Experimental and computational studies of pharmaceuticals crystallization

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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.