Continuous Crystallization for the Control of Solid-State Attributes of APIs

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Crystallization is one of the oldest separation and purification unit operations in chemical industry. During thisprocess, the atoms or molecules are transferred from solution to the solid phase and form solid crystals.Conventionally, crystallization of fine chemicals and pharmaceuticals is conducted in batch mode to allowflexibility to respond to varying customized design requirements and changing market demands; however, thisapproach can also lead to increased manufacturing costs and batch-to-batch variations in product quality.Recently, the development of continuous manufacturing and crystallization techniques has received increasinginterest and research effort from academic and industrial sectors, due to the potential advantages of reducedcosts, shorter development time, more robust scale-up and improved control performance.Imatinib mesylate is a potent and selective inhibitor of the protein tyrosine kinase developed by Novartis. Itwas approved under the trade name "Gleevec/Glivec" by the US Food and Drug Administration (FDA) to treatPhiladelphia chromosome positive chronic myelogenous leukemia (CML) in blast crisis, accelerated phase, orchronic phase after failure of interferon-alpha therapy and kit (CD117) positive unrespectable and/or metastaticmalignant Gastro Intestinal Stromal Tumors (GISTs).Apotex PharmaChem Inc., as a generic pharmaceutical company is developing a continuous process for themanufacture of imatinib mesylate from 2018 when the patent of this drug is released.The objective of this proposal is to design an effective continuous crystallization process for the production ofthis pharmaceutical from an organic solvent. The target crystal form is the metastable form with proper crystalsize distribution. The metastable form is hygroscopic with needle like habit.During the course of the project, the solubility of imatinib mesylate in a series of organic solvents and theirmixture will be measured for solvent screening. The polymorphic transformation and nucleation and growthkinetics will be measured in a continuous mixed suspension mixed product removal crystallizer.