(218a) Modeling and Experimental Investigation of Polymorphic Imatinib Mesylate Crystallization in Batch and Continuous Configurations

Interest in polymorphism has increased markedly in pharmaceutical industry since two decades. The emphasis on polymorphism is due to various factors such as the polymorphic form is known to have direct impact on drug substance processability, drug product manufacturability and product quality or performance such as stability, dissolution and bioavailability [1]. Polymorphic screening in pharmaceutical industry is important not only to provide necessary knowledge for process development but also to deal with intellectual property issues or patent regulations [2]. Imatinib is a ground-breaking first-generation tyrosine kinase inhibitor, and has revolutionized the paradigm of targeted cancer therapy since its inception. It is used in the frontline treatments against chronic myeloid leukemia (CML). Its efficacy was also proven in treatment of gastrointestinal stromal tumors, and also in other malignancies that involve expression of a tyrosine kinase [3]. Due to its potent bioavailability, several flow synthesis methods have been developed for imatinib and its salts. Imatinib-free base is insoluble in water, hence its derivative, Imatinib mesylate salt is used in oral drug formulations and is very highly soluble in aqueous medium of pH < 5.5. Imatinib is classified under biopharmaceutical classification system (BCS) as BCS-class I drug by FDA (high permeability and high dissolution) [4]. Imatinib mesylate displays polymorphism, with both metastable α-form and stable β-form being utilized in commercial drug formulations. Consequently, the polymorphic crystallization of imatinib mesylate has garnered significant interest.

In our work, the effect of process variables such as temperature, solvent, seeding and batch time/residence time on the final polymorphic form produced is studied. As the metastable form has high solubility in methanol compared to the stable form, recrystallizing the stable form from the saturated solution of the metastable form proved beneficial in-terms of creating high supersaturations with respect to stable form and also provide high yields and volume productivity. Batch crystallization experiments revealed that high seeded experiments, seeded with metastable form and performing cooling crystallization with shorter batch times favored the crystallization of metastable form and slower cooling rates with longer holding times favored crystallization of stable form. The possibility of producing various forms selectively by varying residence times and seeding is explored in continuous configuration with a cascade of mixed suspension and mixed product removal crystallizers (MSMPR’s). However, as the main objective is to establish a continuous crystallization model for imatinib mesylate, we combine the knowledge of process analytical technology tools (PAT) (inline infrared spectroscopy, Raman spectroscopy, imaging) and offline characterization (PXRD, particle size distribution) with population balance modeling to investigate the crystallization of stable form from saturated solution of metastable form in a continuous manner at steady state. The solvent mediated polymorphic transformation of α-form form to stable β-form is more suitable for crystallization as β-form crystals are cubic shaped and have better flowability and compaction characteristics compared to needle shaped crystals of α-form. The outcomes illustrated effective model establishment for both batch and mixed-suspension-mixed-product-removal (MSMPR) crystallization configurations. This experimentally validated model, serves as a digital twin of the process which is used to optimize the MSMPR process to produce larger crystals with narrower distributions.

References

1. Chambi, J. T., Fandaruff, C., & Cuffini, S. L. (2024). Identification and quantification techniques of polymorphic forms-A review. Journal of Pharmaceutical and Biomedical Analysis, 116038.
2. Komai, T., Togo, T., Uchiyama, H., Kadota, K., & Tozuka, Y. (2024). Kinetics of crystal transformation of imatinib mesylate during formulation process: Selection of dry granulation in pharmaceutical process. Powder Technology, 119570.
3. Imran, M., Asdaq, S. M. B., Khan, S. A., Unnikrishnan Meenakshi, D., Alamri, A. S., Alsanie, W. F., & Bakht, M. A. (2021). Innovations and patent trends in the development of USFDA approved protein kinase inhibitors in the last two decades. Pharmaceuticals, 14(8), 710.
4. Maddeboina, K., Yada, B., Kumari, S., McHale, C., Pal, D., & Durden, D. L. (2024). Recent advances in multitarget-directed ligands via in silico drug discovery. Drug Discovery Today, 103904.