(702c) Use of Ternary Phase Diagrams and a Process Model for Efficient Solvent Selection and Process Crystallization Development of a Pharmaceutical Cocrystal

Multicomponent crystals, including cocrystals, salts, and solid solutions, are utilized to modify the physical properties of active pharmaceutical ingredients (APIs) without altering its therapeutical properties. Phase diagrams of these multicomponent crystals are essential for developing crystallization processes, particularly when multiple solid phases may coexist, and physical properties and morphology of the crystal products are dictated by the choice of the solvent [1]. This study aims to seamlessly integrate phase diagrams into a process model for the crystallization development of a pharmaceutical cocrystal.

Initially, the eutectic point is identified based on the composition of the coexistence points on the cocrystal phase diagram. Selected congruent ternary phase diagrams of the API, cocrystal and coformer in three different solvents are considered for crystallization process development [2]. The system accounts for ionization and pH effects on the solubility of a cocrystal comprised of a zwitterionic API and a diprotic acidic coformer to determine its solubility product (K_sp). In the process model, as the cocrystal begins to crystallize, the pH and species balance, which depends on all the coupled ionization equilibria, is accounted for by differential equations predicting changes in the crystallization path under different process conditions [3]. The cocrystal dissociation, solution equilibria, species mass balance and the kinetic equations are employed to construct state estimation of the process, calculating the supersaturation of the cocrystal. The process model is built using experimental process data supported by Process Analytical Technology (PAT).

The phase diagram is mapped for different solvents, and key process indicators are directly mapped for various decision criteria such as physical properties of crystals, purity, productivity, and manufacturability for downstream processes. This streamlined framework demonstrates the direct translation of thermodynamic properties to process performance, enabling a more systematic comparison to guide decisions for better control of critical quality attributes through kinetics control within the crystallization process.

References:

[1] Roy, L., Lipert, M. P., Rodríguez, N., & Rodríguez-Hornedo, R. (n.d.). Co-crystal Solubility and Thermodynamic Stability. http://books.rsc.org/books/edited-volume/chapter-pdf/1210598/bk9781849731584-00247.pdf

[2] Codan, L., Daza, L., & Sirota, E. (2023). Method to Rapidly Identify Potential Solvent Systems for Crystallization of Cocrystals. In Organic Process Research and Development (Vol. 27, Issue 3, pp. 513–522). American Chemical Society. https://doi.org/10.1021/acs.oprd.2c00376

[3] Merritt, J. M., Viswanath, S. K., & Stephenson, G. A. (2013). Implementing quality by design in pharmaceutical salt selection: a modeling approach to understanding disproportionation. Pharmaceutical Research, 30(1), 203–217. https://doi.org/10.1007/s11095-012-0863-9