Solubility, aggregation and stability of Amphotericin B drug in pure organic solvents: Thermodynamic analysis and solid form characterization

The solubility of amphotericin B (AmB) has been studied between temperatures of 298-343 K in a range of pure organic solvents including methanol, ethanol, isopropanol, butanol, acetone, tetrahydrofuran, and 1,4-dioxane. The initial solid form used in solubility determinations has been characterized by a series of techniques including powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) and Raman spectroscopy, thermogravimetric analysis and differential scanning calorimetry. Pure AmB melts at 444.5 K with an associated enthalpy of fusion of 177.2 kJ/mol. The equi-librated solids in suspension have been characterized by SEM and PXRD and additionally, the equilibrated saturated solutions have been characterized by in-situ UV-vis to probe the saturation and the aggrega-tion state of AmB. In the explored solvents, in terms of mass ratio, the solubility has been found to be remarkably low, decreasing in the order: ethanol > tetrahydrofuran > butanol similar or equal to 1,4-dioxane ' isopropanol > acetone. The relative order of solubility obtained in the alcohols correlates well with their polarity, revealing important interactions of the solvents' hydroxyl group with the polyol chain and the micosamine sugar carboxylic moiety of amphotericin B. Except in dioxane and isopropanol, the obtained Van't Hoff enthalpies of solution reveal an inverse proportionality to the experimental molar fraction sol-ubility values obtained experimentally, indicating a larger energy requirement to solvate AmB molecules. Aggregation of AmB in the equilibrated solutions was not detected in any of the solvents studied yet HPLC analyses revealed that the API degraded in methanol during the equilibration time for the solubility determinations. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

The solubility of amphotericin B (AmB) was investigated in a range of pure organic solvents, and the order of solubility was found to correlate with the polarity of the solvents. The energy requirement for solvating AmB molecules was found to be relatively high. Degradation of the API was observed in methanol during the solubility determinations.