Interrelation of the dissolution behavior and solid-state features of acetazolamide cocrystals

Abstract

The thermal behavior, phase stability, indicative stability and intrinsic dissolution rates of a series of cocrystals and cocrystal hydrates derived from the pharmaceutically active ingredient acetazolamide (ACZ) and 2-aminobenzamide (2ABAM), 2,3-dihydroxybenzoic acid (23DHBA), 2-hydroxybenzamide (2HBAM), 4-hydroxybenzoic acid (4HBA), nicotinamide (NAM) and picolinamide (PAM) as cocrystal formers have been evaluated. Upon heating in an inert atmosphere most of the cocrystals tested demonstrated first the elimination of the crystal former, followed by ACZ degradation. Only in cocrystals with NAM was melting observed. Under controlled temperature and relative humidity conditions all cocrystals tested were stable. However, phase stability tests in a medium simulating physiological conditions (HCl 0.01N, pH2.0) indicated that cocrystals ACZ-NAM-H₂O and ACZ-PAM gradually transform into ACZ. All cocrystals examined gave enhanced intrinsic dissolution rates when compared to pure ACZ and the largest dissolution rate constants were measured for the cocrystals that transformed in the phase stability test (approximate two-fold increase of the dissolution rate constants). The series of cocrystals examined herein exhibits an inverse correlation between the intrinsic dissolution rates and the melting/decomposition temperatures as well as the dimension of the hydrogen-bonded ACZ aggregates found in the corresponding crystal structure, indicating that solid-state stability is the major influence on dissolution performance.

Keywords: 2,3-Dihydroxybenzoic acid (PubChem CID:19); 2-Aminobenzamide (PubChem CID:6942); 2-Hydroxybenzamide (PubChem CID:5147); 4-Hydroxybenzoic acid (PubChem CID:135); Acetazolamide (PubChem CID:1986); Cocrystal hydrates; Cocrystals; Dissolution rate; Nicotinamide (PubChem CID:936); Picolinamide (PubChem CID:15070); Solution mediated phase transformation; Thermal analysis.