(673e) Sequential Design of Experiments for Design Space Definition of the Crystallization of An Active Pharmaceutical Ingredient

A sequential design of experiments performed at lab scale was used to define the factory design space of an API semi-continuous reactive crystallization. Following risk assessment activities and exploratory experiments, a fractionated design was run to determine statistically significant factors and their interactions. When the contributions of non-statistically significant factors were removed from the model, this fractional DoE collapsed to a full factorial. Curvature in the key responses necessitated further augmenting the design with custom axial points for response surface mapping. This resulted in an empirical model that predicted particle size and facilitated design space definition for the crystallization.

Also discussed will be the design of the reactive crystallization, which employed media milled seed and sonication to reach a desired, unimodal particle size distribution without use of dry milling. The performance of the crystallization process across lab, pilot plant, and factory scale will be discussed.