INTERNATIONAL JOURNAL OF DRUG DELIVERY AND NANOTECHNOLOGY VOL. 1 ISSUE 1, 2015; 53 60; SBT JOURNALS RESEARCH ARTICLE Design, development and evaluation of osmotic drug delivery system using Tramadol HCl Vrushali Ashokrao Dhobe, Bharti Bakde E-mail: vrushalidhobe04@gmail.com Department of Pharmaceutics, P. Wadhwani college of Pharmacy, Maharastra, India Date Submitted: 29 th Aug 2015; Date Accepted: 9 th Sep 2015; Date Published: 11 th Sep 2015 Abstract: This study deals with design of Controlled porosity osmotic tablet of Tramadol HCl. Tramadol HCl is highly soluble drug. It can provide continuous drug release for period of 10-12 hrs. The prepared powder blend was evaluated for flow and compression characteristics prepared osmotic tablet was evaluated for in vitro drug release study. Tramadol HCl release was directly proportional to the level of plasticizer and osmotic pressure generated by osmotic agent but inversely proportional to swellable polymer within the core and coat thickness. Ethyl cellulose was used as coating agent and PEG is \used as pore former. Coating thickness was 8%. Key word: Controlled porosity osmotic pump, poly ethylene glycol, Ethyl cellulose INTRODUCTION Oral route is one of the most extensively used routes of drug administration because of its obvious advantages of easy of administration, improved patient compliance, and convenience. For a drug of short to intermediate half- life (20 min to 8 hours) dosage regimen can be fixed by giving the drug approximately every half- life or more frequently. Drug having high solubility and relatively short halflife suggest its suitability for an extended formulation- Tramadol HCl is a opoid antagonist useful in treatment of pain. T ramadol HCl is a class 1 drug according to Biopharmaceutics Classification System (BCS), possessing both high solubility and high permeability absorption characteristics. tramadol is rapidly and completely absorbed from the gastrointestinal tract but it is subject to extensive first pass metabolism resulting in incomplete bioavailability (about 70%). After oral dosing, Tramadol HCl reaches maximum plasma concentration from 2 to 3 hr post dosing and its elimination half-life ranges from 6 to 7 hr. Tramadol HCl has a short elimination half- life and rapidly absorbed in gastrointestinal tract. If it is formulated by conventional tablets requires multiple daily administration (3-4 times daily) with resulting inconvenience to the patient and the possibility of reduced compliance with prescribed therapy. This limitation has largely been overcome with the development of osmotic drug delivery system. 1 MATERIALS AND METHODS Materials Tramadol HCl was obtained from ALKEM Pharmaceuticals Ltd. Mumbai as gift sample. Mannitol was used as osmogen and lactose used as diluents. Magnesium Stearate were used as lubricant. Ethyl cellulose was used as semi permeable membrane. PEG400 was used as pore former. The other chemicals used were of analytical grade. Methods Preparation of core Tablet: Tramadol HCl, lactose monohydrate, mannitol, magnesium stearate and talc were shifted through fine sieve and mixed for 5 min, all the ingredients were blended properly to form a homogeneous mixture and core tablet was prepared by direct compression method using tablet compression machine. Coating of Tablet In the present study, pan coating method was used to coat the tablets. The formulations F1-F 10 were used as core tablets. b) Analysis of excipients used in the formulation: The following excipients, Ethyl cellulose as polymers, Magnesium Stearate as lubricant, Poly ethylene glycol as a plasticizer are selected for formulating CPOP and these have been evaluated and analyzed for the physicochemical characters. POST COMPRESSION PARAMETERS a.tablet appearance: The prepared tablets were evaluated visually for cracks, depressions, colour. b.thickness: The thickness of tablet was determined using Vernier caliper. Six tablets from each batch of formulation were used and mean thickness value and stand. 53
c. Hardness: For each formulation, the hardness of six tablets was measured using the Monsanto hardness tester and mean value and standard deviation was calculated. Table 1: Formulation batches For F1-F4 INGREDIENTS(Mg) F1 F2 F3 F4 Tramadol HCl 100 100 100 100 Mannitol 70 70 70 70 Lactose 26 26 26 26 Microcrystalline Cellulose 50 50 50 50 Talc 2.5 2.5 2.5 2.5 Magnesium stearate 1.5 1.5 1.5 1.5 Total wt 250 250 250 250 Ethyl cellulose 3 3 3 3.5 Polyethylene Glycol 2 3 4 3.5 (ml) % of coating 8% 8% 8% 8% Table 2: Formulated batches For F5-F8 INGREDIENTS F5 F6 F7 F8 Tramadol.HCl 100 100 100 100 Mannitol 70 70 70 85 Lactose 26 26 Sodium chloride - - 26 11 Microcrystalline 50 50 50 50 Cellulose Talc 2.5 2.5 2.5 2.5 Magnesium Stearate 1.5 1.5 1.5 1.5 Total wt. 250 250 250 250 Ethyl cellulose 4 2.5 3 3 Poly ethylene 4 2.5 3 3 glycol % of coating 8% 8% 8% 8% d.weight variation:the weight variation test is carried out as per the method described in the US Pharmacopoeia-25 NF20, 2002. Method: Twenty tablets were selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weight deviates from the average weight by more than the percentage shown in officials and none deviate by more than twice the percentage shown. Then the resultants weights were compared to the average dose USP weight variation test e.friability Test: The friability of tablets was determined using Roche Friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (Winitial) and transferred into friabilator. The friabilator was operated at 25rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (Wfinal). The % friability was then calculated by % Friability = 100 (1-x / y) x=weight initial, y=weight final % Friability of tablets less than 1% are considered acceptable. g. Drug Content: The test is performed by taking twenty tablets, weighed and powdered. A quantity of powdered tablet equivalent to 20 mg of tramadol.hcl was dissolved in 0.1 N HCl in 100ml volumetric flask. The so formed sample was diluted and the absorbance was measured at 248.4 nm using 0.1 N HCl as blank and the % drug content was estimated using the following formula. h. Dissolution test: Dissolution test was performed using USP XXIV (MOD- EL DISSO, M/s. Labindia) rotating paddle method (Apparatus 2). The stirring rate was 50rpm. 900ml of 0.1N hydrochloric acid was used as dissolution medium and was maintained at 37ºc. Samples of 5ml were withdrawn at predetermined time intervals, filtered and replaced with 5ml of fresh dissolution medium. The collected s samples were suitably diluted with dissolution fluid, wherever necessary and were analyzed for the Tramadol HCl at 271 nm by using UV spectrophotometer. RESULT AND DISCUSSION Organoleptic Properties of drug: Table 3: Comparison of results of identification tests of Tramadol HCl with the reported standards. Identification Test Observed Result Reported Standard Appearance Fine powder Fine powder Colour white White Odour Characteristics Characteristics 54
b. Melting point: Table 4: Melting point of of Tramadol HCl Identification Test Observed Result Reported Standard Melting point 178 0-184 0 C 178 0-184 0 C 7.2. COMPATIBILITY STUDY BY FTIR: It is important to check any kind of compatibility between drug and excipients in formulation. The excipients which are to be incorporated in to formulation should be compatible with drug. Compatibility study was done by Fourier transformed infrared spectroscopy. Fig 1: FTIR spectra of Tramadol HCl Fig 2: FTIR spectra of Ethyl cellulose 55
EVALUATION PARAMETERS: A.PRECOMPRESSION PARAMETERS Table 5: Evaluation of powder blend Batch No. Angle of Repose (ø) Bulk Density (g/cm 3 ) Tapped Density (g/cm 3 ) Carr, s Index (%) Hausner s Ratio F1 33 0 +0.2 0.625+0.02 0.80+0.02 18.75+1.2 1.28+0.02 F2 28 0 +0.1 0.625+0.01 0.71+0.02 11.97+0.02 1.13+0.17 F3 29.1 0 +0.2 0.64+0.03 0.71+0.01 9.58+0.1.16 1.20+0.02 F4 28 0 +0.3 0.657+0.01 0.71+0.21 8.45+0.01 1.13+0.02 F5 25 0 +0.3 0.625+0.01 0.71+0.17 14.38+0.02 1.16+0.01 F6 29 0 +0.02 0.64+0.2 0.73+0.01 10.85+0.02 1.10+0.01 F7 29 0 +0.02 0.651+0.02 0.73+0.02 10.91+0.01 1.12+0.01 F8 28 0.9+0.02 0.651+0.1 0.73+0.02 10.91+0.01 1.12+0.01 Angle of repose was found to be in the range 28.9-33 which is acceptable limit. Carr,s index were found in the range of 8.45-18.75% and hausners ratio 1.12-1.28. All parameters showed satisfactory result. EVALUATION OF OSMOTIC TABLETS: Table6: Physical appearance of tablet Physical parameters Colour Shape Size Weight Observations White Round oval 9mm 250 mg 56
Table7: Evaluation of Tramadol HCl Tablet Batch no Hardness Friability Thickness Diameter Drug content Weight variation Kg/cm 2 (%) Mm mm Mg F1 4+0.1 0.79+0.01 3.32+0.05 9.10+0.03 98.78+0.02 Passes F2 5+0.2 0.6+0.02 3.33+0.06 9.30+0.04 97.67+0.03 Passes F3 6+0.2 0.40+0.02 3.34+0.04 9.10+0.06 98.98+0.02 Passes F4 4+0.1 0.60+0.02 3.33+0.07 9.33+0.02 99.3+0.02 Passes F5 5+0.1 0.70+0.02 3.34+0.07 9.25+0.06 99.25+0.02 Passes F6 4+0.1 0.79+0.03 3.25+0.15 9.25+0.04 96.23+0.15 Passes F7 4+0.2 0.60+0.03 3.32+0.09 7.9+0.07 99.99+0.17 Passes F8 5+0.1 0.81+0.05 3.33+0.25 8+0.08 99.12+0.45 Passes Table 08: Cumulative percent release data of batches F1-F4 Time in hrs F1 F2 F3 F4 0 0 0 0 0 2 29+4.1 16.44+2.5 33.5+ 3.0 48+ 3.2 4 52+ 2.5 31.5+ 3.0 56.8+ 3.5 76.9+ 3.5 6 65.5+ 3.5 45+ 3.5 63+4.5 87+ 4.0 8 74+ 3.8 59.5+ 4.0 69.5+ 3.5 89+4.5 10 72.5+ 3.0 65.5+ 5.0 77.5+ 4.0 93+ 4.7 Fig 3. Cummulative % release data F1,F2,F3,F4 57
Table 9: Cumulative percent release data of batches F5-F8 Time in hrs F5 F6 F7 F8 0 0 0 0 0 2 23+3.4 30+ 4.5 22+ 5.5 33+4.1 4 51+3.4 60+ 4.0 44+ 4.0 70+3.7 6 55+3.5 90+ 4.2 66+ 4.5 90+4.1 8 65+4.5 92+ 3.6 76+ 3.5 98+4.0 10 68+3.8 96+ 4.0 93+ 4.2 101+2.0 Fig 4. Cummulative % release data F5,F6,F7,F8 Table 10: Evaluation parameter of coating film Formulations Folding indurance Tensile strenth Elasticity Appearance F1 18 Good Good Oily F2 20 Good Good Oily F3 14 Good Good Oily F4 13 Good Good Oily F5 20 Good Good Oily F6 19 Good Good Oily F7 18 Good Good Oily F8 20 Good Good Oily KINETICS STUDY Table 11. Drug release kinetics Batch no Zero order R 2 First order R 2 Higuchi Model R 2 Hixon Crowel R 2 F1 0.92205 0.99487 0.98765 0.979566 F2 0.96085 0.99928 0.92347 0.98328 F3 0.87191 0.96966 0.98690 0.94454 F4 0.78978 0.96690 0.95966 0.92034 F5 0.88560 0.94991 0.95085 0.95583 F6 0.8976 0.96350 0.95085 0.95583 F7 0.98628 0.916273 0.94870 0.973780 F8 0.85059 0.80798 0.944903 0.875367 Batch F3 and F8 follows Higuchi kinetics. F5 Follows Hixon crowel. F1, F2, F4 and F6 Follows First order kinetics and F7 follows Zero order kinetic 58
Fig. 5. Kinetic model of Batch F1 to F8 7.4. OPTIMIZED FORMULA Total 8 batches of ethyl cellulose as coating polymers with different concentrations were prepared. Out of these F7 batch containing ethyl cellulose polymer and pore former in ratio of 1:2 was found to be an optimized batch as it showed 93% release of drug in 10 hrs with zero order release rate mechanism. CONCLUSION It can be concluded from the present study osmotic pump for release of tramadol HCl can be developed as twice a day dosage form. Zero order release can be obtained by using ethyl cellulose as polymer poly ethylene glycol as a plasticizer In osmotic delivery system osmotic pressure provides the driving force for drug release. Increasing pressure inside the dosage form from water inclusion causes the drug to release from the system. The major advantage includes precise control of zero order. Controlled delivery via osmotic system also may reduce the side effect profile by moderating the blood plasma peaks typical of conventional (e.g. instant release) dosage form. They have low solubility at a high ph value and reduce fluctuation in drug level. It reruire low dose so they minimize local side effect. ACKNOWLEDGEMENT The authors express their gratitude to the alkem pharmaceuticals ltd. Mumbai for gift sample of Tramadol HCl. REFERENCES: 1. Lewis K, Han N. Tramadol: anew centrally acting analgesic. Amm J health system pharm. 1997; 54: 643-652 2. Prakashrao B, GeethaM, Purushothama N, Utpal S. A research on Optimization and Development of Swellable Controlled Porosity Osmotic Pump Tablet for Theophylline. Tropical Journal of Pharmaceutical Research. 2009; 8: 247-255 3. Nekkala V, Aminnabavi N, Reddy P, Ramkrishna S. Fornulation and Optimisation of extended release of metformin HCl tablets by osmotic technology. International journal of pharmacy and technology 2010; 1: 163-182 4. Krishna V, Reddy P, Keshireddy A. Formulation and optimization of extended release of metformin HCl tablet by osmotic technology. 2010;1: 163-182 5. Kappor D, Chauhan C K, Gupta A. K. Formulation And Evaluation Of Controlled Porosity Osmotic Pump Of Valsartan, International Journal of Pharmaceutical & Biological Archives. 2011; 2: 967-972 6. Rajagopal k, Nallaperumal N and Venkatesans S. A research on development and evaluation of controlled porosity osmotic pump. 2011; 102-108 7. Sudesh E, Shivanand K, Kalyani P, Prakashrao B. Formulation and Optimization of controlled porosity osmotic pump Tablet of diclofenac sodium. International Journal of pharmacy and pceutical science. 2011; 3(1): 0975-1491. 59
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