335 P a g e International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 4(6): November-December 2015 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093*** ICV 5.13*** Pharmaceutical Sciences RESEARCH ARTICLE!!! FOMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF LOPERAMIDE HYDROCHLORIDE USING VARIOUS SUPERDISINTEGRATING AGENTS Asma Begum 1*, D. Nagendrakumar 1, Neetu Sharma 1, S B Shirsand 2 1 Department of Pharmaceutics, S.V.E. Trust s College of Pharmacy, Humnabad, Bidar, Karnataka -585 330 2 Department of Pharmaceutical Technology, H.K.E. Society s College of Pharmacy, Gulbarga, Karnataka -585 105. ABSTRACT KEYWORDS: In the present study, fast dissolving tablets of Loperamide hydrochloride Fast dissolving tablets; Loperamide hydrochloride; super disintegrating agents and in vitro drug release. For Correspondence: Asma Begum * Address: Department of Pharmaceutics, S.V.E. Trust s College of Pharmacy, Humnabad, Bidar, Karnataka -585 330. were prepared by using blend of superdisintegrants (Crospovidone, Croscarmallose sodium, Low-Substituted Hydroxypropyl Cellulose (L- HPC) and Sodium starch glycolate) in different concentration by direct compression method. The prepared formulations were subjected further for hardness, friability, drug content uniformity, wetting time, water absorption ratio, in vitro dispersion time, in vitro drug release (in ph 6.8 phosphate buffer) and stability studies (at 40ºC/ 75% relative humidity for 3 months). Among the tablets prepared, formulation (DCP 3 ) containing 4% w/w Sodium starch glycolate and 3% w/w of Crospovidone has shown in vitro dispersion time of 14 sec, wetting time of 17 sec and water absorption ratio of 88% and has released (t 50% 4.3 min) nearly seven fold faster drug release compared to the conventional commercial formulation (t 50% >30 min). Stability studies on indicated that there are no significant changes in drug content and in vitro dispersion time (p<0.05). From the results it was concluded that fast dissolving tablets of Loperamide hydrochloride can be prepared successfully and reproducible by using different concentration of super disintegrating agents.
336 P a g e International Standard Serial Number (ISSN): 2319-8141 INTRODUCTION: Difficulty in swallowing (Dysphagia) is a common problem of all age groups especially elderly and pediatrics, because of physiological changes associated with this group of patients. The concept of fast dissolving drug delivery system emerged from the desire to provide patient with conventional mean of taking their medication. 1 Loperamide hydrochloride (an opioid drug used against diarrhea). For the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease or gastroenteritis. Also used for reducing the volume of discharge from ileostomies with a view to provide a convenient means of administration to those patients suffering from difficulties in swallowing such as pediatrics, geriatric, uncooperative mentally ill patients and patients who do not ready access to water. 2 The present study aimed at formulating and evaluating fast disintegrating tablets of Loperamide hydrochloride using various concentrations of superdisintegrants. MATERIAL AND METHODS MATERIALS: Loperamide Hydrochloride was a gift sample from Vasudha Pharma Chem Ltd., Hyderabad. Crospovidone and Croscarmallose sodium were gift samples from Wockhardt Research Centre., Aurangabad. Sodium starch glycolate were purchased from Alkem Labs Pvt. Ltd., Mumbai. All other chemicals used were of analytical or pharmacopoeial grade and used as received. METHODS: Preparation of Fast Dissolving Tablets Direct Compression Method: 3 Fast dissolving tablets of Loperamide HCl were prepared by direct compression method. All the ingredients were passed through #60 mesh separately. The drug and mannitol were mixed by small portion of both each time and blending it to get a uniform mixture and kept aside. Then the ingredients were weighed and mixed in geometrical order and tablets were compressed at 8 mm size to get a tablet of 150 mg weight using a Clit pilot press 10 station compression machine. The tablets were prepared according to the formulae shown in table-1. Evaluation of Loperamide HCl Fast Dissolving Tablets: 1. Hardness 4 The resistance of tablets to shipping or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The hardness of each batch of tablet was
337 P a g e International Standard Serial Number (ISSN): 2319-8141 checked by using digital hardness tester. The hardness was measured in terms of kg/cm 2. 3 tablets were chosen randomly and tested for hardness. The average hardness of 3 determinations was recorded. 2. Friability 5 The test was performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for testing the friability of prepared fast dissolving tablets. 20 tablets were accurately weighed and placed in the Friabilator and operated for 100 revolutions. The tablets were re-dusted and reweighed. Friability (F) was calculated using the following formula. 3. Weight Variation 6 The weight of the tablet being made was routinely determined to ensure that a tablet contains the proper amount of drug. The USP weight variation test is done by weighing 20 tablets individually, calculating the average weight and comparing the individual weights to the average weight. 4. Wetting Time and Water Absorption Ratio 7 A piece of tissue paper folded twice was placed in a small petridish containing 6 ml of water. A tablet was put on the paper and 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 (w a - w b )/w b Where, W a = weight of tablet before water absorption, W b = weight of tablet after water absorption. 5. Drug Content Uniformity 7 The tablets were tested for their drug content uniformity. At random 20 tablets were weighed and powdered. The powder equivalent to 50 mg was weighed accurately and dissolved in 50 ml of methanol. The solution was shaken thoroughly. The undissolved matter was removed by filtration through Whatmann No.41 filter paper. Then dilute the solution to obtain 10µg solution. The absorbance of the diluted solutions was measured at 220nm. The concentration of the drug was computed from the standard curve of the loperamide Hcl in methanol.
338 P a g e International Standard Serial Number (ISSN): 2319-8141 6. In vitro Dispersion Time 7 Tablet was added to 10 ml of phosphate buffer solution, ph 6.8 at 37±0.5 C. Time required for complete dispersion of a tablet was measured. The results were shown in table-2. 7. Dissolution Study 7 In-vitro dissolution of a Loperamide HCl fast dissolving tablets were studied in USP TDT- 08L dissolution apparatus (Electrolab) employing a paddle stirrer. 900 ml of phosphate buffer ph 6.8 was used as dissolution medium. The stirrer was adjusted to rotate at 50 rpm. The temperature of dissolution media was previously warmed to 37±0.5 C and was maintained throughout the experiment. One tablet was used in each test, 5 ml of sample of dissolution medium were withdrawn by means of syringe fitted with pre-filter at known intervals of time and analyzed for drug release by measuring the absorbance at 220 nm. The volume withdrawn at each time interval was replaced with fresh quantity of dissolution medium. Percentage amount of Loperamide HCl released was calculated and plotted against time. For comparison the dissolution of Loperamide HCl from conventional commercial formulation was also studied. The results are given in table-2 and figure-1. 8. Stability Testing 3 Accelerated stability studies on the promising formulations (DCP 3 ) were carried out by storing 15 tablets in amber coloured screw-capped bottle at elevated temperature of 40±2 0 C/75±5%RH (Stability chamber, Oswald) over a period 90 days (3 months). At interval of one month, the tablets were visually examined for any physical changes, in drug content and in vitro dispersion time. RESULTS AND DISCUSSION In the present study an attempt has been made to design and evaluate fast dissolving tablets of Loperamide HCl by direct compression method. The formulations were prepared by using blend of super-disintegrants such as sodium starch glycolate (4% w/w) Crospovidone (1-3% w/w), Sodium starch glycolate (4% w/w) - Croscarmallose sodium (1-3% w/w) and sodium starch glycolate(4% w/w) - L-hydroxy propyl cellulose (1-3% w/w) as a superdisintegrants (in different ratios) and directly compressible mannitol as a diluents to enhance mouth feel.
339 P a g e International Standard Serial Number (ISSN): 2319-8141 The hardness of the tablet formulations were found to be in the range of 2.51-2.80 kg/cm² indicating good mechanical strength with an ability to withstand physical and mechanical stress conditions while handling. In all the formulations, friability values were found to be less than 1%. The weights of all the tablets were found to be uniform with low values of standard deviation and within the prescribed IP limits. The percent drug content of all the tablets was found to be in the range of 99.41% - 100.50% of the expected Loperamide HCl content, which was within the acceptable limits (IP limit 99% to 101%) (table-2). In vitro dispersion time, wetting time and water absorption ratio for all the Loperamide HCl tablet formulations were determined and the results are shown in (table-2). Among the tablets prepared, formulation (DCP 3 ) containing 4% w/w sodium starch glycolate and 3% w/w of crospovidone has shown in vitro dispersion time of 14 sec, wetting time of 17 sec and water absorption ratio of 88%. When compared to the control formulation (DC 0 ) which has shown 220 sec, 225 sec and 47% values for the above parameters respectively. In-vitro Dissolution Study: In-vitro dissolution studies were performed in ph 6.8 phosphate buffer, on the above promising formulation (DCP 3 ) along with control and conventional commercial formulation (CCF). The results are shown in table-3. From the above data it is evident that the promising formulations, DCP 3 released 87.53% drug in 30 min (ph 6.8 phosphate buffer) compared to conventional commercial formulation (30.2%). When the drug release from DCP 3 (87.53%) formulation is compared with conventional commercial formulation in ph 6.8 phosphate buffer, it can be seen that conventional commercial formulation has released about 30.2% in 30 min. Thus, it can be seen that drug release from DCP 3 formulation was found to be approximately three fold faster, when compared to the conventional commercial formulation (30.2%). In-vitro dissolution parameters (t 50%, t 70% and t 90% values) of the promising Loperamide HCl formulations in comparison with conventional commercial formulation in ph 6.8 phosphate buffer are shown in table-3. Formulation DCP 3 has shown t 50% value of 4.3 min, t 70% value of 10.3 min and t 90% value of >30 min against the conventional commercial formulation values of t 50%, t 70% and t 90% values of >30 min for the same parameters respectively. Thus, DCP 3 formulation displayed four fold higher dissolution efficiency and almost more than 7 fold
340 P a g e International Standard Serial Number (ISSN): 2319-8141 faster drug release compared to the conventional commercial formulation, when t 50% values are considered in ph 6.8 phosphate buffer. Stability Studies: Stability studies on the above promising formulations (at 40ºC/ 75% RH for 3 months) have shown no significant changes in physical appearance drug content and in-vitro dispersion time. CONCLUSION In the present work, fast dissolving tablets of loperamide HCl were prepared by direct compression method using blend of super-disintegrants such as sodium starch glycollatecrospovidone, sodium starch glycolate - crosscarmellose sodium and sodium starch glycolate - L-hydroxy propyl cellulose as a superdisintegrant (in different ratios). The prepared batches of tablets were evaluated for hardness, friability, weight variation, drug content uniformity, in-vitro dispersion time, wetting time, water absorption ratio, in vitro drug release pattern (for promising formulations), short-term stability and drug-excipient interaction. Thus, promising formulation DCP 3 showed nearly 7 fold faster drug release when compared to the conventional commercial formulation( in 30 min). So the preparation of Loperamide HCl fast dissolving tablets using sodium starch glycollate- crospovidone fulfilling the objectives of the present investigation. ACKNOWLEDGEMENT The authors are thankful to Vasudha Pharma Chem Ltd., Hyderabad for providing gift sample of Loperamide Hydrochloride. The authors are very grateful to management and staff of S.V.E. Trust s College of Pharmacy, Humnabad for providing facilities to carry out the work. REFERENCES: 1. Azharuddin M, Spandana D, Kamath K, Subas SP, Shabaraya AR. Formulation and evalvation of fast dissolving tablets of granesitaron Hcl using natural polymers. Reach in Pharm 2011; 1(2):20-27. 2. [Updated 2015 feb 20; cited 2014 Dec 11]. Available from: http://en.wikipedia.org/wiki/loperamide.
341 P a g e International Standard Serial Number (ISSN): 2319-8141 3. Raghavendra NGR, Venkatesh K, Upendra K, Mettu SR, Kistayya C. Design And development of fast dissolving tablets containing baclofen by direct compression method. Int J Pharm Biomed Res 2012; 3(4):216-221 4. Aulton EM. Pharmaceutics. The science of dosage form design. 2nd ed., ELBS/Chuchill Livingstone, London; 2002. p. 4. 5. Gupta AK. Introduction to pharmaceutics. Vol.1; 2nd ed., New Delhi: CBS Publications; 1991. p. 270. 6. Liberman H, Lachman L. The Theory and Practice of Industrial Pharmacy. 3 rd ed. Bombay: Verghese Publication House; 1991. p. 171-93. 7. Jain CP, Naruka PS. Formulation and evalvation of fast dissolving tablesta of valsartan. Int J Pharm Pharmceu Sci. 2009; 1(1):219-226.
342 P a g e International Standard Serial Number (ISSN): 2319-8141 Table No.1 - Formulations of Loperamide HCl Fast Dissolving Tablets Ingredients (mg/tablet) Formulation code DC 0 DC 1 DCP 1 DCP 2 DCP 3 DCCP 1 DCCP 2 DCCP 3 DL- HPC 1 DL- HPC 2 DL- HPC 3 Loperamide HCl 2 2 2 2 2 2 2 2 2 2 2 Crospovidone - - 1.5 3.0 4.5 - - - - - - Sodium starch glycolate Croscarmallose sodium - 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 - - - - - 1.5 3.0 4.5 - - - L-HPC - - - - - - - - 1.5 3.0 4.5 MCC (Avicel PH102) 30 30 30 30 30 30 30 30 30 30 30 Aspartame 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Sodium stearyl fumarate 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Talc 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Flavour (Pineapple) Mannitol (Pearlitol SD 200) 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 109 103 101.5 100 98.5 101.5 100 98.5 101.5 100 98.5 Total weight 150 150 150 150 150 150 150 150 150 150 150
343 P a g e International Standard Serial Number (ISSN): 2319-8141 Table No.2 - Evaluation of Loperamide HCl Fast Dissolving Tablets Parameters Formulation Code DC 0 DC 1 DCP 1 DCP 2 DCP 3 DCCP 1 DCCP 2 DCCP 3 DL- HPC 1 DL-HPC 2 DL- HPC 3 Hardness*±SD (kg/cm²) 2.7 ± 0.10 2.80 ± 0.15 2.53 ± 0.152 2.68 ± 0.05 2.71± 0.20 2.69 ± 0.05 2.51± 0.14 2.76 ± 0.25 2.63 ± 0.20 2.65 ± 0.152 2.53 ± 0.05 Thickness*±SD (mm) 2.52 2.80 2.62 2.82 2.78 2.78 2.76 2.80 2.90 2.95 2.93 In-vitro Dispersion time*± SD (Sec) 220± 2.0 43 ± 0.58 33 ± 0.69 22 ± 1.10 14 ± 0.69 38 ± 1.53 26 ± 0.69 20 ± 0.82 41 ± 1.10 30 ± 2.90 26 ± 2.08 Wetting Time* ± SD (Sec) 225±0. 58 47 ± 1.10 38 ± 1.53 26 ± 1.59 17 ± 0.82 44 ± 1.59 32 ± 1.06 25 ± 0.98 44 ± 1.19 35 ± 1.82 31± 1.40 Water Absorption ratio*± SD (%) 47 ± 2.78 68 ± 1.13 76± 0.04 84 ± 0.63 88± 1.29 71± 0.04 78± 1.86 83± 0.51 69± 0.04 74± 0.80 780± 1.80 Percent Drug Content *± SD 99.51± 0.5 100.3±0.54 99.77±1.28 99.46±0.64 100.1 6±0.4 85 100.43± 0.61 99.89±1.19 99.89±0.63 100.24± 0.98 100.50±0. 48 100.0±0.69 Weight Variation (%) (149-156mg) Within the IP limits of ± 7.5%
344 P a g e International Standard Serial Number (ISSN): 2319-8141 Table No.3 In Vitro Drug Release Parameters Formulation Code t 50% (min) t 70% (min) t 90% (min) Cumulative % Drug Release in 30 min*±sd PD >30 >30 >30 22.00± 1.88 CCF >30 >30 >30 30.2 ± 1.850 DCP 3 4.3 10.3 >30 87.53 ±1.230 DCCP 3 8.1 20.0 >30 79.92 ±1.550 DL-HPC 3 9.2 24.0 >30 76.84 ± 1.550
345 P a g e International Standard Serial Number (ISSN): 2319-8141 Figure-1: Comparative Cumulative Drug Release of Fast Dissolving Tablet Formulations, Control and Conventional Commercial Formulations (CCF) in ph 6.8 Phosphate Buffer