Process Intensification for Synthesis and Purification of Oncology Drugs

Continuous manufacturing is transforming pharmaceutical production, shifting from large-scale batch processing to small-scale modular systems. The COVID-19 pandemic highlighted the need for small-scale manufacturing near raw material sources (Sharma et al., 2020). Advancements in small-scale development have allowed for the integration of various unit operations like reaction, extraction, and crystallization for purification and polymorphic control, offering improved efficiency, safety, adaptability to the industry in the form of end-to-end manufacturing (Nagy et al., 2021). This work explores modular manufacturing for chemotherapy drugs with process intensification. The mini pharm setup that was developed, implemented, and demonstrated on high-value, low-demand drugs, Lomustine and Imatinib Mesylate.

Lomustine, a chemotherapy drug, affected by monopoly induced price gauging, was successfully manufactured in the mini-pharm platform through process intensification. A two-step synthesis and solvent switch distillation were utilized. Gas chromatography-mass spectrometer was used to analyze the distillation samples. Lomustine was purified via continuous combined cooling and antisolvent crystallization.

For Imatinib Mesylate, three key studies were conducted: solvent screening and solubility, precipitation reactions, and polymorphic crystallization. Solubility experiments identified a suitable solvent. Precipitation reactions produced the metastable form of Imatinib Mesylate. Polymorphic transformation experiments to isolate the stable form of the compound. Stable Imatinib Mesylate was produced via continuous cooling crystallization and verified with analytical technology tools and powder X-ray diffraction.

This study demonstrates the feasibility and advantages of small-scale modular manufacturing for Lomustine and Imatinib Mesylate, highlighting end-to-end continuous manufacturing improvements, even for hazardous anti-cancer drugs. It offers valuable insights for advancing pharmaceutical manufacturing through process intensification.

Keywords: End-to-end drug manufacturing, polymorphism, modular manufacturing

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