Abstract
A methodology has been developed to determine the design space of caffeine–glutaric acid co-crystallization for process development and scale-up. Polymorphic purity is chosen as a critical quality attribute, and its functional relationship with five process parameters is described by a first-principles process model and an empirical supersaturation threshold. After model parameters are estimated and the supersaturation threshold is obtained from a few experiments in a 1 L crystallizer, the risks associated with model parameter uncertainty and operational variability are quantified using Monte Carlo modeling. These risks, while assessed to be significant, could be effectively mitigated by sufficient aging after seeding. Operating ranges of individual process parameters that are robust against operational variability are then modeled sequentially and verified experimentally by scale-up to a 10 L crystallizer.
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