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

结晶是化学工业中最古老的分离提纯单元操作之一。在这个过程中，原子或分子从溶液转移到固相并形成固体晶体。传统上，精细化学品和药物的结晶是以批处理的方式进行的，以允许灵活地响应不同的定制设计要求和不断变化的市场需求；然而，这种方法也会导致制造成本的增加和产品质量的批次差异。最近，由于连续生产和结晶技术的开发具有降低成本、缩短开发时间、更强大的放大能力和改进的控制性能等潜在优势，连续生产和结晶技术的开发受到了学术界和工业界越来越多的关注和研究。甲磺酸伊马替尼是诺华公司开发的蛋白质酪氨酸激酶的一种有效和选择性的抑制剂。它被美国食品和药物管理局(FDA)以“Gleevec/Glivec”的商标批准用于治疗费城染色体阳性的慢性粒细胞白血病(CML)，处于急变期、加速期或干扰素-α治疗和试剂盒(CD117)阳性的慢性粒细胞白血病(CML)失败后的慢性期。不受尊敬的和/或转移性恶性胃肠道间质瘤(GIST)。Apotex Pharmacem Inc.作为一家仿制药公司，自2018年甲磺酸伊马替尼专利发布后，正在开发一种连续生产该药物的连续工艺。该提案的目的是设计一种有效的连续结晶工艺，用于从有机溶剂中生产该药物。目标晶型为亚稳态晶型，晶粒度分布合理。在项目过程中，将测量甲磺酸伊马替尼在一系列有机溶剂及其混合物中的溶解度，以进行溶剂筛选。在连续混合悬浮液混合产物脱除结晶器中测量多晶型转变和形核生长动力学。

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.