Crystallizing the Right Polymorphic Form: An Integrative Approach
Advancing the chemical engineering fundamentals
Crystallization (T2-9)
Keywords: Crystallization, Polymorph, Active pharmaceutical ingredient, Process development
One of the most important issues in the development of crystallization processes for active pharmaceutical ingredients (APIs) is to obtain the desired polymorphic form of the product. While identical in chemical composition, polymorphs of the same API may exhibit markedly different physical and chemical properties. For example, different crystal shapes can have a considerable influence on downstream processing steps such as filtration, washing, and bulk solids handling, while a difference in solubility can affect the bioavailability and efficacy of the drug. Thus, selecting the right polymorph for formulation and being able to produce it in a consistent manner are exceedingly important in pharmaceutical processing. As an additional challenge, interconversion among polymorphs may occur during and after the manufacturing process.
Polymorphic crystallization is controlled by both thermodynamics and kinetics. An integrative approach which combines fragmented and incomplete data, experimental observations, physical insights and modeling related to these factors, has been developed for the development of a process to produce a desired polymorphic form. The approach begins with a representation of the equilibrium phase behavior of the system in the form of a phase diagram. The crystallization compartments and the metastable zones are identified. Crystallization kinetics is determined either qualitatively or quantitatively. The necessary experimental work, calculations and polymorph recovery strategy development are expected to take place side-by-side in an iterative manner. This iterative scheme would converge to an optimum process that satisfies the overall objective. The rationale behind the process alternatives is made clear by visualizing how the process paths venture into different regions in composition space. Experiential heuristics are also identified to guide the user in making decisions during each step. By implementing the proposed approach, the manufacturing process can be strictly monitored and ensuring the correct polymorphic form is consistently obtained.
Presented Wednesday 19, 16:00 to 16:20, in session Crystallization (T2-9).
