Formulation, Optimization and In Vitro Evaluation of Solubility Enhanced Fast Disintegrating Tablets of Mebendazole

Abstract

Mebendazole (MBZ) is used for the treatment of different intestinal helminthic infections (IHIs) and extraintestinal helminthic infections (EIHs). Due to its poor aqueous solubility and high first pass metabolism, MBZ has low bioavailability that can affect the therapeutic efficacy of the drug for EIHs. The aim of the present study is to develop solubility enhanced rapidly disintegrating tablets of MBZ with a simple and industrially feasible manufacturing process. The influence of the selected excipients (nicotinamide (NIC), crospovidone and microcrystalline cellulose to mannitol ratio (MCC: MNTL)) on the physicochemical properties of MBZ were determined by using 32 factorial design. By using the shake flask method, NIC as hydrotropic agent enhanced solubility of MBZ more than 16 times in 40% w/v hydrotropic solution. Formulation (F8) which consisted of 5% crospovidone, 2:1 MCC: MNTL and 1 MBZ: 3 NIC hydrotropic solid dispersion (HSD) prepared by kneading method (KM1:3) had the shortest disintegration time (21 ± 1.7 sec), lowest wetting time (56 ± 3 sec) and largest crushing strength (10.25 ± 0.79 kg/cm2). These properties could be due to the binding and disintegrant properties of MCC and the disintegrant property of crospovidone. All of the formulations released more than 75% of the label claim within 20 min except formulation without NIC (F10). The rapid dissolution behavior is likely due to the formation of hydrotropic system. *Corresponding author: Desta Assefa, College of Public Health and Medical Sciences, Jimma University, Ethiopia, Tel: +251913860017; E-mail: destaassefa24@yahoo.com Received August 04, 2018; Accepted August 23, 2018; Published September 01, 2018 Citation: Assefa D, Belete A, Joseph NM (2018) Formulation, Optimization and In Vitro Evaluation of Solubility Enhanced Fast Disintegrating Tablets of Mebendazole. J Bioequiv Availab 10: 78-83. 382. doi: 10.4172/0975-0851.1000382 Copyright: © 2018 Assefa D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Assefa D, Belete A, Joseph NM (2018) Formulation, Optimization and In Vitro Evaluation of Solubility Enhanced Fast Disintegrating Tablets of Mebendazole. J Bioequiv Availab 10: 78-83. 382. doi: 10.4172/0975-0851.1000382 J Bioequiv Availab, an open access journal ISSN: 0975-0851 Volume 10(4): 78-83 (2018) 79 Materials and Methods The materials used were MBZ (SupharmaChem, India), NIC (Lonza Guangzhou Ltd, China), crospovidone (China Associate Co. Ltd, Shenzhen, China), MCC (Avicel®MicrocelluloseWeissenborn GmbH + KG, Weissenborn, Germany) and MNTL (China Associate Co. Ltd, Shenzhen, China), Whatman® filter paper, etc. Calibration curve of mebendazole As stock solution, 200 μg/ mL were prepared using MBZ (10 mg) and formic acid (20 mL). This solution was made up to 50 mL and diluted to 3 -10 μg/mL solution using 0.1N HCl. They were filtered by Whatman® filter paper (2.5 μm) and absorbance determined using UV-VIS spectrophotometer at 286 nm using formic acid and 0.1N HCl mixture as blank. Finally, calibration curve was developed using absorbance and concentration data. Determination of equilibrium solubility of mebendazole in nicotinamide solutions Excess amount of MBZ was added to accurately measured 10 mL of 10, 20, 30 and 40% w/v of hydrotropic solutions in 0.1N HCl and shaken (5 rpm) on orbital flask shaker for 48 h; allowed to equilibrate for the next 48 h and centrifuged for 15 min at 2000 rpm at room temperature. The supernatant filtered and analyzed spectrophotometrically at 286 nm against corresponding blank reagent (hydrotropic solution in 0.1N HCl). The experiment was performed in triplicate and the solubility of each preparation was estimated using calibration curve formula. Preparation of mebendazole hydrotropic solid dispersion By kneading technique, accurately weighed amount of MBZ and NIC were taken in a glass mortar and mixed for 5 min. Then, 99.5% methanol was added drop by drop while triturating to get slurry like consistency for 15 min. The uniform mass was dried in oven at 60oC for 4 h. The dried HSD was pulverized and passed through sieve No 60 (224 μm) and stored in screw capped glass vial until further evaluation. In the solvent method, 99.5% methanol was used to dissolve the required amount of MBZ and NIC by continuous stirring with a magnetic stirrer for 30 min at room temperature. The paste formed was further dried in oven at 60oC for 4 h. The resulting solid dispersions was scraped, pulverized and sieved through a No 60 (224 μm) sieve and stored in screw capped glass vial at room temperature until further analysis. Physical mixture (PM) was prepared by manually mixing MBZ and NIC of different ratios using glass mortar and pestle for 10 min duration. Finally, the mixture was passed through sieve No 60. Compatibility study: Fourier transform infrared spectroscopy The compatibility between the drug and excipients used in the formulation was studied using Fourier transform infrared spectroscopy (FTIR) (Shimadzu FTIR-8400S spectrometer, Japan). Samples of MBZ and HSD prepared by KM and PM of MBZ and crospovidone were grinded and mixed thoroughly with KBr at a 1:5 sample/KBr ratio. The KBr discs were prepared by compressing the powders at a pressure of 5 T for 5 min in a hydraulic press. The scanning range was 400 to 4000 cm-1 and the resolution was 4 cm-1. In vitro dissolution tests of mebendazole hydrotropic solid dispersion In vitro dissolution rates of pure drug and different HSDs powder were studied using USP 36/NF 31 (Type II) dissolution test apparatus. A USP Apparatus II (paddle) was set-up with a rotational speed of 75 rpm and 500 mL of dissolution medium (0.1N HCl). The temperature was maintained at 37.0 ± 0.5oC throughout the dissolution study. The amount of pure drug and HSD equivalent to 10 mg of MBZ were spread on the surface of the medium (0.1N HCl). The 5 mL sample withdrawn at predetermined time points was filtered and analyzed by UV-VIS spectrophotometer at 286 nm. The dissolution media replenished at each sampling time. All experiments were performed in triplicates and the cumulative amount of drug released from the system was estimated. Measurement of micromeritic properties Micromeritic properties like bulk density (ρb), tapped density (ρt), Hausner ratio (HR) and compressibility index (% CI) of MBZ, HSD and formulations powder blend were studied. Seventy grams of MBZ, HSD and each formulations powder blend were carefully introduced into a 250 mL graduated cylinder and the bulk volume of the powder was noted. After 500 times tapped using a tap densitometer, the tapped volume was noted. Preparation of solubility enhanced fast disintegrating tablets of mebendazole Nine FDT formulations were manufactured using HSD (KM1:3) by direct compression. The composition of tablet formulations (Table 1) were HSD (KM1:3), MCC, MNTL, crospovidone, magnesium stearate, talc and colloidal silicone dioxide (cSiO2). All ingredients were passed through mesh aperture of 224 μm. HSD prepared by KM1:3, MCC, MNTL and crospovidone were blended for 10 min. Magnesium stearate, talc and cSiO2 were added to the blend and the final blend was lubricated for 3 min. Finally, the tablets were prepared by compression machine (punch 16/32) using suitable constant compression force. Formulations HSD (KM1:3) (% w/w) Excipients (% w/w) Crospovidone MCC MNTL Talc Mg stearate cSiO2 F1 66.67 0 14.79 14.79 1 0.75 2 F2 66.67 0 9.86 19.72 1 0.75 2 F3 66.67 0 19.72 9.86 1 0.75 2 F4 66.67 3 13.29 13.29 1 0.75 2 F5 66.67 3 17.72 8.86 1 0.75 2 F6 66.67 3 8.86 17.72 1 0.75 2 F7 66.67 5 12.29 12.29 1 0.75 2 F8 66.67 5 16.39 8.19 1 0.75 2 F9 66.67 5 8.19 16.39 1 0.75 2 Table 1: Compositions of solubility enhanced fast disintegrating 600 mg MBZ tablet formulations. Citation: Assefa D, Belete A, Joseph NM (2018) Formulation, Optimization and In Vitro Evaluation of Solubility Enhanced Fast Disintegrating Tablets of Mebendazole. J Bioequiv Availab 10: 78-83. 382. doi: 10.4172/0975-0851.1000382 J Bioequiv Availab, an open access journal ISSN: 0975-0851 Volume 10(4): 78-83 (2018) 80 Characterization of formulated tablets The tablets were evaluated according to the USP 36/NF 31; based on hardness, friability, disintegration time, wetting time and in vitro dissolution rate evaluation criteria. Six tablets were randomly taken from each formulation and tablet hardness was measured by using hardness tester. Tablet friability was determined by taking previously weighed 10 tablets in friabilator and rotated at 25 rpm for 4 min. The tablets were taken out, dusted and reweighed. The percentage friability of the tablets was calculated. Six tablets from each formulation were randomly selected and placed in a disintegration apparatus filled with 900 mL of distilled water kept at 37 ± 20C. The time required for complete disintegration of the tablets with no palpable mass remaining in the apparatus was recorded as the disintegration time. Three tablets of each formulation were taken and placed on Whatman® filter paper, folded once diametrically and placed in 8 mL water and bromophenol blue containing Petri dish (8.5 cm in diameter). The appearance of the dye on the surface of the tablet was taken as a sign for complete wetting and wetting time. In vitro dissolution studies for the FDTs were carried out by using USP36 Type II dissolution apparatus at 75 rpm in 900 mL of 0.1 N HCl+1% sodium lauryl sulphate as dissolution medium maintained at 37 ± 0.5°C. FDT of desired formulations was taken and placed in the vessels of dissolution apparatus. Sample of 10 mL were collected from the vessels at specified time intervals and replaced by blank medium. The sample filtered, and absorbance determined by UV-Visible spectroscopy at 286 nm. Blank experiments were also performed at 286 nm f