Experimental and computational studies of pharmaceuticals crystallization

80%以上的活性药物成分以固体粉末的形式与辅料以片剂和胶囊的形式混合使用。从溶液中结晶是以结晶形式分离药物的主要过程。这项研究计划的长期目标是开发知识和新的预测性方法，以提高药品的生产。短期目标是：i)解开初级成核的机制；ii)预测溶剂对晶体形态的影响；iii)预测共晶体形成的成功；iv)确定特定药物的多晶型结果的可行区域；v)开发一种新的可靠的颗粒大小和形状表征仪器，用于工业结晶器的有效操作和控制。分子动力学模拟将被用来揭示抗癌药物5-氟尿嘧啶的成核机理，并预测溶剂分子对苯妥英作为模型化合物的形态的影响。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、法韦伦兹和苯妥英。为了筛选的目的，将建立一个作为强氢键供体和受体的共成体数据库。多态是医药生产中的一个重要挑战。将开发一种严格的新方法来确定在间歇和连续结晶器中制备的一些药物的可获得多态结果的区域。基于图像分析技术，研制了一种新型的、坚固耐用、价格低廉的在线颗粒大小和形状表征仪器。将开发一种定制的、具有成本效益的新型图像采集系统，该系统由微型摄像头和基于机器学习的软件接口组成，以捕获颗粒的实时图像，并将进行实验测试，最终实现商业化。拟议的研究计划的新颖性和预期结果包括：理解有机小分子初级成核的机制。为选择适当的溶剂来控制晶体形态制定指南。开发一种稳健的预测方法，从2000多个潜在的共形体中筛选出合适的共构体，以形成药物共晶体。开发一种预测性方法，以确定药物所需多晶型的可达到区域。为一种新型坚固耐用的原位颗粒大小和形状表征仪器申请专利、制造和营销。这一研究计划的成果包括培训一批高素质的人员；提高加拿大公众和加拿大制药商使用的固体药物的有效性、可及性和经济性。

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.