Implementation of Continuous Crystallization to Circumvent Metastable Liquid-Liquid Separation

High concentrations of an organic solute may lead to metastable liquid-liquid separations due to solvent-solute interactions, even in otherwise miscible solvent systems. The formation of such non-ideal phases is undesirable in crystallization operations. Potential side effects of this phenomenon are uncontrolled nucleation and growth, inadequate impurity purge, solvent entrainment in the product, and morphological inconsistencies in the solids. Despite the inherent challenges that arise due to the formation of non-ideal phases, they have become increasingly common in pharmaceutical process development due to the current shift in the industry towards higher-complexity molecular structures. The growing prevalence of these complex systems prompted the implementation of novel development tools that can assist process engineers in creating robust crystallization procedures.

Traditional batch crystallizations may lack the flexibility required to circumvent metastable phenomena due to the reliance on dynamic desupersaturation curves. Such dynamic profiles expose the chemical system to a series of changes in temperature and solvent composition over time, making the crystallization end-state dependent on process history. Continuous crystallization provides an alternative approach, where the product endpoint is locked into a more predictable steady state, governed by the molecule’s crystallization kinetics. Using a Mixed Suspension Mixed Product Removal (MSMPR) continuous crystallizer, we captured a steady state equilibrium point in the saturation curve that avoids the formation of the undesired metastable phase for the purification of a commercially relevant small-molecule. The resulting continuous crystallization process circumvents original design limitations of the system, providing controlled recovery of the desired material without altering the original solvent/antisolvent composition.  

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About the Presenter

Carlos Pons Siepermann

Bristol-Myers Squibb

Born in Caracas, Venezuela. Carlos moved to the USA for his studies at the University of Michigan where he obtained his Bachelor’s Degree in Chemical Engineering. Afterwards, he completed his Masters in Chemical Engineering Practice and PhD in Chemical Engineering at MIT. During his PhD, Carlos worked for Professor Allan Myerson, studying the impact of impurities on crystallization kinetics and the effect of competitive additives on impurity incorporation in crystallization processes. Most recently, Carlos has been a member of the Chemical Process Development team of Bristol-Myers Squibb, where he has focused on designing unit operation sequences for the manufacture of clinical-quality innovative small-molecule drugs. Simultaneously, he has forwarded his passion for crystallization by leading an internal initiative to explore the application of continuous crystallizers to circumvent some of the many unique challenges encountered during pharmaceutical development.