Enhanced dissolution rate of diclofenac by solid dispersion method Avik Kumar Saha,Subhabrata Banerjee, Indrani Das, MD. Farque Ansari, Kaushik Mukherjee*Dr. B C Roy College of Pharmacy and AHS, Durgapur , 713206. Corresponding author:kaushik.pharmacyju08@gmail.com ABSTRACT The objective of this work was to improve aqueous solubility of poorly water soluble drugs by a modified porousstarch as solid dispersion carrier. The yield of the porous starch was found to be 80%. The flow property of theprepared porous starch was found to be good, with good compressibility index. Drugcontent of all the formulations were found to be in the range between 90-100%. The dissolution profile showed thatin solid dispersions prepared by physical mixing process and solvent evaporation method, the dissolution of pure diclofenac is high in comparison with the solid dispersion samples. Whereas in solid dispersions prepared by solvent evaporation method, dissolution of pure diclofenac is very low in comparison with the solid dispersion samples ofdrug with porous starch due to co-habitation of carriers with diclofenac that improved the dissolution rate of thedrug. The predicted drug release mechanism for solvent evaporation method where the drug releasecould be by first order release model. Thus this study confirmed that a porous starch can be developed and utilized as acarrier to improve the aqueous solubility of poorly water soluble BCS class II drugs thereby improving itsdissolution rate and bioavailability. Keywords: Porous starch, diclofenac, solid dispersion, solubility. __________________________________________________________________________________________ INTRODUCTION Solid dispersion technique can be used to increase the dissolution and absorption characteristics of several water insoluble drugs[1,2]. Lately, a number of drugs are not showing complete therapeutic responsedue to their poor solubility and dissolution rate, which in turn leads to poor bioavailability of the drug[3,4]. So, in the modern days, a lot of effort is given to improve the dissolution rate of poorly soluble drugs,to enhance their bioavailability. Among many other techniques, SolidDispersion (SD) technology has been successfully applied to increase the dissolution rate of highlylipophilic drugs thereby improving theirbioavailability [5, 6, 7, 8]. Usually, solid dispersions are two component systemsconsisting of a hydrophilic carrier in whichthe drug is incorporated. The drug that isincorporated in the hydrophilic carrier maybe molecularly dispersed or may occur as nanocrystals or may be amorphous nanoparticles. The improved dissolution rate of the drugmaybe attributed to (i) an increased solubility of the drug because of its amorphous state or small particle size (Kelvin’s law) [9, 10, 11, 12] (ii) an increasing surface area available for drugdissolution because of the small size of the drug particles [13, 14]and (iii) animproved wetting of the drug caused by the hydrophilic carrier[15, 16]. Drug release profiles from such mixtures are driven by the carrier properties [11]. Various hydrophilic carriers employed in preparation of solid dispersions include polyethylene glycols, carbohydrates (lactose), poloxamers, polyvinyl pyrollidone K-25, polyols (such as sorbitol and mannitol), organic acid (citric acid) and hydrotopes (urea) [19-21]. Starch is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. It consists of two types ofmolecules: the linear and helical amylose and the branched amylopectin. Depending on the plant, starch generallycontains 20 to 25% amylose and 75 to 80% amylopectin [10]. Porous starch is a biodegradable starch that has great potential as a solid dispersion carrier for oral poorly water soluble drugs. Porous starch has a nano-porous structure,low density, high specific surface area and pore volume; its distinctive advantages include no toxicity,biocompatibility, and biodegradability [11]. Traditionally porous starch has been prepared by swelling or by heatassisted microwave technique [12]. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) and is poorly water insoluble. It is widely used to treat swelling and pain in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. This work wasaimed at exploring the possibility of improving solubility and dissolution rate of poorly water soluble drug Diclofenac using the prepared porous starch as solid dispersion carrier MATERIALS AND METHODS Chemicals and Reagents Diclofenac was obtained as gift sample from Blue Cross Laboratories Limited, Starch, Methanol was purchased from SD Fine Chem Pvt. Ltd, Mumbai, India. All other analytical grade reagents were obtainedcommercially and used as received. Double distilled water was used throughout the work. 1. Preparation of Starch Phosphate: Starch phosphate was prepared based on the method as described by Choi et al (18) with some modifications. Potato starch (10 g) and di-sodium hydrogen orthophosphate anhydrous (3 g) were suspended in 10 ml of water and continuously stirred for 20 min. This starch slurry was then filtered and the wet starch mixture was conditioned for 12 h at room temperature. To enhance phosphorylation, this mixture was heated in a forced air oven at 130 °C for 3 h. The product obtained was grounded and sized. Figure 1: Phosphorification of Potato Starch to Produce Starch Phosphate 2. Preparation of Solid Dispersions of Diclofenac sodium in Starch Phosphate: Solid dispersions of diclofenac and starch phosphate were prepared in 1:1 (SD-1), 1:2 (SD-2) & 1:3 (SD-3)weight ratios of drug: carrier by solvent evaporation method. Diclofenac sodium (1 g) was dissolved in methanol (5 ml) in a dry mortar to get a clear solution. Starch phosphate (1 g) was then added and mixed. The thick slurry was triturated for 15 min for complete evaporation of dichloromethane and then dried at 55̊C until dry. The dried mass was pulverized and sieved through mesh no. 72 and stored in desiccators till further use. 2.1.Preparation of Diclofenac Tablets The tablets are prepared by conventional wet granulation method. Prepared SD-2 and SD-3 previously passed through #60 mesh screen were mixed in a stainless steel bowl. The powder blend was moistened with the required amount of water and then granulated using #18 mesh screens. The granules were dried at 60°C for sufficient period of time and the moisture content of the granules as measured using the IR Moisture Meter was found to be confined within 0.85% to 1.2%. The dried granules were then passed through #22 mesh screen, mixed with magnesium stearate, and compressed into tablet using a flat-faced 10-mm punch in a ten-station rotary minipress tablet machine (RIMEK, Karnavati Engineering, Gujarat, India). 2.2. Characterization of Starch Phosphate: The starch phosphate prepared was evaluated for following parameters: 2.2.1. Solubility : Solubility of starch phosphate was tested in water, aqueous buffers of pH 6.8 and organic solvents such as alcohol, chloroform, and acetone. (23) 2.2.2.pH : The pH of a 1% w/v slurry was prepared and pH is measured using pH meter (Systonic Limited, Kolkata). 2.2.3. Melting Point: Melting point was determined by using melting point apparatus (24). 2.2.4. Swelling Index: Starch phosphate (200 mg) was added to 10 ml of water and light liquid paraffin was taken in two different graduated test tubes and mixed. The dispersion in thetubes was allowed to stand for 12 h. The volumes of the sediment in the tubes wererecorded. The swelling index of the material was calculated as follows. S.I.(%)= Volume of sediment in water – Volume of sediment in light liquid paraffin ×100 Volume of sediment in light liquid Paraffin 2.2.5. Bulk density : Bulk density (g/cc) was determined by funnel tap method in a graduated cylinder (24). 2.2.6. Angle of repose: Angle of repose was measured by fixed funnel method. For determination of angle of repose (θ), the sample was poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0cm above hard surface. The sample was poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan-1 of the (height of the pile / radius of its base) gave the angle of repose [25] . 2.2.7. Compressibility index: Compressibility index (CI) was determined by measuring the initial volume (Vo) and final volume (V) after hundred tapping of a sample of starch phosphate in a measuring cylinder. CI was calculated using equation(24). Compressibility index (CI) = Vo – V × 100 Vo 2.2.8. Physical Characterisation of Tablets: Weight variation test (using Precisa Electronic Balance, model XB 600M/C, Switzerland), diameter measurement (using Digimatic Caliper, model CD-6″CS, Mitutoyo Corporation, Japan), hardness test (using Monsanto type hardness tester), and friability test (using Friabilator, Veego, Mumbai, India) were done following the usual methods. 2.2.9. In Vitro release study: In vitro drug release study was carried out in acidic solution 0.1 (N) HCl (pH 1.2) for 4 h and in USP PB solution(pH 6.8) using USP II dissolution rate test apparatus (model TDP-06P, Electro Lab, Mumbai, India). One weighedtablet was placed in 900 ml acidic solution (37± 1°C) and rotated with paddle at 75 rpm. Aliquot was withdrawn atdifferent times and replenished immediately with the same volume of fresh solution. The withdrawn samplesfollowing suitable dilution were analyzed spectrophotometrically at 274 nm for acidic and buffer solution. Theamounts of drug released in acidic medium and PB solution were calculated from the calibration curves drawn,respectively, in 0.1 (N) HCl and PB solution (pH 6.8). Each release study was duplicated. RESULT AND DISCUSSION Starch phosphate was prepared by reacting starch with di-sodium hydrogen orthophosphateanhydrous at elevated temperatures. The reactions involved are shown in Fig 1. Starch phosphate prepared wasfound to be white, crystalline, non hygroscopic powder and can easily be grounded to different sizes. Powderwhich passes through mesh no.72 and retained on mesh no.100 was collected. The starch phosphate prepared was characterised by determining various physical properties. The properties of starch phosphate prepared are summarised in Table 2.When tested for melting point, it was charred at 208 ̊C. Starch phosphate prepared was insoluble in water,aqueous fluids and several organic solvents. In water it exhibited good swelling (320%). No gelling/pasting was observed with starch phosphate when its aqueous dispersion was heated at100̊C for 30 min, where as potato starch formed a paste/gel during the above heat treatment. In the micromeriticevaluation, the angle of repose and compressibility index values revealed the excellent flow characteristic ofstarch phosphate prepared(Table no 1). As starch phosphate, a chemically modified starch was found to be insoluble in water and has goodswelling property without pasting or gelling when heated in water it is considered as a promising carrier forsolid dispersions for enhancing the dissolution rate of poorly soluble drugs. Solid dispersions of diclofenac in starch phosphate were prepared by solvent evaporation method employing various weight ratios of drug: starchphosphate. For each designed formulation, a blend of drug and Starch phosphate was prepared and evaluated. Bulkdensity was found0.3627±0.003 gm/cc and 0.374±0.004gm/cc for 1:2 and 1:3 ratios respectively. Fordensity data, Carr’s index was calculated. Flowability of the material was found to be good asindicated by compressibility-flowability correlation data. Angle of repose was found in the range of32.73±0.587 ̊ and 31.42±0.457 ̊ for 1:2 and 1:3ratios respectively. Tablets were prepared by wet granulation method. As the material was a free flowing, tabletwere obtained of uniform weight due to uniform die fill, with acceptable variation as per I.P.specification (Table 3). Hardness of the tablet for each type formulation was 6.5 and 7.5 kg/cm2. Friability was below than 1.0% shows an indication of good mechanical strength resistance of the tablet. The In-Vitro disintegration time for solid dispersion tablet is less than 15 minutes (Table 3). The In-Vitro drug release study indicated that more than 50% drug released in tablet with solid dispersion within 10 minutes whereas only 20% drug was released within 10 minutes from marketed preparation. Formulation with hydrophilic carrier, the dissolution rate of Diclofenac was increased at a significant level when compared other tablets. Many factors contributed to faster drug release rate such as decrease in particle size, decrease in agglomeration of particles, increase wettability and decrease in crystallinity of the drug and might be due to combined effect of improved wettability, emulsifying effect of carriers and reduction in particle size during the formation of solid dispersions. Overall increase in the dissolution performance of the optimized formulation was described in terms of dissolution parametersand when compared with pure drug, all the above parameters were increased in case of SD3 formulation. All these formulation also followed Hixson Crowell cube root dissolution equation this shows the formulation had better dissolution and dispersion characteristics. CONCLUSION Starch phosphate prepared by reacting starch with di-sodium hydrogen orthophosphate anhydrous atelevated temperatures was insoluble in water and has good swelling (320%) property without pasting or gellingwhen heated in water. Solid dispersions of diclofenac in starch phosphate prepared by solvent evaporationmethod employing various weight ratios of drug: starch phosphate gave rapid and higher dissolution of diclofenac when compared to pure drug. Dissolution followed first order kinetics. Solid dispersions of diclofenac prepared employing starchphosphate as carrier showed marked enhancement in the dissolution rate of diclofenac. Table 1: Physical Properties of the Starch Phosphate Prepared Property Results Solubility Insoluble in aqueous and organic solvent pH(1%w/v aqueous dispersion) 7.2 Melting Point Charred at 208 ̊C Swelling Index 320 Gelling property No gelling properties and swollen particle are separated. Bulk Density 0.445 gm/cc Angle of Repose 22.16̊ Compressibility Index 19.23% Table 2: Evaluation of solid Dispersion 1:2 and 1:3 (Diclofenac: Starch phosphate) Parameter Pure Drug Solid dispersion (1:2) Solid dispersion (1:3) Drug content 100 90.056±0.3275 99.52 ± 0.5241 Saturation solubility Slightly Very Very Bulk Density 0.4484±0.0018 0.3627±0.003 0.374±0.004 Carr’s Index 15.52±0.267 23.54±0.265 20.15±0.249 Angle of Repose 29.19±0.187 32.73±0.587 31.42±0.457 Table 3:Evaluation of Diclofenac tablet Parameter SD 2 SD 3 Wt variation Passes Passes Tablet Hardness (kg/cm2) 6.5 7.5 Friability (%) 0.9 0.7 In-Vitro DT (min) 07 (pass) 08 (pass) Table 4: Dissolution Parameters of the Solid Dispersions of Diclofenac Prepared Employing Starch Phosphate as a Carrier Formulation PD15 (%) T50(min) Diclofenac tablet(x) 2.76 >60 SD 2 53.86 <10 SD 3 61.15 <10 PD15 (%): percent dissolved in 15 min; T50 (min):time for 50 % dissolution; Solid dispersion (1:2): Ratio of drug: starch phosphate in solid dispersions: SD-2(1:2); Solid dispersion (1:3): Ratio of drug: starch phosphate in solid dispersions: SD-3(1:3). 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