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

Abstract

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 1 H 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.

The Impact of Water-Soluble Chitosan on the Inhibition of Crystal Nucleation of Alpha-Mangostin from Supersaturated Solutions

“…Based on these data, it was observed that the WSC solution could effectively hinder the crystal growth and reduce nucleation of AM; thus, elevated levels of supersaturation could be maintained for extended periods of time. Polymeric additives have been widely utilized in supersaturated formulations because of their ability to inhibit drug crystallization [ 10 ]. It has been reported that polymers stabilize drugs in supersaturated solutions by intermolecular interactions between drugs and polymers, thus inhibiting drug crystal nucleation in the long term [ 12 ].…”

“…In recent years, various strategies have been developed to improve solubility such as amorphous solid dispersions [ 4 , 5 ], cocrystals, and [ 6 , 7 ] co-amorphous systems [ 8 , 9 ]. These formulation techniques can create the drug in the supersaturation state [ 10 ].…”

“…However, the drug in the supersaturation state is thermodynamically unstable, and the concentration of the dissolved drug quickly decreases due to recrystallization [ 13 ]. This makes an additional excipient very important to stabilize the supersaturated state of the drug and inhibit the crystallization of stable forms [ 10 ].…”

Inhibition of Crystal Nucleation and Growth: A Review

“…Later, they selected polyvinylpyrrolidone (PVP) K12, PVP K25, and 1ethyl-2-pyrrolidone (NEP) as additives and investigated the reasons for their inhibition of chlorthalidone (CLT) crystallization nucleation by using NMR technology. 50 The results showed that PVP could inhibit the crystallization of CLT and keep its solution supersaturated. NMR results showed that the presence of PVP could keep CLT supersaturated for a long time, and the presence of PVP K25 significantly inhibited the molecular mobility of supersaturated CLT.…”

“…They found that hypromellose distributed in amorphous nanodroplets that were rich in ibuprofen molecules strongly inhibited the mobility of ibuprofen molecules. Later, they selected polyvinylpyrrolidone (PVP) K12, PVP K25, and 1-ethyl-2-pyrrolidone (NEP) as additives and investigated the reasons for their inhibition of chlorthalidone (CLT) crystallization nucleation by using NMR technology . The results showed that PVP could inhibit the crystallization of CLT and keep its solution supersaturated.…”