Experimental and computational studies of pharmaceuticals crystallization

药物结晶的实验和计算研究

• 批准号: RGPIN-2021-03595
• 负责人: Rohani, Sohrab
• 金额: $ 3.35万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746703
• 关键词: Experimental; computational; studies; pharmaceuticals; crystallization

More than 80 percent of the active pharmaceutical ingredients are administered as solid powders mixed with excipients in the form of tablets and capsules. Crystallization from a solution is the main process to isolate pharmaceuticals in a crystalline form. The long-term goal of this research program is to develop knowledge, and novel predictive approaches to improve the production of pharmaceuticals. The short-term objectives are: i)unraveling the mechanism of primary nucleation; ii)predicting the effect of solvents on crystal morphology; iii)predicting the success of cocrystal formation; iv)determining the feasible region of polymorphic outcome of a given pharmaceutical; and v)developing a novel robust particle size and shape characterization instrument for the effective operation and control of industrial crystallizers. Molecular dynamic simulation will be used to unravel the mechanism of nucleation of an anticancer drug, 5-fluorouracil; and to predict the effect of solvent molecules on the morphology of phenytoin as a model compound. Molecular dynamic simulations will be validated by extensive experimentation. A novel approach for the prediction of co-crystal formation, will be developed. This will be then followed by experimentation on several model compounds including dasatinib, efavirenz, and phenytoin. A database of coformers as strong hydrogen bond donors and acceptors will be developed for the screening purposes. Polymorphism is an important challenge in the pharmaceutical manufacturing. A rigorous novel approach will be developed to identify the region of attainable polymorphic outcome of a number of pharmaceuticals prepared in batch and continuous crystallizers. A new robust inexpensive on-line particle size and shape characterization instrument will be developed based on image analysis. A customized and cost-effective novel image acquisition system consisting of a micro-camera, and a software interface based on machine learning to capture the real-time images of particles will be developed, tested experimentally, and eventually commercialized. The novelty and expected outcome of the proposed research program include: Understanding the mechanism of the primary nucleation of small organic molecules. Developing guidelines for the selection of a proper solvent to control crystal morphology. Developing a robust predictive approach for the screening of a suitable coformer from among more than 2000 potential coformers to form a pharmaceutical cocrystal. Developing a predictive approach to identify the attainable regions of the desirable polymorph of a pharmaceutical. Patenting, manufacturing, and marketing a novel robust in-situ particle size and shape characterization instrument. The outcome of this research program includes the training of a number of highly qualified personnel; and improving the efficacy, accessibility and economics of solid pharmaceuticals for the use of Canadian public and the pharmaceutical manufacturers in Canada.

超过80%的活性药物成分以片剂和胶囊形式与赋形剂混合的固体粉末形式给药。从溶液中结晶是以结晶形式分离药物的主要过程。该研究计划的长期目标是开发知识和新的预测方法，以改善药物的生产。短期目标是：i）阐明初级成核的机制; ii）预测溶剂对晶体形态的影响; iii）预测共晶形成的成功; iv）确定给定药物的多晶型产物的可行区域;以及v）开发用于工业结晶器的有效操作和控制的新型鲁棒粒度和形状表征仪器。分子动力学模拟将被用来解开抗癌药物，5-氟尿嘧啶的成核机制，并预测苯妥英作为模型化合物的形态溶剂分子的影响。分子动力学模拟将通过广泛的实验进行验证。 将开发一种预测共晶形成的新方法。随后将对几种模型化合物进行实验，包括达沙替尼、依法韦仑和苯妥英。为筛选目的，将开发一个作为强氢键供体和受体的共形成物数据库。多晶型是制药业面临的一个重要挑战。将开发一种严格的新方法来鉴定在分批和连续结晶器中制备的许多药物的可达到的多晶型结果的区域。 基于图像分析技术，研制了一种新的、廉价的在线颗粒尺寸和形状表征仪器。将开发一种定制的、具有成本效益的新型图像采集系统，该系统由微型相机和基于机器学习的软件接口组成，用于捕获颗粒的实时图像，并进行实验测试，最终实现商业化。该研究计划的新颖性和预期成果包括：了解有机小分子初级成核的机制。为控制晶体形态选择合适的溶剂制定指导方针。开发一种稳健的预测方法，用于从超过2000种潜在的共形成物中筛选合适的共形成物以形成药物共晶体。开发一种预测方法，以确定药物理想多晶型的可达到区域。申请专利，制造和销售一种新型的强大的原位粒度和形状表征仪器。该研究计划的成果包括培训一些高素质的人员;并提高加拿大公众和加拿大制药商使用的固体药物的功效，可及性和经济性。