Solubility and preferential solvation of econazole nitrate in binary solvent mixtures of methanol, ethanol and 1,4-dioxane in water

Highlights

• Solubility of econazole nitrate in methanol/ethanol/1,4-dioxane + water were determined.

• Preferential solvation parameters were derived by IKBI method.

• Econazole nitrate was preferentially solvated by alcohol in intermediate composition and alcohol-rich mixtures.

• Econazole nitrate is preferentially solvated by cosolvent in intermediate composition for 1,4-dioxane mixtures.

Abstract

The solubility of econazole nitrate in binary mixed solvents of (methanol + water, ethanol + water and 1,4-dioxane + water) were measured experimentally via the isothermal dissolution equilibrium method in the temperature range of (278.15–318.15) K under 101.2 kPa. For the (1,4-dioxane + water) system, at a certain composition of 1,4-dioxane, the solubility of econazole nitrate increased with an increase in temperature; nevertheless at the same temperature, they increased at first and then decreased with an increase in mass fraction of 1,4-dioxane. At the same temperature and mass fraction of methanol, ethanol or 1,4-dioxane, the solubility of econazole nitrate was greater in (methanol + water) than in the other two mixed solvents. The solubility values were correlated by using Jouyban-Acree model, and the dissolution enthalpies of the dissolution process were computed. Preferential solvation parameters of econazole nitrate were also derived by means of the inverse Kirkwood-Buff integrals method. The preferential solvation parameter by water δx_1,3 is negative in water-rich mixtures but positive in compositions from 0.31 to 1.0 in mole fraction of methanol and from 0.24 to 1.0 in mole fraction of ethanol. It is conjecturable that in intermediate composition of alcohol and alcohol-rich mixtures the interaction by acidic hydrogen-bonding by methanol/ethanol on the basic sites of econazole nitrate played a relevant role in the drug solvation. However in 1,4-dioxane (1) + water (2) mixtures with 0.18 < x₁ < 0.50 positive δx_1,3 values were observed, but with 0.50 < x₁ < 1.0 negative δx_1,3 values were observed again. The solubility data presented in this work expand the physicochemical information about drugs in binary aqueous-co-solvent mixtures.

Introduction

The solubility behaviour of drugs in co-solvent mixtures as a function of composition and temperature is assessed essentially for the purposes of raw material purification, design of liquid dosage forms, and understanding of the mechanisms relating to the physical and chemical stability of pharmaceutical dissolutions [1], [2]. Thus, the solubility of active ingredients is an important physicochemical property to be considered in pharmaceutical design because it affects the drug efficacy, influencing several biopharmaceutical and pharmacokinetic properties [3], [4]. On the other hand, temperature-dependence of the solubility allows performing a thermodynamic analysis to insight into the molecular mechanisms relating to the drug dissolution processes [5]. Moreover, drug solubility in co-solvent systems is employed to estimate the preferential solvation of the solute by the solvent components in mixtures. This information provides a powerful tool in the understanding of molecular interactions relating to the drug dissolution processes [6], [7].

Econazole nitrate (CAS Reg. No. 24169-02-6; chemical structure shown in Fig. 1) is an essential class of chemical drugs. It is an efficient and safe broad-spectrum antifungal drug [8], [9], [10]. This drug has shown important microbiological activities against fungal infections, such as dermatophytoses and microzyme, and it has been used in treatment of majority mycosis like the jock itch, foot moss, tinea versicoeor and the Candida dermatitis [11], [12], [13], [14]. Due to its good properties, econazole nitrate has been received great attention. Nevertheless, despite the usefulness of this drug, physicochemical properties of econazole nitrate in solution have been studied but the data on its solubility in aqueous and organic media are still not complete [14], [15]. Up to yet, only Xie and co-workers determine the econazole nitrate solubility in several pure organic solvent [15]. Its solubility data in co-solvent mixtures have not been reported in the previous works.

Some theoretical and semi-empirical models can be employed to predict drug solubilities in solvent mixtures. However the availability of experimental data is still fundamental for the pharmaceutical scientists [16]. Because the solubility of econazole nitrate in neat water is too low [14], some aqueous and non-aqueous mixtures may be employed to increase the solubility of the drug. Although co-solvency as the drug solubilizing technique has been widely used in pharmacies long ago, recently the mechanisms involving in the increase or decrease in drugs’ solubility start to be approached from a deep thermodynamic point of view, including the analysis of the preferential solvation of solute by the components of mixtures [5], [6], [7], [17], [18].

In this way, the main goal of this article is to determine the equilibrium solubility of ECN (3) in several mixtures of {methanol (1) + water (2)}, {ethanol (1) + water (2)} and {1,4-dioxane (1) + water (2)} at different temperatures to evaluate the preferential solvation of this drug, based on well-established thermodynamic definitions [17], [18]. It is important to keep in mind that methanol and 1,4-dioxane is not used to develop liquid medicines due to its high toxicity. But in some instances methanol is used in drug purification procedures [19], as well as solvent in some drug microencapsulation techniques [20]. Moreover, methanol is widely used as mobile phase in high performance liquid chromatography [21]. Besides, 1,4-dioxane is widely used as a model co-solvent because it is miscible with water in all the range of compositions although it exhibits a low polarity as described by its dielectric constant, i.e. 2.21 at 298.15 K [22]. Even more, the Jouyban–Acree model has been used to correlate the solubility of a lot of drugs in {methanol/1,4-dioxane (1) + water (2)} mixtures [23].