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

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 (1)H 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.