www.ddtjournal.com Drug Discov Ther 2008; 2(2):XX-XX. Using factorial design to improve the solubility and in-vitro dissolution of nimesulide hydrophilic polymer binary systems Ibrahim S. Khattab * , Saleh M. Al-Saidan, Aly H. Nada, Abdel-Azim A. Zaghloul Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, Kuwait. 1. Introduction Nimesulide is a non-steroidal anti-inflammatory agent that differs from many similar compounds in that it is acidic by virtue of a sulfonanilide rather than a carboxyl group. It is an inhibitor of cyclo-oxygenase 2, hence it inhibits the synthesis of destructive prostaglandins and spares cytoprotective prostaglandins. Nimesulide is practically insoluble in water (0.01 mg/mL). The poor aqueous solubility and wettability of the drug give rise to difficulties in the pharmaceutical formulation of oral preparations or solutions and may lead to its varying bioavailability. Increasing the aqueous solubility of nimesulide is an important way to overcome these drawbacks (1). The improvement of both solubility and dissolution rate by inserting a drug into a solid dispersion has been widely discussed and reported in a number of articles (2-6). The selection of the carrier has ultimate influence on dissolution characteristics. Research has shown that water soluble carriers result in a fast release of the drug from the matrix. Poorly soluble carriers, however, lead to slow release of the drug from the matrix (7). To date, several methods have been used to increase the water solubility of poorly soluble drugs such as physical modification of the drug and use of co-solvents, nanoparticles, a film coating, a complexation approach, and solid dispersion technology (8-13). Polyethylene glycols have been used extensively as water-soluble carriers and stabilizers for pharmaceutical dosage forms because of their favorable solution properties and low toxicity and cost (14-16). D-Mannitol is primarily used in pharmaceutical preparations as a diluent. It has been also used to improve the dissolution and bioavailability of thiazolidinedione and triamterene (17-19). The purpose of the present study was to employ an experimental design to develop an optimization strategy to increase the water dissolution of nimesulide by using carriers such as D-mannitol and polyethylene glycol at various drug/polymer concentrations. A two-factor, two-level factorial experimental design was employed to determine whether a particular treatment or combination of treatments was satisfactorily significant P1 * Correspondence to: Dr. Ibrahim S. Khattab, Pharmaceutics Faculty of Pharmacy, Kuwait University, Kuwait; e-mail: Khattab@hsc.edu.kw ABSTRACT: The aim of the present study was to use factorial design to enhance the dissolution rate of nimesulide using solid binary systems with the hydrophilic carriers D-mannitol and polyethylene glycol (PEG 4000). Two-factor full factorial design was employed to investigate the effects of the drug/ carrier ratio (X 1 , 10 and 20%) and the method of preparation (X 2 , physical or co-melted mixture) on the percent drug release after 60 min (Y 1 ). Drug- carrier co-melted mixtures were prepared by melting the carriers D-mannitol or PEG with the drug. For physical mixtures, the drug and carrier were mixed thoroughly in a mortar until a homogeneous mixture was obtained. Drug-carrier interactions were investigated by differential scanning calorimetry (DSC). All prepared mixtures were filled in hard gelatin capsules, size 0, and then their dissolution rate was tested. The results showed an increase in the solubility of the drug with increasing polymer concentrations. Thermal analysis revealed no notable differences regarding thermal events of nimesulide, D-mannitol, PEG 4000, and their physical or co- melted mixtures. The percent drug released after 60 min was 29.5% for nimesulide alone, 37.14 and 32.0% for a PEG/Physical mixture with a 10 or 20% drug/polymer ratio, and 69.7 and 53.1% for a PEG/Co-melted mixture with the same ratios. For nimesulide/D-mannitol, this percent drug released was 33.57 and 29.6% for a physical mixture and 63.13 and 48.04% for a co-melted mixture. Formulations with PEG showed an increase in solubility as well as dissolution in comparison to those prepared with D-mannitol. Factorial design was successfully used to optimize the dissolution rate of nimesulide. The chosen polymers caused a notable increase in drug solubility and co-melted formulations generally showed a higher dissolution than those prepared with physical mixtures. Keywords: Nimesulide, Binary systems, Factorial design Original Article