Nucleation of Insoluble\nDrugs in Solvents with Different\nHydrogen Bond Donor and Acceptor AbilitiesA Case Study of\nProbenecid

Probenecid (PB), as a pharmacotherapeutic agent for treating\ngout,\nconfronts challenges associated with heterogeneous particle size distribution\nand irregular morphology, impacting postprocessing efficiency. Therefore,\nfurther investigation of the nucleation behavior of PB is necessary\nto address these issues. The nucleation behavior of PB in four solvents\nwas investigated using metastable zone width (MSZW) experiments, the\nNývlt model, and the modified Sangwal’s theory. The\nresults revealed that the MSZW broadened, and the interfacial energy\n(γ) and pre-exponential factor (<i>A</i>) increased\nwith higher cooling rates and lower saturation temperatures. As the\nchemical potential increases, the critical nucleus size (<i>r</i><sub>crit</sub>) and Gibbs free energy (Δ<i>G</i><sub>crit</sub>) decrease. Infrared (FTIR) spectral analysis suggested\nthat the distinct nucleation behavior of PB in various solvents can\nbe attributed to the competition between intermolecular interactions,\npredominantly hydrogen bonding and dimerization. Radial distribution\nfunction (RDF) analysis and solvation energy calculation suggested\nthat the nucleation behavior becomes more difficult as the solute–solvent\nintermolecular interactions become stronger.