Systematic workflow for crystallization process design for a polymorphic system: an experimental case study of imatinib mesylate

Abstract

Crystallization plays a vital role in pharmaceutical manufacturing by defining critical quality attributes such as purity, particle size, and polymorphic form. With the growing adoption of continuous manufacturing (CM) and increasing regulatory emphasis on process understanding, there is a clear need for systematic workflows that can ensure robust and reproducible crystallization outcomes. In this study, we develop and demonstrate a structured workflow for crystallization process design using imatinib mesylate, a high-value oncology drug that exists in two polymorphic forms. The approach integrates advanced process analytical technology (PAT) tools and offline characterization methods to characterize crystal properties, track phase transitions, and monitor process performance. A kinetically informed thermodynamic (KIT) design procedure is implemented through small-scale experiments to rank potential solvents not only by yield and polymorph control, but also by incorporating critical kinetic factors. Batch crystallization studies were used to identify key parameters influencing polymorph formation, which informed the design of a continuous crystallization process. The resulting process reproducibly produced the desired stable form, offering advantages in downstream handling and product quality. This case study illustrates how a stepwise, data-driven workflow can support polymorph selection and control, while enabling consistent performance in both batch and continuous crystallization systems. The proposed methodology contributes to the broader goals of modern pharmaceutical manufacturing, supporting quality-by-design (QbD) and continuous processing initiatives aligned with regulatory expectations.