Tejaswi M. et al. / International Journal of Biopharmaceutics. 2013; 4(1): International Journal of Biopharmaceutics

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1 27 e- ISSN Print ISSN International Journal of Biopharmaceutics Journal homepage: IJB DESIGN AND EVALUATION OF FELODIPINE EXTENDED RELEASE TABLETS EMPLOYING A NEW STARCH BASED POLYMER Tejaswi M 1, Vasanth PM 1, Suresh K 3, Ramesh T 2, Ramesh Malothu 2 1 Department of Pharmacy, UCEV-JNTUK, Vizianagaram, A.P, India. 2 Department of Biotechnology, UCEV-JNTUK, Vizianagaram, A.P, India. 3 Department of Pharmaceutics, Vignan Inst of Pharm Sciences, Vishakapatnam, A.P, India. ABSTRACT The objective of the present investigation is to synthesize starch urea borate, a new starch based polymer and to evaluate its application in extended release of felodipine in tablet dosage form in comparison with other known polymers (HPMC, sodium CMC and ethyl cellulose). Starch urea borate polymer was synthesized by gelatinization of starch in the presence of urea and borax. Matrix tablets each containing 10 mg of felodipine were formulated employing starch urea borate, HPMC, sodium CMC and ethyl cellulose in different proportions of drug and polymer. Prepared felodipine tablets were evaluated for characterizing the release retarding efficiency of new polymer in comparison with known polymers. Drug release from the formulated tablets was slow and spread over 24 h and depended on percent polymer in the tablet. Release was diffusion controlled and followed zero order kinetics. Non fickian diffusion was the drug release mechanism from the formulated tablets. Felodipine release from matrix tablets F4 and F7 formulated employing starch urea borate were similar to that from Renedil extended release tablets, a commercial extended release formulation of felodipine. Starch urea borate polymer was found suitable for the design of oral controlled release tablets of felodipine. Key words: Starch urea borate polymer, Extended release, Felodipine, Matrix tablets. INTRODUCTION Oral drug delivery is the most preferable route of drug delivery due to the ease of administration and patient compliance (Ami1 M et al., 2012). In the last two decades, modified release dosage forms have made significant progress in terms of patient compliance and clinical efficacy when compared to conventional dosage forms (Chowdary KPR et al., 2011). Drug release from the dosage forms should be at a desired rate, reproducible and predictable to achieve desired systemic effects with Corresponding Author Vasanth PM vasanthpharma@gmail.com minimum side effects (Kumar KPS et al., 2012). Polymers which are used as release retarding materials in the design of controlled release dosage forms play a key role in controlling the delivery of drug from these dosage forms. Though a wide range of polymers and other release retarding materials are available, there is a continued need to develop new, safe and effective release retarding polymers for controlled release. Starch is a natural, biodegradable polymer and modified starches are reported as fillers, (Kottke MK et al., 1992; Herman J and Remon JP, 1990) disintegrants and dry binders. In the present investigation a new starch based polymer, starch urea borate was synthesized and evaluated for its application in controlled release. Among the various approaches, preparation of drug embedded matrix tablet is one of the least complicated approaches for obtaining

2 28 controlled release. Felodipine containing matrix tablets were prepared employing starch urea borate and evaluated for controlled release of felodipine. Felodipine is an effective oral calcium antagonist (calcium channel blocker) belongs to the dihydropyridine drug class (Product monograph for Plendil). The recommended daily dosage of felodipine is mg. Felodipine is a BCS Class II drug having low aqueous solubility and high permeability. Following oral administration, felodipine is completely absorbed and undergoes extensive first-pass metabolism. Hence its systemic bioavailability is limited to 20%. The mean peak and trough steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given once a day to normal volunteers, were 20 and 0.5 nmol/l, respectively. The trough plasma concentration of felodipine in most individuals was substantially below the concentration needed to effect a half-maximal decline in blood pressure (EC50) [4 6 nmol/l for felodipine], thus precluding once-a-day dosing with the immediaterelease formulation. Thus controlled release formulation is needed for felodipine for better control of blood pressure and to enhance patient compliance. A few controlled release formulations of felodipine are available commercially. MATERIALS AND METHODS Materials Felodipine is a gift sample from M/s. Dr. Reddy s Laboratories Limited, Hyderabad. All other materials used were of pharmacopoeial grade. Methods Preparation of starch urea borate polymer Potato starch (50 g) was dispersed in 100 ml of purified water to form starch slurry. Borax (12.5 g) and urea (12.5 g) were dissolved separately in 400 ml of purified water and the solution was heated to boiling. While boiling, the starch slurry was added and mixed. Mixing while heating was continued for 10 minutes to gelatinize starch to form starch urea borate polymer. The mass formed was spread on to a stainless steel plate and dried at 80 0 C for 6-8 h. The dried polymer was powdered and passed through mess no The possible mechanism of starch urea borate polymer matrix development is represented in figure 1. Micromeritic testing of starch urea borate polymer Angle of repose The angle of repose of powdered gum was determined by the funnel method. Accurately weighed granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface (Cooper J and Gunn C, 1986). The diameter of the powder cone was measured and angle of repose was calculated using the following equation: θ = tan 1 (h/r) Where h and r are the height and radius of the powder pile respectively. Bulk density Both bulk density (BD) and tapped bulk density (TBD) were determined. A quantity of 2 g of powder from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight on to a hard surface from the height of 2.5 cm at 2 second intervals (Martin A, 2001). The tapping was continued until no further change in volume was noted. BD and TBD were calculated using the following formulas: BD = Weight of the Powder/Volume of the packing TBD = Weight of the powder /Tapped volume of the packing Compressibility index/carr s index The flow property was also determined by measuring the compressibility index (CI). It is an important measure that can be obtained from the bulk and tapped densities. According to the theory, the less compressible materials are more flowable. A material having values of less than 20 to 30% is defined as the free flowing material. Based on the apparent bulk density and tapped density, the percentage compressibility of the bulk drug was determined by using the following formula: CI = TBD BD/TBD x 100 Preparation of tablets Matrix tablets each containing 10 mg of felodipine were prepared employing starch urea borate, HPMC, sodium CMC and ethyl cellulose in different proportions of drug and polymer according to the formulas mentioned in table 1. The required quantities of medicament and matrix materials were mixed thoroughly in a mortar by following geometric dilution technique. The binder solution (mixture of isopropyl alcohol and purified water at 1:1 ratio) was added and mixed thoroughly to form dough mass. The mass was passed through mesh no. 12 to obtain wet granules. The wet granules were dried at 60 for 4 h. The dried granules were passed through mesh no. 16 to break the aggregates. The lubricants, talc (2%) and magnesium stearate (2%) were passed through mesh no. 100 onto dry granules and blended in a closed polyethylene bag. The tablet granules were compressed into tablets on a rotary multi-station tablet punching machine (Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 8-10

3 29 kg/cm 2 using 9 mm round and flat punches. The compressed tablets were evaluated for weight variation, hardness, friability, disintegration and assay. Hardness of tablets was tested using a Monsanto hardness tester. Friability of tablets was determined in a Roche friabilator. Disintegration time was determined in a Thermonic tablet disintegration test machine using water, 0.1 N HCl and phosphate buffer of ph 6.5 with 1% SLS as test fluids (Dash S et al., 2010). Estimation of Felodipine Felodipine content of the tablets was estimated by UV spectrophotometric method based on the measurement of absorbance at 360 nm in phosphate buffer of ph 6.5 with 1% SLS. The method was validated for linearity, precision and accuracy. The method obeyed Beer s Law in the concentration range g/ml. When a standard drug solution was assayed repeatedly (n=6), the mean error (accuracy) and relative standard deviation (precision) were found to be 0.6 and 0.8 %, respectively. No interference from the excipients used was observed. Drug release study Drug release from matrix tablets was studied using 8 station dissolution rate test apparatus (Lab India, Disso 2000) employing a paddle stirrer at 50 rpm and at 37 1 C. Phosphate buffer of ph 6.5 with 1% SLS (900 ml) was used as dissolution fluid. Samples of 5 ml each were withdrawn at different time intervals over a period of 24 h. Each sample withdrawn was replaced with an equal amount of fresh dissolution medium. Samples were suitably diluted and assayed at 360 nm for felodipine using a Shimadzu UV-150 double beam UVspectrophotometer. For comparison, felodipine release from Renedil tablets (commercially available felodipine extended release tablets) was also studied. The drug release experiments were conducted in triplicate. Drug release kinetics Various kinetic models were used to describe the release kinetics. Release data were analyzed as per zero order, first order, Higuchi and Peppas models. The zero order rate Eq. (1) describes the systems where the drug release rate is independent of its concentration (Dash S et al., 2010). The first order Eq. (2) describes the drug release from system where release rate is concentration dependent. 10 Higuchi describes the release of drugs from insoluble matrix as a square root of time dependent process based on Fickian diffusion Eq. (3). C = K 0 t (1) Where, K 0 is zero-order rate constant expressed in units of concentration/time and t is the time. Log C = Log C 0 - kt / (2) Where, C 0 is the initial concentration of drug and K is first order constant and t is the time (Bourne DW, 2002). Q = K t 1/ 2 (3) Where, K is the constant reflecting the design variables of the system. Hence drug release rate is proportional to the reciprocal of the square root of time (Higuchi T, 1963). Mechanism of drug release To find out the mechanism of drug release, first 60% drug release data was fitted in Korsmeyer-Peppas model Eq. (4): M t /M = K t n (4) Where M t /M is fraction of drug released at time t, k is the rate constant and n is the release exponent. The n value is used to characterize different release mechanisms as given in table 2 for cylindrical shaped matrices. Figure 1. The possible mechanism of starch borate urea polymer matrix development Table 1. Release exponent (n) and drug release mechanism for cylindrical shape Release exponent (n) Drug release mechanism 0.45 Fickian diffusion 0.45 < n < 0.89 Non-fickian transport (anomalous transport) 0.89 Case II transport > 0.89 Super case II transport

4 30 Table 2. Composition of Felodipine extended release tablets S.No. Contents (mg/tab) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 1 Felodipine Starch-ureaborate HPMC K Sodium CMC Ethyl cellulose Lactose Dicalcium phosphate Talc Magnesium stearate Granulating fluid q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s 11 Total weight RESULTS AND DISCUSSION Starch urea borate was synthesized by gelatinizing potato starch in the presence of borax and urea. Starch urea borate, a new starch based polymer developed in our laboratory was found suitable for controlling the release rate of drugs from the matrix tablets (Chowdary KPR and Krishna MNM, 2009; Figure 2. The DSC thermogram of starch urea borate polymer Ramakrishna S et al., 2011). The starch urea borate polymer formed was found to be fine and free flowing powder upon drying. It was insoluble in water, aqueous fluids of acidic and alkaline ph. When tested for melting point the polymer charred at 210 C. The DSC and IRspectra of starch urea borate are presented in figure 2 and 3 respectively. Figure 3. The IR-spectra of Starch urea borate polymer Table 3. The assay, hardness, friability and disintegration time for felodipine formulations Formulation Assay (mg) Hardness (Kg/cm 2 ) Friability (%) Disintegration (min) Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating F Non-disintegrating

5 31 Table 4. Dissolution data of felodipine extended release tablets Time (h) Mean percent of felodipine released ( x ) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 Renedil ER tablets Cumulative percent drug released versus time profiles were presented in figure 4 (F1 to F8 vs. Renedil), figure 5 (F4 vs. F7 vs. F9 to F14 vs. Renedil) and figure 6 (F4 vs. F7 vs. Renedil) Figure 4. Cumulative percent drug released vs. time profiles (F1 to F8 vs. Renedil) Figure 5. Cumulative percent drug released vs. time profiles (F4 vs. F7 vs. F9 to F14 vs. Renedil) Figure 6. Cumulative percent drug released vs. time profiles (F4 vs. F7 vs. Renedil) Matrix tablets each containing 10 mg of felodipine could be prepared employing different proportions of starch urea borate, HPMC, sodium CMC and ethyl cellulose polymers by conventional wet granulation method. As felodipine is a low dose drug, lactose (water soluble) and dicalcium phosphate (water insoluble) were added as diluents. A total number of fourteen formulations were prepared and evaluated. The data of evaluated tablets such as assay, hardness, friability and disintegration are provided in table 3. All the matrix tablets prepared contained felodipine within 100 4% of the labeled claim. Hardness of the tablets was in the range of 8 10 kg/cm 2. Weight loss in the friability test was less than 0.4% in all the cases. Weight variation was within the standards of Indian Pharmacopoeia (IP) and United States Pharmacopoeia (USP). All the tablets were found to be non disintegrating in water and

6 32 aqueous, acidic (ph 1.2) and alkaline (ph 6.5 phosphate buffer with 1% SLS) fluids. As such the prepared tablets were of good quality with regard to drug content, weight variation, hardness and friability. As the tablets formulated employing polymers were non disintegrating with acidic and alkaline fluids, they are considered suitable for oral controlled release. Felodipine release from the prepared tablets was slow and spread over 24 h and depended on the concentration of polymer. When the release data were analyzed as per zero and first order kinetic models, the best fit with higher correlation (r > ) was observed with zero order model indicating that the drug release from all the tablets followed zero order kinetics. As the polymer concentration was increased, release rate was decreased. Good linear relationship was observed between percent polymer and release rate (K 0 ). Thus drug release from the matrix tablets could be controlled by varying the proportion of drug: polymer in the matrix. When the release data were analyzed as per peppas equation, the release exponent n was found in the range indicating non fickian (anomalous) diffusion as the release mechanism from all the tablets prepared. Plots of percent released versus square root of time was found to be linear (r > ) with all tablets prepared indicating that the drug release from the tablets was diffusion controlled. Release kinetics of the dissolution data of tablets are summarized in table 5 and 6. Table 5. Correlation coefficient (r) values in the analysis of release data as per zero order (K 0 ), first order (K), Higuchi and Peppas equation models Formulation Correlation coefficient (r-value) Zero order model (K 0 ) First order model (K) Higuchi Peppas equation F F F F F F F F F F F F F F Renedil ER tablets Table 6. Release characteristics of Felodipine matrix tablets Formulation T 50 (h) T 90 (h) K 0 (mg/h) n in peppas equation F F F F F F F F F F F F F F Renedil ER tablets

7 33 Felodipine release from prepared tablets was compared with Renedil. Drug release profiles of formulations prepared using starch urea borate polymer (F4 and F7) and Renedil tablets were compared by calculating difference factor f 1 and similarity factor f 2. The values of f 1 and f 2 were found to be 11.0 and 86.8 respectively for the comparison of release profiles of formulation F4 and Renedil tablets and the values of f 1 and f 2 were found to be 14.6 and 81.3 respectively for the comparison of release profiles of formulation F7 and Renedil tablets indicating that the release profiles of these products are similar. Hence matrix tablets formulated employing starch urea borate (F4 and F7) are considered suitable for controlled release of felodipine over 24 h. All the release parameters indicated variations or differences in drug release from the tablets formulated with different polymers though all the polymers were used at the same strength in the formula (F4, F8 and F9 to F14). The drug release was relatively rapid in the case of HPMC and sodium CMC and ethyl cellulose gave very slow release. Whereas in the case of starch urea borate the release was slow, gradual and spread over 24 hours. The order of increasing release retarding effect observed with various polymers was ethyl cellulose > starch urea borate > sodium CMC > HPMC in both the series formulated with lactose and dicalcium phosphate as diluents. Overall matrix tablets with lactose as diluent gave higher release rates than those with dicalcium phosphate with all the polymers. This could be due to the more water soluble nature of lactose compared to dicalcium phosphate. Thus starch urea borate was found to be a better release retarding polymer than HPMC and sodium CMC and could be used in the formulation of controlled release matrix tablets. CONCLUSION The results of the study indicated that the new polymer synthesized i.e. starch urea borate is suitable for the design of oral controlled release tablets providing good release retarding effect than HPMC and sodium CMC. Felodipine extended release tablets formulated employing starch urea borate provided controlled release of drug over 24 h comparable with that of Renedil, a commercial felodipine extended release tablet. REFERENCES Ami1 M, Krunal S, Hejal P, Yogi. Advancements in controlled release gastroretentive drug delivery system. Journal of Drug Delivery & Therapeutics. 2012; 2(3): Bourne DW. Pharmacokinetics In: Banker GS, Rhodes CT, eds. Modern Pharmaceutics. 4th ed, New York, NY: Marcel Dekker Inc, 2002: Chowdary KPR, Krishna MNM. Synthesis and evaluation of starch-urea-borate for controlled release application. Asian Journal of Chemistry. 2009; 21(6); Chowdary KPR, Satyanarayana KV, Kumar DSS, Priya YDG. Preparation and evaluation of controlled release diltiazem hcl tablets by using ethyl cellulose and ethylene-vinyl acetate polymers as retardant. International Journal of Pharmacy. 2011; 1; Cooper J, Gunn C. Powder flow and compaction. Carter SJ, eds. Tutorial Pharmacy. New Delhi, India: CBS Publishers and Distributors; 1986; Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Poloniae Pharmaceutica-Drug Research. 2010; 67(3); Herman J, Remon JP. Modified starches as hydrophilic matrices for controlled oral delivery III. Evaluation of sustainedrelease theophylline formulations based on thermal modified starch matrices in dogs. International Journal of Pharmaceutics. 1990; 63 (3); Higuchi T. Mechanism of sustained action medication: theoretical analysis of rate of release of solid drugs dispersed in solid matrices. Journal of Pharmaceutical Sciences. 1963; 52(12); Kottke MK, Chueh HR, Rhodes CT. Comparison of disintegrant and binder activity of three corn starch products. Drug Development and Industrial Pharmacy. 1992; 18: Kumar KPS, Bhowmik D, Srivastava S, Paswan S, Dutta AS. Sustained release drug delivery system potential. The Pharma Innovation. 2012; 1(2): Martin A. Micromeritics. Martin A, ed. Physical Pharmacy. Baltimore, MD: Lippincott Williams & Wilkins; 2001; Product monograph for Plendil (felodipine) extended release tablets. accessed 8 July Ramakrishna S, Mihira V, Tabitha K. Design and evaluation of drug release kinetics of diltiazem hydrochloride sustained release tablets. International Journal of Medical and Pharmaceutical Sciences. 2011; 1(4); 1-13.