Dissolution rate enhancement of the novel antitumoral beta-lapachone by solvent change precipitation of microparticles

Abstract

beta-Lapachone [betaLAP] is a novel antitumor drug, which was recently on clinical trials with promising preliminary results. Problems derived from its low water solubility, its instability in solution and its high therapeutic dose constitute some challenges for pharmaceutical researchers. The purpose of the present work is to enhance the limited dissolution rate of betaLAP by the design of particles using a solvent change precipitation process. The procedure induces the spontaneous crystalline growth of the betaLAP in the presence of a stabilizing polymer (Hydroxypropylmethylcellulose) that limits the size of the particles generated. Physicochemical characterization of microparticles and the betaLAP dissolution rate was carried out. The utility of the betaLAP microcrystals in the development of tablets with adequate dissolution properties was also stated. The procedure was optimized in order to obtain stable and homogeneous particles with a small mean particle size (approximately 3 microm) and a narrow particle size distribution. There were no differences between the drying methods evaluated (in an oven and freeze-drying) with regard to particle morphology or dissolution behaviour, which is almost instantaneous. Tablets having suitable mechanical properties were produced by dry granulation prior to compression. The compression process did not compromise betaLAP dissolution characteristics.