Investigation of metastable zones and induction times in glycine crystallisation across three different antisolvents

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes

Enabling model-predictive design : rapid development of a PBM for an anti-solvent and cooling crystallisation in two different reactor geometries

The study aimed to develop a rapid model using gProms Formulated Products for a proprietary single polymorph active pharmaceutical ingredient (API) crystallisation at small scale for early process understanding. The model outcomes are then later used to inform the experimental design of continuous crystallisation for multi-addition antisolvent and cooling crystallization in both continuous oscillatory baffled reactor (COBC) and mixed-suspension and mixed- product removal (MSMPR) crystallise

Investigation of wet milling and indirect ultrasound as means for controlling nucleation in the continuous crystallization of an active pharmaceutical ingredient

This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d50 of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed