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

Abstract

The use of an amorphous drugs system to generate supersaturated solutions is generally developed to improve the solubility and dissolution of poorly soluble drugs. This is because the drug in the supersaturation system has a high energy state with a tendency to precipitate. In the amorphous solid dispersion (ASD) formulation, it was discovered that polymer plays a critical role in inhibiting nucleation or crystal growth of the drugs. Therefore, this study aimed to evaluate the crystallization inhibition of water-soluble chitosan (WSC) on nucleation as well as crystal growth from alpha-mangostin (AM) and elucidate its inhibition mechanism in the supersaturated solutions. During the experiment, WSC was used as a polymer to evaluate its ability to inhibit AM nucleation. The interaction between WSC and AM was also estimated using FT-IR, NMR, and in silico study. The result showed that in the absence of polymer, the concentration of AM rapidly decreased due to the precipitation in one minute. Meanwhile, the addition of WSC effectively inhibited AM crystallization and maintained a supersaturated state for the long term. FT-IR measurement also revealed that the shift in the amine primer of WSC occurred because of the interaction between WSC and AM. In the 1H NMR spectra, the proton peaks of WSC showed an upfield shift with the presence of AM, indicating the intermolecular interactions between AM and WSC. Moreover, in silico study revealed the hydrogen bond interaction between the carbonyl group of AM with hydrocarbon groups of WSC. This indicated that WSC interacted with AM in the supersaturated solution and suppressed their molecular mobility, thereby inhibiting the formation of the crystal nucleus. Based on these results, it can be concluded that the interaction between drug polymers contributed to the maintenance of the drug supersaturation by inhibiting both nucleation and growth.

Inhibition of Crystal Nucleation and Growth: A Review

“…The interactions between organic additive molecules and solutes include hydrogen bonding, hydrophobic interaction, π–π stacking, and other chemical forces. Budiman et al ’s study on maintaining alpha-mangostin (AM) , found that hydrocarbyl groups of water-soluble chitosan molecules and methyl groups of PVP molecules could form hydrogen bonds with the carbonyl group of AM through Fourier transform infrared (FT-IR), NMR, and computer studies, thereby inhibiting the molecular mobility of alpha-mangostin and inhibiting the formation of crystal nuclei. Liu et al found that the hydrophobic interaction between cyclodextrin and two drugs with low water solubility, namely carvedilol and chlorthalidone, could effectively inhibit the crystallization of the two drug molecules, and the ability of cyclodextrin to inhibit crystallization was closely related to its hydrophobicity.…”

Biobran-loaded core/shell nanofibrous scaffold: a promising wound dressing candidate

“…This suggests that the physical interactions between the PVA and Biobran in the core effectively slowed down the Biobran release from the nanobrous scaffolds. [98][99][100] Notably, despite the higher hydrophilicity of B30 than B10 and B20, its Biobran release rate is comparatively slower. This can be attributed to its high crystallinity, small ber diameter, and pore size, which also contributed to its enhanced stability during degradation.…”

Sugars and Polyols of Natural Origin as Carriers for Solubility and Dissolution Enhancement

“…In comparison with the fusion method, SDs prepared via solvent evaporation often show evidence of intermolecular interactions, which could explain the absence of the "parachute" effect during dissolution studies. Intermolecular interactions can suppress molecular mobility, thereby inhibiting the formation of the crystal nucleus and recrystallisation [48]. Nevertheless, several challenges were reported, including the limited solubility of sugars in organic solvents and the necessity of removing organic solvents to avoid solvation during storage.…”