Thermodynamic stability relationship of ternary and binary cocrystals of isoniazid: why pH and coformer concentration matter

Abstract

Thermodynamic stability relationships between binary and ternary cocrystals of isoniazid and their components were investigated using predictive equations based on the ionization constant (K_a) and the solubility product (K_sp). The ternary cocrystal of isoniazid exhibits multiple pH_max values and a narrow stability zone between pH 2.8 to 5.7. Ternary to binary cocrystal conversion occurs at pH < 1.8. In addition, ternary cocrystal solubility decreases with increasing coformer concentration. We expect the approach presented herein to be applicable to other ternary cocrystals to better understand the factors that can alter cocrystal solubility, which is critical during the pre-formulation stage of development, and to avoid the risk of solid phase conversion during more advanced stages.