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

用于控制 API 固态属性的连续结晶

• 批准号: 520466-2017
• 负责人: Rohani, Sohrab
• 金额: $ 1.82万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Engage Grants Program
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=639902
• 关键词: Continuous; Crystallization; Control; Solid; State

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.

结晶是化学工业中最古老的分离和纯化单元操作之一。在此过程中，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以批量模式进行，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间变化。最近，伊马替尼（Imatinib mesylate）是诺华公司（Novartis）开发的一种高效、选择性的蛋白酪氨酸激酶抑制剂，由于其具有成本低、开发周期短、放大效果好、控制效果好等优点，其连续化生产和结晶技术的发展受到了学术界和工业界的广泛关注。美国食品药品监督管理局（FDA）批准其商品名为“Gleevec/Glivec”，用于治疗费城染色体阳性慢性髓细胞性白血病（CML）的急变期、加速期或干扰素-α治疗失败后的慢性期以及kit（CD 117）阳性的不值得注意和/或转移性恶性胃肠道间质瘤（GIST）。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。目标晶型是具有合适的晶粒尺寸分布的亚稳晶型。亚稳态形式具有吸湿性，具有针状习性。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，用于溶剂筛选。在连续混合悬浮液混合产物移出结晶器中测定了多晶型转变和成核生长动力学。