(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

(347b) Intensification of the Solution-Mediated Phase Transformation of a Pharmaceutical Cocrystal through the Integration of a Static Mixer and a Stirred Tank Crystallizer

Authors 

Lakerveld, R. - Presenter, The Hong Kong University of Science and Technology
Mak, A., The Hong Kong University of Science and Technology
Pharmaceutical cocrystals are a rising class of drug products. They consist of a neutrally charged drug molecule and a coformer in a crystal lattice with fixed stoichiometric ratio. The large number of pharmaceutically acceptable coformers creates a rich design space to tailor essential drug product properties such as their stability, aqueous solubility, and processability. Solution crystallization is an attractive method to synthesize cocrystals, which requires understanding of the solubilities of the cocrystal, the target molecule, and a coformer.1 Crystallization of multiple solid-state forms may occur when solute concentrations exceed multiple solubilities, which may lead to a product with low phase purity. A cocrystal and the crystalline phase of the target molecule generally have a different solubility. Therefore, a solution-mediated phase transformation (SMPT) will occur when both forms exist in suspension, thereby purifying the cocrystal product if the solution conditions are chosen such that the cocrystal is more stable. Process intensification can potentially be achieved by deliberately creating high driving forces for crystallization so that cocrystal formation including possible SMPT proceeds rapidly. Furthermore, relying on SMPT processes to obtain a product with high phase purity avoids a need for detailed knowledge of the phase diagram and may correct local formation of an undesired solid-state form due to concentration gradients, which can lead to shorter process development times and an increased process robustness. Intensification of SMPT processes in general requires the generation of large crystal surface areas of both forms to enhance the growth and dissolution kinetics that are driving the SMPT process. Conventional methods include the use of wet milling or using rotor stators to achieve such favorable conditions through breakage and secondary nucleation.2 Although such methods based on creating high shear can be effective, potential disadvantages include the possible creation of defects in the crystal lattice, the notion that broken crystals can exhibit low growth rates, heat generation, and unpredictable scale-up behavior. Increasing the primary nucleation rate of the desired form is an attractive alternative, or supplementary, method to conventional milling, as primary nuclei generally grow well and can rapidly create a large surface area to consume supersaturation. Static-mixer crystallizers3 are promising devices to enhance nucleation rates of solution crystallization processes. They promote fast heat and mass transfer so that uniform conditions for nucleation can be created. Furthermore, they are easily parallelizable and shear rates and residence times can be controlled when designed modularly.4 We recently discovered that a high nucleation rate of lysozyme crystals can be obtained in static-mixer crystallizers, which allowed for flexible seed generation to shape the crystal size distribution in a batch crystallization.5 Furthermore, simplified control around steady-state conditions of the static-mixer crystallizers allowed for predictable model-based design.6 We hypothesize that the integration of a static-mixer crystallizer with a batch crystallizer can also intensify SMPT processes of cocrystallization systems by enhancing the primary nucleation rate of the cocrystal, which has not been explored yet.

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.

References

1. Karimi-Jafari, M.; Padrela, L.; Walker, G. M.; Croker, D. M., Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications. Crystal Growth & Design 2018, 18 (10), 6370-6387.

2. Lo, E.; Mattas, E.; Wei, C.; Kacsur, D.; Chen, C.-K., Simultaneous API Particle Size Reduction and Polymorph Transformation Using High Shear. Organic Process Research & Development 2012, 16 (1), 102-108.

3. Alvarez, A. J.; Myerson, A. S., Continuous Plug Flow Crystallization of Pharmaceutical Compounds. Cryst. Growth Des. 2010, 10 (5), 2219-2228.

4. Mathew Thomas, K.; Nyande, B. W.; Lakerveld, R., Design and Characterization of Kenics Static Mixer Crystallizers. Chemical Engineering Research and Design 2022.

5. Nyande, B. W.; Thomas, K. M.; Takarianto, A. A.; Lakerveld, R., Control of crystal size distribution in batch protein crystallization by integrating a gapped Kenics static mixer to flexibly produce seed crystals. Chemical Engineering Science 2022, 263, 118085.

6. Nyande, W. B.; Nagy, Z.; Lakerveld, R., Data-driven identification of crystallization kinetics. AIChE J. 2024, e18333.