(347b) Intensification of the Solution-Mediated Phase Transformation of a Pharmaceutical Cocrystal through the Integration of a Static Mixer and a Stirred Tank Crystallizer
AIChE Annual Meeting
2024
2024 AIChE Annual Meeting
Separations Division
Crystallization and Precipitation of Pharmaceutical and Biological Molecules I
Tuesday, October 29, 2024 - 12:51pm to 1:09pm
The objective of this work is to characterize and compare the ability of a static-mixer crystallizer to intensify the SMPT of a pharmaceutical cocrystal when compared to a conventional standalone stirred tank crystallizer. An integrated setup was constructed to study different process conditions. The SMPT process was then characterized as a function of the initial concentrations of the drug and coformer, slurry flow rates, design of the static-mixer crystallizer, and the ratio of residence times of the slurry in the static mixer and the stirred tank. Carbamazepine was selected as the model drug compound with saccharin as the coformer to form a carbamazepine-saccharin cocrystal, which is a frequently studied anti-solvent cocrystallization system when using methanol and water as the solvent and anti-solvent, respectively. The results showed that kinetically favored carbamazepine-dihydrate crystals completely transformed into the thermodynamically stable cocrystal at substantially shorter batch times when using the static-mixer crystallizer compared to operation in a standalone stirred tank. This difference was attributed to higher nucleation rates in the static-mixer crystallizer at the start of the batch. The nucleation rates of both the solid-state forms did not vary significantly when the surface area of the tubes and shear rates were varied by removing or changing the internal mixing elements. Additionally, the time required to complete the SMPT did not vary significantly when changing the flow rates in the static-mixer crystallizer. The time for completion of the SMPT did vary with the initial supersaturation and was the longest when the ratio of the cocrystal supersaturation to the carbamazepine-dihydrate supersaturation was the lowest. Overall, the identified process trends showed that integration of a tubular crystallizer like a static mixer or a hollow tube with a conventional stirred tank can substantially intensify SMPT processes by providing rapid primary nucleation at the start of a batch to enhance growth and dissolution kinetics when the undesired crystalline phase of the drug is kinetically favored, which occurred over a broad range of tested conditions for our case. Exploiting this effect for other process configurations that require increased primary nucleation rates and obtaining a better mechanistic understanding of the observed phenomena are of interest for future work.
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