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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 4 pp. 1037ñ1043, 2016 ISSN 0001-6837 Polish Pharmaceutical Society FORMULATION, EVALUATION AND IN VITRO DISSOLUTION PERFORMANCE OF ENALAPRIL MALEATE SUSTAINED RELEASE MATRICES: EFFECT OF POLYMER COMPOSITION AND VISCOSITY GRADE AAMNA SHAH1, GUL M. KHAN2, HANIF ULLAH3, KAMRAN AHMAD KHAN1, KALEEM ULLAH3 and SHUJAAT A. KHAN3* Department of Pharmaceutics, Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan 2 Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan 3 Department of Pharmacy COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan 1 Abstract: The present study aimed at developing the sustained release matrix tablets of enalapril maleate and evaluating the effect of polymer concentration and viscosity grade on drug release. The sustained release enalapril maleate tablets were successfully formulated by direct compression method using nonionic cellulose ethers HPMC K15, HPMC K100 and HPC polymers either alone or in combination. In-vitro drug release study was carried out in phosphate buffer (pH 6.8) for a period of 24 h following USP dissolution apparatus II i.e., paddle apparatus. Model dependent approaches like zero-order, first order, Higuchiís model and KorsmeyerPeppas model were used to assess drug release from various formulations. All the three polymers alone or in combination sustained the drug release. The drug release characteristics from HPMC and HPC polymer followed zero order release kinetics except for 45% concentration of all polymers alone or in combination where by the drug release followed Higuchiís model. In all cases, the drug release mechanism was both diffusion as well as erosion. Keywords: enalapril maleate, HPMC, HPC, sustained release, viscosity grades Different types of sustained release (SR) formulations have been formulated for improving clinical efficacy of active pharmaceutical ingredients (APIs) and patient compliance. The SR oral dosage forms have been documented for improvement in therapeutic efficacy and maintenance of steady state plasma concentration of drug (1). Nonionic cellulose ethers and hydroxypropylmethyl cellulose (HPMC) have been extensively considered for the purpose of formulating oral SR formulations. Such hydrophilic and water soluble polymers are wellliked due to their broad regulatory acceptance, cost effectiveness and flexibility in order to get a desired drug release profile (2). HPMC always finds preference in formulation of hydrophilic matrices due to cost effectiveness, choice of viscosity grades, nonionic nature, robust mechanism and utilization of existing conventional equipment and methods (3). It has been most extensively employed as a gel forming agent in the formulations of controlled release, semisolid, liquid and solid dosage forms. Variation in viscosity grades, polymer concentration and the addition of various excipients to the matrices can alter the release of drug (4). HPC is used as film coating agent or tablet coating agent at a 5% (w/w) concentration. Similarly, HPC in a concentration of 15-35% (w/w) is used for the preparation of SR, controlled release (CR) and extended release (ER) dosage forms. Additionally HPC in a concentration of 2-6% is used as tablet binder in both dry and wet granulation processes used for tablet manufacturing (5). Enalapril is angiotensin-converting enzyme (ACE) inhibitor that is administered orally. It undergoes in vivo hydrolysis to form its bioactive metabolite. Biotransformation most likely takes place in the liver. Biotransformation beyond bio-activation is not observed in human (6). Enalapril maleate (EM) is considered as effective candidate for SR dosage forms due to its gastric absorption, high water solubility and shorter half-life (7). Foods do not affect its bioavailability. It is primarily excreted through renal * Corresponding author: e-mail: [email protected] 1037 1038 AAMNA SHAH et al. route. It reduces blood pressure (BP) by lessening systemic vascular resistance. The reduction in BP is not associated with reflex tachycardia. Moreover, there is slight increase in cardiac output without any impairment in cardiovascular reflexes (8). Direct compression (DC) is the most inexpensive, fast, and simple method for the preparation of SR tablet formulations (9). Moreover, it does not change the physical nature of the drug. It is most commonly used in the formulation of crystalline powders due to good cohesive properties (10). DC can be effectively used for drugs sensitive to moisture and humidity as this technique do not require water and any other solvent (9). MATERIALS AND METHODS Materials Disodium hydrogen orthophosphate and potassium dihydrogen phosphate were procured from Guideís Corporation (Pvt.), Ltd., Islamabad. Sodium hydroxide and hydrochloric acid (37%) was purchased from Merck, Germany, EM was supplied as a gift by Warrick Pharmaceuticals, Islamabad. Lactose and magnesium stearate were procured from BDH Chemical Ltd., England. PVP K-30, Talc, AvicelÆ (PH-102 and PH-200) were procured from Guideís Corporation (Pvt.) Ltd., Islamabad. Moreover, Methocel K100M Premium, Methocel K 15 and HPC (Dow Chemicals Co. Midland USA) were supplied as a gift by Allied Pharmaceuticals, Islamabad. All the chemicals were used as such without any further purification. Compositions and preparation of enalapril maleate matrix tablets SR matrix tablets of EM were formulated using Methocel K15, Methocel K100 and HPC in different drug to polymer ratio i.e., D : P ranging from 4 : 3 to 4 : 10. Moreover, they were also used concomitantly in some formulations and their combined effect on drug release profile was observed. Lactose MH and Lactose SD, Avicel 102 and 200, magnesium stearate, talcum powder and PVP K-30 were used as excipients. Formulations pattern using HPMC K15, HPMC K100 and HPC alone or in combination are shown in Table 1. Direct compression technique was used for the preparation of tablets. This method is used for drugs or substances with crystalline form and having good cohesive and compressibility properties. For tablet preparation Methocel K-15, Methocel K-100M premium and HPC were used as polymers. In this method drug, polymer and all the excipients except magnesium stearate were thoroughly mixed with one another and geometrically blended in pestle and mortar for 5-10 min. The mixture was passed through sieve number 24 followed by addition of magnesium stearate and mixed for 2 min. Again, the mixture was passed through sieve number 24. The powder mixture was compressed using rotary tableting machine (ZP-19, Lahore, Pakistan). Eight mm flat punches were used for tablet preparation. The batch size selected for each formulation was 300 tablets while the compression weight was 200 mg per tablet. The compositions of all formulations are shown in Table 1. Table 1. Compositions of various formulations (F1-F12). Composition (mg) per tablet (200 mg) Code HPC Methocel K15 Methocel K100 Drug : Polymer Lactose Drug Talc Magnesium stearate PVPK30 F1 30 -- -- 4:3 92.68 52.32 10 5 10 F2 60 -- -- 4:6 62.68 52.32 10 5 10 F3 90 -- -- 4:9 32.68 52.32 10 5 10 F4 -- 30 -- 4:3 92.68 52.32 10 5 10 F5 -- 60 -- 4:6 62.68 52.32 10 5 10 F6 -- 90 -- 4:9 32.68 52.32 10 5 10 F7 -- -- 30 4:3 92.68 52.32 10 5 10 F8 -- -- 60 4:6 62.68 52.32 10 5 10 F9 -- -- 90 4:9 32.68 52.32 10 5 10 F10 10 10 10 4:3 92.68 52.32 10 5 10 F11 20 20 20 4:6 62.68 52.32 10 5 10 F12 30 30 30 4:9 32.68 52.32 10 5 10 1039 Formulation, evaluation and in vitro dissolution performance of Table 2. Mathematical models applied to formulations. Kinetic model Zero-order kinetics W = k1 t Higuchi kinetics W = k2 t1/2 First order kinetics ln (100 - W) = ln 100 ñ k3 t Korsmeyer-Peppas equation Mt / M8 = k4 tn Table 3. Physical properties of formulations. Formulation Weight (mg) Thickness (mm) Friability (%) Hardness (kg/cm2) Average SD (±) Average SD (±) Average SD (±) F1 203.6 2.836 3.0 0.07 0.19 8.1 0.152 F2 203.2 3.553 3.1 0.05 0.17 7.5 0.217 F3 202.3 2.584 3.3 0.07 0.15 6.8 0.295 F4 202.8 2.44 3.3 0.05 0.25 8.9 0.109 F5 203.4 3.627 3.5 0.07 0.19 7.7 0.336 F6 203.2 3.293 3.6 0.07 0.13 6.4 0.179 F7 203.7 3.860 3.4 0.09 0.11 7.1 0.123 F8 202.8 2.440 3.6 0.04 0.08 6.6 0.152 F9 202.8 3.293 3.7 0.07 0.04 5.4 0.144 F10 202.3 2.214 3.5 0.08 0.13 7.6 0.219 F11 204.6 3.718 3.6 0.07 0.10 6.4 0.192 F12 202.8 3.327 3.7 0.08 0.08 5.6 0.261 Physical evaluation of prepared formulations After tablet preparation, tablets were evaluated by applying various official tests according to USP. Dimensional test which was applied on tablets include thickness, while the QC test include weight variation, friability and hardness test. For weight variation test, 20 tablets were taken and weighed individually using the electronic weighing balance (AX-120, Shimadzu, Japan). Then, average weight of all the 20 tablets was calculated. According to USP, the individual weight of not more than 2 tablets should vary from average weight by not more than 5%. For hardness test, 10 tablets were selected randomly and their hardness/average breaking strength was tested using the hardness tester (PTB3112, Germany). USP acceptable limit of hardness is 5-10 kg/cm2. For friability test, 10 pre-weighed tablets were taken and placed in friabilator (FB0606, Curio, Lahore, Pakistan). The friability apparatus was turned on for 100 revolutions at 25 rpm and the tablets were weighed again. The % friability was then calculated using the equation: W1 ñ W2 Friability (%) = ñññññññññ × 100 (1) W1 USP limit of friability is less than 0.8% w/w. For dimensional test, 10 tablets were selected randomly for checking tablet thickness using the digital Vernier caliper (China). The USP acceptable range for thickness is 2-4 mm for the tablets having diameter of 4-13 mm. In vitro drug release studies In vitro drug release test of controlled release matrix tablets of EM was performed on prepared tablets in accordance with the ìDissolution Procedureî described by USP applying Apparatus 2 and involving use of Paddle Dissolution System. Pharma test dissolution apparatus (DT/7-13372, Germany) was used for the study. Phosphate buffer solution of pH 6.8 was used as dissolution medium. Volume of the medium was 900 mL, temperature was maintained at 37 ± 1OC while rotating speed of paddles was 50 rpm. The test was performed on six tablets from each batch. The drug release pattern was evaluated by taking 5 mL samples at specific time interval of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h. The samples collected were filtered through Whatman filter paper or through filter mem- 1040 AAMNA SHAH et al. brane having pore size of 0.45 µm and then analyzed with UV-visible spectrophotometer (7200, Cecil, England) at λmax of 206 nm. The analysis of dissolution data was performed using various kinetic models i.e., zero order release kinetics, first order release kinetics, Higuchi and Korsmeyer-Peppas models. Drug release kinetics The data obtained from the dissolution studies were fitted into the mathematical models shown in Table 2. In these equations, ëWí represents the percent drug released at time ëtí compared with total amount of drug present in tablets. k1, k2 and k3 are rate constants depending upon the models. Mt/M∞ designates fractional drug release form the matrix tablet into the dissolution medium. Diffusion exponent ëní characterizes the release mechanism of drug. The mechanism of drug release was elucidated by calculating the value of ëní from the dissolution data obtained from the initial 60% release. If the ëní value is greater than 0.43 and less than 0.85 then, release of drug is anomalous or non-Fickian, while if value of ëní is greater than 0.85 then, in that case release kinetics is super case-II transport. RESULTS Physical evaluation of prepared formulations The weight variation test was performed for all formulations (F1-F12) and results were found to be in the range of 202.3 ± 2.584 mg to 204.6 ± 3.718 mg (Table 3). No tablet deviate from the official limit, which is 5% for 200-250 mg tablet. Thus, all formulations were within limits and passed the weight variation test. The friability tests performed for the formulations (F1-F12), were in the range of 0.04 to 0.25%, which fall within the limit of standard (less than 0.8%). The thickness was carried out according to the procedure. The thickness of the tablets ranges from 3.0 ± 0.07 to 3.8 ± 0.08 mm. The hardness for all formulations ranged from 5.6 ± 0.261 to 8.1 ± 0.154 kg/cm2, which showed that hardness was within the limits. The release profile from SR tablet matrices of EM using different polymers i.e., HPMC K100, HPMC K15 and HPC in varying drug to polymer ratio are shown in Figure 2. As shown in Figure 2, the release profile for formulation (F1) with 15% of HPC was extended to about 99% of drug in 12 h. The drug release was found to be about 91% for Figure 1. Physical properties of formulations F1-F12: A. Weight (mean ± SD), B. Thickness (mean ± SD), C. Friability (%), D. Hardness (mean ± SD) 1041 Formulation, evaluation and in vitro dissolution performance of Table 4. Drug release kinetics. Determination coefficient (R2) Zero-order First-order Higuchi Korsmeyer-Peppas Value of n for Korsmeyer-Peppas F1 0.905 0.803 0.778 0.966 0.638 F2 0.959 0.702 0.877 0.94 0.838 F3 0.942 0.664 0.982 0.99 0.903 F4 0.951 0.749 0.846 0.988 0.741 F5 0.985 0.541 0.947 0.987 0.833 F6 0.917 0.681 0.982 0.994 0.95 F7 0.959 0.68 0.862 0.966 0.765 F8 0.982 0.724 0.978 0.973 0.862 Formulation F9 0.91 0.772 0.978 0.973 0.994 F10 0.981 0.566 0.926 0.99 0.843 F11 0.984 0.789 0.984 0.984 0.933 F12 0.96 0.821 0.995 0.941 0.855 Figure 2. Drug release profile of all formulations (F1-F12) 30% (F2) and 72% for 45% of HPC (F3) in 12 h, respectively. In case of HPMC K15, the formulation with 15% of HPMC K15 (F4) extended drug release and about 99% of drug was released in about 12 h. Therefore, for obtaining further extended release profile, the concentration of polymer was increased and proportional decrease in percent drug release was observed. The formulation with 30% (F5) and 45% of HPMC K15 (F6) released about 88% of drug and 62% of drug in 12 h, respectively. Similarly, the formulation with 15% of HPMC K100 (F7), the release profile was extended, however, the release extent was higher than the desired results and about 96% of drug release was observed in about 12 h. And the formulation with 30% of HPMC K100 (F8) released about 77% of drug in 12 1042 AAMNA SHAH et al. h. The formulation with 45% of HPMC K100 (F9) released 55% of drug in 24 h. When assessed combination of all the three polymers in equal ratios, the drug release in 12 h, was 92, 72 and 52% for 15, 30 and 45% of polymers blend, respectively. Moreover, the polymer blend retarded the drug release more efficiently than that of polymer used alone in the same corresponding ratios (15, 30 and 45%). The release rate of drug was reduced significantly when HPMC K100, HPMCK 15 and HPC were used in combination. Drug release kinetics Table 3 represents the results of in vitro drug release kinetic models applied to the sustained release matrix tablets of EM using HPMC K15, HPMC K100, HPC and all these three polymers in combination. Drug release from HPC, HPMC K15 and HPMC alone as well as in combination followed zero order at concentration of 15% and 30%, whereas at concentration of 45% all three polymers alone or in combination followed Higuchiís model. The value of ëní in Korsmeyer-Peppas equation was observed to be greater than 0.45 for all the prepared formulation which indicates that all the formulations were exhibiting non-Fickian or anomalous drug diffusion. The drug release mechanisms followed by all formulations was found to be the combination of two mechanisms i.e., diffusion and erosion (Table 4). DISCUSSION In order to mimic the physiological conditions of lower GIT, all the formulations were subjected to drug release studies in phosphate buffer (pH = 6.8) for 24 h. HPMC K100 showed more efficient drug release retardant property than HPMC K15 due to relatively higher viscosity, good gelling characteristics and strong linking capacity of HPMC K100. Furthermore, the slow release profile observed with combination of polymers may be due to the high concentration of polymers, high viscosity, strong cross linking and high molecular weight achieved. The swelling of matrix tablets were detected during the dissolution process. HPMC is well known for swelling controlled release mechanism and hydrophilic drug are released from this polymer by diffusion process (2). The hydration of polymer is the reason for swelling of tablets. Glass transition temperature of the polymer is reduced as compared to the temperature of the dissolution medium due to swelling of the tablets. The dissolution solvent exerts stress on the polymeric chains due to which there occurs relaxation effect within polymeric chains. This relaxation effect, in turn, increases distance among the polymeric chains. In hydrated polymer the molecular volume of polymer is increased that reduces the free volume due to the presence of microspores, which is observed clearly as shift in the drug release mechanism. Other researchers also observed similar type of results in their studies (11). In all cases, an increase in polymer concentration retarded the drug release from the matrices. This might be due to the reasons that an increase in the concentration of polymer and drug to polymer ratio lags the release of drug while reducing the amount of polymer and D : P ratio enhance the drug release from the polymeric matrices (11). Moreover, an increase in concentration and/or viscosity grade of polymer may lead to an increase in gel viscosity upon absorption of water, which acts as a barrier to diffusion that, in turn, may lead to a decrease of the diffusion coefficient. Thus, the drug release may be retarded. The gel barrier also provides hindrance to the penetration of water thus preventing the wetting of tablet core. Consequently, the tablet disintegration is hindered, which further sustains the drug release (12). CONCLUSION The SR tablet matrices of EM were successfully formulated using HPC and different viscosity grades of HPMC. As evident from in vitro drug release studies, the drug release was retarded by increasing viscosity grade or quantity of polymer as well as changing the type of polymer. The findings of this study obviously documented that matrix tablets of HPC and HPMC are a promising and effective drug delivery tool for once daily administration of enalapril maleate. The analysis of the release profiles in the light of distinct kinetic models led to the conclusion that the drug release characteristics from HPMC polymer matrices follows zero order kinetics except for 45% of all polymers alone or in combination where the drug release was following Higuchiís model. 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