PREPARATION AND INVITRO EVALUATION OF RABEPRAZOLE SODIUM DELAYED RELEASE ENTERIC COATED TABLETS

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1 Page1000 Indo American Journal of Pharmaceutical Research, 2014 ISSN NO: Journal home page: INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH PREPARATION AND INVITRO EVALUATION OF RABEPRAZOLE SODIUM DELAYED RELEASE ENTERIC COATED TABLETS Farha Amna Shaik 1 *, Shubhrajit Mantry 1, K.Venkata Narapa Reddy 2, Srikanth 3 1 Department of Pharmaceutics, Kottam Institute of Pharmacy, Mahaboobnagar, AP, INDIA 2 Department of Pharmaceutics, Chilkur Balaji Institute of Pharmacy, R.V.C.Nagar, Moinabad Road, AP, INDIA 3 Department of Pharmaceutics, JPNES group of Institutions, Mahaboobnagar, AP, INDIA ARTICLE INFO Article history Received 16/02/2014 Available online 28/02/2014 Keywords Rabeprazole sodium, Delayed Release, Enteric coated tablets, Crospovidone. ABSTRACT The objective of the study is to formulate and evaluate Rabeprazole Delayed Release Enteric tablets comparable to the innovator product. Five formulations of enteric coated tablets of Rabeprazole were developed by preparing core tablets using mannitol as diluents and Crospovidone as super disintegrant in different proportions and varying the compositions of sub coating and enteric coating using opadry white and enteric yellow.the core tablets were prepared by direct compression method. In the preformulation studies the micromeritic flow properties of the API were assessed by determining angle of repose, compressibility index, Hausner ratio. The results indicated good free flow of Rabeprazole. As such formulation F5 developed is considered as an efficient delayed release formulations of Rabeprazole comparable to the innovator product. Thus the study fulfilled the objective of developing efficient Rabeprazole delayed release tablets. Corresponding author Farha Amna Shaik Department of Pharmaceutics, Kottam Institute of Pharmacy, Erravally X Roads, Andhra Pradesh farha.khatoon@gmail.com Telephone: Please cite this article in press as Farha Amna Shaik et.al. Preparation and invitro evaluation of rabeprazole sodium delayed release enteric coated tablets. Indo American Journal of Pharm Research. 2014:4(2). Copy right 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Page1001 INTRODUCTION Delayed release dosage form is best formulations which are used for drugs that are destroyed in the gastric fluids, or cause gastric irritation or are absorbed preferentially in the intestine. Such preparations contain an alkaline core material comprising the active substance, a separating layer and enteric coating layer [1,2]. Rabeprazole sodium is a substituted benzimidazole. Benzimidazole are anti ulcerous compounds known for decreasing gastric acid secretion. These compounds, also known as Proton Pump Inhibitors (PPI) are commonly indicated for the treatment of Gastric ulcer, Peptic ulcer, Duodenal Ulcers, Erosive or Ulcerative GERD (Gastro Esophageal reflux Disease), Symptomatic GERD[3]. Rabeprazole sodium is very soluble in water and in alkaline media. The stability of Rabeprazole sodium is a function of ph; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The degradation is catalyzed by acidic reacting compounds and PPIs are usually stabilized in mixtures with alkaline reacting compounds. Therefore exposure of Rabeprazole sodium to the acidic content of the stomach would lead to significant degradation of the drug and hence, reduced bioavailability[4]. Now a day, many pharmaceutical companies are manufacturing the drugs for their commercial purpose with insufficient active ingredient in the dosage form as they claimed on the strip. So, the study was undertaken with the objective of evaluating different brands of commercially available Rabeprazole enteric coated tablets to get awareness about the pharmaceutical company that gives appropriate active ingredient present in dosage forms released into the market. Rabeprazole tablets are available in 20mg and 10mg doses in the market. In the present study we are comparing 20mg and 10mg tablets of different brands available in the market. An enteric coating is a barrier that controls the location of oral medication in the digestive system where it is absorbed. The word enteric indicates small intestine; therefore enteric coatings prevent release of medication before it reaches the small intestine. The enteric coated polymers remain unionise at low ph, and therefore remain insoluble. But as the ph increases in the GIT, the acidic functional groups are capable of ionisation, and the polymer swells or becomes soluble in the intestinal fluid [5]. Enteric coating tablets are composed of three layers, a drug containing core tablet (rapid release function), the press coated swellable hydrophobic polymer layer (Hydroxy propyl cellulose layer (HPC), time release function) and an enteric coating layer (acid resistance function).[6] The tablet does not release the drug in the stomach due to the acid resistance of the outer enteric coating layer. The enteric coating layer rapidly dissolves after gastric emptying and the intestinal fluid begins to slowly erode the press coated polymer (HPC) layer. Rapid drug release occurs when the erosion front reaches the core tablet since the erosion process takes a long time as there is no drug release period (lag phase) after gastric emptying [7,8]. Figure 1: Design of enteric coated timed-release press coated tablet MATERIALS AND METHODS Rabeprazole Sodium obtained as gift sample from Alkem (pvt.ltd) Mumbai, Mannitol (Pearlitol SD200), Light Magnesium Oxide, Crosspovidone (KOLLIDON CL), L Hydroxypropylcellulose(LH-11), Talc, purchased from Sd Fine Chem (pvt.ltd) Mumbai, Opadry Organic Powder (OY-C-7000A), Opadry Enteric Yellow 94S52698, Isopropyl Alcohol, Isopropyl Alcohol, Di chloro methane obtained from (Loba Chemical Pvt. Ltd, Mumbai), Sodium

3 Page1002 Table 1: Formulation of Rabeprazole sodium Enteric coated Tablets S. Formula-1 Formula -2 Formula 3 Formula-4 Formula-5 Excipients No Mg/Tablet Mg/Tablet Mg/Tablet Mg/Tablet Mg/Tablet 1 Rabeprazole sodium Mannitol (Pearlitol SD 200) Light Magnesium Oxide L-HydroxyPropylCellulose (LH-11) Crosspovidone (Kollidon-CL) Talc Magnesium Stearate SUB COATING 1 Opadry White (7%) 6.8 (7%) 6.8 (5%) 6.8 (5%) 2 IsoPropyl Alcohol --- Q.S Q.S Q.S Q.S 3 Dichloro Methane --- Q.S Q.S Q.S Q.S ENTERIC COATING 1 Opadry Enteric Yellow (8%) 12.8 (9%) 12.8 (9%) 12.8 (9%) 2 IsoPropyl Alcohol --- Q.S Q.S Q.S Q.S 3 Dichloro Methane --- Q.S Q.S Q.S Q.S Total Weight (mg) Procedure Step 1 Weighing All the ingredients were weighed accurately as per manufacturing formula. Step 2 Presieving &mixing: Rabeprazole sodium was sifted through mesh#30. Mannitol (Pearlitol SD200) was sifted through mesh#30. Light magnesium oxide was sifted through mesh#30. Crosspovidone was sifted through mesh#30. L-Hydroxy propyl cellulose (LH-11) was sifted through mesh#30 Step 3 Sifting Magnesium stearate was sifted through mesh#40. Talc was sifted through mesh#40 Step 4 Blending Sifted Rabeprazole Sodium, Mannitol, Light Magnesium Oxide, Crosspovidone, L-Hydroxy propyl cellulose was together and mixed for 20 min in a blender. Sifted magnesium stearate and Talc together and added to the above Material and mixed for 20 min in Blender. Step 5 Compression Blended material were transferred to a tablet machine and compression using 27 Stationed compression machine with 7.2 mm standard concave Punches. Blended material was loaded in a Hopper and Powder was compressed to Tablets by operating tablet machine. Maintained room temperature c and relative humidity at 30-40%. Checked for Weight variation, disintegration, thickness,hardness, friability to meet the parameters. Collected the tablets in a cleaned double poly Bag indicating the product and Batch number. Step 6 Sub coating 210 ml of Isopropyl alcohol was loaded in a beaker and stirrer was turned on to operate with speed sufficient to produce vortex. Opadry organic powder was then added slowly to the vortex and the suspension was mixed for 45 min and added 210ml of dichloromethane to the beaker while at stirring. Coated the tablets in a coating pan till the average weight gain was 5% w/w build up using the specification.

4 Page1003 Step 7 Enteric coating 210 ml of Isopropyl alcohol was loaded in a beaker and stirrer was turned on to operate with speed sufficient to produce vortex. Opadry Enteric yellow was then added slowly to the vortex and the Suspension was mixed for 45 min and added 210 ml of dichloromethane to the beaker while at stirring. Coated the tablets in a coating pan till the average weight gain 9% w/w build up using specification. RESULTS AND DISCUSSION Rabeprazole were developed by preparing core tablets using mannitol as diluent and Crospovidone as super disintegrant in different proportions and varying the compositions of sub coating and enteric coating using opadry white and enteric yellow.the core tablets were prepared by direct compression method. In the preformulation studies the micromeritic flow properties of the API were assessed by determining angle of repose, compressibility index, Hausner ratio. The results indicated good free flow of Rabeprazole. Based on the analysis of innovator product the specifications for the core tablets are prescribed. The core tablets formulated with out super disintegrant F1 failed to fulfill the core specifications. When Crospovidone, a super disintegrant was added the formulations F2, F3, F4 fulfilled all the specifications prescribed for core tablets. The sub coating and enteric coating of the core tablets was done using Ganscoater(GAC-275).The finished products F1to F4 were evaluated for various physical properties such as uniformity of weight, content uniformity, thickness, hardness, disintegration and dissolution rate prescribed for enteric coated tablets. The results indicated that the finished product formulations F2, F3, and F4 fulfilled all the specifications of the physical properties prescribed for finished product. Product F2 failed in the acid stage of the dissolution rate testing due to in sufficient enteric coating. Formulation F3 though fulfilled the acid stage requirement it failed to provide the dissolution requirement of NLT 85%in the alkaline fluids. Formulation F4 fulfilled all the specifications including dissolution rate test in acid and alkaline fluids. Hence formulation F4 is considered as effective enteric coated product of Rabeprazole. Formulation F5 a replicated of formulation F4 was prepared and subjected to complete evaluation including stability testing.formulation F5 fulfilled all the specifications prescribed for Rabeprazole delayed release tablets and comparable to the innovator product. The dissolution of Rabeprazole from the delayed release products developed followed first order kinetics and also obeyed Higuchi diffusion model and peppas equation model. When the release data were analyzed as per peppas equation the n value was found to be in the range of indicating that non-fickian (Anomalous) diffusion as the release mechanism. The dissolution profiles of formulation F5 and innovator product were compared by calculating differential factor (F1) and similarity factor (F2). The F1 and F2 were found to be 3.37 and respectively for the comparison of dissolution profiles of formulation F5 and innovator product. Hence these two products were considered similar and comparable. In the accelerated stability testing carried out at 40 0 c and 75% RH for three months, no significant change in the physical properties, drug content, and dissolution rate of formulation F5 was observed. PHYSICOCHEMICAL PARAMETERS [8] Weight Variation The test was carried out on 20 tablets as per the procedure specified in USP. The average weight and maximum % deviation were calculated. Hardness Test The hardness test was carried out for 5 tablets using Monsanto hardness tester. The average hardness of the tablets was obtained. Thickness The thickness of the tables was calculated by the use of vernier calipers. Friability test The % friability of the tables of each brand was calculated by the use of Roche friabilator. It should be less than 1%. % Friability = (1- W/W0) X 100 Where, W = Initial weight of 20 tablets. W0 = Weight of 20 tablets after 100 revolutions.

5 Page1004 Disintegration Test The disintegration test was carried out according to USP procedure on six tablets using disintegration test apparatus with discs in 0.1N HCL (ph 1.2) maintained at 37 C ± 2 C for 2 hours. After 2 hours 0.1N HCL was replaced with phosphate buffer 6.8 ph. A disc was added to each tube and operated for further 60 minutes. The disintegration time of each tablet was recorded. Dissolution Study Drug release studies were carried out using a USP type II dissolution test apparatus at 100 rpm for 2 hr in 0.1 N HCl (900 ml) maintained at 37 C ± 0.5 C. 10 ml of sample was taken and sample was analyzed using UV spectrophotometer at 260 nm. Then the dissolution medium was replaced with ph 7.4 phosphate buffer (900 ml) and tested for drug release for 1 hr at same temperature and same rotation speed. After 10, 20, 30, 40, 50 and 60 minutes, 10 ml of the samples were taken out and 10 ml Volume of fresh phosphate buffer ph 6.8 was added to kept volume of dissolution medium constant and sample was analyzed using UV spectrophotometer 284 nm. Table2: Evaluation of Rabeprazole Sodium Tablets S. No TEST F 1 F 2 F3 F4 F5 MARKETED 1 Weight variation of the tablet (mg) Hardness (kg/cm 2 ) Thickness (mm) Friability (%) Disintegration time (min) Content uniformity (mg) Figure 2: Thickness of all formulations Figure 2: Thickness of all formulations Figure 3: Average Weight of all formulations

6 Page1005 Figure 4: Hardness of all formulations Figure 5: Disintegration of all formulations Figure 6: Content Uniformity of all formulations

7 Page1006 Figure 7: Friability of all formulations Table 3: Comparative Dissolution profile of Rabeprazole sodium Enteric Coated Tablet Formulations with Innovator (Razo 20mg) TIME(min) %Drug Release F-1 F-2 F-3 F-4 F-5 M Figure 8: Dissolution profile of all formulations Figure 8: Dissolution profile of all formulations

8 Page1007 CONCLUSION An efficient delayed release formulation of Rabeprazole could be designed as enteric coated tablets. The core tablet consists of Rabeprazole sodium (21.5mg), Mannitol (95mg) and Crospovidone (5mg) along with light magnesium oxide (stabilizer), L-Hydroxy propyl cellulose, talc and magnesium stearate (lubricants).the core tablets were given a sub coating with opadry white (5%).An enteric coating was then given with opadry enteric yellow (9%).This enteric coated formulation F5 is comparable to the innovator product. The developed delayed release tablet formulation is quite stable with regard to drug content, physical properties and dissolution rate in the accelerated stability testing REFERENCE 1. Thomas WYL and Robinson J. The Science and Practice of Pharmacy, 20th ed, Lippinkette, William and Willins: Howard C. Ansel, Loyd V. Allen and Nicholas G. Popovich. Ansel s Pharmaceutical Dosage forms and Drug Delivery Systems, 6th ed: Goodman and Gilman: The pharmacological basis of Threapeutics. 10th edition. p Cole G.C. Pharmaceutical Coating Technology, Taylor and Francis Ltd; p Singh Deep Hussan et al. Volume 2 Issue 6 Nov-Dec PP Gazzaniga A, Iamartino P, Maffino G and Sangalli ME, Oral delayed release system for colonic specific drug delivery, Int J Pharm, 108, 1994, Hita V, Singh R, Jain SK. Colonic targeting of metronidazole using azo aromatic polymers, development and characterization. Drug Del 1997; 4: International Journal of Advances in Pharmacological Sciences Volume 2, No.1-2, January-December 2012, pp Submit your next manuscript to IAJPR and take advantage of: Access Online first Double blind peer review policy No space constraints Rapid publication International recognition Submit your manuscript at: editorinchief@iajpr.com