265 e- ISSN 0976-1047 Print ISSN 2229-7499 International Journal of Biopharmaceutics Journal homepage: www.ijbonline.com IJB FORMULATION AND EVALUATION OF FAST DISSOLVING TABLET OF PROCHLORPERAZINE MALEATE BY USING SUPERDISTINEGRANTS J.Gomathi 1*, R.Margret Chandira 1, B.Jaykar 2 1 Department of Pharmaceutics, 2 Department of Pharmaceutical Chemistry, Vinayaka Mission s College of Pharmacy, Salem-636008, Tamilnadu, India. ABSTRACT Prochlorperazine maleate (PCZM) is a phenothiazine antipsychotic and widely used in prevention and treatment of nausea, vomiting including that associated with migraine or drug-induced emesis. The concept of formulating fast dissolving tablets containing prochlorperazine maleate offers a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristics with increased bioavailability. Fast dissolving tablets of prochlorperazine maleate were prepared by direct compression methods. The tablets were prepared by using crosscarmellose sodium, crospovidone, and sodium starch glycolate, as super disintegrants in different concentration (4-8%) along with microcrystalline cellulose. Total seven formulations and a control formulation (without superdisintegrant) were prepared and evaluated for hardness, friability, weight variation, content uniformity, wetting time, water absorption ratio, disintegration time and invitro drug release. In-vitro dissolution studies are performed by using 6.8PH buffer at 50 rpm by paddle method. Overall, the formulation F6 containing 8% w/w of SSG was found to be promising and has shown an In vitro dispersion time 8 sec and disintegration time 7sec, wetting time of 16 sec and water absorption ratio of 87.83% The stability studies were performed for two months (accelerated studies) as per ICH guidelines. The optimized formulation (F6) showed no significant variations for the tablets parameters and it was stable for the specified time period. Key words: Prochlorperazine maleate, Superdisintegrants, Fast dissolving tablets, Disintegration time. INTRODUCTION Recent advance in novel drug delivery system aims to enhance the safety and efficacy of the drug molecule by formulating a dosage form being for the administration (Debjit B et al., 2009; Arumugam V, 2001). The most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. Often times people Corresponding Author J.Gomathi E-mail: gomathidinesh1@gmail.com experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in the case of the motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic condition and bronchitis. For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. he basic approach in development of FDT is the use of superdisintegrants like cross linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate (primogel, explotab), polyvinylpyrollidone (polyplasdone) etc, which provide instantaneous disintegration of tablet after putting on tongue, their by release the drug in saliva.(arthur H. Kibber, 1999). The bioavailability of some drugs may be increased due to absorption of drug in oral cavity and
266 also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. The technologies used for manufacturing fast-dissolving tablets are freeze-drying, spray-drying, tablet molding, sublimation, sugar-based excipients, tablet compression, and disintegration addition. (Manivannan R, 2005) The concept of formulating orally disintegrating tablets of prochlorperazine maleate offer a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristic with increase bioavailability (Arora SC et al., 2010). Therefore, in order to get better patient compliance in the treatment, it is necessary to design a new drug delivery system of the drug i.e. prochlorperazine emaleate (Anonymous 1) orally disintegrating tablets. The focus of the present investigation is to minimize disintegration time and improved drug release with faster onset of action. MATERIALS AND METHODS Materials Prochlorperazine maleate Gifted by Mehta Pharmaceutical Ltd., Mumbai. Crospovidone, Croscarmellose Sodium Starch glycolate, Microcrystalline cellulose Gifted by Adcock Imgram Medrich Limited, Bangalore. Method Direct compression method Preparation of prochlorperazine maleate Fast dissolving tablets (Masaredy RS et al., 2008). The direct compression technique was selected for developing novel fast dissolving tablets. In direct compression technique all materials accurately weighed and shift the drug, crosspovidone, microcrystalline cellulose, mannitol, aspartame, pass through a 60 mesh prior to mixing for 5 min in poly bag. The solid dispersion complex was properly mixed with superdisintegrant, and then with diluents microcrystalline cellulose. The mixture was mixed with talc, sodium sodium stearyl fumarate (Paul JS and Owen SC, 2006). The blend is compressed using multiple tolling ten stations rotary with single punch (8mm), to produce round shaped tablets. Weighing150gm each. The compression force adjusted to obtain tablets with hardness 3-5kg/cm 2. Shown in table 1. Characterization of blends (Kundu S et al., 2008) The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. The characterization of mixed blend done for the flow property of powder that are bulk density, tapped density, Hausner s ratio, Compressibilty index, angle of repose. Bulk Density (Db) It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weight powder (passed through standard sieve # 20) into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume. From this the bulk density is calculated according to the formula mentioned below. It is expressed in g/ml and is given by Db = M/ Vb Where, M is the mass of powder Vb is the bulk volume of the powder. Tapped Density (Dt) It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume was noted if the difference between these two volumes is less than 2%. If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. Tapping was continued until the difference between successive volumes is less than 2 % (in a bulk density apparatus). It is expressed in g/ml and is given by Dt = M / Vt Where, M is the mass of powder Vt is the tapped volume of the powder. Angle of Repose (θ) The friction forces in a loose powder can be measured by the angle of repose (θ). It is an indicative of the flow properties of the powder. It is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane tan θ= h / r ; θ = tan-1 (h / r) Where, θ is the angle of repose. The powder mixture was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Care was taken to see that the powder particles slip and roll over each other through the sides of the funnel. Relationship between angle of repose and powder flow property. Shown in table 2 Carr s index (or) % compressibility It indicates powder flow properties. It is expressed in percentage and is give compressibility index = Bulk volume Taped volume/bulk volume 10 is Shown in table 3 Hausner ratio Hausner ratio is an indirect index of ease of powder flow. It is calculated by the following formula. Hausner ratio =Dt/Db Where, Dt is the tapped density, Db is the bulk density. Lower hausner ratio (<1.25) indicates better flow properties than higher ones (>1.25).
267 Characterization of fast dissolving tablets (Shukla D et al., 2009). After compression of powder, the tablets were evaluated for diameter, thickness and physical characteristics like hardness, friability, disintegration time, wetting time, dispersion time and dissolution studies. Weight variation test 20 tablets were selected randomly from the lot and weighted individually to check for weight variation. Weight variation specification as per I.P. is shown in table 4 Hardness test Hardness or tablet crushing strength (fc), the force required to break a tablet in a diametric compression was measured using Monsanto tablet hardness tester. It is expressed in kg/cm 2. Thickness The thickness of tablets was determined suing a Digimatic veriner caliper (Mitutoya, Japan). Three tablets from each batch were used, and average values were calculated. Friability (F) Friability of the tablet determined using Roche friabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at height of 6 inches in each revolution. Pre-weighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were dusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula. F=W initial -W final x100/w initial Acceptance criteria for % friability, %weight loss should be less than 1% Disintegration time testing (Shirshand SB et al., 2009) It was determine using USP tablet disintegration test apparatus, using 900ml of distilled water without disk at room temperature. Test was performed on 6 tablets. Limit set for the disintegration time: not more than 30 seconds. Wetting time of tablet Wetting time test gives the idea on porosity, compressibility as well as absorption capacity of the tablets. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting times may be used as another confirmative test for the evaluation of tablets. Procedure For determination of wetting time, piece of tissue paper folded twice was placed in a small Petri dish (internal diameter of 5 cm) containing 6ml of wager. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets was noted as the wetting time. The test was repeated on the three other tablets of the same batch in same Petri dish and average of the three readings gives then means wetting time of the tablets. Water absorption Ratio A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper & the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using following equation, R=100(Wb-Wa) /Wa Where, Wa is weight of tablet before water absorption Wb is weight of tablet after water absorption. In vitro dispersion time (Pandit V et al., 2012) For determination of In vitro dispersion time, one tablet was placed in a beaker containing 10ml of PH 6.8 phosphate buffer at 37±0.5ºc and the time required for complete dispersion was determined. The test was repeated on three other tablets of same batch, the average gives In vitro dispersion time. Content uniformity test Crush one table and extract with three quantities, each of 10ml, of ethanol containing 1 per cent v/v of strong ammonia solution. Filter the extract and to the combined filtrates add sufficient ethanol to produce 50ml.dilte10ml for this solution to 100ml with ethanol. Dilute further with ethanol, of necessary to give a final solution, containing 10mg of prochlorperazine maleate per 1ml and measure the absorbance of the resulting solution at the maximum at about 254nm. In vitro drug release study (Wan S et al., 2012) The release rate of drug from FDT was determined using USP Dissolution testing apparatus II (paddle method). The dissolution medium was 6.8PH phosphate buffer, the volume being 900ml. the temperature was maintained at 37±0.5ºc. The rotation speed was 50rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at 2, 4, 6, 8, 10, 15, and 20 minutes. And the samples were replaced with fresh dissolution medium. The samples were filtered through a membrane filter and absorbance of these solutions was measured at 254nm using a UV/V is double-beam spectrophotometer of Cumulative percentage drug release was calculated using linear equation obtained from a standard curve.
268 Infra-red Spectrophotometric analysis (Chown ZT et al., 1986) The pellets were made with mixing 1gm of drug and 100gm of dried potassium bromide powder. Mixer was then compressed under 10-ton pressure in a hydraulic press to form a transparent pellet. The thin pallet was put on pellet disc to get IR Spectra. Stability studies (Ed L Hamilton L et al., 2005) Stability of a drug can be define as the time from the date of manufacture and the packaging of the formulation, until its chemical or biological activity is not less than a predetermined level of labeled potency and its physical characteristics have not changed appreciably or deleteriously. In any design and evaluation of dosage forms for drugs, the stability of the active component must be a major criterion in determining their acceptance or rejection. RESULTS AND DISCUSSION Evaluation of powder blends As per flow ability scale, the drug has good characteristics to flow. The excipients did not make any effect on the flow of blend. Thus it was decided to use direct compression method. Shown table 5 Evaluation parameters of batch F0-F6 Overall, the formulation F6 containing 8% w/w of SSG was found to be promising and has shown an In vitro dispersion time 8 sec and disintegration time 7sec, wetting time of 16 sec and water absorption ratio of 87.83% when compared to control formulation (F0) which shows 140sec, 130 sec, 145 s and 58.92% values respectively for the above parameter. The experimental data also shows that the results obtained from SSG are comparable and even slightly better than those of crospovidone. Shown table 6. Infra-Red Spectrophotometric analysis Using IR spectrometer carried out the analytical studies of the drug and fast dissolving tablet product. The characteristic peaks are shown below figure 1,2,3,4 IR spectroscopic studies indicated that the drug is compatible with all the excipients. The IR spectrum of pure drug shows the characteristic absorption bands around 3299 cm 1 for hydroxyl group of acid, 1735 and 1663 cm 1 for carbonyl group of acid, while the aromatic and aliphatic CH stretching were observed around 2970, 2953, 2938 and 2917 respectively. The IR spectrum of sodium starch glycolate with pure drug showed all the characteristic peaks of prochlorperazine maleate pure drug, thus confirming that no interaction of drug occurred with the components of the formulation DISSOLUTION PROFILE OF FAST DISSLOVING TABLET FORMULATIONS In vitro drug release: Release of the drug in-vitro was determined by estimating the dissolution profile. Dissolution test Standard USP apparatus have been used to study In vitro release profile using rotating paddle. In-vitro release rate study of fast dissolving tablets of prochlorperazine maleate were carried out using 900ml of phosphate buffer PH6.8, at 37±0.5 0 c at 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at 2,4,6,8,10,15,20 min and withdrawn volume was replaced with fresh dissolution media. The withdrawn samples were diluted with dissolution medium and then filtered with whattman filter paper and assayed at 254nm. The percentage release of prochlorperazine maleate was calculated. The observations for different batches were shown in Table. Percentage release of prochlorperazine maleate with respect to time for each batch, were graphically shown in figure The formulation prepared by using sodium starch glycolate has shown better release characteristics all the batches. Batch F-6 has shown the release of 100%drug within 15 min which is very rapid when compared to formulations containing crospovidone and croscarmellose sodium. In the case of sodium starch glycolate also as the concentration is increased the drug release rate is enhanced. Table 7 and figure 5 are shown below. Percentage Cumulative drug release profile of Marketed tablet (stemetil) with formulated tablets In vitro dissolution studies on the promising formulation (F1-F6), the control (F0) and commercial conventional formulation (CCF) were carried out in ph 6.8 phosphate buffers, various dissolution profiles of F0, F1- F6 and CCF are shown in figure 6. STUDY OF OPTIMIZED FORMULATION F-6 USING (STARCH GLYCOLATE IN 8%) Accelerated stability studies as per ICH guidelines The optimized formulation (F6) was wrapped in aluminum foils and kept in Petri-dish at (40 0 C±2 0 C/75% RH ±5%) in humidity chamber. The stability studies were conducted after 30 and 60 days and percentage Drug release at (40 0 C±2 0 C/75% RH ±5%) 0f optimized Batch F6. table 8 shown below In vitro dissolution profile of F-6 formulation The In vitro dissolution indicated faster and maximum drug release from formulation F-6 is fabricated by using 8% concentration of sodium starch glycolate. Stability studies shown that there was no significant change when compared with zero day of formulation (F- 6). Table 9 shown below.
269 Figure 1. IR Spectra of pure prochlorperazine maleate Figure 2. IR Spectra of prochlorperazine maleate + crosspovidone Figure 3. IR Spectra of prochlorperazine maleate + crosscarmellose Figure 4.IR Spectra of prochlorperazine maleate + sodium starch glycolate
270 Figure 5. Cumulative drug release profile of batch F0,F1,F2,F3,F4,F5 and F6 Figure 6. Cumulative drug release comparison of marketed tablet (stemetil) with formulated tablets Figure 7. Dissolution profile of optimized Batch F6 at 15 and 30 days with comparison to 0 day formulation Table 1.Formulation of fast dissolving tablet of prochlorperazine maleate Ingredients F0 F1 F2 F3 F4 F5 F6 Prochlorperazine maleate 5 5 5 5 5 5 5 Crospovidone (SD) - 6 12 - - - - Crosscarmellose sodium (SD) - - - 6 12 - - Sod.Starch glycolate (SD) - - - - - 6 12 Microcrystalline cellulose (Avicel 102 (Diluent) 60 60 90 60 90 60 90 Aspartame (Sweetener) 3 3 3 3 3 3 3 Sodium stearyl fumarate (Lubricant) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Talc (Glient) 3 3 3 3 3 3 3 Flavour (strawberry) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Up to mannitol(diluent) 76 70 34 70 34 70 34 Table 2. Angle of Repose as an Indication of Powder Flow Properties Angle of repose Flow 25-30 Excellent 30-35 Good 35-40 fair 40-45 Poor 45-50 Very poor
271 Table 3. Relationship between % compressibility and flow ability Carr s index Flow 5-15 Excellent 12-16 Good 18-21 Fair 23-35 Poor 35-38 Very poor More than 40 Extremely poor Table 4. Weight Variation Specification as per IP Average Weight of Tablet % Deviation 80 mg or less ±10 More than 80 mg but less than 250 mg ±7.5 250 mg or more ±5 Table 5. Evaluation of powder blends Batch code Bulk Density (gm/ml) Tapped Density Angle of Hausner Carr s index (gm/ml) repose ratio F0 0.58 0.67 29 0 77 13.43 1.155 F1 0.55 0.63 28 0 60 12.69 1.188 F2 0.544 0.54 29 0 81 11.47 1.129 F3 0.53 0.58 27 0 95 14.86 1.094 F4 0.57 0.66 29 0 42 13.63 1.157 F5 0.53 0.60 28 0 59 11.66 1.132 F6 0.56 0.65 27 0 23 13.84 1.160 All values mean± S.D Table 6. Evaluation parameters of Batch F0-F6 Parameters F0 F1 F2 F3 F4 F5 F6 Weight variation (mg) 148.48 146 144.80 151 147 146.40 148 Thickness(mm) 3.50±0.05 3.51±0.017 3.53±0.025 3.52±0.04 3.52±0.04 3.50±0.251 3.54±0.05 Hardness(kg/cm 2 ) 3.23±0.04 3.21±0.08 3.20±0.03 3.33±0.09 3.25±0.04 3.30±0.05 3.25±0.01 Friability(%w/w) 0.36% 0.22% 0.25% 0.26% 0.39 0.35 0.34 Disintegration time (sec) 130 sec 13 sec 8.5 sec 17.5 sec 14sec 10sec 7sec Wetting time(sec) 145±1.527 17.2±1.57 14.5±0.577 23.5±0.547 22±0 18±0.527 16±0 In-vitro Dispersion Time(sec) 140±0 15±1 12±0.52 20±0.77 18±0 14±1 8±0 Assay (%) 97.85 98.52 100.10 99.67 99.75 99.63 100.15 Water Absorption Ratio (%) 58.92 75.30 85.52 65.72 68.96 77.92 87.83 Table 7. Percentage Cumulative drug release profile of Batch F0-F6 Time Cumulative drug release (%) F0 F1 F2 F3 F4 F5 F6 0 0 0 0 0 0 0 0 2 14.77 47.89 52.37 39.81 42.72 50.79 56.76 4 28.66 50.84 61.50 44.32 47.97 58.41 64.35 6 38.59 56.25 72.32 48.25 52.51 66.42 77.02 8 42.91 64.07 77.83 55.03 61.50 70.86 85.49 10 48.06 71.03 87.03 62.91 69.59 84.37 96.50 15 58.35 85.25 98.58 74.93 77.37 93.47 106.94 20 65.49 93.84 100.78 83.69 85.85 99.79 110.62
272 Table 8. Physical Characteristics of Prochlorperazine maleate Fast dissolving tablet of optimized Batch F6 at Temperature (40 0 C±2 0 C/75% RH ±5%) Physical parameters 0day 15days 30days Percentage drug content (%) 100.15 100 99.99 Hardness (kg/cm 2 ) 4.25 4.10 4.0 Disintegration time(sec) 7sec 8sec 9sec Wetting time(sec) 16sec 18sec 20sec Table 9. %Drug release at (40 0 C±2 0 C/75% RH ±5%) of optimized Batch F6 Time (min) %Drug release in 0day %Drug release in 15days %Drug release in 30days 0 0 0 0 2 56.76 55.10 52.95 4 64.35 63.22 60.74 6 77.02 75.95 72.59 10 86.49 85.19 82.34 15 96.50 94.54 91.68 20 106.94 100.21 99.65 CONCULSION The oral fast dissolving tablet of prochlorperazine maleate were formulated and evaluated for various parameters from the compatibility studies by IR of drug it was found to be compatible with other formulation excipients. All evaluation parameter were within specification. The sodium starch glycolate shown faster drug release than crospovidone and crosscarmellose sodium. Formulation F6 release maximum drug within the 15 mins.ie.100% and shown minimum disintegration time i.e. 7 sec, wetting time i.e.16sec, and water absorption ratio i.e. 87.83% than other formulation and hence considered best formulation. It was concluded that the successful formulation of fast dissolving tablets of prochlorperazine maleate could be prepared by using 8% concentration of sodium starch glycolate. In which 8% concentration of sodium starch glycolate shows good result as compared to the crosspovidone. ACKNOWLEGEMENT We wish to thank Prof. Dr. B. Jaygar, Principal Vinayaka Mission s College of Pharmacy, Salem and Mehta pharmaceutical Ltd. for providing Prochlorperazine mealate gift sample and Adcock Imgram Medrich Ltd. for providing excipients required for my research work. REFERENCES Arora SC, Sharma PK, Irchaiya R, Khatkar A, Singh N, Gagoria J, Development Characterization and solubility study of solid dispersion of cefuroxime axetil by solvent evaporation method. J.Adv.Pharma.Tech. 2010; 1: 326-329. Arumugam V. Fast Dissolving Tablet. Indian J. Pharm. Educ. 2001; 35: 150-152. Chown ZT, Chi L-H. Drug-excipient interactions resulting from powder missing 111; solid state properties and their effect on drug dissolution. J Pharm Sci. 1986; 75: 534-541 Debjit B, Chiranjib B, Krishnakanth, Pankaj. Fast Dissolving Tablet: An Overview. J of Chem and Pharm. 2009; 1(1): 163-177. Kundu S, Sahoo PK. Recent trends in the developments of orally disintegrating technology. Pharma Times. 2008; 40(4): 15. Masaredy RS, Kadia RV, Manvi FV. Development of mouth dissolving tablet of clozapine choosing two different techniques. Ind.J. Pharma. Sci. 2008; 570: 526-528. Pandit V, Sai RS, Devi K, Sarasija S. In- vitro and in-vivo evaluation of fast dissolving tablet containing solid dispersion of pioglitazone. J Adv Pharm Technol Res. 2012; 3(3): 160 170. Wan S, Sun Y, Qi X, Tan F. Improved bioavailability of poorly water soluble drug curcumin in cellulose acetate solid dispersion. AAPS Pharma. Sci. Tech. 2012; 13: 159-16. Shirshand SB, Sarasija S, Para MS, Swamy PV. Plantago Ovata Mucilage in Design of Fast Disintegrant Tablet. Indian J. Pharm. Sci. 2009; 71(1): 41-45. Shukla D, Chakraborty S, Singh S, Mishra B. Mouth dissolving Tablet II: An Overview Evaluation Techniques. Sci Pharm. 2009; 77: 327 341. Ed L Hamilton L, Eugene M Lutz. Orally disintegrating tablets. Drug Delivery Technology, 2005; 5(1). Arthur H. Kibber. Handbook of Pharmaceutical Excipient Third Edition, 1999; 102-103.
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