Crystallization Design to Avoid Liquid-Liquid Phase Separation

Crystallization is a critical purification and separation process used in the pharmaceutical industry. A well-developed crystallization process should not only deliver exceptional chemical purity, high yield and throughput, but also the ability to control physical properties and improve downstream processes (e.g., drug substance filtration and drying and formulation of the drug substance into the drug product).

This presentation reviews a case study involving a small molecule drug substance where the challenge of liquid-liquid phase separation (or oiling out) was encountered during process development. Crystallization design changes were required to avoid liquid-liquid phase separation and control residual solvent levels in the final drug substance. The regressed-UNIFAC group contribution theory methodology was used to model the phase behavior and predict liquid-liquid phase boundaries in binary solvent systems including the effects of the drug substance; this data was then used to design a crystallization process that avoided the two-phase liquid region.

Process Analytical Technology (PAT) tools were used to collect in-situ data for modeling the crystallization and to guide the selection of optimal process parameters. Crystal morphology and particle size were controlled through seed surface area, control of the crystallization kinetics (nucleation and growth), and application of slurry milling. The combined in-silico and in-situ techniques from this work provide the basis for understanding and predicting liquid-liquid phase separation during crystallization and can be used to design future processes in complex solvent systems.

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