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

基本信息

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

项目摘要

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，精细化学品和药品的结晶以间歇模式进行，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增加和产品质量的批次差异。最近，由于降低成本的潜在优势，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工作。、更短的开发时间、更稳健的放大和改进的控制性能。甲磺酸伊马替尼是诺华开发的一种有效的、选择性的蛋白酪氨酸激酶抑制剂。经美国食品和药物管理局（FDA）批准，商品名为“Gleevec/Glivec”，用于治疗干扰素-α治疗和试剂盒失败后处于急变期、加速期、慢性期的费城染色体阳性慢性粒细胞白血病（CML）。 CD117) 阳性不值得尊敬和/或转移性恶性胃肠道间质肿瘤 (GIST)。Apotex PharmaChem Inc.，作为一家仿制药公司，从 2018 年该药物专利发布之日起，正在开发一种连续生产甲磺酸伊马替尼的工艺。该提案的目的是设计一种有效的连续结晶工艺，用于从有机原料生产该药物。溶剂。目标晶型是具有适当晶粒尺寸分布的亚稳态晶型。亚稳态形式具有吸湿性，具有针状习性。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。多晶型转变、成核和生长动力学将在连续混合悬浮液混合产物去除结晶器中测量。