(224b) Design and Implementation of a pH Driven in-Situ Salt Switching Crystallization for Improved Yield, pH Mitigated Impurity Formation for Better Physical Properties

Given the shortening development times for API drug substance development and an increase in needle morphology for final API has made it challenging for final crystallization to enable particle properties for downstream drug product continuous processing. There has been an increasing trend of salt form APIs with poor solubility in process relevant solvents making the final salt formation¹ step tentatively a reactive crystallization step. In the process of forming a salt a pH range which can traverse multiple protonation states of the API before mass transfer from liquid phase to solid phase making the API susceptible to different degradation pathways. Here-in, we cover a case study for designing a crystallization process with an objective to maximize physical properties, impurity rejection² and yield through an in-situ salt switching process. We discuss the application of pH-driven speciation models³ coupled with method of moments based growth and nucleation model⁴ to design a successful process.

References

(1) McDonald, M. A.; Salami, H.; Harris, P. R.; Lagerman, C. E.; Yang, X.; Bommarius, A. S.; Grover, M. A.; Rousseau, R. W. Reactive crystallization: a review. Reaction Chemistry & Engineering 2021, 6 (3), 364-400.

(2) Agrawal, P.; Rawal, S. H.; Reddy, V. R.; Viswanath, S. K.; Merritt, J. M. Case studies in the application of a workflow-based crystallization design for optimized impurity rejection in pharmaceutical development. Organic Process Research & Development 2023, 27 (4), 610-626.

(3) McGinty, J.; Wheatcroft, H.; Price, C. J.; Sefcik, J. Modelling solution speciation to predict pH and supersaturation for design of batch and continuous organic salt crystallisation processes. Fluid Phase Equilibria 2023, 565, 113676.

(4) Aamir, E.; Nagy, Z. K.; Rielly, C. D.; Kleinert, T.; Judat, B. Combined Quadrature Method of Moments and Method of Characteristics Approach for Efficient Solution of Population Balance Models for Dynamic Modeling and Crystal Size Distribution Control of Crystallization Processes. Industrial & Engineering Chemistry Research 2009, 48 (18), 8575-8584. DOI: 10.1021/ie900430t.