Development and Evaluation of Sustained Release Matrix Tablets of Tramadol Hydrochloride

Transcription

1 3364 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 9 Issue 4 July August 2016 Research Paper MS ID: IJPSN BASARKAR Development and Evaluation of Sustained Release Matrix Tablets of Tramadol Hydrochloride Ganesh Basarkar*, Vijay Suryawanshi, and Dinesh Hire SNJB s SSDJ College of Pharmacy, Chandwad, Nashik , Maharastra, India. Received April 11, 2016; accepted May 25, 2016 ABSTRACT The objective of the present study was to control the release of freely water soluble Tramadol hydrochloride over a prolonged period of time by embedding the drug into novel wax matrix system. The matrix granules were prepared by melt granulation technique. The need for the administration two to four times a day when larger dose are required can decrease patient compliance. Sustained release formulation that would maintain plasma levels for 24 hrs for once daily dosing of Tramadol hydrochloride was prepared. The compatibility of the drug and wax examined using Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectrophotometer (FTIR). The effect of wax concentration (5 to 35%) and channeling agents (Avicel PH-101 and Di-calcium phosphate) on the in vitro KEYWORDS: Rice Bran Wax; Melt granulation; Sustain Release; Lipid matrix; Tramadol. drug release at 24 hrs. was studied. Results of DSC confirmed drug-wax compatibility. Increasing the wax concentration resulted in a significant retardation of drug release. The drug release study revealed that the optimized formulation (F6) 30% novel wax sustained drug release for 24hrs. At the same wax concentration, drug release from tablets decreased with Di-calcium phosphate and increased with Avicel PH 101. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-fickian transport. A hydrophobic matrix system is thus useful technique for prolonging the drug release of freely water soluble drugs such as Tramadol hydrochloride. Introduction Tramadol, chemically (+/-) cis-2-(dimethylamino) methyl) -1-(3-methoxy phenyl) cyclohexane hydrochloride, is a synthetic opioid of the aminocyclohexanol derivative. It is a centrally acting non-steroidal antiinflammatory drug (NSAID) with weak opioid agonist properties. It has been used since 1977 for the relief of strong physical pain and has been the most widely sold opioid analgesic drug in the world. It also proved to be effective in both experimental and clinical pain without causing serious cardiovascular or respiratory side effects (Jackson and Marrow, 2011). Tramadol inhibits reuptake of norepinephrine, serotonin and enhances serotonin release. It alters perception and response to pain by binding to mu-opiate receptors in the CNS. After oral administration, Tramadol is rapidly and completely absorbed (Jackson and Marrow, 2011). The half-life of Tramadol is about 5.5 hours and the usual oral dosage regimen is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400 mg/day. However, its mean absolute bioavailability is only 65-70% due to the first-pass hepatic metabolism. The extent of bioavailability increases to 77% after the rectal administration of Tramadol suppositories and to 100% after an intramuscular administration, in hours after the oral administration of drops, in 1-3 hour after the oral administration of tablet or capsule, and in 2-6 hour after the rectal administration of suppositories. Long term treatment with sustained release once daily is generally safe in patients with osteoarthritis or refractory low back pain and is well tolerated. The drug is freely soluble in water and hence judicious selection of release retarding excipients is necessary to achieve a constant in vivo input rate of drug (Reynolds, 1993). The matrix system is commonly used for manufacturing sustained-release dosage forms as it makes such manufacturing easy (Cardinal, 1984). The Non-bioerodible polymer and wax are commonly used as matrix forming components. The use of wax seems to have particular advantage due to wax s chemical inertness against other materials, good stability varying at ph and moisture levels, well established safe application in humans their non swellable and water insoluble nature. Preparation of matrix system has been discussed elsewhere (Bianhini and Vecchio, 1989; Cardinal, 1984; El-Egakey et al., 1971, Follonier and Doellcer, 1994; McTaggart et al., 1984). Hence, many ABBREVIATIONS: DSC: Differential Scanning Calorimetry; FTIR: Fourier Transform Infrared Spectrophotometer; NSAID: Non-Steroidal Anti-Inflammatory Drug; TB: Tapped Density; BD: Bulk Density. 3364

2 Basarkar: Development and Evaluation of Sustained Release Matrix Tablets of Tramadol Hydrochloride 3365 reports are published as techniques such as melt granulation, melt extrusion, pastillation, melt dispersion, and melt solidification. Design and application of these techniques depend on the physicochemical properties of the drug and excipients, as well as desired properties of the final product. Waxes like Bees wax, carnauba wax, cersine, micro crystalline wax, Percirol AT05, Gelucire 64/02, glyceryl monosterate, hydrogenated castor oil are used to prepare matrix granules and tablets. The aim of this study was to prepare sustain release lipid matrix tablets of Tramadol hydrochloride using Rice bran wax as insoluble lipid matrix. In the present study, a novel wax (Rice bran wax) was used to prepare matrix granules by melt granulation method. Rice bran wax is an important by product of Rice bran oil industry and belongs to (Oryza sativa) Family Graminae and is abundantly available (Sabale et al., 2003). The wax is reported to be chiefly Melissyl cerotate. Research at Southern Regional Research Laboratory has shown that the properties of refined and bleached wax are similar to that of the presently imported carnauba wax. Rice bran wax is better as a drug retardant or sustained release, confectionery and chewing gum than paraffin s or petrochemical waxes (Obaidat and Obaidat, 2000). Materials and Methods Tramadol hydrochloride was gifted from Sun pharma Limited & Neon pharma Limited, Rice bran wax was procured from Bajaj Rice mills Warangal (AP), lactose anhydrous was obtained from Zydus Cadilla, (Ahmedabad) Microcrystalline cellulose, Magnesium state, Di-calcium phosphate and talc were of analytical grade (Loba Chemie Pvt. Limited. Mumbai.) Purification and standardization of Rice Bran Wax The crude wax (100 g) was soxhleted with ethyl acetate (300 ml) for 30 min at 85 o C. The mixture in thimble was cooled up to 25 o C and was subjected to decolourization with 2% H 2 O 2 at 90 ºC for 1h and secondary decolourization with NaOCl 15% at 100 ºC for 1 h. The purified wax obtained was then used for further study. Drug-Excipients Compatibility Study The drug-excipients interaction study was carried out by using Differential scanning calorimetry (DSC) and FTIR spectrophotometer. FTIR Spectrophotometer The IR spectrum of Tramadol hydrochloride, Rice bran wax and combination of drug with Rice bran wax were recorded on KBR pellet with FTIR spectrophotometer. The IR absorption band in cm -1 of the drug and Rice bran wax used in the study were similar (Fig 1, 2, 3 and 4). Fig. 1. IR spectra for the drug Tramadol Hydrochloride. Fig. 2. Infrared spectrum of Rice bran wax. Fig. 3. IR spectrum of mixture of Tramadol hydrochloride and Rice bran wax (2:0.5). Fig. 4. IR spectrum of mixture of Tramadol hydrochloride and Rice bran.

3 3366 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 Differential Scanning Calorimetry Thermal behavior of drug, wax and combinations with different ratios were studied by differential scanning calorimetry (DSC) using DSC-50, Shimadzu, Kyoto, Japan). The instruments were calibrated using indium standards. Accurately weighed samples (5-10 mg) were hermetically sealed in flat bottom aluminium standard 40 μl pans and heated from 50 to 300 o C at a rate of 10 o C/min. Melting endotherms of drug, wax and drug-wax combination were determined in the same way. Thermograms were normalized and rescaled as needed before overlapping. An empty Aluminium pan was used as reference (Fig. 5, 6, 7 and 8). Fig. 8. DSC thermogram of Tramadol and Rice bran wax (2:0.5). Preparation of Matrix Granules and Tablets Fig. 5. DSC thermogram of Tramadol wax. Fig. 6. DSC thermogram of Rice bran Hydrochloride. Sustained release granules were prepared using wax as a retarding material. For the preparation of sustained release formulation, purified Rice bran wax was used in different concentrations by trial and error basis. Rice bran wax granules were prepared by melting waxes by heating at constant temperature of 85 C. Drug and diluents were gradually added to the molten mass with continuous stirring (Miyagawa et al., 1996). Lactose anhydrous was used as diluents and channeling agent within the matrix of prepared tablets (Rezowanur et al., 2010). The molten mixture was then allowed to cool and solidify at room temperature and pulverized in mortar and sized through a 16 mesh sieve (Obaidat and Obaidat 2001) Prior to compression 0.5% (w/w), magnesium stearate was mixed with each batch of granules in poly bag for 5 min. A rotary tabletting machine (Karnavati Engg. Ltd. Rimek Minipress 2D), equipped with 10-mm flat faced circular punches was used to prepare tablets at a constant compression force. The composition with respect to wax concentration was selected on the basis of trial preparation of tablets. The composition of various prototype formulations with their codes is listed in Table 1. TABLE 1 Compositions of sustained release matrix tablets of Tramadol hydrochloride Formulations (Prototype formulations) (F1 - F7). Ingredients (mg) Tramadol hydrochloride Rice Bran Wax Lactose Anhydrous Magnesium Stearate Talc F1 F2 F3 F4 F5 F6 F (5%) 30 (10%) 45 (15%) 60 (20%) 75 (25%) 90 (30%) 105 (35%) (0.5%) 1.5 (0.5%) Total Fig. 7. DSC thermogram of Tramadol hydrochloride and Rice bran wax (2:2).

4 Basarkar: Development and Evaluation of Sustained Release Matrix Tablets of Tramadol Hydrochloride 3367 Physical Characterization of the Granules The packing properties were determined by measuring the difference between bulk density (BD) and the tapped density (TB) using standard procedures. In the procedure, a 30g quantity of granule sample was placed into 250 ml clean, dry measuring cylinder and the volume, V 0 occupied by the sample without tapping was determined. After 100 taps using Tap density tester (Electrolab Model ETD-1020), occupied volume, V 100 was also determined. The bulk and tap densities were calculated from these volumes (V 0 and V 100 ) using the formula: Density = Weight of sample/volume occupied by sample. From the data compressibility index (CI) values of the granules were calculated as CI = {(TB-BD)/ (TB} 100%. The flowability of the granules was determined by measuring the angle of repose formed when a sample of the granules (10 g) was allowed to fall freely from the stem of a funnel to a horizontal surface (Richards, 1972). Characterization of Tablets Uniformity of weight, fribiality was carried out as per IP, Hardness was measured using a simple Monsanto hardness tester (Tiwari et al., 2003; IP, 2007). Thickness was measured by using vernier caliper scale. Drug Content Twenty tablets were weighed individually and powdered in pestle mortar, and an amount equivalent to 100 mg of Tramadol hydrochloride was extracted with 100 ml of phosphate buffer (ph 6.8) and sonicated for 10 min. The solution was filtered through Whatman filter, and the content of Tramadol hydrochloride in the solution was determined by measuring absorbance on double beam UV spectrophotometer at 271 nm after suitable dilution (Tiwari et al., 2003). Dissolution Study For any formulation drug release from the dosage form is the foremost parameter to be measured. Drug release is evaluated by the in-vitro dissolution test apparatus. The In vitro dissolution studies were conducted using USP type II apparatus (TDT-08 L, Electrolab, Mumbai, India). The dissolution media is comprised of 0.1 N hydrochloric acid for the first 2 h and the phosphate buffer (ph 6.8) until 24 h (900 ml) kept at 37.0 ± 0.5 C and 50 rpm. An aliquot of 5 ml sample was withdrawn and replaced with another 5 ml of fresh dissolution medium at various time intervals. The contents of Tramadol hydrochloride in sample were determined by measuring absorbance at 271 nm in a UV- Visible spectrophotometer (JascoV-630). The absorbance values were transformed to concentration by reference to a standard calibration curve obtained experimentally. The release study was performed in triplicate (Tiwari et al., 2003). Effect of Channelling Agents The effect of different channelling agents like Avicel PH101 and di-calcium phosphate on in-vitro drug release was studied (Scott and Perry, 2003) and their composition is shown in Table 2. TABLE 2 Compositions of sustained release matrix tablets of Tramadol hydrochloride with different concentrations of channeling agents (F8 & F10). Ingredients (mg) F6 (Optimized) F8 F9 Tramadol hydrochloride DCP Lactose anhydrous Avicel PH Rice Bran Wax (%) 90 (30%) 90 (30%) 90 (30%) Magnesium stearate 1.5 (0.5%) 1.5 (0.5%) 1.5 (0.5%) Talc 1.5 (0.5%) 1.5 (0.5%) 1.5 (0.5%) Total Stability Studies The stability studies were carried out on the optimized formulation (F6), at 40 o C/ 75% RH for a period of three months as per ICH guidelines. The sample tablets were wrapped in the laminated aluminum foils and were placed in the accelerated stability chamber at 40 0 C/75% RH. Sampling was done at a predetermined time intervals of 30, 60 and 90 days. The tablets were evaluated for different physico-chemical parameters. Results and Discussion Drug-Excipient Compatibility Study Fig. 7 and 8 shows the thermogram of Tramadol hydrochloride and its physical mixtures (2:0.5 & 2:2 ratio, w/w) with the wax used. The DSC thermogram of the drug alone had main prominent sharp endothermic peak at 183 ºC which was reported to be corresponding melting point of Tramadol hydrochloride molecule. The thermograms of physical mixtures of the drug with wax used shown drug endothermic peak together with characteristic peak of the wax used, indicating that there was no interaction between the drug and wax used. Fig. 3 and 4 shows the IR spectra of Tramadol hydrochloride and its physical mixture (2:0.5 & 2:2 ratio, w/w) with the wax used. IR spectra of Tramadol hydrochloride show a broad peak at 3355 cm -1 may be due to hydrogen bonding, 3020 cm -1 may be due to aromatic C-H stretching of -OCH 3, the 2858 cm -1 may be due to C-H stretching of CH 2 group, 1585 & 1604 cm -1 may be due to C=C ring stretching, 1288, 1365 cm -1 CH bending of symmetric and asymmetric of CH 2 and CH 3 groups cm 1 may be due to C-0-C group and symmetric and asymmetric alkyl groups. 3529, 3610 & 3683 cm 1 may be due to free and bonded hydroxyl group of acidic compound present, 1604 to 1890 cm -1 may be due to C=O functional group of acid, ketone and ester containing molecules. 756 cm 1 one of the broad peak of the substituted aromatic compound. 1461, 1423 contain C=C group (Fig. 1). In addition to this IR spectrum of the drug: wax (2:0.5 & 2:2) shows characteristic absorption bands with negligible difference of absorption band values. Since there is no change in physical mixtures, it can be concluded that the drug maintains its identity

5 3368 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 without going any chemical interaction with the wax used. Physicochemical Characterization of Rice Bran Wax The results of physicochemical properties of Rice bran wax are shown in Table 3. The wax was insoluble in maximum solvents except chloroform. The Acid value, Iodine value, Saponification value, peroxide value and all were within official limits. DSC Thermogram of rice bran wax is shown in Fig. 6. TABLE 3 Physicochemical properties of Rice bran wax. Test Unorganized wax Organized wax Solubility Chloroform Chloroform Melting range o C o C Acid value 25.94ml/gm 9.44ml/gm Peroxide value 63.8 meq/kg meq/kg Saponification value Iodine value 12 7 Evaluation of Granules: (Prototype Formulation) The granules were evaluated for BD, TBD, and angle of repose, Car s compressibility index and Hausner s ratio and shown in in Table 4. The angle of repose of matrices of all the formulation was found in the range of º to 27.04º indicating good properties. The BD and TBD for all the formulations were found in the range of to gm/cm 3 and to gm/cm 3 respectively. This result may further influence properties such as compressibility and tablet dissolution. The percentage of Car s compressibility index for all formulation lies within the range of to 16.8% and Hausner s ratio was found to be in the range of 1.13 to 1.23 showed good compressibility and good flow properties. Evaluation of Tablets Uniformity of weight: Uniformity of weight complies as per Indian Pharmacopoeia 2007 and shown in Table 5. This indicates that the drug content uniformity of all tablets was found to be satisfactory. Hardness and friability: The hardness values of the tablets ranged from 3.0 ± 0.52 to 4.2 ± 0.24 kg/cm 2 shown in Table 5. As the concentration of wax is increased, hardness of tablet also increased. However hardness alone cannot be considered as absolute indicator of the tablet strength. Hence, another parameter measured was the friability of the tablets. The friability of the tablets was found to be less than 1.0% and complies with IP. The measure of these two parameters gives the strength of the tablets during handling, packaging, shipping etc. Content of active ingredients: The drug content was found to be above 98.00% in all formulations and shown in Table 5. In Vitro Drug Release Profiles In-vitro drug release depends on several factors, such as the manufacturing process, the type of excipients and the amount of drug. In this work the effect of some diluents on Tramadol hydrochloride release was also studied. The result of dissolution studies on prototype formulations (F1 to F7) of Rice bran wax shown in Fig.9. Tablets F1, F2 and F3 released 41.59%, 28.58% and 24.06% of Tramadol hydrochloride at the end of 2 hrs and 96.80%, 81.37% and 67.51% respectively at the end of 8 hrs. F4, F5, F6 and F7 composed of Rice bran wax (20 to 35%) the released profile of formulations shows 21.36%, 19.79%, 17.39% and 15.92% of Tramadol hydrochloride at the end of 2 hrs and 95.60%, 85.80%, 73.12% and 67.55% at the end of 18 hrs respectively, shown in Table 6(a) and 6(b). TABLE 4 Evaluation data for matrix granules for formulations (Prototype formulations) F1-F7. Parameters Formulation Angle of Repose (θ) Bulk Density gm/cm 3 Tapped Density gm/cm 3 Hausner s Ratio (HR) Car s Index (%) F ± ± ± ± ± 1.9 F ± ± ± ± ± 1.0 F ± ± ± ± ± 1.76 F ± ± ± ± ± 0.74 F ± ± ± ± ± 1.3 F ± ± ± ± ± 1.89 F ± ± ± ± ± 0.32 TABLE 5 Evaluation data for matrix tablets for formulations ( Prototype formulations) F1-F7. Formulation Uniformity of Weight (mg) Thickness (mm) Hardness (kg/cm 2 ) Friability (%) Drug content (%) F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± All values are expressed as mean± SD, n=3

6 Basarkar: Development and Evaluation of Sustained Release Matrix Tablets of Tramadol Hydrochloride 3369 Time Formulations(% Cumulative drug release) (hr) F5 F6 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.58 All values are expressed is mean ± SD, n=3 Drug Release Kinetics Fig. 9. The dissolution profile of matrix tablets (F1-F7) of Tramadol hydrochloride containing Rice bran wax. The wax ratio (F1 to F7) on release profile of Tramadol hydrochloride was studied and the decrease in drug release was observed when Rice bran wax content in the matrix was increased which is shown in Fig 9. It may be due to increased lipophilicity of waxy substance. In formulations F1 to F3 containing different concentrations of Rice bran wax the release of Tramadol hydrochloride get less retarded than those formulations of F4 to F7 it may be due to higher lipophilicity of wax. From the release study it is observed that, the F6 formulation shows 98.00% drug release in 24 hrs. This was the main aim of the present study. TABLE 6(a) The in-vitro dissolution data of matrix tablets for formulations F1- F4 containing different amounts of Rice bran wax (Prototype formulations). Time Formulations(% Cumulative drug release) (hr) F1 F2 F3 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.71 All values are expressed is mean ± SD, n=3 TABLE 6(b) In vitro dissolution data of matrix tablets for formulations F5-F7 containing different amounts of Rice bran wax (Prototype formulations). Time Formulations(% Cumulative drug release) (hr) F5 F6 F ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.14 The release kinetics of the matrices is shown in Table 7. The best fit model representing the mechanism of drug release from the matrices was of zero order. This is further confirmed by Higuchi, the value of n is less than 1 showing anomalous drug release, indicating that the drug release mechanism are diffusion coupling with slowly erosion. TABLE 7 The dissolution models for matrix tablets (F1-F7) of Tramadol hydrochloride. Formulation code R 2 Zero order N First order Higuchi Korsmeyer Peppas Korsmeyer Peppas F F F F F F F Effect of Channelling Agents The effect of channelling agents on in-vitro drug release study of matrix tablet was studied (Rezowanur et al., 2010). In this case, Avicel PH101 (F8) showed higher drug release than Lactose anhydrous (F6) and Dicalcium phosphate (F9) and shown in Table 8 and Fig. 10. This may be due to better network of channelling throughout the system to diffuse out the active into the dissolution medium by Avicel PH101. TABLE 8 Effect of channeling agents on in-vitro dissolution of Tramadol hydrochloride matrix tablets. Time (Hr) Formulations(% Cumulative drug release) F6 ( Lactose anhydrous) F8 (AvicelPH101)) F9 (DCP) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.52 All values are expressed is mean ± SD, n = 3

7 3370 Int J Pharm Sci Nanotech Vol 9; Issue 4 July August 2016 Fig. 10. Drug release profile different channeling agents from 5% to 35%. TABLE 9 Stability Data of Optimized Formulation. Stability (40 0 C ± 2 o C, 75 ±5% RH) Drug Release (%) after 24 hrs Assay (%) Initial Month Month Month Stability Studies The stability studies of optimum formulation revealed that no significant changes in the physicochemical parameters when stored at temperature and humidity conditions of 40 o C/ 75% RH and shown in Table 9. No significant reduction in the content of the active drug was observed over a period of three month. Conclusions Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-fickian transport. A hydrophobic matrix system is thus useful technique for prolonging the drug release of freely water soluble drugs such as Tramadol hydrochloride. Acknowledgments Authors would like to thank Principal and management of SSDJ College of Pharmacy, Neminagar, Chandwad for providing all necessary facilities. Bianhini R and Vecchio C (1989). Oral controlled releaseoptimization of pellets prepared by extrusionspheronization processing. IL Farmaco 44: Cardinal J (1984). Matrix systems. In: Langer R., and Wise, D., (Eds.), Medical applications of controlled release, vol. 1, Classes of system, CRC Press, Boca Ralton, FL, El-Egakey M, Soliva M and Speiser P (1971). Hot extruded dosage forms, Part I, Technology and dissolution kinetics of polymeric matrices. Pharm Acta Helv 46: Follonier N and Doellcer E (1994). Evaluation of hot-melt extrusion as a new technique for the production of polymer-based pellets for sustained release capsule containing high loading of freely soluble drug. Drug Dev Ind Pharm 20: Ghali E, Klinger G and Schwartz J (1989). Thermal treatment of beads with wax for controlled release. Drug Dev Ind Pharm 15: IP (2007). Volume I, Government of India and Ministry of Health and Family welfare, Published by Indian Pharmacopoeia Commission, Ghaziabad, Jackson L and Marrow J (2011). Analgesic-Antipyretic & antiinflammatory agent and drug employed in the treatment of gout. In: Hardman JG, Limbird LE (Eds). Goodman and Gilman s The Pharmacological basis of Therapeutics. 10th edition. Mc-Graw Hill: McTaggart C, Ganley J, Sickmuller A and Walker S (1984). The evaluation of formulation and processing conditions of a melt granulation process. Int J Pharm 19: Miyagawa Y, Okabe T, Yamaguchi Y, Miyajima M, Sato H and Sunada H (1996). Controlled-release of diclofenac sodium from wax matrix granule. Int J Pharm 138: Namdeo T, Vidya R and Sushilkumar S (2010). Sustained-release from Layered Matrix System Comprising Rice Bran Wax and Sterculia Foetida Gum. International Journal of Pharm Tech Research 2: Obaidat A and Obaidat R (2000). Controlled release of tramadol hydrochloride from matrices prepared using glyceryl behenate. Eur J Pharm Biopharm 52: Reynolds J (1993). Eds., In; Martindale; The Extra Pharmacopoeia, 29th Edn., The Royal Pharmaceutical Society of Great Britain, London, pp Rezowanur MR, Jahan ST, Sadat SMA and Jalil R (2010). Preparation and evaluation of mucoadhesive hydrophilic hydroxyl propyl methyl cellulose based extended release matrix tablets of niacin (nicotinic acid). American Journal of Scientific and Industrial Research 1(3): Richards J (1972). Powder flow and compaction In: Carter, S., (ed) Tutorial Pharmacy, Pitman Medical Publishing Ltd, London, 6 th, pp Roland A and Bodmeier C (2002). Waxes, Encyclopedia of Pharmaceutical Technology, 3: Sabale V, Sabale P and. Lakhotiya C (2003). Comparative Evaluation of Rice Bran Wax as an Ointment Base with Standard Base. Indian J Pharm Sci 71: Scott L and Perry C (2003). Tramadol: a review of its use in preoperative pain. Pain 60: Tiwari S, Krishna, M, Raveendra P, Mehta P and Chowdary P (2003). Controlled release formulation of tramadol hydrochloride using hydrophobic & hydrophilic matrix system. AAPS Pharm Sci Tech 4: References Banker G and Anderson N (1987). Tablets. In: Lachman L, Liberman HA, Kanig JL (Eds). The theory and practice of industrial pharmacy, 3rd edition, Varghese Publishing House, Bombay, pp Address correspondence to: Ganesh Basarkar, SNJB s SSDJ College of Pharmacy, Chandwad, Nashik , India. Ph: & basarkarg@yahoo.com & dinesh.hire11@gmail.com