raw materials used were passed through a sieve no. 60 prior to mixing. Prepared DPC, mannitol, microcrystalline cellulose PH 101, starch 1500 and superdisintegrant/s were mixed for 15 minutes. Talc and magnesium stearate were added lastly before compression and mixed properly. The final mixture, ready for compression was directly compressed into tablets using a single-punch tablet machine equipped with 6.5 mm flat punch. Each tablet of 125 mg containing 10 mg ODH was prepared. Table 1 Formulation compositions of taste masked ODH orodispersible tablet Ingredients (mg per tablet) Batch A Batch B Batch C DPC(equivalent to 10mg ODH) Starch Microcrystalline cellulose Mannitol Croscarmellose sodium Crospovidone Kyron T Magnesium stearate (1%) Talc (1%) Pineapple flavor q.s q.s q.s Total Evaluation of tablet The prepared orodispersible tablets were evaluated for dimensional uniformity, weight variation, hardness, friability, assay and content uniformity. The thickness and diameter of the tablets were

5 Impact factor: /ICV: measured by vernier caliper. The weight variation test was performed according to the official method. Hardness of the tablets was tested using a Pfizer hardness tester. Friability of the tablets was determined in a Roche friabilator. Wetting time and water absorption ratio The wetting time of the tablets was measured by following method. Five circular tissue papers of 10 cm diameter were placed in a glass petri dish with 10 cm diameter. Ten ml of water containing eosin, a water soluble dye, was added to the petri dish. A tablet was weighed and carefully placed on the top surface of the tissue paper. The time required for water to reach the center of the upper of the tablet was noted as wetting time [12]. The tablet was weighed again after complete wetting and the water absorption ratio was calculated using the following equation, = 100 (2) Where R= water absorption ratio, W b = weight of the tablet after wetting W a = weight of the tablet before wetting In vivo disintegration time In vivo disintegration was performed on 6 healthy human volunteers. One tablet was held in the mouth after rinsing and the time required for complete disintegration of the tablet was recorded [4]. In vitro drug release In vitro drug release study from orodispersible tablet was performed using USP XXIV type II dissolution apparatus in 500ml of 0.1N HCl. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. Drug content in the filtrate of the sample was analyzed spectrophotometrically at λmax 310 nm [11]. In vitro drug release from the DPC was also performed in deionized water and simulated salivary fluid ph 6.8 by repeating the same procedure. Stability study The prepared tablets were subjected to short term stability study for a period of three months as per ICH guidelines. In the present study, stability studies were carried out at 25 0 C/60% RH and 40 0 C/75% RH for a specific time period up to three months for all formulations [13]. Photostability chamber Osworld JRIC -11B was used for storing samples at 40 0 C/75% RH.

6 Impact factor: /ICV: Physical stability was analyzed by change in appearance and chemical stability was analyzed by the change in the assay at the interval of each month upto three months. RESULTS AND DISCUSSION Summary of optimized conditions The taste masked complex of ODH and Carbopol was prepared by neutralization method. For optimization of DPC, variables like type of alkali, concentration of alkali, grades of Carbopol and concentration of Carbopol 971G were used. It was observed that NaOH gave complete phase separation after complex formation, so it was selected. Equimolar NaOH was employed for complete precipitation of free base from acid salt, ODH prior to complexation. Equimolar NaOH was selected rather than bimolar and halfmolar concentration because bimolar solution when employed made the cabopol gel swell and increased the viscosity of dispersion thereby impeding proper phase separation, whereas halfmolar solution when employed, it led to incomplete precipitation of free base. 0.6% carbopol 971G gave optimized taste masking. Concentrations of cabopol above 0.6% were highly viscous and those below 0.6% gave inefficient taste masking hence 0.6% cabopol concentration was selected. Characterization of DPC The FTIR spectra of pure drug, carbopol 971G and DPC are shown in the Fig. 1. The FTIR spectrum of DPC was found to exhibit some significant difference in the characteristic peaks of ondansetron HCl, revealing modification of the drug environment. As shown in Figure 1, a broad band of bonded -OH of ondansetron HCl was observed from to cm 1. DPC showed diminution and shifting of this peak from to 3343 cm 1. Diminution and shifting of DPC peaks suggests the formation of new N-H stretching, which was previously absent in the pure drug. This shows the probability of formation of cation on the indole ring of ondansetron HCl that would have formed a complex with polymer by electrostatic force of attraction due to the negative charge of the carboxylate ions.

7 Impact factor: /ICV: Fig. 1. Infrared spectrum of (a) ODH, (b) Carbopol and (c) DPC The X ray diffractogram of ODH confirms its crystalline nature, as evidenced form the number of sharp and intense peaks (Fig. 2 a). The diffractogram of polymer (carbopol 971G) showed diffused peaks, indicating the amorphous nature (Fig. 2 b). However in the diffractogram of DPC (Fig. 2 c), the intensity of characteristic peaks of pure drug was reducedd and peaks were also found to be broadened. These findings suggest the formation of a new solid phase with a lower degree of crystallinity due to complexation. Fig. 2. X Ray diffractograms of (a) ODH (b) Carbopol 971G and (c) DPC Evaluations of DPC Taste evaluation Taste evaluation revealed that Carbopol 971G completely masked the bitter taste of ondansetron hydrochloride.

8 Impact factor: /ICV: Results of physical properties of DPC and its drug cotent are shown in Table 2. From results, it was observed that DPC has compressibility index less than 15 %, Hausner s ratio less than 1.25 and angle of repose less than 30⁰. All these results show excellent flowability and compressibility giving the applicability of DPC in directly compressible formulations i.e. orodispersible tablets. Table 2 Physical properties of DPC and its drug content Angle of repose Bulk density (gm/ml) Tapped density (gm/ml) Carr s index Hausner s ratio Assay 27.7 ± 0.14⁰ 0.25 ± ± % % In vitro drug release from DPC In vitro drug release from DPC was performed in 0.1N HCl, SSF and deionized water. DPC showed 100% drug release within 2 minutes in 0.1N HCl. Drug release from DPC in SSF and deionized water is shown in Fig. 3. Fig. 3. In vitro drug release from DPC in SSF and deionized water Evaluations of tablet Pharmacotechnical properties of tablet Results of pharmacotechnical parameters of tablet are shown in Table 3. Tablets were obtained of uniform weight due to uniform die fill, with acceptable weight variation as per pharmacopoeial specification. The drug content found in the range of % (acceptable limit) and the tensile strength of the tablet was found kg/cm 2. Friability of tablet was found below 1% indicating good mechanical resistance. The wetting time of alll the batches was found in the range of sec and water absorption ratio was found in the range of %. Amongst all the prepared batches, Batch C showed minimal wetting time and disintegration time. Hence it is used for comparison of drug release with the marketed tablet.

9 Impact factor: /ICV: Table 3 Evaluation of tablet Parameter Batch A B C M* Diameter (mm)** 6.55± ± ± ±0.015 Thickness (mm)** 3.18± ± ± ±0.124 Weight variation (Mean ±limit) 123.6± ± ± ±13.91 Hardness (kg/cm 2 )** 4.43± ± ± ±0.05 Friability (%) Assay (%) ± ± ± ±0.24 Content uniformity (%) ± ± ± ±0.34 Wetting time (sec)** 21.33± ± ± ±0.94 Water absorption ratio, R (%)** ± ± ± ±0.37 In vivo disintegration time (Sec)** 29.67± ± ± ±1.53 *M = marketed product (Emset, Cipla Ltd, 8mg ondansetron); ** Mean± SD (n=6 determinations) In vitro drug release In vitro release of ondansetron HCl in 0.1N HCl, SSF, and SSF and deionized water are shown in Fig. 4, 5 and 6 respectively. In 0.1N HCl, the prepared orodispersible tablets showed 100% drug release release within 10 minutes while marketed product showed 100% drug release within 15 minutes. In SSF and deionized water, there was no significant drug release within 5 min from the prepared batch, hence the taste masked complex showed potential application to be formulated as orodispersible tablet. There was significant drug release from marketed product since in the marketed product the bitter taste abatement is done using artificial sweeteners only. Cumulative % Release Time (min) Fig. 4. In vitro drug release in 0.1N HCl C M

10 Impact factor: /ICV: Cumulative % release Time (min) Fig. 5. In vitro drug release in SSF C M Cumulative % release Batch C 60 Marketed Time (min) Fig. 6. In vitro drug release in deionized water Stability study There was no change observed in the physical appearance and assay of the tablets after three months storage at both 25⁰C / 60%RH and 40⁰C / 75%RH. The results of stability study indicate that all formulations are stable. CONCLUSION The study conclusively demonstrated complete taste masking of ondansetron HCl was successfully done using carbopol and rapid disintegration and dissolution of ODT. Taste masking and rapid disintegration of tablets formulated in this investigation may possibly help in administration of ondansetron HCl in a more palatable form without water during emesis. REFERENCES 1. Thomson Micromedex Healthcare. Ondansetron hydrochloride (systemic), In: Drug Information for Health Care Professionals: USP DI, Greenwood Village, CO: Micromedex Thomson Healthcare, 2001, B. A. Johnson, J. D. Roache, M. A. Javors, et al., Ondansetron for reduction of drinking among biologically predisposed alcoholic patients, JAMA, 2000; 284:

11 Impact factor: /ICV: H. G. Brittain, Florey K., Analytical profiles of Drug Substances and Excipients, 2001, S. Khan, P. Kataria, P. Nakhat, P. Yeole, Taste Masking of Ondansetron Hydrochloride by Polymer Carrier System and Formulation of Rapid-Disintegrating Tablets., AAPS PharmSciTech. 2007; 8: E1-E7. 5. Bi Y., Sunada H., Yonezawa Y., Danjo K.and Lida K., Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity, Chem. Pharm. Bull. 1996; 44: Bruk G.M.; Mendes R.W. and Jambhekar,S.S.; Drug. Dev. Ind.Pharm, 1986;12: Mundada A S, Meshram D R, Banbale H B, Bhalekar M R, Avari J G, Formulation and evaluation of dispersible taste masked tablet of roxithromycin. Asian Journal of Pharmaceutics, 2008; Panchkula H et al. Tasteless, directly compressible, fast dissolving complexes and pharmaceutical formulations thereof, EP B1. 9. Shridhar, Carbopol and its applications in pharmaceutical dosage forms, October 2007, Dibbern HW, Muller RM, Wirbitzki E, UV and IR Spectra of Pharmaceutical substances and IR spectra of Pharmaceutical and cosmetic excipients, Editio Cantor Verlag, 2002, Indian Pharmacopoeia, 6 th Edn, Ministry of Health and Family Welfare, Govt. of India. The controller of publications, New Delhi, 2010, pp Gosai AR, Patil SB, Sawant KK, Formulation and evaluation of orodispersible tablets of ondansetron hydrochloride by direct compressing using superdisintegrants. International Journal of Pharmaceutical Sciences and Nanotechnology. 2008; 1: Natalie MC, Clure. Stability studies in overview of ICH Guidelines for Drug Products. Matrix Pharmaceutical Inc ( For Correspondence Ankita Patel ankita.upatel@utu.ac.in