Enhancement in Dissolution Rate of Piroxicam by Two Micronization Techniques

Piroxicam is a nonsteroidal anti-inflammatory drug that is practically insoluble in water. The oral absorption rate of piroxicam is dependent on its dissolution rate in the GI tract. The aim of this study was to enhance the dissolution of piroxicam by a microcrystallization technique. The preparation of microcrystals of piroxicam was done by two methods, solvent change and pH shift. In the solvent-change method, the drug was dissolved in acetone, and the stabilizer was dissolved in water. The aqueous phase was added to acetone under homogenization in an ice bath for 1 min. In the pH-shift method, the drug and stabilizer were both dissolved in 0.1 N NaOH (pH 12) using homogenization. The pH was adjusted to 3 using 0.1 N hydrochloric acid. Dissolution testing was carried out in a hydrochloric acid medium using the rotating basket method. Particle size and morphology, FTIR, DSC, XRD, and surface area of the microcrystals were studied. The effects of drug and stabilizer concentration and homogenization rate on particle size and dissolution efficiency were studied statistically using a D-optimal design. The dissolution efficiency in both methods was increased about 3to 4-fold. The particle size in both methods was decreased in comparison with untreated drug. Maximum dissolution and minimum particle size were obtained by the solvent-change method. According to the results, both microcrystallization methods are effective in the modification of the crystalline the habit of piroxicam. INTRODUCTION Poor solubility is one of the major challenges in drug development today (1). An estimated 40% of drugs fall under BCS Class 2 (low solubility and high permeability) or Class 4 (low solubility and low permeability) (2, 3). These drugs show limited bioavailability because of their low solubility (4). Piroxicam, one of the most potent nonsteroidal anti-inflammatory drugs, is a BCS Class 2 drug with high membrane permeability but low water solubility (5). Different techniques have been studied to enhance the dissolution rate of piroxicam. Cavallaria et al. (6) used beta-cyclodextrin to improve the dissolution of piroxicam powder by wet granulation. Results showed advantages such as better powder flow and compressibility and improved bioavailability. Other methods such as liquid–solid compacts (5, 7), wet granulation using betalactose and PVP (8), and solid dispersions (9, 10) have been proposed to enhance the dissolution rate of piroxicam. Micronization is an effective way to enhance the dissolution rate of poorly water-soluble drugs (11, 12). However, mechanical methods such as milling or grinding have inevitable drawbacks, including the tendency of the produced particles to agglomerate, reducing the available surface area (13). In addition, the potential for physical instability or chemical degradation from disruptions in the crystal lattice (14, 15) and the high energy input makes this micronization method extremely inefficient (16). Several other methods have been introduced to produce micron-sized drug particles such as high-pressure homogenization (17), supercritical fluid micronization (18, 19), liquid–solid techniques (20), and hydrosol formation (11). In situ micronization has been proposed recently to overcome the above-mentioned problems of mechanical techniques. Since particles are prepared directly in the micronized state (21) and the newly formed microcrystal surface is simultaneously stabilized by a stabilizer (usually a polymer), particles have a much lower tendency for crystal growth and agglomeration (11). Two methods of microcrystallization are pH shift and solvent change. In the solvent-change method, an organic solvent and an aqueous solvent with a stabilizing agent are used. The drug microcrystals are formed by mixing the aqueous solution of the stabilizer with the organic drug solution; this leads to a reduction of interfacial tension, since the stabilizing agent would be adsorbed on the precipitated drug particles. A drug powder with a high drug load is obtained after drying this dispersion (22). Disodium cromoglycate microcrystals have been prepared for pulmonary delivery using this method (22). Zimmermann et al. (23) reported that the adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride changes the physicochemical properties of the drug such as particle size, morphology, and dissolution rate. Aspirin, mebutamate, and quinine sulfate microcrystals with a particle size of less than 10 μm were prepared using the solvent-change method (24). In the pH-shift method, an aqueous solution is used instead of organic solvent. A supersaturated solution is *Corresponding author. e-mail: [email protected] dx.doi.org/10.14227/DT200313P15