(243c) A Systematic Approach to Understand Impurity Incorporation during the Crystallization of Pharmaceutical Drug Substance

Impurity generation during reactions is an inevitable and undesirable event in pharmaceutical drug substance synthesis, which is often tackled by introducing isolation methods downstream. Workups like distillation and liquid-liquid extraction are not well suited for rejection of related substance impurities that do not partition during extraction, and typically crystallization is the method of choice for impurity rejection. However, uncontrolled, or an ill-designed crystallization process may not reject impurities within the specification limits. While process improvements exist for overcoming this challenge, a streamlined approach which involves identification of the impurity incorporation mechanism prior to designing the rejection process provides mechanistic understanding for the development of a robust control strategy. Utilizing such an approach at the time of initial process design can significantly decrease the time required to design a controlled process and reduce the reliance on spiking studies for impurity control.

In this talk, we present a bottom-up approach for impurity control based on a previously demonstrated workflow for understanding impurity incorporation in organic synthetic molecules. [1] Through a case study involving an example organic molecule and its derivative impurity generated during a relevant synthesis process, we uncover the impurity incorporation mechanism. The novel experimental design presented limits the amount of input material required, making this analysis feasible even in scenarios with tight material constraints, which is typically the case in most pharmaceutical process development efforts. Through isothermal equilibration, agglomeration assessment, and slurry washing experiments, we explore solubility-limited impurity retention as well as physical incorporation during crystallization. Lastly, we present a scenario in which unintended reactions can occur during antisolvent crystallization that result in impurity generation and retention. We suggest ways to track the formation and purge of impurities in such a case. Ultimately, we make suggestions for process improvement to achieve a higher degree of impurity rejection and show the effect of their implementation on the API-impurity system discussed.

References

1. Urwin, S.J., et al., A structured approach to cope with impurities during industrial crystallization development. 2020. 24(8): p. 1443-1456.