Method to Rapidly Identify Potential Solvent Systems for Crystallization of Cocrystals

Abstract

This study aims at easing the design of crystallization and the cake washing step of cocrystals. It is assessed if solvent systems can be classified based on the dissolution behavior of the cocrystal by leveraging on the solubility of its pure components. Solubility data of pure components are typically readily accessible data in the pharmaceutical industry at an early stage of development. For the three model systems considered in this study, the composition of eutectic liquid phases was determined at 20 °C in numerous solvent systems and compared with the solubility of pure components at the same conditions. In the solvent systems in which the cocrystal dissolves congruently, the solubilities of the pure components are similar. Incongruent dissolution behavior is in turn consistently observed if the solubilities of the pure components differed by at least one order of magnitude. For these solvent systems, the eutectic liquid phases are consistently enriched in the more soluble component. Comparison of the solubilities of the pure components thus enables determination of the component that needs to be charged in excess to reach thermodynamic stability of the cocrystal, which is particularly relevant for the design of screening and solubility experiments. Finally, highly asymmetric phase diagrams, which are not suitable for crystallization and cake washing purposes, are easily identifiable by highly dissimilar solubilities of pure components.

Stoichiometric Diversity of Caffeine and 4-Hydroxybenzoic Acid Cocrystals in Batchelor Vortex Flow

“…The phase solubility diagram (PSD) and TPD were crucial tools for identifying cocrystal formation regions, understanding solution chemistry, and analyzing solubility behavior. − Additionally, the PSD offered insights into the thermodynamic stability of various stoichiometric cocrystals and informed on the pathway of cocrystal formation. , To gain a deeper understanding of the cocrystallization process between CAF and 4-HBA, the PSD of the CAF/4-HBA/methanol system at 10 °C was determined (refer to Supporting Information Figure S4). The graph’s symbols represent experimental solubility data for the CAF crystalline, (2:1), (1:2), and (1:3) cocrystals, and 4-HBA crystalline phases.…”

Prediction and De-Risking of an Unusual API:Epimer Cocrystal in the Commercial Synthesis of Belzutifan

“…The theoretical background can be found elsewhere. 32 The operating point for the crystallization process must always lie within the L + S API -phase region to ensure rejection of the diastereomer. As the L + S API + S cocrystal -phase region is adjacent to the targeted phase region, crystallization of the cocrystal is more likely to occur than the crystallization of the diastereomer.…”

“…The two solvents can be lumped to a single solvent. The theoretical background can be found elsewhere …”