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纯化装置之一。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。通常，精细化学品和药品的结晶是在批量模式下进行的，以便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批次之间的差异。近年来，连续制造和结晶技术的发展受到了学术界和工业界越来越多的关注和研究，因为它具有降低成本、缩短开发时间、更强大的规模扩展和改进控制性能的潜在优势。甲磺酸伊马替尼是诺华公司开发的一种有效的选择性酪氨酸激酶抑制剂。它被美国食品和药物管理局（FDA）批准以商品名“Gleevec/Glivec”治疗费城染色体阳性慢性粒细胞白血病（CML），在干扰素- α治疗和kit （CD117）阳性的不受欢迎和/或转移性恶性胃肠道间质瘤（gist）失败后的母细胞危化期、加速期或慢性期。Apotex PharmaChem公司作为一家仿制药公司，从2018年该药物的专利发布开始，正在开发一种连续生产甲磺酸伊马替尼的工艺。本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。目标晶型为亚稳晶型，晶体尺寸分布合适。亚稳形态吸湿，有针状习性。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，进行溶剂筛选。在连续混合悬浮液混合产物去除结晶器中测量晶型转变、成核和生长动力学。

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.