Non-classical Nucleation and Crystallization and Liquid Precursors of Pharmaceutical Compounds

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This project aims to investigate conditions for non-classical crystallization pathways for three common painkiller drugs Diclofenac, Ibuprofen and Flurbiprofen. These drugs have in common that they are BCS class 2 drugs (poorly water soluble but highly permeable) and they are carboxylic acids. The basis of the experimental approach is a titration set-up where the water soluble salt of the drugs is titrated with acid to make it insoluble and thus supersaturation is increased until nucleation and growth occurs, while the concentration of soluble and insoluble species is known at each time. By taking samples at the different relevant stages (prenucleation-, nucleation- and growth phase), we will be able to detect all species involved in the crystallization process by a number of techniques (AUC, ESI-MS, ITC, Cryo-(HR)TEM, SEM, AFM, light/polarization microscopy, XRD). By varying relevant experimental conditions (concentration, temperature, pH, non-solvents etc.) we try to identify conditions for non-classical crystallization pathways involving pre-nucleation clusters and liquid precursors. The role of these precursor species for polymorph control as well as a better drug bioavailability using liquid precursors shall be investigated. The phase diagrams shall also be determined. Overall, with this study we want to achieve a better understanding of the so-far barely explored non-classical crystallization pathways of organic molecules, their mechanisms as well as related important practical aspects like polymorph control and drug delivery with a far higher bioavailability than possible so far.