TY - JOUR
T1 - Solubility, aggregation and stability of Amphotericin B drug in pure organic solvents
T2 - Thermodynamic analysis and solid form characterization
AU - Soto, R.
AU - Patel, P.
AU - Albadarin, Ahmad B.
AU - Diniz, M. O.
AU - Hudson, S. P.
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/11/15
Y1 - 2022/11/15
N2 - 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 equilibrated 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 aggregation 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 ≃ 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 solubility 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.
AB - 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 equilibrated 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 aggregation 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 ≃ 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 solubility 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.
KW - Aggregation
KW - Amphotericin B
KW - Solid-state characterization
KW - Stability
KW - Thermodynamic solubility
UR - http://www.scopus.com/inward/record.url?scp=85138073719&partnerID=8YFLogxK
U2 - 10.1016/j.molliq.2022.120276
DO - 10.1016/j.molliq.2022.120276
M3 - Article
AN - SCOPUS:85138073719
SN - 0167-7322
VL - 366
SP - -
JO - Journal of Molecular Liquids
JF - Journal of Molecular Liquids
M1 - 120276
ER -