NMR-Based Mechanistic Study of Crystal Nucleation Inhibition in a Supersaturated Drug Solution by Polyvinylpyrrolidone

In this study, the molecular states of supersaturated drugs and crystallization inhibitors in aqueous solutions were characterized using NMR to elucidate the inhibition mechanism of drug crystal nucleation in drug-supersaturated solutions. Polyvinylpyrrolidone (PVP) K12, PVP K25, and 1-ethyl-2-pyrrolidone (NEP) were used as additives to evaluate their ability to inhibit chlorthalidone (CLT) crystal nucleation. Although an inhibitory effect of NEP on the crystal nucleation of CLT was not observed, PVP effectively inhibited CLT crystallization and maintained CLT in a supersaturated state in the long term. In the 1D 1H NMR spectra, the aromatic proton peaks of CLT showed an upfield shift with increasing CLT concentration, reflected by the self-association of CLT in aqueous solution; the number of self-associates increased with increasing supersaturation level. The presence of the additives in the aqueous solution induced downfield shifts of the CLT peaks, which were the largest in the PVP K25 solution and the smallest in the NEP solution. Nuclear Overhauser effect spectroscopy (NOESY) measurements revealed that the PVP formed a hydrophobic interaction with CLT via the carbon chain of PVP. Furthermore, the spin–spin relaxation rate of the supersaturated CLT was significantly increased by the addition of PVP K25, indicating the mobility suppression of supersaturated CLT by PVP K25, which can be caused by the intermolecular interactions between CLT and PVP K25. Furthermore, CLT mobility suppression by PVP K25 became more significant with increasing CLT supersaturation levels. This implies that PVP K25 interacted particularly with CLT self-associates formed in the supersaturated solution and suppressed their molecular mobility, thereby inhibiting the reorientation from the CLT self-associates to the crystal nucleus. The present study highlights the importance of the molecular weight of crystallization inhibitors on the ability of mobility suppression of a self-associated drug due to the nucleation inhibition effect.