Two major pre-nucleation species that are conformationally distinct and in equilibrium of self-association

To understand how solution chemistry governs polymorphic formation of organic crystals, solution NMR measurements of tolfenamic acid were conducted in ethanol. It was unveiled by chemical shift and diffusivity results that the solute molecules self-associated as dimers in solution. Further nOe (nuclear Overhauser effect) analyses indicate that a more twisted conformation became dominant over a planar conformation under the solution conditions that favored the dimer formation. This discovery is rationalized in terms of the energy balance between the conformation and intermolecular hydrogen bonding of the solute molecule, suggesting a significant role of the cooperability between a molecule's conformation and its intermolecular interaction in determining the nucleation outcome of distinct crystal structures.