From discovery to scale-up: alpha-lipoic acid : nicotinamide co-crystals in a continuous oscillatory baffled crystalliser

Zhao, Lihua and Raval, Vishal and Briggs, Naomi E. B. and Bhardwaj, Rajni M. and McGlone, Thomas and Oswald, Iain D. H. and Florence, Alastair J. (2014) From discovery to scale-up: alpha-lipoic acid : nicotinamide co-crystals in a continuous oscillatory baffled crystalliser. CrystEngComm, 16 (26). pp. 5769-5780. ISSN 1466-8033

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    Abstract

    The crystalline nutritional supplement alpha-lipoic acid degrades rapidly on exposure to temperatures above its melting point 65 degrees C and to light. A small-scale experimental co-crystal screen has produced three novel co-crystals of alpha-lipoic acid that each display enhanced thermal stability and differences in aqueous solubilities compared to alpha-lipoic acid. In each case, the initial screening procedure produced tens of milligrams of material enabling initial identification, characterisation and crystal structure determination. The structure of the alpha-lipoic acid : nicotinamide co-crystal was determined by single crystal X-ray diffraction and used for subsequent phase identification. Scale-up of the co-crystallisation process of alpha-lipoic acid with nicotinamide was then investigated in a continuous oscillatory baffled crystalliser. Over 1 kg of solid co-crystals was produced using a continuous crystallisation process in a continuous oscillatory baffled crystalliser at a throughput of 350 g h-1 yielding a purity of 99% demonstrating this as an effective route to rapid scale-up of a novel co-crystal system.