Supersaturation and phase behavior during dissolution of amorphous solid dispersions.

Amorphous solid dispersion (ASD) is a promising strategy to enhance solubility and bioavailability of poorly water-soluble drugs. Due to higher free energy of ASD, supersaturated drug solution could be generated during dissolution. When amorphous solubility of a drug is exceeded, drug-rich nanodroplets could form and act as a reservoir to maintain the maximum free drug concentration in solution, facilitating the absorption of the drug in vivo. Dissolution behavior of ASD has received increasing interests. This review will focus on the recent advances in ASD dissolution, including the generation and maintenance of supersaturated drug solution in absence or presence of liquid-liquid phase separation. Mechanism of drug release from ASD including polymer-controlled dissolution and drug-controlled dissolution will be introduced. Formation of amorphous drug-rich nanodroplets during dissolution and the underlying mechanism will be discussed. Phase separation morphology of hydrated ASD plays a critical role in dissolution behavior of ASD, which will be highlighted. Supersaturated drug solution shows poor physical stability and tends to crystallize. The effect of polymer and surfactant on supersaturated drug solution will be demonstrated and some unexpected results will be shown. Physicochemical properties of drug and polymer could impact ASD dissolution and some of them even show opposite effect on dissolution and physical stability of ASD in solid state, respectively. This review will contribute to a better understanding of ASD dissolution and facilitate a rational design of ASD formulation.

Crystallization inhibitory effects of konjac glucomannan, sodium alginate and xanthan gum on curcumin in supersaturated solution.

Supersaturating drug delivery system (SDDS) is a promising approach to enhance the solubility of hydrophobic functional components. However, SDDS is thermodynamically unstable and crystallization tends to occur. In this work, curcumin was used as a model compound, and the crystallization inhibitory effect of konjac glucomannan (KGM), sodium alginate (SA) and xanthan gum (XTG) on curcumin in supersaturated solution was investigated. Amorphous solubility of curcumin was determined using ultraviolet extinction, fluorescence spectroscopy and dynamic light scattering methods. Nucleation induction time (NIT) and crystal growth rate of curcumin were evaluated using ultraviolet probe in the absence and presence of various natural polysaccharides (NPs). Results showed that amorphous solubility of curcumin was approximately 30 µg/mL in pH 6.8 phosphate buffer. NPs used in this work restrained nucleation or crystal growth of curcumin effectively. The NITs of curcumin in the absence of NPs and in the presence of XTG, KGM and SA (1 µg/mL) were 3.7, 60.7, 20.0 and 8.0 min, respectively. The crystal growth rate of curcumin in the absence of NPs and in the presence of XTG, SA and KGM (1 µg/mL) were 0.0103, 0.00752, 0.00286 and 0.000306 min-1, respectively. The nucleation inhibitory effect of NPs on curcumin was ranked as XTG > KGM > SA. The order of crystal growth inhibition capacity of NPs was KGM > SA > XTG. In conclusion, NPs could be incorporated into SDDS to maintain supersaturation of hydrophobic components for enhanced bioavailability.