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Continuous Production of Active Pharmaceutical Ingredients Using Recycle

Derek W. Griffin, Duncan A. Mellichamp, and Michael F. Doherty. UCSB, Department of Chemical Engineering, Santa Barbara, CA 93106

In the pharmaceutical and solids processing industry, it is important to consistently produce a product with specific properties such as size, shape, and morphology. Currently, the industry is dominated by batch processing where it can often be difficult to achieve the same product quality consistently from batch to batch. Thus, there has been a recent move to continuous processing because of the improved capacity usage, flexibility, and controllability offered by a continuous process compared to a batch one. A goal of solids processing is to make a product with a desired mean size and a certain size distribution. For certain active pharmaceutical ingredients (API's), such as paracetemol, the ideal product size is 20-50 microns to improve characteristics such as solubility and formulation. Since the size distribution from a crystallizer is generally larger than this target size there is the need for further processing, such as wet milling, to reduce the mean particle size. This study is aimed at the optimal operation of a continuous crystallization flowsheet in order to reduce the mean size of the crystal product and lower the operating costs of the entire plant. The proposed flowsheet is shown in Figure 1 which includes a cooling crystallizer followed by a solids separation step, such as a pusher centrifuge, that can be used for product classification. The solid product is taken off at a desired classification/cut size and part of the product stream is sent back the crystallizer as classified product removal. The remaining part of the solution is separated by filtration where the product is taken off and the mother liquor is recycled back to a dissolver to be mixed with the solute and make-up solvent. A fines destruction system (not shown) is also considered as part of the flowsheet which generally leads to higher levels of supersaturation, faster growth rates, and larger median crystal sizes at the expense of higher capital and operating costs. It is shown that it is possible to reduce the mean product size through the optimal operation of the mother liquor recycle and product classification system. The effects of various process operating parameters- such as crystallizer residence time, product classification cut size, and recycle flow rates- are investigated by tracking the crystal size distribution throughout the entire process.