Decoupling Primary and Secondary Nucleation for Pharmaceutical Crystallization

Objetivo

Crystallization is essential in the pharmaceutical industry to produce solid forms of active pharmaceutical ingredients (APIs). Precise control over the crystal properties, especially polymorphic form, is crucial as it affects bioavailability and more than 85% of APIs exhibit polymorphism. Current approaches often rely on seed crystals to promote secondary nucleation with the expectation that the resulting crystals match the seed’s properties. However, we found that when a seed crystal is exposed to conventional process conditions, primary nucleation is still dominant resulting in a loss of control of the required crystal properties. Moreover, while flow affects primary nucleation, we observed that it has no impact on secondary nucleation. This reveals a lack of fundamental understanding of primary and secondary nucleation mechanisms and their link to process conditions, posing an issue for the production of bioactive APIs.
With CRYSTALCONTROL we will improve the control over crystal properties by decoupling primary and secondary nucleation. We will contribute to the fundamental understanding of nucleation by studying how defined fluid shear influences primary nucleation and how secondary nucleation is enhanced by crystal contact between crystal surfaces exhibiting rough growth (Objective 1). We will apply this fundamental understanding of primary and secondary nucleation to the design of novel crystallizer platforms supported by fluid dynamic simulations (Objective 2). We will assess to which extent the fundamental understanding of primary nucleation is applicable to the crystallization of macromolecules, e.g. proteins, and thus extend the scope of the project beyond small API molecules (Objective 3).
In conclusion, CRYSTALCONTROL will provide a fundamental understanding of primary and secondary nucleation, needed to control crystal properties and aid the switch from batch operations to continuous crystallization of different API molecule classes.