Elsevier

Thermochimica Acta

Volume 640, 20 September 2016, Pages 1-7
Thermochimica Acta

The solubility of ethionamide and structural analogues in buffer solutions, octanol and hexane at several temperatures

https://doi.org/10.1016/j.tca.2016.07.020Get rights and content

Highlights

  • Solubility of compounds in buffers, octanol and hexane was measured.

  • Solubility in octanol is higher than in buffer solutions and hexane.

  • Dissolution thermodynamic functions were calculated using the van’t Hoff equation.

  • Solubilities are well predicted using partitioning coefficients and descriptors.

Abstract

The solubility of antituberculosis drug ethionamide and structural analogues in buffer solutions, octanol and hexane within the temperature range from (293.15–313.15) K was measured using the shake-flack method. All the compounds studied appeared to have the solubility neither more than 10−3 mol fraction in aqueous solutions. At that the solubility in buffer pH 7.4 is lower than that in pH 2.0 which is determined by the ionization state. The solubility in octanol was estimated to be essentially higher than in hexane that is explained by the specific interactions of the compounds with the solvent. Thermodynamic solubility and solvation functions for the substances in the solvents studied were calculated. The partition coefficients of the compounds were measured in the octanol – buffer pH 7.4 system. The solubility values of the unionized molecular species of the investigated compounds using the partition coefficients and HYBOT descriptors for the biologically active substances were calculated. Comparison of the experimental and calculated solubility values showed the acceptability of the proposed approach for predicting the solubility of the compounds of aromatic thioamide series.

Introduction

Pulmonary tuberculosis is currently one of the major health problems worldwide. A variety of drugs with good efficiency have applied against tuberculosis, including ethionamide, which is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium. Although ethionamide is a structural analogue of isoniazid, both are pro-drugs that need to be activated by mycobacterial enzymes to exert their antimicrobial activity [1]. It is used in combination with other agents in cases where the first-line drugs are ineffective or are contraindicated. Its effective bacteriostatic action against organisms having resistance to isoniazid has been demonstrated by animal experiment and clinical trials by many authors [2], [3], [4]. Despite the fact that ethionamide and its structural analogues are commonly used in therapeutics and the literature contains information about their crystal structure [5], [6], to date, the information on their important physicochemical parameters such as solubility, partitioning in pharmaceutically important solvents, and membrane permeability is rather limited [7], [8].

It is well known that the solubility of organic compound in aqueous solutions is determined both by the solid state structure and the interactions of the solute with the solvent. In its turn, the solubility dramatically depends on the molecules being either in the ionized or unionized state due to the presence of donor and acceptor fragments. The ionization degree of the substance is determined by the solution pH and the ionization constants (pKa), which influence the passive transport of the drug compound through the membranes: at that, a single form of the compound – either neutral or ionized reveals an affinity to the biological receptor.

The objects of the present investigation were the compounds of aromatic thioamide series: 2-ethyl-4-pyridinecarbothioamide (ethionamide), 2-pyridinecarbothioamide, and 4- pyridinecarbothioamide. The last two are the parent compounds of ethionamide. Thioamide group in the structures of the studied compounds determines the biological activity of a broad spectrum of drugs. So, the investigation of physicochemical properties of the compounds studied in the present work is important for the design of effective antituberculosis drug substances.

This study is a continuation of our investigations on the relationship of the structure of drug and drug-like substances with solubility, lipophilic-hydrophilic properties and biological activity [9], [10]. The aim of the present work: studying the solubility of the compounds of aromatic thioamide series in pharmaceutically relevant solvents: phosphate buffer pH 7.4 and muriatic buffer pH 2.0 solutions, octanol and hexane; as well as measuring the partitioning coefficients of the investigated substances in octanol/buffer pH 7.4 system.

Section snippets

Materials

All the compounds studied in this work were obtained from commercial sources. The origin, CAS numbers, and purity of all samples are presented in Тable 1. All chemicals were used without additional purification.

Bidistilled water (with electrical conductivity 2.1 μS cm−1) was used for preparation of buffer solutions. Phosphate buffer pH 7.4 (I = 0.15 mol/l) was prepared by combining the KH2PO4 (9.1 g in 1 L) and Na2HPO4·12H2O (23.6 g in 1 L) salts. For the preparation of the buffer solution pH 2.0 (I = 0.10

Protolytic properties of the compounds

The objects of the investigation were the compounds of aromatic thioamide series: 2-ethyl-4-pyridinecarbothioamide (ethionamide)(I), 2-pyridinecarbothioamide(II), and 4- pyridinecarbothioamide(III), the structural formulae and melting points of the compounds are given in Table 2. Melting points of the compounds identified by DSC are consistent with the literature [5], [6].

Pyridine moiety and an amide group are present in the structure of the tested substances. Because the thioamide functional

Conclusions

The solubility of antituberculosis drug ethionamide and its structure analogues in pharmaceutically relevant solvents: phosphate buffer pH 7.4, muriatic buffer pH 2.0, octanol and hexane within the temperature range from (293.15–313.15) K was measured using the shake flask method. The solubility of the investigated substances in aqueous solutions was estimated to be less than 10−3 mol fraction. Solubility in buffer solution pH 7.4 is lower than that in pH 2.0, due to the protolytic properties of

Acknowledgements

This work was supported by the grant of Russian Science Foundation No. 14-13-00640.

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