Nucleation of Insoluble Drugs in Solvents with Different Hydrogen Bond Donor and Acceptor Abilities─A Case Study of Probenecid

Probenecid (PB), as a pharmacotherapeutic agent for treating gout, confronts challenges associated with heterogeneous particle size distribution and irregular morphology, impacting postprocessing efficiency. Therefore, further investigation of the nucleation behavior of PB is necessary to address these issues. The nucleation behavior of PB in four solvents was investigated using metastable zone width (MSZW) experiments, the Nývlt model, and the modified Sangwal’s theory. The results revealed that the MSZW broadened, and the interfacial energy (γ) and pre-exponential factor (A) increased with higher cooling rates and lower saturation temperatures. As the chemical potential increases, the critical nucleus size (rcrit) and Gibbs free energy (ΔGcrit) decrease. Infrared (FTIR) spectral analysis suggested that the distinct nucleation behavior of PB in various solvents can be attributed to the competition between intermolecular interactions, predominantly hydrogen bonding and dimerization. Radial distribution function (RDF) analysis and solvation energy calculation suggested that the nucleation behavior becomes more difficult as the solute–solvent intermolecular interactions become stronger.