Elucidating the Complex Phase Behavior of a Cocrystal System Containing Two APIs and One Coformer

A method has been developed to determine the phase behavior of a cocrystal system that contains two APIs (active pharmaceutical ingredients) and one coformer. Isoniazid, nicotinamide, and succinic acid (denoted as A, B, and C, respectively, hereafter) can form a ternary cocrystal ABC, along with two binary cocrystals, A(2)C and B2C, making the phase behavior very complex because of a variety of eutectic points. The phase diagram of such a complex system has never been reported. During experiment, solids of A, B, C, or A(2)C were added in lots to suspensions of pure ABC cocrystal or a mixture of ABC and another solid phase. Attenuated total reflectance Fourier transform spectroscopy (ATR-FTIR) was used to measure the concentrations of A, B, and C during the process. The constitution of solid phases in suspension at each equilibrium point was determined in a real-time manner by performing mass balance between the liquid and solid phase. Multiple eutectic points in equilibrium with a mixture of ABC and A(2)C, a mixture of ABC and B2C and a mixture of ABC and A, respectively, were obtained. In the 3D phase diagram spanned by the concentrations of A, B and C, these eutectic points constitute the boundary for a surface where pure ternary cocrystal can be obtained. Eutectic points in equilibrium with three solid phases simultaneously were not reached. With such a phase diagram, a cocrystallization process can be designed that thermodynamically guarantees the production of pure ABC cocrystal. In addition, practical issues and resolutions in applying ATR-FTIR to phase diagram measurement were discussed.