Malleswari et.al Indian Journal of Research in Pharmacy and Biotechnology ISSN: (Print) ISSN: (Online)

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1 Comparative in-vitro dissolution study of five brands of Diclofenac sodium delayed release tablets in QbD environment V Malleswari Bai* 1, M Prasada Rao 1, M Chandana 1, K Naga Harini 1, B Naga Deepthi 1, K Thirumala Devi 1, P Lakashmana Rao 1, Vinay U rao 2 and J Naga raja 1 1. Department o f Pharmaceuitical Analysis, Medarametla Anjamma Masthanrao College of Pharmacy, Narasarao Pet, Guntur district, Andhra Pradesh, India. 2. Institutes of Pharmaceutical Sciences, Hyderabad *Corresponding author: E.Mail:malleswari.v4@gmail.com ABSTRACT Diclofenac sodium tablets are available as delayed release tablets in the market. Delayed release tablets are typically produced by coating the tablet with enteric coating polymers. These polymers provide the resistance of drug release in acidic environment of stomach and allow the drug to be released in alkaline environment of the intestine. A large number of enteric polymers are available which provide excellent protection to drug release in acidic environment. However, each polymer dissolves at different alkaline ph. For e.g. Eudragit L-100 dissolves at ph 6 and above while Eudragit S-100 dissolves at ph 6.5 and above. HPMC Phthalate P5.5 dissolves at ph 5.5 and above while HPMC Phthalate P dissolves at ph 6 and above. Hence, for the same drug the bioavailability can subtly but significantly change based on which enteric polymer is used to provide the delayed release. The aim of the current work was to comparatively evaluate five brands of Diclofenac sodium enteric coated tablets and determine which brands may be equivalent to each other based on in vitro testing. Comparative dissolution profile testing was carried out in ph 5.5, ph 6 and ph 6.8 buffers. It was determined that brand 1 and 5 are equivalent to each other while brands 2, 3 and 4 are equivalent to each other. Similarity factor f2 was used for comparing the dissolution profiles. Alcohol dumping studies indicated that only brand 1 was able to withstand the enteric effect at 40% level of alcohol. All other marketed brands fail the alcohol dumping test. This indicates that patients may have to counsel not to concomitantly consume alcohol while on Diclofenac sodium delayed release tablets. Key words: Diclofenac sodium, Quality by design (QbD), Delayed release, Dissolution test INTRODUCTION Quality by Design (QbD) is a concept first outlined by well-known quality expert Joseph M Juran in various publications, most notably Juran on Quality by Design. Juran believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned in the first place. While Quality by Design principles has been used to advance product and process quality in every industry, and particularly the automation industries, they have most recently been adopted by the U.S Food and Drug administration (FDA) as a vehicle for the transformation of how drugs are discovered, developed, and commercially manufactured (Juran, 1992). MATERIALS AND METHODS Development of a predictive dissolution method: The effects of dissolution medium ph, stirring speed, volume of the dissolution medium, type of apparatus used were systemically evaluated to develop the predictive dissolution method Effect of dissolution medium: An initial attempt at developing the discriminating dissolution method that would be predictive of in vivo performance was made using USP apparatus 2.Effect of dissolution medium phof both the innovator product and the four brands were subjected to dissolution testing using USP apparatus 2 at 50 rpm in 900 ml of various media including water, 0.1 N HCl, ph 5.5 phosphate buffer, and ph 6.8 phosphate buffer. The drug release of the marketed samples in comparison with the innovator at different time intervals was obtained in all the mediums. The similarity factor of the brands using innovator product as the reference is calculated Effect of dissolution medium volume: The drug release of innovator products and all the marked brands was evaluated using ph 1.2(0.1N HCl) dissolution medium volumes of1000ml and 500ml. The stirring speed was 50 rpm in each case. The drug release profile of the marketed samples in comparison with the innovator product at various time intervals were obtained in all two volumes. The similarity factor of the brands using innovator product as the reference is calculated Effect of stirring speed: Dissolution testing of all the marketed samples and the innovator product was conducted at25, 50, 75, and 100 rpm in 900 ml of ph 1.2(0.1NHCl) dissolution medium. The similarity IJRPB 1(6) November December 2013 Page 772

2 factor of the brands using innovator product as the reference is calculated Effect of type of dissolution apparatus: Dissolution testing of all the marketed samples and the innovator product was conducted using both USP1 (Basket) and USP2 (Paddle) apparatus in 900ml of ph 1.2(0.1NHCl) dissolution medium. The drug release profiles of all the marketed samples in comparison with the innovator product at various time intervals were obtained. The similarity factor of the brands using innovator product as the reference is calculated QbD development process includes: Begin with the target product profile that describes the use, safety and efficacy of the product. Defining a target quality profile that will be used by formulators and process engineers as a quantitative surrogate for aspects of clinical safety and efficacy during product development. Gather relevant prior knowledge about the substance, potential excipients and process operation. Design a formulation and identify the quality attributes to the final product that must be controlled to meet the target product quality profile. Design a manufacturing process to produce a final product having this critical material attributes. Identify the critical process parameters and raw material attributes that must be controlled to achieve these critical material attributes of the final product. Establish a control strategy for the entire process that may include input material controls, process controls and monitors design space around individual or multiple unit operation and/ or final product tests. Continually monitor and update the process to assure consistent quality. Quality by Design for drug release Two primary aspects: 1. Clinical relevance of release and stability specifications 2. Correlation between process parameters and ability to achieve specifications (and therefore remain clinically relevant) Dissolution testing and drug release: Dissolution testing has been widely used as the primary tool to evaluate drug release Dissolution is the process by which a solid solute enters a solution, and is characterized by rate (amount dissolved by time). In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Dissolution is the quality control measure and potential to provide in sight into the in vivo performance of the drug product. In vitro release test that predicts the drug in vivo would be optimal and highly desirable. A variety of designs of apparatus for dissolution testing have been proposed and tested, varying from simple beaker with stirrer to complex systems. Different apparatus, procedures and techniques are required for different dosage forms because of significant differences in formulation design and the physicochemical properties of the drugs. Dissolution tests have been developed for various drug delivery systems including immediate release solid dosage forms, several controlled release solid dosage forms and many novel and special dosage forms. Most of the tests with recommended apparatus and other specifications are now available as compendial standards in Pharmacopoeias and are used in pharmaceutical analysis and drug development for the various drug delivery systems. RESULTS AND DISCUSSION Five brands of Diclofenac sodium delayed release tablets 50 mg were procured from the market and subjected to assay and comparative dissolution profile testing as per USP guidelines for determining in vitro equivalence of modified release products. Assay of Diclofenac sodium delayed release tablets: Twenty tablets were weighed and crushed using mortar and pestle. Quantity of powder equivalent to 100 mg of Diclofenac sodium was weighed accurately and transferred to 100 ml volumetric flask. Approximately 70 ml of methanol AR grade was added and syndicated for 15 minutes. The volume was made up to 100 ml with methanol and filtered. From the clear filtrate and aliquot equivalent to 100 ppm was pipette out and transferred to 10 ml volumetric flask. The volume was made up to 10 ml with Methanol (10 µg/ml solution). The absorbance of this IJRPB 1(6) November December 2013 Page 773

3 solution was measured on UV spectrophotometer at 276 nm wavelength. The drug content was calculated by simultaneously measuring the absorbance of a standard 10 µg/ml solution of Diclofenac sodium. The assay values for all five brands are given in Table 1. Disintegration test for Enteric coated tablets (IP): The DT test for enteric coated tablets as described in IP was performed for 6 tablets of each brand and it was observed that all brands pass this test Comparative dissolution testing in 0.1N HCl: It is mandatory for all delayed release products to show < 10% drug release in 0.1N HCl when in vitro dissolution testing is performed for 2 hours in this medium. The results for the dissolution testing of the 5 brands are given in Table 2 and shown in Figure.1. All five brands passed the criteria of <10% in two hours in ph 1.2 medium. Comparative dissolution testing in ph 5.5: ph 5.5 simulates the duodenum and upper intestinal portion. Comparative dissolution testing was conducted in ph 5.5 acetate buffer for 1 hour (Figure.2) The dissolution profiles were statistically compared by calculating the similarity factor (f2). The f2 factor for brand 2, 3, 4 and 5 was calculated by comparing with brand 1. Only brand 5 showed f2 > 50. Hence this may be considered as equivalent to brand 1 for dissolution profile testing in ph 5.5. The f2 factor for brand 1, 3, 4 and 5 was calculated by comparing with brand 2. Brand 3 and 4 showed f2 > brand 2 for dissolution profile testing in ph 5.5. The f2 factor for brand 1, 2, 4 and 5 was calculated by comparing with brand 3. Brand 5 showed f2 > 50. Hence this may be considered as equivalent to brand 3 for dissolution profile testing in ph 5.5. The f2 factor for brand 1, 2, 3 and 5 was calculated by comparing with brand 4. Brand 2 showed f2 > 50. Hence this may be considered as equivalent to brand 4 for dissolution profile testing in ph 5.5. The f2 factor for brand 1, 2, 3 and 4 was calculated by comparing with brand 5 as standard. Only brand 1 showed f2 > 50. Hence this may be considered as equivalent to brand 5 for dissolution profile testing in ph 5.5. Comparative dissolution testing in ph 6.0: ph 6.0 simulates the duodenum and upper intestinal portion. Comparative dissolution testing was conducted in ph 6.0 Phosphate buffer for 1 hour. (Figure.3) The dissolution profiles were statistically compared by calculating the similarity factor (f2). The f2 factor for brand 2, 3, 4 and 5 was calculated by comparing with brand 1. Only brand 5 showed f2 > 50. Hence this may be considered as equivalent to brand 1 for dissolution profile testing in ph 6.0. The f2 factor for brand 1, 3, 4 and 5 was calculated by comparing with brand 2. Brand 3 and 4 showed f2 > brand 2 for dissolution profile testing in ph 6.0. The f2 factor for brand 1, 2, 4 and 5 was calculated by comparing with brand 3. Brand 2 and 5 showed f2 > brand 3 for dissolution profile testing in ph 6.0. The f2 factor for brand 1, 2, 3 and 5 was calculated by comparing with brand 4. Brand 2 and 3 showed f2 > brand 4 for dissolution profile testing in ph 6.0. The f2 factor for brand 1, 2, 3 and 4 was calculated by comparing with brand 5. Brand 1 and 3 showed f2 > brand 5 for dissolution profile testing in ph 6.0. Comparative dissolution testing in ph 6.8: ph 6.8 simulates the middle and lower portion of the gut. Comparative dissolution testing was conducted in ph 6.0 Phosphate buffer for 1 hour. (Figure.4). The dissolution profiles were statistically compared by calculating the similarity factor (f2). The f2 factor for brand 2, 3, 4 and 5 was calculated by comparing with brand 1. Brand 2 and 4 showed f2 > brand 1 for dissolution profile testing in ph 6.8. The f2 factor for brand 1, 3, 4 and 5 was calculated by comparing with brand 2. Brand 3 and 4 showed f2 > brand 2 for dissolution profile testing in ph 6.8. The f2 factor for brand 1, 2, 4 and 5 was calculated by comparing with brand 3. Brand 1 and 5 showed f2 > brand 3 for dissolution profile testing in ph 6.8. The f2 factor for brand 1, 2, 3 and 5 was calculated by comparing with brand 4. Brand 2 and 5 showed f2 > brand 4 for dissolution profile testing in ph 6.8. The f2 factor for brand 1, 2, 3 and 4 was calculated by comparing with brand 5. Brand 1, 2 and 3 showed f2 > brand 5 for dissolution profile testing in ph 6.8. The multimedia dissolution study indicates that the differences in the rate and extent of dissolution between different brands are significantly more at ph 5.5 and ph 6 than at ph 6.8. This may most likely be due to the fact that each brand may have been coated with enteric materials of different chemistries having different solubility profiles in IJRPB 1(6) November December 2013 Page 774

4 alkaline ph. For e.g. the reported solubility of Eudragit L100 is ph 6 and above while that of Eudragit L is ph 5.5 and above. Consequently, tablets coated with L will show significantly faster and more complete dissolution at ph 5.5 as compared to Eudragit L-100. All ph dependent enteric polymers completely dissolve at ph 6.8 and above. Hence the difference between the brands is significantly reduced in case of dissolution profile testing in ph 6.8 buffer. In order to simulate the way the dosage form is exposed to ph change in vivo, dissolution profile testing for all brands was conducted by using the in situ ph change method. The in situ ph change method of dissolution testing indicates that all five brands achieve > 80% release within 30 minutes of reaching the ph 6.8. However, dissolution profiles for Brand 1 and brand 5 are significantly faster at ph 6 than those of brands 2, 3 and 4. Hence, from this study it may be predicted that Brands 1 and 5 may show therapeutic equivalence to each other while brands 2, 3 and 4 may be equivalent to each other. But brand 1 and 5 may not show therapeutic equivalence to brands 2, 3 and 4.(Figure.7). Alcohol dumping study: For modified release products, different types of polymers are used to get the same kind of effect. Each of these polymers has different solubility profiles in commonly used solvents. The probability that this may affect the intended release profile in vivo is very genuine if we consider that patients may consume alcohol when under treatment with modified release products. The solubility profile of the polymer in alcohol may adversely affect the release rate of the drug from the dosage form and the actual drug release may be entirely different from the intended release. Hence, the US FDA in its latest guidelines has mandated that the alcohol dumping studies should be carried out for modified release products in order to demonstrate that the dosage form is able to perform within its specified standards even in presence e of significant levels of alcohol. For the five marketed brands of Diclofenac sodium delayed release tablets, a comparative alcohol dumping study was performed in 0.1N HCl without alcohol, and 0.1N HCl with 5%, 10% 20% and 40% v/v of alcohol respectively. The dissolution profile testing was carried out for two hours. The study indicates that only Brand 1 is able to maintain the enteric effect of < 10% release in acidic ph even in presence of 40% alcohol. All other brands fail the alcohol dumping test at 40% level of alcohol. Brand 2 fails the test even at 10% and 20% level of alcohol. (Figure.8). Table.1. Assay values for all five Brands of Diclofenac sodium 50 mg delayed release tablets BRANDS Brand 1 Brand 2 Brand 3 Brand 4 Brand 5 % Assay Table.2.Comparative dissolution profile testing in 0.1N Hcl Time Brand1 Brand2 Brand3 Brand4 Brand Figure.1. Dissolution profiles for 5 brands of Diclofenac sodium delayed release tablets in 0.1N HCl Figure.2.Comparative dissolution profile of five brands in ph 5.5 IJRPB 1(6) November December 2013 Page 775

5 Figure.3.Comparative Dissolution Profile In Ph 6.0 Figure.4.Comparative Dissolution Profile In Ph 6.8 Figure.5. Comparative Dissolution Profile In Ph 6.0 Figure.6.Comparative Dissolution Profile In Ph 6.8 Figure.7. Dissolution profile by in situ ph change method SUMMARY AND CONCLUSION Diclofenac sodium tablets are available as delayed release tablets in the market. Delayed release tablets are typically produced by coating the tablet with enteric coating polymers. These polymers provide the resistance of drug release in acidic environment of stomach and allow the drug to be released in alkaline environment of the intestine. A large number of enteric polymers are available which provide excellent protection to drug release in acidic environment. However, each polymer dissolves at different alkaline ph. For e.g. Eudragit L-100 dissolves at ph 6 and above while Eudragit S-100 dissolves at ph 6.5 and above. HPMC Phthalate P5.5 Figure.8.Alcohol Dumping study for Diclofenac sodium delayed release tablets market brands dissolves at ph 5.5 and above while HPMC Phthalate P dissolves at ph 6 and above. Hence, for the same drug the bioavailability can subtly but significantly change based on which enteric polymer is used to provide the delayed release. The aim of the current work was to comparatively evaluate five brands of Diclofenac sodium enteric coated tablets and determine which brands may be equivalent to each other based on in vitro testing. Comparative dissolution profile testing was carried out in ph 5.5, ph 6 and ph 6.8 buffers. It was determined that Brand 1 and 5 are equivalent to each other while brands 2, 3 and 4 are equivalent to IJRPB 1(6) November December 2013 Page

6 each other. Similarity factor f2 was used for comparing the dissolution profiles. Alcohol dumping studies indicated that only brand 1 was able to withstand the enteric effect at 40% level of alcohol. All other marketed brands fail the alcohol dumping test. This indicates that patients may have to counsel not to concomitantly consume REFFERECES 1. Juran JM, Juran on Quality by Design, The Free Press, A Division of Macmillan, Inc., New York, 1992, Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C: Do selective cyclooxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials, BMJ, 3, 2006, Solomon DH, Avorn J, Sturmer T, Glynn RJ, Mogun H, Schneeweiss S: Cardiovascular outcomes in new users of coxibs and Nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk, Arthritis Rheum, 54(5), 2006, FitzGerald GA, Patrono C, The coxibs, selective inhibitors of cyclooxygenase-2, N Engl J Med, 345(6), 2001, Graham DJ: COX-2 inhibitors, other NSAIDs, and cardiovascular risk: the seduction of common sense, JAMA, 296(13), 2006, Brater DC, Renal effects of cyclooxygyenase-2- selective inhibitors, J Pain Symptom Manage, 23(4 Suppl), 2002, Sigma Aldrich Gan TJ: Diclofenac: an update on its mechanism of action and safety profile, Curr Med Res Opin, 26(7), 2010, alcohol while on Diclofenac sodium delayed release tablets. ACKNOWLEDGEMENT The authors are grateful thanks to Indian Pharmaceutical Sciences, Arabindo pharma lim, EMCO industries-hyd, FMC-US, Ashaland specialty chemicals-us for providing gift samples of Diclofenac Sodium. IJRPB 1(6) November December 2013 Page 773 Page 777