Isavuconazole: Thermodynamic Evaluation of Processes Sublimation, Dissolution and Partition in Pharmaceutically Relevant Media.

Marina Ol’Khovich,German Perlovich,Angelica Sharapova,Svetlana Blokhina

doi:10.3390/molecules26164759

Marina Ol’Khovich, German Perlovich + Show 2 more

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https://doi.org/10.3390/molecules26164759

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Abstract

A temperature dependence of saturated vapor pressure of isavuconazole (IVZ), an antimycotic drug, was found by using the method of inert gas-carrier transfer and the thermodynamic functions of sublimation were calculated at a temperature of 298.15 K. The value of the compound standard molar enthalpy of sublimation was found to be 138.1 ± 0.5 kJ·mol−1. The IVZ thermophysical properties—melting point and enthalpy—equaled 302.7 K and 29.9 kJ mol−1, respectively. The isothermal saturation method was used to determine the drug solubility in seven pharmaceutically relevant solvents within the temperature range from 293.15 to 313.15 K. The IVZ solubility in the studied solvents increased in the following order: buffer pH 7.4, buffer pH 2.0, buffer pH 1.2, hexane, 1-octanol, 1-propanol, ethanol. Depending on the solvent chemical nature, the compound solubility varied from 6.7 × 10−6 to 0.3 mol·L−1. The Hansen s approach was used for evaluating and analyzing the solubility data of drug. The results show that this model well-described intermolecular interactions in the solutions studied. It was established that in comparison with the van’t Hoff model, the modified Apelblat one ensured the best correlation with the experimental solubility data of the studied drug. The activity coefficients at infinite dilution and dissolution excess thermodynamic functions of IVZ were calculated in each of the solvents. Temperature dependences of the compound partition coefficients were obtained in a binary 1-octanol/buffer pH 7.4 system and the transfer thermodynamic functions were calculated. The drug distribution from the aqueous solution to the organic medium was found to be spontaneous and entropy-driven.

Highlights

Invasive fungal infections, such as aspergillosis and the rather rare mucormycosis, remain the main cause of disease and death in immunocompromised patients [1,2,3,4,5]
The IVZ excess partial thermodynamic functions were calculated based on the linear dependences of lnγ on reciprocal temperature (Figure 8), with the results summarized in
The vapor pressure of IVZ was measured by the transpiration method in the temperature range 365.15–383.15 K and the sublimation thermodynamic functions were calculated by the Clark–Glew equation

Summary

Introduction

Invasive fungal infections, such as aspergillosis and the rather rare mucormycosis, remain the main cause of disease and death in immunocompromised patients [1,2,3,4,5]. The triazole class of antifungal drugs includes first-line preparations for treatment of diseases caused by a number of medicinally important strains of opportunistic fungi [6,7,8,9]. Isavuconazole (IVZ) is a new second-generation hybrid of thiazole and triazole with a wide spectrum of antifungal activity and favorable pharmacokinetic and pharmacodynamic profiles and is the only new antimycotic agent for systemic use that has been registered in the last 10 years.

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