Solubility of chloroxine in aqueous co-solvent mixtures of N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and 1,4-dioxane: Determination, solvent effect and preferential solvation analysis

Highlights

• Chloroxine solubility in four co-solvent mixtures was determined and correlated.

• Preferential solvation of chloroxine in four mixtures were derived by IKBI method.

• Solvent effect was studied based on solute-solvent and solvent-ssolvent interactions.

Abstract

The equilibrium solubility of amorphous chloroxine in four co-solvent mixtures of dimethyl sulfoxide (DMSO) (1) + water (2), N,N-dimethylformamide (DMF) (1) + water (2), N-methyl-2-pyrrolidone (NMP) (1) + water (2) and 1,4-dioxane (1) + water (2) is reported. Experiments were performed by using the saturation shake-flask technique over the temperature range from (293.15 to 333.15) K. The maximum solubility was observed in neat DMF (DMSO, NMP or 1,4-dioxane) for the four co-solvent mixtures. By using the Jouyban-Acree model, the chloroxine solubility was well correlated obtaining RAD values lower than 3.64% and RMSD values lower than 8.82 × 10⁻⁶. Quantitative values for the local mole fraction of DMSO (DMF, NMP or 1,4-dioxane) and water around the chloroxine were computed by using the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. Chloroxine was preferentially solvated by water for the studied mixtures in water-rich compositions; while within intermediate and co-solvent-rich compositions, chloroxine is preferentially solvated by DMSO (DMF, NMP or 1,4-dioxane) in DMSO (DMF, NMP or 1,4-dioxane) + water mixtures. Moreover, in the light of Kamlet and Taft linear solvation energy relationships model, the co-solvency effect was rationalized, and the relative importance of solvent-solute and solvent-solvent interactions was recognized. It was shown that the change in solvent-solvent interaction energy accounted by cavity term governed the solubility variation of chloroxine in all aqueous mixtures.

Introduction

Knowledge of the solubility of drugs in aqueous co-solvent mixtures is important for designing liquid dosage forms, purifying raw material, and understanding mechanisms concerning the chemical and physical stability of pharmaceutical dissolution [1], [2], [3], [4], [5]. As a result, the knowledge of solubility of active ingredients is a noteworthy property in the pharmaceutical field because it influences the drug efficacy and pharmacokinetic and biopharmaceutical properties [3], [4], [5], [6]. An effective solubilization method to increase the drugs’ solubility is co-solvency, because the co-solvent mixtures are generally employed as a reaction medium or crystallization for drug purification [1], [2], [5], [6]. Poor solubility in water may result in low bioavailability or formulation difficulty through the clinical development process. Alternatively, the drugs’ solubility in co-solvent mixtures may be employed to perform a thermodynamic analysis to provide insight to the molecular mechanisms relating to the drug dissolution procedure. Moreover, the drugs’ solubility in co-solvent mixtures is generally used to estimate the preferential solvation of a solute by solvent components in the mixtures [7], [8], [9], [10], [11].

Chloroxine (CAS Reg. No. 773-76-2; chemically named as 5,7-dichloro-8-hydroxyquinoline, structure given in Fig. 1) is one of the important 8-hydroxyquinoline derivative. It has effective antibacterial, antifungal, antiprotozoal, fungistatic, bacteriostatic, and antiamoebic activities, especially used in treating the intestinal amebiasis [12], [13], [14]. At present, researchers continue to extend its application in a shampoo [15]. As an extensive use in the field of drug, the required purity of chloroxine is actual high. However, the chloroxine solubility in water is very poor (1.5 × 10⁻⁴ mol·L⁻¹ at 298 K) [16]. In the previous works, cosolvency, surfactant addition, pH alteration and complexation are the most approaches which are commonly used in pharmaceuticals to solubilize drug candidates with lower solubility in water [1], [2], [3], [4], [5], [6]. The most effective and powerful technique for improving the poor aqueous solubility of drugs is using (co-solvent + water) mixtures [1], [2], [5], which requires accurate solubility data. Nevertheless, regardless of usefulness of this drug, the physico-chemical properties of chloroxine in co-solvent mixtures, especially in aqueous co-solvent mixtures have not yet been inspected. A comprehensive literature study demonstrates that only the chloroxine in binary solvent mixtures of ethyl acetate plus methanol, ethanol, n-propanol, and isopropanol [16] are available in the literature. However, chloroxine solubility is observed up to only approximately A 9-fold rise in going from neat alcohol to ethyl acetate. Examination OF the structure of chloroxine molecule reveals that it presents high dipole moments. Because of its OH group (Fig. 1), it may offer strong interactions of non-specific dipole-dipole with aprotic solvents such as N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and 1,4-dioxane to increase its solubility. This case encourages us to make in-depth investigation upon the chloroxine solubility in these aqueous co-solvent mixtures.

For the co-solvency method, selection of THE solvent is essential. The practical solvents should be thermally commercially available, non-toxic, stable and noncorrosive. The general co-solvents employed in the pharmaceutical industry are DMSO, ethanol, isopropanol, ethylene glycol (EG), DMF and so on [1], [2], [5], [6]. DMSO, a polar aprotic solvent, is of great biological importance [17]. It can dissolve non-polar and polar compounds and is miscible covering the whole composition range of water. It is generally selected to get broader insight about the solvation of amino acid in aqueous solutions [18]. DMF is an aprotic solvent and is miscible with water, so it is widely used as a co-solvent in investigating the interrelation between drug solubility and medium polarity [19]. The DMF‑water solutions show very strong non-ideal, therefore it acts in the solute‑solvation process via the hydrophobic interactions and preferential solvation [20]. It is notable that 1,4-dioxane presents high toxicity, so it is not usually used in liquid medicine. On the other hand, 1,4-dioxane is entirely miscible with water [21]. It is widely employed as a model co-solvent. Especially, the solubility of many drugs dissolved in {1,4-dioxane (1) + water (2)} mixture is correlated through the Jouyban–Acree model [22]. NMP is a common co-solvent in the pharmaceutical industry. It presents very strong solubilization ability and is a significant solvent in crystallization, extraction and purification of drugs [23]. Considering the above points-of-view, the chief objectives of the work are to report the solubility of chloroxine in aqueous co-solvent mixtures of DMF, DMSO and NMP as well as 1,4-dioxane from 293.15 K to 333.15 K under local atmospheric pressure and evaluate the preferential solvation of this drug by the co-solvents of DMF, DMSO, NMP and 1,4-dioxane.

While the solvent polarity is well-defined in the description of the solvent effect on chemical systems, complexity of interactions, particularly in mixed solvents, makes quantification of polarity effect on the basis of only macroscopic properties of solvent problematic [24]. One promising approach to this challenge is first to separate intermolecular interactions into two specific and non-specific parts, then gauge the solvent capability to participate in each distinct interaction by establishing empirical solvent parameters, and finally combine these parameters to quantify the polarity [24]. Among empirical solvent parameters, the solvato-chromic Kamlet-Abboud-Taft, KAT, parameters π*, α and β are very popular [25], [26], [27]. The descriptor π* reflects dipolarity-polarizability of solvent in Keesom-type, Debye-type and London-type interactions. The descriptors α and β reflect respectively the acidity and basicity of solvent in specific Lewis acid-base and hydrogen bonding-type interactions [25], [26], [27]. The main advantage of KAT parameters is that they are derived from direct determination of interaction energy at microscopic level, and thereby are well suited for definition of energy terms for different solute-solvent interactions in the solvent effect modelling. The method of linear solvation energy relationships in which KAT parameters are used as solvent descriptors, KAT-LSER, is an empirical approach that partitions the change in free energy caused by solvent effect into various intermolecular interaction energy components [25], [26], [27], [28]. In practice, molecular insight can be provided on solute-solvent and solvent-solvent interactions by the use of KAT-LSER model through examination of linear correlation between the free energy of solvent effect-related property and various combinations of solvent descriptors. Therefore, one objective of this work is to analyse the solvent effect on the solubility variation of chloroxine in aqueous solutions of DMSO, DMF, NMP and 1,4-dioxane via the KAT-LSER model, in order to elucidate the relative importance and the nature of intermolecular interactions that give rise to solvent effect.