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

Abstract

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, A2C 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 A2C 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 A2C, 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.

Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities

“…Salt cocrystal, as one of the prominent cocrystalline types, gathers both salifying and cocrystallizing traits tactfully, of which the ternary salt cocrystal is a challengeable extension at the binary dimension, attracting a substantial amount of intrigue from researchers. − Aiming to remedy the drawbacks of cardiotonic medicine MIL and maximize the superiorities of ternary salt cocrystal system in perfecting physicochemical properties in vitro and pharmacokinetic behaviors in vivo of MIL, the present work concentrates on the MIL’s directional self-assembly with different phenolic acids. For this purpose, two diverse phenolic acid compounds of GLC and HGA are severally served as the cocrystal coformer and salt-forming reagent to participate in the cocrystallization procedure with MIL in view of their structural features, splendid physicochemical performances, and pharmacological effects.…”

“…Admittedly, such aggregation shaped by the combination of salt and cocrystal converging the superiority of both presents a novel measure to simultaneously improve the solubility and permeability of parent drugs. , For all we know, there are relatively scarce reports about MIL cocrystals presumably being attributable to alkalescency and the presence of stabilized dimers in MIL itself . Moreover, the assembly procedures of ternary cocrystals are packed with challenges due to the unbalanced nature of the interaction forces among different molecules, and the complexity of the spatial hierarchy of molecular stacking, restricting its vigorous development. − Nonetheless, given the numerous merits of ternary cocrystals, including the expansion of the quantity of drug crystalline forms considerably and regulation of APIs’ behaviors with multiple factors involved, together with the facilitation of the compounded formulations development in cocrystal form, many investigators have been aggressively exploring the underexploited field of such ternary cocrystal systems for the past decades. − Within all the ternary cocrystal system, the studies primarily emphasizes methodological explorations, such as preparation strategy, and structural characterization or analysis, without practical value from a pharmacological viewpoint. The reason may be mainly ascribed to the poor medicinal function of the selected CCFs, which leads to scarcely druggability significance.…”

Investigation of the Phase Behavior of a HNIW·TNT Cocrystal System and Construction of Ternary Phase Diagrams

“…Therefore, the solubilities of the two components play an essential role in the size and position of the thermodynamic stability region of the cocrystal. The wider the cocrystal region, the easier the process design and control of manufacturing. , The symmetric phase diagrams can be obtained if the cocrystal dissolves congruently. Under the guidance of the phase diagrams, a cocrystal could be prepared by simple cooling crystallization.…”

“…The wider the cocrystal region, the easier the process design and control of manufacturing. 28,29 The symmetric phase diagrams can be obtained if the cocrystal dissolves congruently. Under the guidance of the phase diagrams, a cocrystal could be prepared by simple cooling crystallization.…”