A Novel Crystallization Methodology To Ensure Isolation of the Most Stable Crystal Form

Abstract

It is critical to consistently achieve the desired crystal form for an active pharmaceutical ingredient (API) because crystal form may affect the compound's chemical stability, bioavailability, and pharmaceutical processing performance. The extent to which a crystallizing system is driven by growth vs nucleation is dependent upon the level of supersaturation, defined as the difference between solution concentration and solubility. We describe a method for the accurate measurement of real-time supersaturation, which enabled us to develop and optimize an API crystallization via a feedback-control loop based on concentration measurement with online FTIR. In this contribution we discuss a novel extension of the published work [Zhou, G. X.; et al. Cryst. Growth Des. 2006, 6, 892-898] which ensured robust isolation of the thermodynamically most stable crystal form of an API. The system of interest is a monotropic polymorphic system with overlapping metastable zones. In order to ensure exclusive isolation of the desired form within a reasonable cycle time, a three-pronged approach was appliedsmaximize seed surface area through the use of milled seed, run the crystallization at a high temperature to increase crystal growth rate, and perform the crystallization at a high level of supersaturation relative to the desired, more stable form while keeping the concentration below the equilibrium solubility of the less stable polymorph. By carefully selecting the seed loading, we were also able to dial-in the target particle size directly via a growth-dominated crystallization, thus eliminating the need for post-crystallization product milling. As a result, a robust, efficient, and reliable crystallization process has been achieved to ensure isolation of the desired polymorph at target particle size.

Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association

“…On account of this, prediction and precise control of a specific polymorph are critical for achieving desired solubility and stability requirement. Recent efforts have been devoted to the development of consistent and reliable crystallization processes for producing desirable polymorphs, including on-line, spectroscopy-based monitoring designs of crystal growth in solution (3)(4)(5). Polymorphic formation is known to be affected by a wide variety of growth conditions, such as type of solvent (6)(7)(8), supersaturation (4,9), temperature (10), and use of additives (11,12).…”

Detection of the II–I Etiracetam solvent-mediated polymorphic transformation through the online monitoring of the suspension apparent viscosity

“…Some of these forms may be undesirable from a pharmaceutical point of view. New crystallization methodologies and online control techniques have therefore to be developed to assure the quality and nature of the end product [4][5][6].…”

Supersaturation tracking for the development, optimization and control of crystallization processes

“…Much focus has recently been given to the extension of quantitative ATR-FTIR models to supersaturation setpoint control (Cote et al, 2009;Nagy et al, 2008;Yu et al, 2006;Fujiwara et al, 2005). Extending the presented supersaturation methodology to supersaturation setpoint control is assessed here.…”

“…Many case studies have been presented demonstrating the effectiveness of quantitative supersaturation assessment and control, from polymorphic assessment (Pöllanen et al, 2006;Cornel et al, 2008;Howard et al, 2009), to supersaturation control (Fujiwara et al, 2002(Fujiwara et al, , 2005Liotta and Sabesan, 2004), to anti-solvent crystallization development (Zhou et al, 2006;Woo et al, 2009;Cote et al, 2009). Although extremely beneficial for process understanding and control, these techniques are rarely transferred to industrial crystallization process development, optimization and scale-up.…”