Development of diclofenac sodium controlled release tablet from solid dispersion by spray drying using optimization method

Abstract

Diclofenac sodium (DS) controlled release solid dispersions were prepared by spray drying using ethylcellulose (EC), methacrylic acid copolymer (Eudragit), chitosan, hydroxypropyl methylcellulose (HPMS), and carbomer as single carriers and EC-chitosan as combined carriers. Among solid dispersions of 3:1 drug:single carrier, the system of chitosan exhibited the slowest dissolution followed by the systems of Eudragit, EC, HEMS, and carbomer, respectively. Combined carriers of EC-chitosan exhibited higher dissolution retarding effect than single carrier of EC or chitosan. An Hadamard matrix H[8] was employed to estimate the main effects of four parameters; spray feeding volume and contents of absolute ethanol, EC, and chitosan, on dissolution of DS:(EC+chitosan) solid dispersions. Optimization strategy using multiple linear regression and a feasibility computer program was utilized to obtain the optimum quantities of the four parameters that would result in a required DS controlled release solid dispersion. An optimum set of conditions for preparing spray-dried DS controlled release solid dispersion, containing 10 g of drug, were spray feeding volume of 200 ml, absolute ethanol fraction of 0.7, ethylcellulose content of 2.5 g, and chitosan content of 0.02 g. The optimum DS solid dispersion was prepared and formulated into tablet dosage form by direct compression. Optimization strategy using a central composite design and multiple regression was used to study the influences of four parameters; compression force, the amount of spray-dried rice starch (Era-TabR), croscarmellose sodium (Ac-Di-SolR), and magnesium stearate, on tablet physical properties and dissolution. The optimum conditions of those parameters were searched and an optimum DS controlled release tablet formulation was formulated. An optimum condition in preparing DS controlled release tablet, containing 100 mg of drug, was found to be compression force of 700 psi, Era-Tab content of 194.8 mg per tablet, Ac-Di-Sol content of 6.4 mg per tablet, and magnesium stearate content of 1.6 mg per tablet. The optimum DS solid dispersion and tablet were prepared and validated by statistical analysis. Their experimental dissolution profiles lied almost completely within the 99% confidence band of their predicted dissolution profiles. The dissolution profile of the optimized DS controlled release tablet was similar to that of the optimized DS controlled release solid dispersion. Scanning electron microscope, differential thermal analysis and X-ray diffraction were used to study the completion of solid dispersion formation. The mechanisms of drug release from the optimum DS controlled release solid dispersion and tablet were found to be diffusion controlled.