Can the Crystal of Conformational Polymorph Nucleate Directly from Its Conformer? The Case of Flufenamic Acid

The combination of solution IR spectroscopy measurement, fast cooling crystallization experiments, conformational search, and molecular computation was investigated in detail in this study to explore the link between the solution species and the crystallization outcome. It was found that dimerization cannot occur in the flufenamic acid (FFA) solutions of ethanol and acetonitrile, and the probabilities of the solvated conformer I in acetonitrile, 2-propanol, and ethanol are below 8%, while those of conformer III are higher than 85%. Form III of FFA nucleated directly from conformer III when the temperatures are above 42 °C. The formation of stacked dimers through π···π interactions was verified to be the key step in the molecular preassembly during nucleation.