Formulation and in-vitro evaluation of pregabalin mini tablets for sustained release

Available online at www.scholarsresearchlibrary.com Scholars Research Library Der Pharmacia Lettre, 2016, 8 (2):277-283 (http://scholarsresearchlibrary.com/archive.html) ISSN 0975-5071 USA CODEN: DPLEB4 Formulation and in-vitro evaluation of pregabalin mini tablets for sustained release S. B. Thirumalesh Naik 1*, Kambham Venkateswarlu 1 and K. B. Chandrasekhar 2 1 Faculty of Pharmacy, Department of Pharmaceutics, Oil Technological and Pharmaceutical Research Institute, Jawaharlal Nehru Technological University Anantapur, Ananthapuramu, Andhra Pradesh, India 2 Oil Technological and Pharmaceutical Research Institute, Jawaharlal Nehru Technological University Anantapur, Ananthapuramu, Andhra Pradesh, India ABSTRACT The present research was aimed to develop sustained release mini tablets of Pregabalin by direct compression method. These were prepared by using chitosan, locust bean gum, microcrystalline cellulose (MCC), Xanthan gum, polyvinyl pyrrolidine K-30 (PVP K30). The precompression parameters like angle of repose, bulk density, true density, Carr s index, Hausner s ratio and post compression parameters like thickness, hardness test, friability and weight variation, drug content uniformity were evaluated and the results were lies within the limits. In-vitro dissolution study was performed by using 0.1 N HCl for first 2 h and it was replaced by ph 6.8 phosphate buffer for further study. It was found from the results that the formulation F6 showed sustained release of 12 h and followed zero order kinetics with non fickian mechanism. Key words: Pregabalin, Sustained release, Mini tablets. INTRODUCTION The best new therapeutic entity in the world is of little value without an appropriate delivery system [1]. Tablet delivery system can range from simple immediate release formulations to complex extended or modified release dosage forms [2]. The most important role of drug delivery system is to get the drug delivered to the site of action in sufficient amount and at the appropriate rate [3-4]. However, it should meet other important criteria such as physical and chemical stability, ability to be mass-produced in a manner that assures content uniformity [5]. Mini-tablets are flat or slightly curved tablets with a diameter ranging between 1.0-3.0 mm. They are usually filled into a capsule, occasionally compressed into larger tablets [6]. Pregabalin is used in the treatment of epilepsy and neuropathic pain. It also uses in the treatment other diseases like diabetic neuropathy, surgical dental pain and pain syndromes. A considerable research has been done on the drug Pregabalin for sustained release property [7-8]. The present study was aimed to formulate the sustained release mini tablets of Pregabalin by direct compression method. MATERIALS AND METHODS Materials Pregabalin was obtained from Dr. Reddy s laboratories, India and PVP K-30 from Hetero Drugs, India. Remaining all ingredients was purchased from Vijlak Pharma Limited, India. 277

FTIR studies The pure drug and its physical mixtures were analysed by FTIR spectrophotometer for determining the chemical interactions between pure drug and its excipients. Samples were mixed thoroughly with 100 mg of potassium bromide IR powder and compacted under vacuum at a pressure of about 12 psi for 3 minutes. The resultant disc was mounted in a suitable holder in Perkin Elmer IR spectrophotometer and the IR spectrum was recorded from 4000cm -1 to 400cm -1. The resultant spectrum of pure drug was compared with the spectra of its physical mixtures. Preparation of mini (core) tablets All the ingredients were accurately weighed as per formula (Table 1) and were dispensed in clean polythene cover, mixed well and sieved through 60 mesh and subjected to compression. Direct compression of mini tablets was done in rotary compression tablet machine (Rimek mini press I) using 4 mm concave punch. Table 1. Formulation of Pregabalin mini tablets Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 Pregabalin 10 10 10 10 10 10 10 10 10 Chitosan 10 20 30 - - - - - - Locust bean gum - - - 10 20 30 - - - Xanthan gum - - - - - - 10 20 30 PVP-k30 5 5 5 5 5 5 5 5 5 Magnesium stearate 2 2 2 2 2 2 2 2 2 Talc 2 2 2 2 2 2 2 2 2 MCC 21 11 1 21 11 1 21 11 1 Total Weight 50 50 50 50 50 50 50 50 50 Evaluation studies The powder blends were evaluated for precompression parameters like angle of repose, bulk density, true density, Carr s index, Hausner s ratio and prepared tablets for post compression parameters like thickness, hardness test, friability and weight variation according to standard procedures [9-10]. Drug Content estimation The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch. Four mini tablets were weighed and crushed in the mortar. The powder equivalent to 1.25 mg of the drug was weighed and dissolved in 100 ml ph 6.8 phosphate buffer. The appropriate dilutions were done and the absorbance of the prepared solution was measured at 214 nm using UV-Visible spectrophotometer (Lab India, UV-3200). In-vitro dissolution studies 900 ml of 0.1N HCl was placed in vessel and the USP apparatus-ii (Paddle Method) was assembled (Electro lab TDT-06N USP dissolution test apparatus). The medium was allowed to equilibrate to the temperature of 37 C±0.5 C and set at the rotation of 50 rpm. Tablet was placed in the vessel and operated for 2 h. Then this medium was replaced with ph 6.8 phosphate buffer and operated for upto 12 h. At definite time intervals, 5 ml of the receptor s fluid was withdrawn, filtered and again 5 ml receptor fluid was replaced. Suitable dilutions were done with receptor fluid and analyzed by spectrophotometrically using UV-spectrophotometer. Application of Release Rate Kinetics to Dissolution Data Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release and kinetics of the dosage form, the obtained data were fitted into zero order, first order, Higuchi and Korsmeyer- Peppas release models. Stability studies The formulation F6 was subjected to stability studies at room temperature (RT) at 30 0 C/60% RH and accelerated stability studies (ASS) at 40 0 C/75% RH for 1 month and evaluated for thickness, hardness, drug content and drug release studies. RESULTS AND DISCUSSION The present study was aimed to develop sustained release mini tablets of Pregabalin using various polymers. All the formulations were evaluated for physicochemical properties and in vitro drug release studies. Drug-excipient Compatibility studies FTIR techniques have been used to study the physical and chemical interaction between drug and excipients. From the infrared spectral analysis, it was clear that the characteristic absorption peaks of pure drug found in physical 278

mixture of drug and excipients, so it indicates that there was no reciprocal action between the drug and excipients (Table 2-5 & Figure 1-4). Figure 1. FTIR spectra of Pregabalin pure drug Table 2. Interpretation of FTIR Spectra of Pregabalin pure drug Groups General range (cm -1 ) Observed range (cm -1 ) C-H stretch 2960-2850 2919.15 Figure 2. FT-IR spectra of Pregabalin with chitosan Table 3. Interpretation of FTIR Spectra of Pregabalin with chitosan Groups General range Observed range (cm -1 ) (cm -1 ) C-H stretch 2960-2850 2928.47 279

Figure 3. FTIR spectra of Pregabalin with Locustbean gum Table 4. Interpretation of FTIR spectra of Pregabalin with locust bean gum Groups General range (cm -1 ) Observed range (cm -1 ) C-H stretch 2960-2850 2928.47 Figure 4. FTIR spectra of Pregabalin with Xanthan gum Table 5. Interpretation 0f FTIR spectra 0f Pregabalin with Xanthan gum Groups General range (cm -1 ) Observed range (cm -1 ) C-H stretch 2960-2850 2928.47 Precompression studies Angle of repose was carried out and it was found to be 24.11 0 to 28.51 0, the results were indicates that the Pregabalin blends had shown good flow properties. Bulk density of blend was carried out and it was found to be 0.60-0.70 gm/cc and tapped density of blend was found to be 0.71-0.81mg/cc which indicates that powder was not bulky. Compressibility index was found to be 13.22-13.74%, the Hausner s ratio was found to be 1.03-1.07, indicates that the Pregabalin blends had shown good to fair flow properties for compression (Table 6). 280

Table 6. Evaluation of precompression parameters of powder blend Formulation Angle of repose (θ) Bulk density (gm/cc) Tapped density (gm/cc) Compressibility index (%) Hausner s ratio F1 24.82±1.732 0.68±0.06 0.71±0.024 13.74±0.14 1.05±0.04 F2 26.35±0.456 0.70±0.05 0.80±0.018 13.40±0.15 1.04±0.06 F3 25.18±1.456 0.69±0.03 0.79±0.014 13.22±0.52 1.03±0.05 F4 24.11±0.921 0.70±0.02 0.76±0.018 13.53±0.24 1.05±0.03 F5 28.05±0.225 0.66±0.01 0.75±0.016 13.43±0.28 1.07±0.01 F6 27.76±0.258 0.70±0.02 0.77±0.017 14.45±0.34 1.07±0.08 F7 26.12±0.167 0.69±0.07 0.80±0.012 13.50±0.38 1.04±0.07 F8 25.29±0.169 0.66±0.09 0.81±0.07 13.51±0.39 1.07±0.01 F9 28.51±0.991 0.60±0.08 0.77±0.024 13.29±0.45 1.07±0.02 Results were expressed in Avg ± SD (n=3) Post compression studies The hardness of the tablet formulations was found to be in the range of 3.44 to 3.86 kg/cm 2. The friability values were found to be in the range of 0.33 to 0.46 %. All the formulations showed less than 1% friability ensuring that the tablets were mechanically stable. All the prepared tablets of Pregabalin were evaluated for weight variation. The weight of all the tablets was found to be uniform with low values of standard deviation and lies within the prescribed IP limits of ±10%. The low values of standard deviation indicate uniform drug content within the tablets. The percent drug content of all the tablets was found to be in the range of 93.68 to 98.30 percent (which was within the acceptable limits of ±5 %) (Table 7). Table 7. Evaluation of post compression parameters of Pregabalin mini tablets Formulation Thickness Hardness Weight variation Friability Drug content (mm) (kg/cm 2 ) (mg) (%) (%) F1 1.66±0.157 3.48±0.34 49.11±0.305 0.36±0.02 95.56±0.45 F2 1.70±0.172 3.44±.67 49.86±0.563 0.45±0.03 95.63±0.65 F3 1.66±0.147 3.48±0.533 50.86±0.485 0.46±0.01 96.55±0.43 F4 1.59±0.150 3.45±0.563 49.02±0.423 0.38±0.04 94.76±0.62 F5 1.60±0.156 3.88±0.137 50.98±0.445 0.34±0.03 93.68±0.42 F6 1.60±0.164 3.77±0.193 50.86±0.810 0.33±0.02 95.26±0.52 F7 1.61±0.170 3.65±0.183 49.07±0.515 0.36±0.02 94.64±0.44 F8 1.63±0.155 3.86±0.573 49.15±0.764 0.37±0.01 96.20±0.63 F9 1.65±0.162 3.73±0.294 49.10±0.47 0.42±0.02 98.30±0.43 Results were expressed in Avg±SD (n=6) In -vitro drug release studies From the dissolution data it was evident that the formulations prepared with Chitosan as polymer were unable to retard the drug release up to desired time period i.e., 12 hours. Whereas the formulations prepared with Locust bean gum retarded the drug release in the concentration of 90 mg (F6 Formulation) showed required release pattern i.e., retarded the drug release up to 12 h and showed maximum of 96.10% in 12 hours with good retardation. The formulations prepared with Xanthan gum showed more retardation even after 12 h, they were not shown total drug release. Hence, they were not considered for further study (Table 8 & Figure 5). Table 8. In-vitro drug release of all the Formulations Time (h) Cumulative Percent Drug Release F1 F2 F3 F4 F5 F6 F7 F8 F9 0 0 0 0 0 0 0 0 0 0 0.5 21.1±0.07 24.5±0.09 15.4±0.01 16.25±0.16 15.12±0.24 13.62±0.31 9.4±0.02 8.9±0.01 10.2±0.32 1 38.4±0.08 45.7±0.08 25.7±0.12 37.24±0.12 24.74±0.06 18.72±0.21 15.3±0.23 14.5±0.05 15.4±0.14 2 54.3±0.09 74.5±0.04 33.8±0.14 53.16±0.08 35.63±0.21 21.34±0.38 27.5±0.28 20.5±0.09 19.5±0.21 3 74.3±0.08 98.4±0.05 41.4±0.79 71.01±0.07 44.64±0.09 30.40±0.24 30.40±0.24 35.7±0.06 24.6±0.11 4 86.7±0.06 56.4±0.24 87.26±0.06 57.25±0.24 38.81±0.32 38.81±0.15 41.4±0.17 27.6±0.06 5 98.4±0.05 66.5±0.12 96.10±0.17 66.33±0.31 44.26±0.21 44.26±0.18 48.6±0.12 35.8±0.03 6 84.4±0.25 75.41±0.31 57.24±0.24 57.24±0.29 56.3±0.04 41.2±0.04 7 90.5±0.35 83.42±0.14 65.73±0.23 65.73±28 61.7±0.23 45.4±0.24 8 97.5±0.16 96.80±0.23 70.34±0.28 71.4±0.28 50.8±o.19 9 74.53±0.31 82.8±0.29 62.7±0.16 10 81.16±0.21 87.7±23 69.5±0.12 11 87.19±0.13 95.2±28 75.3±0.18 12 97.15±0.09 Results were expressed in Avg±SD (n=3) 281

Figure 5. In-vitro drug release profiles of all the formulations Application of release rate kinetics to dissolution data Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release and rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi and Korsmeyer- Peppas release model (Table 9). Table 9. Release kinetics data for optimised formulation Formulation Zero order First order Higuchi Korsemeyer R 2 R 2 R 2 R 2 Type of release F1 0.298 0.852 0.783 0.914 Nonfickian F2 0.735 0.893 0.932 0.982 Nonfickian F3 0.695 0.841 0.914 0.989 Fickian F4 0.725 0.892 0.879 0.986 Nonfickian F5 0.816 0.867 0.962 0.972 Nonfickian F6 0.986 0.898 0.985 0.992 Nonfickian F7 0.941 0.855 0.962 0.982 Nonfickian F8 0.766 0.846 0.965 0.962 Nonfickian F9 0.917 0.825 0.948 0.970 Nonfickian Stability studies The formulation F6 was subjected to stability studies for 1 month at room temperature 30 0 C/60% RH and accelerated condition 40 0 C/75% RH shows that there is no significant change in the parameters like thickness, hardness, drug content and in-vitro drug release. Results of the dissolution studies for best formulation F6 values were compared with the results of the same formulation at room temperature and accelerated stability conditions after one month shows no significant change (Table 10-11). Table 10. Evaluation of formulated tablets F6 tablets in stability condition S. No. Parameters 30 0 C/60% RH 40 0 C/75% RH 1 Thickness (mm) 7.43 7.54 2 Hardness (N) 4.6 4.5 3 Drug content 95.43 95.59 282

Table 11. Cumulative % drug release of F6 formulation at stability conditions Time intervals F6 formulation at different conditions At RT At ASS F6 0 0 0 0 0.5 14.2 14.1 14.6 1 19.6 19.5 19.8 2 22.1 24.1 22.3 3 30.4 30.9 31.5 4 38.7 38.6 39.8 5 44.9 44.1 45.2 6 57.9 58.3 58.4 7 65.8 66.5 66.7 8 70.6 70.4 71.8 9 74.2 75.6 75.8 10 80.6 81.8 82.3 11 87.4 86.9 87.6 12 95.2 95.4 96.1 CONCLUSION The present investigation aimed to formulate Pregabalin Sustained release tablets by using Chitosan, locustbean gum, Xantham gum, PVP K30 for the better treatment of neurological diseases like neuroglia and seizures. Among all the formulations, F6 is considered to be the best formulation because of the drug release was retarded up to 12 h with 96.78% of release. Based on mathematical data revealed from release kinetic models, it was concluded that F6 formulation followed zero order kinetics with non- fickian mechanism. Stability studies were performed for one month for the best formulation in controlled room temperature 30 o C/60% RH and accelerated condition 40 C/75% RH and the results indicated that there is no significant change in evaluation parameters. REFERENCES [1] A. Srikanth, Y. Prasanna Raju, N. Devanna, K. Venkateswarlu. Int. J. Med. Pharm. Res., 2014, 2(3), 662-668. [2] K. Venkateswarlu, J. Thirumaran. Int. J. Pharm. Sci. Rev. Res., 2013, 18(1), 56-64. [3] S. B. Thirumalesh Naik, K. Venkateswarlu, K. B. Chandrasekhar. J. Chem. Pharm. Res., 2016, 8(1), 177-181. [4] S. B. Thirumalesh Naik, K. Venkateswarlu, K. B. Chandrasekhar. Indo. Am. J. Pharm. Res., 2016, 6(01), 4179-4184. [5] K. Venkateswarlu. Am. J. Phytomed. Ther., 2013, 1(6), 491-497. [6] M. Leela Keerthi, R. Shireesh Kiran, V. Uma Maheshwar Rao, Aparna Sannapu, A. Geetha Dutt, K. Sai Krishna. Int. J. Pharm. Sci. Rev. Res., 2014, 28(1), 214-221. [7] N. Tehseen, Vinay Rao, M. Abdul Hadi. Int. J. Pharm. Pharm. Sci., 2013, 5(1), 168-175. [8] D. Pawar. Int. J. Pharm. Res. Develop., 2012, 4(2),153-159 [9] K. Venkateswarlu, A. Shanthi. IOSR J. Pharm. Biol. Sci., 2012, 2(5),17-23. [10] K. Vijayabhaskar, K. Venkateswarlu, S. B. Thirumalesh Naik, R. Kiran Jyothi, G. Nethra Vani and K. B. Chandrasekhar. Br. J. Pharm. Res., 2016, 10(2), 1-12. 283