Abstract

DEVELOPMENT AND EVALUATION OF CO-CRYSTALS OF FUROSEMIDE THROUGH POLYMER ASSISTED CO-CRYSTALLIZATION.

K. D. Khatavkar*, Dr. S. V. Patil, M. V. Mane, Prof. P. B. Patil and Prof. P. B. More

ABSTRACT

The poor solubility and related low bioavailability are a major concern for a large number of small molecule drugs, both on the market and in development. Several formulation strategies exist to overcome this issue. Among them, particle size is of outmost importance. The aim of this work is to present the potential of Ball milling, a new technology for drug particle engineering. To assess the potential of Ball mill technique, we carried out a case study on the crystallization of furosemide, a BCS class IV drug. A thorough characterization of the obtained crystals is presented along with a study of dissolution which highlights the solubility improvement provided by crystals produced via Ball mill technology. The obtained results show a particle size reduction when compared to the raw material, as well as an increase of the dissolution rate. Co-crystallization is a promising approach to improving both the solubility and the dissolution rate of active pharmaceutical ingredients. Crystal structure determination from powder diffraction data plays an important role in determining co-crystal structures, especially those generated by mechanochemical means. Here, two new structures of pharmaceutical interest are reported: a 1:1 co-crystal of furosemide with malic formed by polymer-assisted grinding and a second polymorphic form of a 1:1 co-crystal of furosemide with acetone, formed by solvent evaporation. Energy minimization using dispersion-corrected density functional theory was used in finalizing both structures. In the case of Furosemide and Acetone, this energy minimization step was essential in obtaining a satisfactory final Rietveld refinement.

Keywords: Pharmaceutical cocrystals, crystallization, solubility, stability, bioavailability.