Use of additives to regulate solute aggregation and direct conformational polymorph nucleation of pimelic acid

Abstract

Understanding the nucleation pathway and achieving regulation to produce the desired crystals are mutually beneficial. The authors previously proposed a nucleation pathway of conformational polymorphs in which solvation and solute self-assembly could affect the result of the conformational rearrangement and further nucleation outcomes. Based on this, herein α,ω-alkanedicarboxylic acids (DAn, where n represents the number of carbon atoms in the molecule, n = 2–6, 8–11) were designed as homologous additives to interfere with the self-assembly of pimelic acid (DA7) to further induce the form II compound, which differs from form I only in conformation. Interestingly, longer-chain additives (DA6–11) have a stronger form II-inducing ability than short-chain ones (DA2–4). In addition, an apparent gradient of the degree of interference with solute self-assembly, consistent with form II-inducing ability, was detected by infrared and nuclear magnetic resonance spectroscopy. The calculated molecular electrostatic potential charges also clearly indicate that additive–solute electrostatic interactions gradually increase with increasing carbon chain length of the additives, reaching a maximum value with DA6–11. This novel use of additives demonstrates a direct link between solute aggregation and conformational polymorph nucleation.