Use of Amino Acids as Counterions Improves the Solubility of the BCS II Model Drug, Indomethacin

Amr      ElShaer; Sheraz      Khan; Dhaya      Perumal; Peter      Hanson; Afzal      R. Mohammed

doi:10.2174/156720111795767924

Abstract

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility of less than 20 μg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance (1HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Keywords: Salt formation, fourier transform infrared, 1H nuclear magnetic resonance, thermogravimetric analysis, pH solubility profile, IND solubility, physicochemical characteristics, hygroscopicity, BCS II Model Drug, Amino Acids as Counter Ions