(406b) Development of a pH Driven, Reactive Crystallization of a Pharmaceutical Compound
AIChE Annual Meeting
Wednesday, November 6, 2013 - 8:55am to 9:20am
Purpose: Develop a robust reactive crystallization and drying procedure for the isolation of the hydrate form of a pharmaceutical compound with consistent particle size distribution and other solid state properties to meet the requirements of the formulation process.
Methods: The crystallization is performed by adjusting the pH of an aqueous solution of substrate with seeding. Effects of seed source and seed load on product particle size are discussed in the development of a growth dominant crystallization. The use of buffered systems and modeling of the equilibrium of the system are used to screen reagents/conditions and to improve the robustness of the crystallization with respect to particle size distribution. Propensity for particle breakage and attrition is investigated. Process analytical tools such as FBRM probes, in-situ pH probes, and hyrgometer are utilized to gain a better understanding of the process.
Results: Seed type and seed load were determined to have a strong influence on the product particle size distribution with the growth dominant system. Inconsistencies in pH at the seed point resulted in seeds dissolving in some cases and inconsistent product particle size distributions. The use of an appropriate buffer system widened the seeding window with respect to pH and improved the reproducibility of the product particle size distribution across multiple scales. The particles’ propensity for breakage and attrition during filtration and drying were observed.
Conclusions: A growth dominant, pH driven, reactive crystallization was developed and the factors with the greatest influence on the product particle size were determined. The robustness of the crystallization with respect to product particle size was improved through alternative buffer systems and pH monitoring. The use of a hygrometer on the dryer effluent line was utilized to indicate the end of drying.