(324e) Effect of Lattice Incorporated Impurities on Crystallization of a Pharmaceutical Compound. a Case Study in Early Development.

Control of API purity in early development is a common challenge as the chemical synthesis is not fully developed and tested at scale. Higher levels of impurities are typically produced and carried all the way to the API step. Crystallization is the key unit operation that is relied upon to effectively remove these impurities and control the purity of the API used for non-clinical studies. While the main focus of the crystallization at this stage is to remove impurities, reciprocal effects are often encountered where the impurities tend to affect the performance of the crystallization itself.

Presented herein is a pharmaceutical case study describing how relatively low levels of impurities exerted a dramatic impact on the success and robustness of the crystallization by affecting the API solubility, seed step, yield and apparent crystallization kinetics. In addition, the extent and severity of encrustation during the crystallization was directly linked to the presence of impurities. The underlying mechanism responsible for these adverse effects was found to be formation of solid solutions between the API and impurities, in concert with a very efficient crystal packing of the API from where slight disturbances to the crystal lattice afforded significant thermodynamic changes. This case study provides an important example of how lattice incorporated impurities have the ability to interfere with basic thermodynamic and kinetic parameters, which without a priori detection can turn a well-behaved isolation into a process failure.