Diastereomer salt crystallization: Comprehensive process modeling and DoE-driven comparison of custom-coded and user-friendly simulators

Abstract

Process modeling is gaining attention in the pharmaceutical industry due to the promise of exploring the design space with less experimentation. However, the associated numerical apparatus can be prohibitive for many, undermining the attainable benefits. This study aims to demonstrate the readiness of modeling by guiding the reader through the essential steps of model development, from experimentation to kinetic model identification and in-silico DoE execution, implemented and executed in a user-friendly but restrictive simulator and a highly technical, custom-coded environment. The crystallization of (S)-pregabalin l-tartrate from a racemic aqueous solution is applied as a surrogate system, involving secondary nucleation, growth, and agglomeration. The distomer may act as an impurity. This process is sufficiently complex to be representative but straightforward enough to be familiar to a broad audience. Despite their differences, both modeling environments resulted in the same kinetic model structure and fitted the measurements well. The models are compared based on the in-silico DoE outcomes rather than the goodness of fit. The analysis revealed that the key conclusions are identical, which validates the utilization of the user-friendly simulator in time-constrained applications.