Designing a Robust Crystallization Process
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Crystallization is the last step in the synthesis of an Active Pharmaceutical Ingredient (API) and its importance is sometimes underestimated. The crystallization step is important to ensure that specifications with respect to physical and chemical purity are met, as well as, particle size and its effect on dissolution and solubility. A well designed crystallization process will lead to a robust drug substance. Crystallics has developed a streamlined small-scale approach to the development of a robust crystallization process that translates to large scale production and can be transferred and implemented at your CMO of choice.

A robust crystallization process is founded on the following three pillars:

1) selection of the appropriate solvents;

2) knowledge of the metastable zone width;

3) seeding.

Batch crystallization process is a combination of solvents and anti-solvents with cooling crystallization and the selection of the solvents and anti-solvents is a matter of solubility. Hence, a crystallization process should start with solubility determination in ICH class 2 and 3 solvents. The solubility should be determined at high and low temperatures and based on the data the appropriate solvent/anti-solvent combinations are selected for detailed analysis. Not only is solubility important in the solubility determinations but also parameters such as purity, physical form of the precipitated solids and yield are taken into account. Based on these parameters the four optimal combinations of solvent and anti-solvent are selected for further investigation.

A seeded crystallization process usually results in a high quality outcome and the MetaStable Zone Width (MSZW) provides the roadmap to a robust seeding protocol. The MSZW is the region between the solubility line and the nucleation line in the solubility vs temperature plot (see Figure 1). At Crystallics the Crystal16® is the workhorse to determine metastable zones. This parallel miniature crystallization reactor with turbidity measurements allows for the rapid determination of the metastable zone in multiple solvent systems at the same time.

Figure 1.  The metastable zone width

Next all obtained data is utilized to design a combined anti-solvent/cooling crystallization process at mL scale.  Critical parameters such as degree of saturation, initial and final temperature and cooling rate will be evaluated in relation to the crystal form, purity and yield.  The optimal conditions will be reproduced at 8 mL scale using the Crystalline® crystallizer.  Crystalline® is equipped with Particle Viewer (optical camera) and allows for direct observation of the crystallization process including crystal generation and growth.  Other parameters, such as the aging temperature and the final ratio of anti-solvent will also be evaluated at this stage.

The MultiMax™ or EasyMax™ system with in-situ Focused Beam Reflectance Measurement (FBRM) is used in the last step for the validation and robustness of the batch crystallization.  In these final experiments the reproducibility of the process is validated and the quality and consistency of the drug substance is verified.  See Figure 2 for a schematic summary of the crystallization process.

Figure 2.  A schematic summary of the crystallization process

By following this process the complexity of the crystallization process is significantly reduced and a robust process can be transferred to the CMO with consistency in the solid form, yield, purity and particle size distribution.