Crystallization Solvent Design Based on a New Quantitative Control Model
of Crystal Morphology
Abstract
Solution crystallization is an important separation unit operation in
active pharmaceutical ingredient (API) production. Solvent is one of the
important factors affecting crystal morphology. How to select/design
suitable crystallization solvents is still one of the most urgent
problems in the crystallization field. In this paper, a framework for
crystallization solvent design based on the developed quantitative
control model of crystal morphology is proposed. First, molecular
dynamics is used to predict the crystal morphology in solvents. Next,
nine solvent descriptors are selected. Then, the quantitative
relationship between crystal aspect ratio and solvent descriptors is
developed. Subsequently, Computer-Aided Molecular Design (CAMD) method
is integrated with the developed quantitative control model. The
crystallization solvent design problem is expressed as a Mixed-Integer
Non-Linear Programming (MINLP) model, which is solved by the
decomposition algorithm. Finally, the crystallization solvent design
framework is applied to two cases: benzoic acid and ibuprofen, and
experimental verification is implemented.