Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28, ISSN 974-3618 www.rjptonline.org RESEARCH ARTICLE Formulation and Evaluation of Effervescent Floating Tablet of Amlodipine besylate Pare A, Yadav SK and Patil UK* V N S Institute of Pharmacy, V N S Campus, Vidya Vihar, Barkheda Nathu, Neelbud, Bhopal (M P)-46244 * Corresponding Author E-mail: umeshpatil29@yahoo.com ABSTRACT Amlodipine besylate effervescent floating tablets were developed in ten different formulations (F1 to F1) by employing different grades of polymers and effervescent agents such as sodium bicarbonate and citric acid. The formulations were evaluated for various physical parameters, buoyancy studies, dissolution parameters and drug released mechanisms. F1 formulation showed maximum floating time of 24 hours and gave slow and maximum drug release of Amlodipine besylate spread over 24 hours and whereas Amlodipine besylate released from marketed tablet was rapid and maximum within 12 hours. KEY WORDS Amlodipine besylate, Effervescent floating tablet. INTRODUCTION: Effervescent floating drug delivery systems generate gas (CO 2 ), thus reduce the density of the system and remain buoyant in the stomach for a prolonged period of time and released the drug slowly at a desired rate. 1,2,3 Amlodipine is long acting calcium channel blocker and used in the treatment of hypertension, and chronic stable angina. In hypertension or angina, initially 5 mg. one daily and adjusted to maximum dose 1 mg one daily dose of Amlodipine is given orally. 4 Amlodipine has maximum solubility in acidic ph. Amlodipine has some adverse effect such as nausea, abdominal pain. Effervescent floating tablet of Amlodipine besylate retain in stomach improves solubility, bioavailability, reduces drug waste and decrease side effect such as gastric irritation and nausea. 5, 6 In present work, effervescent floating tablets of different formulation were developed with an objective of achieving 24 hrs floating and drug release time and the effervescent floating tablet was compared with marketed formulation of Amlodipine besylate for drug released time. Received on 2.7.28 Modified on 23.8.28 Accepted on 25.8.28 RJPT All right reserved Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28;Page 526-53 EXPERIMENTAL Materials Amlodipine besylate was procured from Signa Pharma Pvt. Ltd. Kanpur. HPMC K1 M, HPMC K15 M, Carbapol 934 p, Sodium biacarbonate, Citric acid, poly vinyl pyrrolidine and Talc were obtained from Colorcon Asia Pvt. Ltd and Loba chemicals. Amlosafe 1 (marketed brand of Amlodipine besylate) tablets were purchased from local market. Methods Effervescent Floating tablets containing Amlodipine besylate were prepared by direct compression technique using varying concentrations of different grades of polymers with Sodium bicarbonate and citric acid. All the ingredients were accurately weighed and passed through different mesh sieves accordingly. Then, except Magnesium stearate all other ingredients were blended uniformly in glass mortar After sufficient mixing of drug as well as other components, Magnesium stearate was added, as post lubricant, and further mixed for additional 2-3 minutes. The tablets were compressed using rotary tablet machine. The weights of the tablets were kept constant for all formulation. Evaluation of effervescent floating tablet formulations Hardness of the tablets was tested using a Monosanto hardness tester. Friability of tablets was determined in Roche friabilator. Ten tablets were selected randomly from each batch and weighed individually to check for weight variation. The results are given in table no. 2 526
Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28, Invitro Dissolution Release 12 1 8 6 4 2 5 1 15 2 25 3 Time(hrs) Figure 1: In-vitro dissolution profile of formulations F 1 to F 9 Invitro Dissolution Data 12 F1 F2 F3 F4 F5 F6 F7 F8 F9 Log Cumulative % Drug Retained 2.5 2 1.5 1.5 First Order Release Kinetics y = -.729x + 2.996 R 2 =.9475 5 1 15 2 25 3 Log Cum % Drug Retained Time (hrs) Linear (Log Cum % Drug Retained) Figure 4: Plot of log cumulative percentage drug retained vs. time of optimized formulation (F1) [First order] Higuchi Release Mechanism 1 8 6 4 2 5 1 15 2 25 3 Time (Hrs) Figure 2: In-vitro dissolution profile of optimized formulation (F 1) Zero Order Relaese Kinetics F1 12 1 8 6 4 2 y = 23.761x - 12.922 R 2 =.9924 1 2 3 4 5 6 cumulative % drug release Root Of Time Linear Cumulative % drug release Figure 5: Plot of cumulative percentage drug released vs. root time of optimized Formulation (F1) [Higuchi Matrix] 12 1 8 6 4 2 y = 4.2369x + 11.43 R 2 =.9528 5 1 15 2 25 3 Cum % Release Linear (Cum % Release) Time (hrs.) Log Cumulative % Drug Released 2.5 2 1.5 1.5 Korsmeyer & Peppas Release Mechanism y =.691x + 1.848 R 2 =.9959.5 1 1.5 Log Time Figure 3: Plot of cumulative percentage drug released vs. time of optimized formulation (F1) [Zero Order] The buoyancy lag time (BLT) and total floating time (TFT) 7 On immersion of tablets of different formulations in.1n HCl solution at 37±5 C, the tablets floated, and remained buoyant without disintegration, the results of the buoyancy lag time (BLT) and total floating time (TFT) were shown in Table 3. Estimation of Amlodipine besylate 8 Amlodipine besylate content in the tablets was estimated by using UV spectrophotometric method based on the measurement of absorbance at λ max 239 Log Cum % Drug Release Linear (Log Cum % Drug Release) Figure 6: Plot of log cumulative percentage drug released vs. log time of optimized formulation (F1) [Korsmeyer and Peppas Model] nm in phosphate buffer 7.4. Amlodipine besylate content of the tablets are given in Table 4. Drug release study In vitro release studies of F1 to F1 formulations and one brand of Amlodipine besylate were carried out in the dissolution test apparatus (USP Type II). The tests were carried out in 9 ml of dissolution media 7.4 ph buffers for 24 hrs at 5 rpm at 37±.5 C 1 ml of the aliquot were withdrawn at different predetermined time intervals (.5, 1, 527
Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28, Table 1: Composition of all the Formulations (F1 F1) Ingredient F1 F2 F3 F4 F5 F6 F7 F8 F9 F1 Amlodipine 1 1 1 1 1 1 1 1 1 1 HPMC K1M --- 1 --- 5 --- 1 1 1 11 125 HPMC K15M 1 --- --- 1 1 --- 5 5 4 4 Carbopol 934P --- --- 1 --- 5 5 --- 5 5 4 MCC 1 1 1 5 5 5 5 --- --- --- Sodium Bicarbonate 6 6 6 6 6 6 6 6 6 6 Citric Acid 3 3 3 3 3 3 3 3 3 3 Poly vinyl Pyrrolidine K3 1 1 1 1 1 1 1 1 1 1 Magnesium Stearate 1 1 1 1 1 1 1 1 1 5 Talc 5 5 5 5 5 5 5 5 5 5 Aerosil 5 5 5 5 5 5 5 5 5 5 Total weight 33 33 33 33 33 33 33 33 33 33 *All the quantities are in mg Table 2: Hardness, Friability, Weight variation of tablets of different formulation F1 to F1 Formulation Hardness (Kg/cm 2 ) Friabilit y (%) Weight Variation (mg) F1 4.5 ±.47.96 334±5% F2 4.4 ±.32.72 331±5% F3 4.4 ±.54.91 328±5% F4 4.3 ±.42.86 329±5% F5 4.5 ±.35.79 327±5% F6 4.5 ±.54.97 334±5% F7 4.5 ±.54.72 333±5% F8 4.3 ±.42.72 327±5% F9 4.4 ±.32.72 332±5% F1 4.4 ±.32.86 329±5% *Values are mean± S.D 2, 4, 6, 8, 1, 12, 16, 2, 24 hr) and filtered. The required dilutions were made with and the solution was analyzed for the drug content by using UV detector detecting at λ max 239 nm 1 ml of sample was replaced in the vessel after each withdrawal to maintain sink condition. From this percentage drug release was calculated and this was plotted against function of time to study the pattern of drug release. The in-vitro drug release profiles of tablet from each batch (F1 to F1) were shown in Table 5. The plot of cumulative percentage drug release versus time (hr) was plotted and depicted as shown in Figure 1 and 2 Analysis of release mechanism In order to examine the release mechanism of Amlodipine besylate from the prepared floating tablets of the optimized formulation (F1), the results of the dissolution study was examined in accordance to the kinetic models. The regression coefficient R 2 value nearer to 1 indicated the model fitting of the release mechanism. The results are shown in Table 6 and Figure 3 to 6. Comparison with marketed product: The promising formulation (F1) as found by evaluation studies was compared with marketed product Amlosafe (Amlodipine besylate). The evaluation parameters tested and compared were drug content uniformity and in-vitro dissolution profile. The values of comparative in-vitro dissolution study of optimized formulation (F1) and marketed product are recorded in Table 7 and the result had come that the F1 formulation was sustained released as compare with Amlosafe tablet. Cumulative % Drug Released 12 1 Comparative Invitro Dissolution Drug Released 8 6 4 2 F 1 Marketed Product 1 2 3 Time (hrs) Figure 7: Plot of Comparative dissolution profile of optimized formulation (F1) and marked product RESULTS AND DISCUSSION: Amlodipine is a potent drug for the treatment of angina, hypertension and also suitable in the treatment diabetic hypertension. Amlodipine had maximum solubility in acidic ph. Amlodipine has some adverse effect such as headache, nausea, abdominal pain. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in high ph environment. Effervescence production, decrease the several local GIT side effect, such as gastric irritation, nausea and gastritis. The effervescent floating tablets of Amlodipine besylate were formulated in ten different batches F1 tof1 by using hydrophilic polymers HPMC K1M, HPMC K15M and hydrophobic polymer carbopol 934P along with effervescing agent sodium bicarbonate and citric acid. It was found that carbopol has a negative effect on floating behavior but it was used only for the drug release retardant characteristics. All the formulations were prepared by direct compression 528
method. The prepared tablets of all the formulations were evaluated for physical characters like tablet hardness, friability, weight variation buoyancy lag time, total floating time, assay, in-vitro drug release. The main aim was to optimize the formulation for 24 hours in-vitro release and total floating time to more than 24 hours. Table 3: Buoyancy Lag Time, Total Floating Time of formulations (F1toF1) Formulation Buoyancy Lag Total Floating Time (Sec) Time (hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9 F1 133 sec 13 sec Fail 12 sec 12 sec 15sec 14sec 141sec 138sec 11sec >12 hrs >14 hrs Fail >16 hrs >16 hrs >2hrs >2hrs The measured hardness of tablets of each formulation ranged between 4.1 to 4.5 kg/cm 2. The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable. All the tablets passed weight variation test as the % weight variation was within the Pharmacopoeial limits of ±5% of the weight. Buoyancy lag time (BLT) and total floating time (TFT) of different formulation were noted, where F1 BLT of 133 sec and TFT of >12 hours, F2 BLT of 13 sec and TFT of >14 hours, F3 fails to buoyancy because of absence of H P M C polymers, F4 BLT of 12sec and TFT of >16 hours, F5 BLT of 12 sec and TFT of >16 hours, F6 BLT of 15 sec and TFT of >2 hours, F7 BLT of 14 sec and TFT of >2 hours, F8 BLT of 141 sec and TFT of >24 hours, F9 BLT of 138 sec and TFT of >24 hours, F1 BLT of 11 sec and TFT of >24 hours, With reference to buoyancy studies results it can be concluded that the batch containing HPMC polymers showed good buoyancy lag time (BLT) and total floating time (TFT). Formulation F1 containing HPMC K15M, HPMC K1M and carbopol 934P showed good BLT of 11 sec and TFT of more than 24 hrs. Amlodipine besylate release from the effervescent floating tablets was studied in phosphate buffer ph 7.4. The release profile of various formulations are shown in table no. Figure no. 1 and 2. Formulation F1 released 98.4% of the drug in 12 hours. Formulation F2 released 98.4% of the drug in 16 hours. Formulation F3 released 96.2% of the drug in 8 hours. Formulation F4 released 98.3% of the drug in 16 hours Formulation F5 released 98.7% of the drug in 16 hours Formulation F6 released 98.4% of the drug in 16hours.Formulation F7 released 98.3% of the drug in 16 hours. Formulation F8 released Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28, 98.8% of the drug in 2 hours. Formulation F9 released 98.4% of the drug in 2 hours. F1 released 98.6 % of drug in 24 hours. Thus F1 formulation was said to be optimized formulation. Table 4: Drug Content Uniformity of Tablets of Batch F1 to F1 Batches Drug content uniformity (%) F1 97.1 F2 99.51 F3 98.1 F4 97.42 F5 98.41 F6 99.5 F7 99.5 F8 98.46 F9 98.45 F1 99.82 Optimized formulation F1 was subjected to curve fitting analysis, zero order, and first order, Higuhi Kinetics, Korsmeyer and Peppas model. The slope and r 2 are shown in Table 6 and graphs in Figure 3 to 6. Optimized formulation F1 fitted best for Korsemeyer Peppas equation with R 2 value of.9959. Comparison study with marketed product of Amlodipine besylate1mg (Amlodipine 1) showed that the optimized formulation F1 has better control over release rate in comparison to the commercial product. The marketed product released the drug 98.3% in 12 hours whereas the optimized formulation F1 released the drug 72.1% in 12hrs. And the optimized formulation F1 remained floatable in the stomach for 24 hours.and give the maximum released 98.6 at 24 th hours. It is, thus concluded that effervescent floating tablet containing Amlodipine besylate (F1 formulation) gave slow and complete drug release spread over 24 hours. ACKNOWLEDGMENT: The authors are grateful to Centre for development action and community research (CDACR) for help in literature survey and procurement of drug sample. REFERENCES: 1. Deshpande AA, Shah NH, Rhodes CT and Malick W. Development of a novel controlled release system for gastric retention. Pharm. Res. 1997; 14(6): 815-819. 2. Klausner EA, Lavy E, Friedman M and Hoffman A. Expandable gastroretentive dosage form. J. Control. Rel. 23; 9: 143-162. 3. Singh BN and Kim HK. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Control. Rel. 2; 63: 235-59. 4. Barar FSK. Essentials of pharmacotherapeutis.3 rd S. Chand and Company Ltd. New Delhi. 246 5. Gutierrez-rocca J, Omidian H and Shah K. Progress in Gastroretentive Drug Delivery System Bussiness Briefing, Pharmatech. 23: 152-156. 529
Research J. Pharm. and Tech. 1(4): Oct.-Dec. 28, Table 5: In-vitro drug release profile of tablets of F1 to F1 Time Cumulative Percentage Drug Release (hr) F1 F2 F3 F4 F5 F6 F7 F8 F9 F1.5 18.5 15.8 2.2 15.3 13.5 12.8 13.6 1.7 1.2 7.3 1. 3.2 27.3 32.5 26.8 28.2 27.4 22.3 15.8 16.1 11.7 2. 42.8 39.8 45.2 37.1 39.8 38.3 35.2 24.6 23.5 19.4 3. 55.2 51.5 57.3 49.9 51.5 5.2 48.4 32.4 3.3 25.9 4. 68.5 61.9 69.8 6.8 62.9 61.1 59.2 42.7 41.6 32.1 6. 76.8 72.7 88.5 71.8 73.7 72.4 69.3 55.2 53.1 43.2 8. 89.6 81.5 96.2 83.1 84.9 84.1 78.8 7.8 68.7 52.8 12. 98.4 96.2 93.2 95.3 94.5 89.2 84.7 79.8 72.1 16. 98.4 98.3 98.7 98.4 98.3 96.2 95.5 85.8 2. 98.8 98.9 96.8 24. 98.6 Table 6: Kinetic Release Data of Different Model for Optimized Formulation (F1) Model Slope R 2 value Zero order 4.2369.9528 First order -.729.9475 Higuchi 23.761.9924 Korsemeyer-Peppas model.691.9959 Table 7: Comparative dissolution profile of optimized formulation (F1) and marketed product. Time (hr) Cumulative percentage drug release F1 Marketed product.5 7.3 15 1. 11.7 25.1 2. 19.4 4.3 3. 25.9 65.42 4. 32.1 66.4 6. 43.2 7.8 8. 52.8 92. 12. 72.1 98.3 16. 85.8-2. 96.8-24. 98.6-6. Hou SY, Cowles VE and Berner. Gastric Retentive Dosage Forms: A Review, Crit. Rev.Ther. Drug Carrier Syst. 23; 2(6): 459-497. 7. Aulton ME. Pharmaceutics: The Science of Dosage Form Design. 2 nd Ed. London: Churchill Livingstone. 22. 8. Patil SB, Murthy RSR. Preparation and in vitro evaluation of mucoadhesive chitosan microspheres of amlodipine besylate for nasal administration. Iijpsonline. 28; July3: 66-67. 53