Role of Cocrystal and Solution Chemistry on the Formation and Stability of Cocrystals with Different Stoichiometry

Abstract

The objective of this study is to identify factors and conditions governing the formation and stability of cocrystals with different stoichiometry. Carbamazepine−4-aminobenzoic acid (CBZ−4ABA) cocrystals were chosen as the model system. A 1:1 CBZ−4ABA cocrystal was discovered by the reaction crystallization method. This cocrystal is characterized by carboxylic acid···acid and amide···amide homosynthons. The stability of 2:1 and 1:1 cocrystals is shown to be dependent on ligand solution concentration. The cocrystal richer in ligand component is more stable at higher ligand solution concentrations. Solubility of cocrystals and crystalline drug is explained by 1:1 solution complexation, and both cocrystals follow solubility product behavior. Mathematical models based on cocrystal and solution chemistry were fit to experimental data to generate phase solubility and triangular phase diagrams.

Imatinib mesylate cocrystals: synthesis, screening, and preliminary characterization

“…Moreover, this stoichiometric ratio was confirmed by DMF-assisted grinding of the 1:2 mixture of IM and caffeic acid. Cocrystallization from solvent is, in general, a more complicated procedure than cogrinding, because the solubility of all the components and thermodynamic aspects must be considered [22,23]. The feasibility of cocrystal formation from solution was also tested for sparingly soluble 5-fluorouracil (5FU) and 5-chlorouracil (5CU).…”

Engineering cocrystal solubility, stability, and pHmax by micellar solubilization

“…The contributions of ionization and complexation of cocrystal components to cocrystal solubility have been reported and quantitative models have been developed that allow for tailoring cocrystal solubility behavior. [3][4][5] Although surfactants are Additional Supporting Information may be found in the online version of this article. Supporting Information…”

Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development

“…123 A study by Jayasankar A, et al which revealed reactant solution composition and identification isothermal invariant points (cocrystal pHmax) are crucial for the stability of cocrystals. 124 The effectiveness of a surfactant to stabilize cocrystals is related to the differential solubilization of cocrystal components (Ks) which also applicable to other processes involving differential affinities of components such as complexation, adsorption, etc. 125 It was reported that solution stability of carbamazepine-cinnamic Acid cocrystal depends upon solubility of coformers while further shown that carbamazepine-nicotinamide cocrystal was unstable in water, addition of ethanol could improve stability.…”