(528b) Computer-Aided Design of Solvent Blends for the Crystallisation of Ibuprofen – Regulating Crystal Morphology By the Spiral Growth Model
- Conference: AIChE Annual Meeting
- Year: 2020
- Proceeding: 2020 Virtual AIChE Annual Meeting
- Group: Pharmaceutical Discovery, Development and Manufacturing Forum
- Time: Wednesday, November 18, 2020 - 8:15am-8:30am
Despite the many material, time and cost constraints present during initial design stages, solvent selection for the crystallisation of novel API molecules is currently performed via time-consuming and expensive experiments, heavily reliant on past experience and rules-of-thumb2. Over the last decades, computer-aided molecular design (CAMD) methods have been developed to overcome such difficulties3, with the aim of guiding lab-based experiments towards optimal candidate molecules for crystallisation4,5. Whilst it is generally agreed that crystal shape has a significant role when designing optimal solvents, the integration of shape considerations within CAMD methods has principally focused on empirical approaches4 combining an understanding of the underlying chemistry with prior experimentation. Direct, quantitative methods, where mechanistic interpretations of crystal growth are considered6, have not yet received significant attention in formulating the solvent design problem. This is likely due to the absence of applicable group contribution approaches to these models, as well as the additional complexity of formulating and resolving a mixed-integer optimisation problem to represent these design choices.
We extend the recent work of Watson et al.7, in which the SAFT-Î³ Mie equation of state8 was employed in a CAMD framework to identify optimal solvent blends and process conditions for integrated cooling and antisolvent crystallisation, to include the target morphology of the pharmaceutical product. By assuming a low supersaturation growth environment â a standard condition for industrial crystallisation â it is possible to calculate the relative growth rates of corresponding crystal faces6, thus providing a quantitative measure of aspect ratio of the crystalline API. The design formulation is implemented in gPROMS and is applied to the design of solvent mixtures for the crystallisation of ibuprofen, whereby the impact of crystal shape on the optimal solvent molecules and process conditions is investigated.
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