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Academic Sciences International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 5, Issue 3, 2013 Research Article FABRICATION AND EVALUATION OF EXTENDED RELEASE MATRIX TABLETS OF TRAMADOL HYDROCHLORIDE B.SELVARAJa, P.MALARVIZHIa AND P.SHANMUGAPANDIYANb * aPrist University, Thanjavur - 613403, Tamilnadu, India, b Mohamed Sathak A.J College of Pharmacy, Sholinganallur, Chennai- 600119, Tamilnadu, India. Email: [email protected] Received: 14 Jan 2013, Revised and Accepted: 26 Apr 2013 ABSTRACT Objective: Tramadol Hydrochloride is an opiod analgesic which acts centrally by blocking the transmission of pain signals sent by the nerves to the brain. It is widely used in the treatment of osteoarthritis. In this study an attempt was made to prepare extended release matrix tablets of Tramadol Hydrochloride using Ethyl cellulose and Chitosan. Ethyl cellulose and Chitosan have been extensively studied in microencapsulation and film forming experiments; however their candidature for matrix tablets were not studied in detail in the past. Methods: Various formulations were tried with Ethyl cellulose and Chitosan matrix forming agents individually and in combinations. Direct compression method was employed for preparing tablets with Dicalcium Phosphate, Magnesium Stearate, Colloidal Silicondioxide as excipients. The precompression parameters were evaluated for flow properties, compressibility index, etc. The rate retarding effects of polymers were studied by invitro dissolution studies. Results and conclusion: Chitosan in higher concentrations resulted in poor tablets and lower concentration gave less hours retardation of drug release. Higher concentration of Ethyl cellulose gave a good release profile when compared to Chitosan. Combinations of Ethyl cellulose and Chitosan also retarded the release of drug from matrix. It is evident from this study that Ethyl cellulose is a satisfactory candidate for preparing extended release matrix tablets of Tramadol Hydrochloride. Keywords: Matrix, Extended Release, Ethyl Cellulose, Tramadol Hydrochloride INTRODUCTION Patients suffering from painful conditions are in deliberate need of analgesics continuously. However due to various reasons like patient compliance, half life of drug, poor bioavailability etc, patients miss their drug requirement. To overcome these issues extended release tablets come in handy to provide required levels of drug in systemic circulation. Tramadol Hydrochloride is one such drug which finds immense requirement for long periods in patients who suffer from osteoarthritis [1]. It is an opiod analgesic used to treat moderate to moderately severe pains. It is a centrally acting drug which acts by blocking the transmission of pain signals sent by the nerves to the brain [2]. Tramadol Hydrochloride is a very weak opioid receptor agonist which induces serotonin release and inhibits the uptake of nor-epinephrine. It is white or almost white crystalline powder freely soluble in water [3]. Matrix tablets are one of the choices for preparing extended release tablets which contain an intimate mixture of drug and release rate retarding polymers along with excipients in a defined proportion. In this present study an attempt was made to prepare and characterize extended release matrix tablets [4] of Tramadol Hydrochloride by using Ethyl cellulose and Chitosan [5] as rate retarding polymers. The polymers were used in formulation as standalone rate retardants and also in combinations at various proportions [6]. MATERIALS AND METHODS Tramadol Hydrochloride was obtained as gift sample from M/s. Stedman Pharmaceuticals Pvt Ltd, Chennai. Excipients like Dicalcium phosphate, Ethyl cellulose, Magnesium stearate, Colloidal silicon dioxide of Pharmacopoeial grades were obtained as gift samples from M/s Safetab Life sciences, Pondicherry. Chitosan (Chitopharm M) was obtained as gift sample from M/s Cognis. Other materials, reagents and solvents used were of an analytical grade. Preparation of Matrix Tablets Preformulation studies were performed to characterize the drug and excipients (as shown in table 1). Tramadol Hydrochloride and excipients like Dicalcium Phosphate, Magnesium Stearate, Colloidal Silicon dioxide including the polymers [7] (Ethyl cellulose and Chitosan individually as well as in combinations) were admixed thoroughly (as shown in table 2) after sieving through 30. This blend was directly compressed using 9 mm circular standard concave punches in a 16 station rotary tablet punching machine [8]. Direct compression was chosen to make the process very simple and thereby to provide better product stability with conservation of energy and resources. In the Design of Experiment, three level of polymer concentration with two variables (polymers) [9] were selected which resulted in a 32 factorial design. Evaluation of Matrix Tablets Prepared extended release matrix tablets were evaluated for weight variation, hardness, friability, thickness, diameter, drug content, dissolution and stability. Weight variation for the tablets were done by weighing twenty tablets collectively and individually and then compared with average weight of the tablet. The crushing strength of the tablets and friability were evaluated using hardness tester and friabilator. Digital Vernier was engaged to determine the thickness and diameter of tablets. Invitro dissolution studies were conducted using USP Type I basket apparatus in 0.1N HCl at 37º C ± 0.5º C with 100 rpm. Aliquots were withdrawn for upto 8 hours and perfect sink conditions maintained by replenishing the media samples are subjected to UV absorbance at 270 nm to evaluate the percentage of drug release. Marketed product was also used to compare the dissolution profile along with the test formulations. RP-HPLC method was employed to estimate the drug content in tablets using Hypersil BDS C18 column. Acetonitrile/ Triflouro acetic acid (295 ml Acetonitrile: 705 ml, 0.02% v/v Triflouro acetic acid) was used as mobile phase with flow rate of 1.0 ml/min and UV detector was engaged to measure the absorbance at 270 nm. Compatibility Studies were performed by using FT-IR to compare the spectra of pure drug, polymer [10] and tablet. Accelerated stability studies were conducted for the test formulation F3 for 6 months at 40º C ± 2º C and 75% RH ± 5% RH and evaluated for physico-chemical properties. Release rate studies were performed for F3 by applying Zero order, First order, Higuchi, Hixson-Crowell and Korsmeyar-Peppas equations. Shanmugapandiyan et al. Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971 RESULTS AND DISCUSSION containing Ethyl cellulose at 40% is a better formula for maximum period of release [13]. Nine formulations of Tramadol Hydrochloride 100 mg sustained release tablets were prepared using Ethyl Cellulose and Chitosan as rate retarding polymers [11]. The polymers were used at various concentrations (20%, 30% & 40%) individually and also in combinations (10% + 10%, 15% + 15%, & 20% + 20%) (as shown in table 3). Most the formulations exhibited good flow properties and compressibility index except for Chitosan at higher concentration. The bulk density, tapped density, angle of repose, compressibility index and hausner’s ratio of the blend were in the range of 0.50 - 0.74, 0.58 – 0.92, 24.1 – 29.20, 11.11 – 23.59 and 1.12 – 1.30 respectively. Release rate studies indicate that F3 followed Higuchi, Hixson Crowell and Korsmeyer Peppas equations with a regression value of 0.9165, 0.9759, and 0.9221 respectively (as shown in table 6). First order and Zero order plots gave regression values of 0.8401 [14]. Formulation F3 was subjected to FT-IR studies and the results indicated that there was no incompatibility between the drug Tramadol HCl and polymer Ethyl cellulose. The IR Spectrum of pure drug-Tramadol HCl, polymer - Hydroxy propyl cellulose [15] and tablet F3 were taken and investigated for any additional peaks. Prominent sharp peaks at 1606, 1578 of pure drug-Tramadol HCl and sharp peaks at 1604, 1579 of Tablet F3 were visible in the spectrum. This clearly proves that there is no incompatibility (as represented in figure 2 a,b,c). It is evident that only slight shift in some of the functional groups of the drug-Tramadol HCl took place with overlapping and broadening. No prominent new peaks were detected in the FT-IR spectra of tablet F3 indicating no interaction between the drug-Tramadol HCl and polymer Ethyl cellulose. The stability studies performed on F3 for a period of 3 months at accelerated conditions gave satisfactory results on physico chemical properties [16]. These results indicated that the F3 is a stable composition. The weight variation of the tablets was within acceptable limits and ranged within ± 5%. The tablets possessed satisfactory friability and were <2% except for Chitosan at higher concentration formulation with a hardness ranging from 1 kg/cm3 to 8.5 kg/cm3. The thickness and diameter of the tablets was within 3.50 mm to 4.27 mm and 9.00 to 9.06 mm. Drug content was found to be in the range of 97.98% to 99.28% indicating a very good blend of the tablet.(as shown in table 4) Formulation F6 with stand alone Chitosan at higher level concentration (i.e, 40%) rendered poor tablets which resulted crumbling during evaluation and hence friability & hardness data could not be generated. The results of dissolution studies indicated that all the formulations retarded the release at various degrees. All the formulations retarded the release of drug from matrix tablets for extended periods. Formulation F3 containing Ethyl cellulose at 40% concentration gave a release for upto 8 hours when compared to F2 at 30% concentration and F1 at 20% concentration which gave upto 6 hours & 4 hours respectively (as shown in table 5). CONCLUSION The overall evaluation of formulations F1 to F9 indicate that F 3 containing Ethyl cellulose at 40 % is a suitable composition for producing sustained release matrix tablets of Tramadol Hcl (100 mg) where an action of upto 8 hours is desired. This is comparable with the Marketed Product which also gave a release for upto 8 hours. The Hixson Crowell and Higuchi equation best defines the release pattern indicating both dissolution and diffusion. Korsmeyer Peppas equation indicated the fickian diffusion with an ‘n’ value of 0.40. Formulations of Chitosan F4, F5, and F6 are not comparable with Ethyl cellulose in retarding the release rate of drug for an extended period. However combinations of polymers gave a satisfactory retardation of release. The present study indicates that proportion of polymers is also directly influential in retarding the release of drug. Higher concentration of polymers yield much more extended period of release. Compositions containing Chitosan were not comparable to Ethyl Cellulose containing formulations. However the period of release for Chitosan formulations were upto 4 hours for F6, F5 and 2 hours for F4 formulations. Combinations of Ethyl Cellulose & Chitosan formulations also delivered delayed release in which F7, F8 & F9 gave a release for upto 2 hours, 4 hours and 6 hours respectively (as represented in figure 1 a,b). Marketed product gave a release for upto 8 hours under similar conditions [12]. Dissolution studies indicated formulation F3 Table 1: Evaluation of blend S. No. 1 2 3 4 5 Parameters Angle of Repose Bulk Density Tapped Density Compressibility Index Hausner’s Ratio F1 24.6 0.56 0.63 11.11 1.12 F2 24.1 0.54 0.61 11.47 1.13 F3 25.2 0.50 0.58 13.79 1.16 F4 28.2 0.74 0.92 19.56 1.24 F5 28.5 0.70 0.90 22.22 1.28 F6 29.2 0.68 0.87 23.59 1.30 F7 27.8 0.70 0.79 11.39 1.13 F8 28.1 0.66 0.76 13.15 1.15 F9 27.9 0.62 0.74 16.21 1.19 Table 2: Formulations S. No. 1 2 3 4 5 6 Total (mg) Ingredients (mg) Tramadol HCl Dicalcium Phosphate Ethyl Cellulose Chitosan Colloidal Silicondioxide Magnesium Stearate F1 100 134 60 3 3 300 F2 100 104 90 3 3 300 F3 100 74 120 3 3 300 F4 100 134 60 3 3 300 F5 100 104 90 3 3 300 F6 100 74 120 3 3 300 F7 100 134 30 30 3 3 300 F8 100 104 45 45 3 3 300 F9 100 74 60 60 3 3 300 Table 3: Design of Experiment Polymer P 1 – 20 % P 2 – 30 % P 3 – 40 % Ratio 1:0 Ethyl Cellulose F1 F2 F3 1:0 Chitosan F4 F5 F6 1:1 Ethyl Cellulose : Chitosan F7 F8 F9 967 Shanmugapandiyan et al. Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971 Table 4: Evaluation of Tablets S. No. 1 2 Parameters Weight Variation % Thickness in mm F1 ±2.2 4.21 ±0.05 F2 ±3.6 4.20 ±0.06 F3 ±2.6 4.27 ±0.02 3 Diameter in mm 9.03 ±0.02 9.02 ±0.01 9.01 ±0.01 4 Friability % 0.76 ±0.15 0.88 ±0.10 0.87 ±0.10 4 Hardness in kg/cm3 8.20 ±0.5 8.50 ±0.4 5 Assay (Drug Content) 7.80 ± 0.6 99.28 ±0.54 98.70 ±0.68 98.85 ±0.14 F4 ±4.5 3.50 ±0.04 9.00 ±0.01 1.52 ±0.14 1.50 ±0.2 98.43 ±0.11 F5 ±5.2 3.52 ±0.02 9.02 ±0.03 1.78 ±0.16 1.00 ± 0.4 98.10 ±0.20 F6 ±5.4 3.54 ±0.06 9.05 ±0.03 97.98 ±0.60 F7 ±3.8 3.82 ±0.02 9.06 ±0.01 1.21 ±0.18 4.20 ±0.2 98.52 ±0.42 F8 ±4.2 3.87 ±0.04 9.02 ±0.02 1.07 ±0.12 4.66 ±0.3 99.02 ±0.33 F9 ±3.9 3.80 ±0.02 9.03 ±0.02 0.90 ±0.06 4.80 ±0.2 99.14 ±0.17 Table 5: Dissolution Profile Sampling Time in hours 1 2 4 6 8 Percentage Drug Released F1 F2 F3 F4 F5 F6 F7 F8 F9 51.96 76.43 96.75 - 76.08 96.87 - 68.24 89.12 98.17 - 69.14 89.80 98.68 - 60.38 96.97 - 54.19 80.07 96.48 - 48.43 72.18 89.37 97.27 - 45.78 70.01 87.15 96.28 - 40.12 68.75 82.46 91.22 97.94 Market Product 30.54 45.68 70.51 83.92 96.14 Table 6: Stability Studies of F 3 No. of Months Initial 1 3 6 Temperature in º C ± 2ºC 40 40 40 40 Relative Humidity in %±5% 75 75 75 75 Hardness in kg/cm3 8.50 8.60 8.60 8.50 Thickness mm 4.20 4.22 4.24 4.21 Diameter mm 9.01 9.03 9.01 9.02 Friability % 0.74 0.81 0.82 0.88 Assay in % 98.85 99.26 99.10 98.66 Fig. 1: a) Dissolution Profile 968 Shanmugapandiyan et al. Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971 Fig. 1: b) Dissolution Profile a: Pure Drug – Tramadol Hydrochloride 969 Shanmugapandiyan et al. Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971 b: Polymer – Ethyl Cellulose c: Tablet F 3 Fig. 2: FT-IR Spectrum 970 Shanmugapandiyan et al. Int J Pharm Pharm Sci, Vol 5, Issue 3, 966-971 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. Aiman A Obaidat, Rana M Obaidat: Control Release of Tramadol hydrochloride from matrices prepared using glyceryl behenate. European Journal of Pharmaceutics & Biopharmaceutics 2001; 52: 231- 235. Stefan Grond, Lukas Radbruch, MD, Thomas Meuser, MD, George Loick, MD, Rainer Sabatowski, MD, and Klaus A. Lehmann, MD: High – Dose Tramadol in comparison to lowdose Morphine for cancer pain relief. Journal of pain and symptom management 1999; 18(3): 174 - 179. Julide Akbuga: The effect of the physicochemical properties of a drug on its release from chitosonium malate matrix tablets. 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