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International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 Comparative In-Vitro Evaluation of Different Brands of Paracetamol Tablets Marketed in Maharashtra State D. R. Jadge, A. N. Deshpande *, A. B. Gadgul, Y.A. Pandilwar, O. P. Patil Dayanand College of Pharmacy, Latur, Maharashtra, India- 413 531 Mobile: +919890879742. ABSTRACT: Paracetamol tablets are popular OTC products among patients marketed by a lot of suppliers around the world, being extensively used as antipyretic and general analgesic. The purpose of this research work was to compare and evaluate quality standards in the various brands of paracetamol tablets marketed in Maharashtra state. Six different brands of paracetamol 500mg manufactured by multinational companies and local companies were randomly sampled from different Pharmacy shops. The study was exclusively experimental that used BP, USP and other official books to assess the in vitro quality of paracetamol tablet using different analytical techniques and procedures. Evaluations of parameters were performed through the determination of weight variation, hardness, friability, drug content, and disintegration time and dissolution profile. All brands showed acceptable weight variation and friability except one which was more fragile. Percentage content for analyzed samples by UV method ranges from 92.32-102.2% indicating none of the brand contains less than 92% of the active principle. The physical and chemical tests like in-vitro dissolution, disintegration, hardness etc were found to be varying but within the specified limits. It can be concluded that paracetamol brands of local companies are safe enough and could be used to achieve desired therapeutic effects. Keywords: Paracetamol, Multinational brands. Quality Control Parameters, Evaluation, Local brands, Corresponding Author: Mr. A. N. Deshpande R S. Publication, [email protected] Page 40 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 1. INTRODUCTION: The quality of pharmaceuticals is a global concern, counterfeit medicines are increasingly detected worldwide.[1] Constant screening of marketed drugs by the drug regulatory authority or a consumer organization, using pharmacopoeias method enables consumer to be aware of the quality of drug. [2] Drug products that are chemically and pharmaceutically equivalent must be identical in strength, quality, purity, active ingredient release profile and should be in the same dosage form, for the same route of administration. [3] In order to ensure the requisite quality, drug manufacturers are required to test their products during and after manufacturing and at various intervals during the shelf life of the product. [4] As such the need to ensure that the generic and branded drugs products are pharmaceutically equivalent cannot be overemphasized and the necessity to select one product from several generic drug products of the same active ingredients is the cause for concern. [5] When there is shortage in market of the multinational brand and some life saving drugs, the patients are always reluctant to take the alternate local brands of same generic. If the patient does so, he would not psychologically satisfy & ultimately results in poor patient compliance. Some multinational brands are out of reach from buying due to high prices and comparatively local brands of same generic are available at much lower prices. [6] Paracetamol (4-hydroxy acetanilide) is a nonsteroidal anti-inflammatory drug (NSAID) and is prescribed most frequently. The chemical structure of paracetamol is shown in (Figure.1). It is widely used over the counter analgesic and antipyretic drug. [7] Generally it is used to treat headache, other minor aches, pain and as in cold and flu remedies. It is also useful in osteoarthritis therapy and management of cancer pain. When taken at recommended doses it has an excellent safety profile, notably lacking the gastrointestinal side effects of aspirin and ibuprofen, but overdoses of paracetamol can cause potentially fatal liver damage. [8] Tablet formulation of the drug product can have a significant effect on the quality parameters such as weight variation, hardness, friability, disintegration time, dissolution profile etc. and therapeutic effectiveness tablet relay on minimum of two factors, i.e. content uniformity (the actual label claim) and its adequate bioavailability.[09] Depending upon these facts, the present study was conducted to check, compare and prove the quality standards of commercially available local pharmaceutical brands with that of multinational pharmaceutical brands of paracetamol tablets marketed in Maharashtra as prescribed by B.P. and U.S.P. NH CH3 O HO Fig. 1: Chemical Structure of Paracetamol 2. MATERIALS AND METHODS 2.1 Chemicals and Reagents The reagents used were ferric chloride, Hydrochloric acid, potassium dichromate, Sodium Hydroxide (Loba Chemie Pvt Co., India) all analytical grade reagent and freshly deionised distilled water used throughout the work. R S. Publication, [email protected] Page 41 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 2.2 Apparatus and Equipments Double beam UV-Visible Spectrophotometer (Jasco 630), Analytical balance (Shimadzu AUW220D), Hardness Tester (Monsanto, Mht-20), Tablet Friability Tester (Roche, FTV-2), Disintegration apparatus (Electro Lab ED-2L), Dissolution apparatus (Electro Lab, EDT-08LX ) Drying oven (Meta Lab.) and Ultrasonicator (Toshcon, SW 4). 2.3 Sample Collection To perform the study paracetamol tablets of six different brands of multinational and local companies were purchased from the pharmacy shops within Marathwada region and coded as A, B, C, D, E and F respectively. All paracetamol brands were labeled to contain 500 mg of paracetamol per tablet. The commercial brands selected were of different manufacturers. The labeled shelf life of all of the tablets was three years from the date of manufacturing and was taken for the evaluation before two years of the labeled expiry date (Table 1). 2.4 Study Design Comparative in-vitro quality control parameters between commercially available local pharmaceutical brands with that of multinational pharmaceutical brands were studied through the evaluation of weight variation, hardness, friability, disintegration time, dissolution profile and drug content. 3. METHODOLOGY Various analytical methods and tests are important for the development and manufacture of pharmaceutical formulations. The evaluation was done according to USP and BP standards. 3.1 Identification Test of Paracetamol Two identification tests were conducted in the compliance to the British pharmacopeias. 3.2 Weight Variation Tablets of each brand were weighed individually using a digital analytical balance Shimadzu. The percentage deviation of the individual tablets from the mean was determined according to USP. 3.3 Hardness Test A tablet was placed vertically on the Monsanto Hardness tester. The load was then applied along the radial axis of the tablet. The weight or load required for breaking the tablet was noted down. Similarly it was done for 10 tablets. 3.4 Friability It was performed using Roche Friabilator, 10 tablets were weighed and placed in apparatus. The apparatus was rotated at a speed of 25 rpm. The apparatus was made to rotate for 4 min. The tablets were then weighed and the weights were compared with the initial weights. The % friability was calculated using the formula. % F = [1 - (W/Wo)] x 100 Where, % F = Friability in %, Wo = Initial weight of tablets, W = Weight of the tablets after revolution. 3.5 Tablet Disintegration It was performed using Electro Lab disintegration apparatus, 6 tablets were placed in disintegration test apparatus. It was maintained at 37 ± 0.2oC containing simulated gastric fluid (0.1N HCl). Noted down the time taken for tablets to disintegrate. R S. Publication, [email protected] Page 42 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 3.6 Dissolution Test For this test USP Type-1 (Basket) 6 Paddle Apparatus was used. The tablets formed were immersed into 900 ml. of dissolution medium, simulated gastric fluid (0.1N HCl). The temperature of the dissolution medium was maintained at 37 ± 0.2oC. The basket was rotated at a speed of 150 rpm. After an interval of every 10 minutes, 2 ml. of the medium was pipette out and replaced with fresh medium (0.1N HCl). This was continued all along for one hour. The pipetted out samples were then diluted to 10 ml. with fresh dissolution medium and were then filtered. The absorbances of the filtered samples were determined using U.V. Spectroscopy at λ max 222 nm. According to USP [10] specifications not less than 80% (Q) of the labeled amount of acetaminophen is dissolved within 30 minutes. 3.7 Assay The assay was done to find out any difference between the actual amount of active ingredient and the labeled amount. 10 tablets from each brand weighed and finely powdered then an accurately weighed portion of powder equivalent to 150mg paracetamol were transferred to a 200ml volumetric flask , 50 ml of 0.1M sodium hydroxide and 100ml of distilled water was added and sonicated for15 minutes, then diluted to the volume and filtered.10ml of the filtrate was transferred to100mlvolumetric flask and further diluted to 100ml with distilled water. Then 10ml of the filtered solution with 10ml 0.1M NaOH was transferred to another 100ml volumetric flask and the volume was completed with distilled water. The UV spectrophotometer was put at zero by running a baseline (200-400nm) using 0.1 M NaOH solution as blank The absorbances of the assay preparation was determined against the E1% at λ max 257nm with Double beam UV Spectrophotometer using 0.1 M NaOH solution as a blank. The same procedure was repeated for the standard using 150mg of powdered standard and the absorbance determined, which was used to calculate the percentage content and content in mg of paracetamol from each brand. The concentration of each sample was also deterrnined using Beer Lambert’s law according to BP. [11] 4. RESULTS AND DISCUSSION The results of the present study conducted on six different brands of paracetamol tablets, met the USP and BP requirements of quality control tests within specified limits. 4.1 Weight Variation According to official books, the specified limit on weight variation for tablets more than 324 mg is ± 5 %. It was found that all the tablets passed the USP specifications for weight variation as none of the brands deviated by upto ±5% from the mean value. Weight variation gives a rough idea of content uniformity, but not a confirmatory test. 4.2 Friability Friability is another important parameter that is related to hardness, disintegration and dissolution. According to the USP. [12] the allowed limit of friability is not more than 1.0 % of weight Loss. The friability was carried out for all the brands. It was less than 1% for all the brands except F tablets that were more fragile (2.0%), which may be due to the nature of the binders and additives used in the manufacturing procedures. 4.3 Hardness In the pharmaceutical industry, hardness of the tablets is an important parameter because pharmaceutical tablets must have sufficient ability to survive the handling forces during packaging and shipping. However, if the hardness exceeds a certain limit, it increases R S. Publication, [email protected] Page 43 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 the disintegration time, which ultimately affects the bioavailability. [13] Hardness is not an official test so there is no such a compendial limit for hardness but a crushing strength of between 4 kg/cm2 to 10 kg/cm2 is considered minimum requirement for a satisfactory tablets. The average hardness of the local and multinational brands was within the limits. 4.4 Disintegration Time Disintegration could be related to dissolution and similarly availability of drug to body (absorption) and finally the therapeutic efficacy of product. The result showed that disintegration time of all the selected tablets was found to be within specified limits of USP and BP. According to BP [14] (Figure 2), which specifies 15 minutes as disintegration time where as uncoated USP tablets have disintegration time standards as low as 5 minutes. Total of the results of above evaluated physicochemical parameters were presented in (Table 2) . 4.5 Assay Test for percentage of content is based on the assay of the individual content of active ingredient of a number of single dose units. All the paracetamol tablets i.e., multinational and local brands, contained the paracetamol with in 100 ±10 % of the labeled claim. The USP and BP specifications for assay are that the paracetamol contents should not be less then 90 % and not more then 110 (Table 3). Therefore, the assay results ascertain the presence and compendial quality of the drug in all products (Figure 3). 4.6 Dissolution Dissolution of the all the selected brands of paracetamol tablets was found to be within the specified limits of not less than 80 % in 30 min (USP) and not less than 70% (BP). Excellent results were obtained for all brands of tablets (Table 4). Depending upon the above facts & cost effectiveness it can be clearly stated that the commercially available local brands are of same quality and clinical effectiveness as the multinational brands available (Figure 4). So, the trends about the local brands should be changed. Since the analgesic and antipyretic medications containing paracetamol are used by patients to relief pain within short time to give the onset of action which depends mainly on the release of the drug.[15]. Table 1: Manufacturing date and expiry date of various paracetamol brands under test Multinational Manufacturing Tablet Code date Expiry date A B C D Nov. 2016 Nov. 2016 March 2016 Feb. 2017 Dec. 2013 Dec. 2013 March 2013 March 2013 Local Tablet Code E F Manufacturing date Expiry date Sept. 2013 Nov. 2013 Aug. 2016 April 2015 Table 2: Comparative evaluation of different quality control parameters of paracetamol tablets Tablet Code A B C D E F Weight Variation % 0.6 0.9 0.65 0.7 1.0 1.2 Friability % 0.45 0.34 0.43 0.36 0.55 2.0 R S. Publication, [email protected] Hardness (kg/cm2 ) 4.3 5.3 4.6 5.1 4.4 4.0 Disintegration Time (Min.) 2 3.2 2.5 3 2.43 2.12 Page 44 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 Table 3: Showing result obtained for percent content of paracetamol tablets by UV method Tablet Code Concentration (mg/ml) 0.000731 0.000700 0.000696 0.000718 0.000685 0.000660 A B C D E F Absorbance % Content Content (mg) 0.523 0.501 0.498 0.514 0.490 0.472 102.23 97.0 97.34 100.41 95.80 92.32 511.15 485 486.7 502.05 479.05 461.6 Table 4: Comparative Evaluation of dissolution profile of paracetamol tablets Time interval ( Minutes) 10 20 30 40 50 60 % Release of Paracetamol content B C D E 77 74 70 67 87 90 84 82 94 93 94 91 96.5 97 95 94.5 91 90 99 89 89 88.5 94 87 A 71 81 93 97 99.5 97 F 63 80 90 92 88 86 3.5 Time (Min.) 3 A 2.5 B 2 C 1.5 D 1 E 0.5 F 0 A B C D E F % Content Fig 2: Disintegration time (Min.) of different brands of Tablets 104 102 100 98 96 94 92 90 88 86 A B C D E F A B C D E F Fig 3: Assay of different brands of Paracetamol tablets R S. Publication, [email protected] Page 45 International Journal of Pharmaceutical Science and Health Care Available online on http://www.rspublication.com/ijphc/index.html Issue 4, Vol. 4. July-August 2014 ISSN 2249 – 5738 % Drug Release Comparative Dissolution Profiles of all Paracetamol Brands 120 100 80 60 40 20 0 A B C D E 0 10 20 30 40 50 60 F Time (Min.) Fig 4 : Dissolution profile of different brands of Paracetamol tablets CONCLUSION The in-vitro physical and chemical evaluation of selected commercial brands i.e., Multinational & Local brands of paracetamol available in Maharashtra state proved the quality and efficacy according to the standards of USP and BP requirements. As quality control parameters are related to one another from initial step to pharmacological action of the drug, a high-quality tablet should meet all the standard quality parameter for getting its desired therapeutic response. Quantitative variation often exists among drugs of different product. However, despite the variation most drug products are within the official limit. It reflects that these formulations will be definitely producing desired effects as analgesic & anti pyretic in patients. So the prescribing patterns should be changed depending upon the socio-economic status of patients. In conclusion, all the brands tested in this study were physically and chemically equivalent and it is preferred to be stored at 25ºC. ACKNOWLEDGEMENT The authors are grateful to GSK Pharmaceuticals for their kindly donation of paracetamol working standard. REFERENCES 1. D. Saurabh, K.M. Anil, K.K. Roop, C. Madhu, and C. Aruna, Counterfeit Medicines- The Global Hazard. Pharmaceutical Reviews, 6(4), 2008, 122-126. 2. J. Roy, P. Saha, S. Sultana, and A. Kenyon. Rapid screening of marketed paracetamol tablets: use of thin-layer chromatography and a semi quantitative spot test. Bulletin of the World Health Organization, 75 (1), 1997, 19-22. 3. O. Adegbolagun, O.A. Ololade and S.E.Osamah. 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Analgesics, British National Formulary, UK, 58, 2009, 233. 8. Acetaminophen, The American Society of Health-System Pharmacists, 2011, 453-58. 9. A. Chandrasekaran, C.Yittan, A.Chin Yang Chung, L.,Wei Cheang, and L. Sing Ping, Post market in vitro equivalency evaluation of Paracetamol tablets in kedah, Malaysia, Journal of pharmaceutical sciences and nanotechnology. 4, 2012, 567-71. 10. US Pharmacopoeia, The Official Compendia of Standards , 2, 2007, 1269-90. 11. British Pharmacopoeia , H. M. Stationary office, London, 3, 2008, 2968. 12. US Pharmacopoeia, 28 (30-NF25), 2007, 618-690. 13. L. Allen, Ansel’s Pharmaceutical Dosage form and Drug Delivery System. Lippincott Williams and Wilkins, Wolters Kluwer health, 9, 233. 14. British Pharmacopoeia, UK London, Appendix IIB, 2007, 1678. 15. E. Bamigbola, M. Ibrahim, and A. Attama. Comparative in-vitro assessment of soluble and plain brands of aspirin tablets marketed in Nigeria. Sci Res Essay, 11, 1412-1414. R S. Publication, [email protected] Page 47