Equilibrium solubility determination, modelling and thermodynamic aspects of 6-chloroguanine in aqueous co-solvent mixtures of N,N-dimethylformamide, isopropanol, 1,4-dioxane and dimethyl sulfoxide

Highlights

• Solubility of 6-chloroguanine in four co-solvent mixtures was determined and correlated.

• Solvent effect analysis was made according to solute-solvent and solvent-solvent interactions.

• Preferential solvation of 6-chloroguanine in four mixtures were derived by IKBI method.

• Transfer Gibbs free energy, enthalpy and entropy were derived.

Abstract

The equilibrium solubility of 6-chloroguanine in four co-solvent mixtures of dimethyl sulfoxide (DMSO) (1) + water (2), N,N-dimethylformamide (DMF) + water (2), isopropanol (1) + water (2) and 1,4-dioxane (1) + water (2) over the temperature range from (278.15 to 333.15) K were reported. At the same temperature and composition of DMSO, DMF, isopropanol or 1,4-dioxane, the mole fraction solubility of 6-chloroguanine was highest in DMSO (1) + water (2) mixtures, and lowest in 1,4-dioxane (1) + water (2) mixtures. By using the Jouyban-Acree, van’t Hoff-Jouyban-Acree and Apelblat-Jouyban-Acree models, 6-chloroguanine solubility was well correlated obtaining RAD lower than 5.83% and RMSD lower than 4.82 × 10⁻⁴. Quantitative values for the local mole fraction of DMSO (DMF, isopropanol or 1,4-dioxane) and water around the 6-chloroguanine were computed by using the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. For the DMF (1) + water (2) mixture with composition 0.20 < x₁ < 0.69, DMSO (1) + water (2) mixture with composition 0.20 < x₁ < 1 and 1,4-dioxane (1) + water (2) mixture with composition 0.18 < x₁ < 0.35, 6-chloroguanine is preferentially solvated by the co-solvent. For the isopropanol (1) + water (2) mixture with composition 0.25 < x₁ < 0.70, 6-chloroguanine is preferentially solvated neither by isopropanol nor by water. However, in the other regions for the four co-solvent mixtures, 6-chloroguanine is preferentially solvated by water. The dissolution process of 6-chloroguanine in solvent solutions was endothermic. Furthermore, transfer Gibbs energy (Δ_trG°), enthalpy (Δ_trH°), and entropy (Δ_trS°) were calculated, demonstrating that the solubilization capacity was more favorable with the increase in the co-solvent concentration.

Introduction

Recently, investigation of the solubility of drugs and pharmaceutical intermediates and its improvement has become an increasing research subject in pharmaceutical areas. Solubility of drugs and pharmaceutical intermediates in co-solvents mixtures is one of the most important physicochemical properties, which plays a significant role in various biological and physical processes [1], [2], [3], [4]. The solubility in co-solvent solutions as a function of composition and temperature is evaluated importantly for raw material purification and understanding the mechanisms relating to the physical and chemical stability of a solid dissolutions [3], [5], [6]. It provides important data and is generally considered as an essential factor in the design of crystallization process, where knowledge of the solubility is needed in controlling the supersaturation, particle size, desired polymorphicform and yield. Co-solvency is an optional and effective solubilization technique which is considered to alternate the solubility, as aqueous co-solvent solutions is necessary for pharmaceutical and chemical industries since the mixtures could be used as synthesis reaction medium of some compounds [1], [6]. Poor aqueous solubility is likely to cause formulation difficulty or low bioavailability during clinical development [1], [5], [7]. In addition, solid solubility in co-solvent mixtures allows carrying out a thermodynamic analysis to insight deeply into the molecular mechanisms regarding the drug dissolution process and to estimate the preferential solvation of a solute by solvent components in mixtures [8], [9], [10], [11].

The compound 6-chloroguanine (CAS Reg. No. 10310-21-1, structure shown in Fig. 1) is an useful intermediate for preparing nucleoside analogue antiviral agents, such as famciclovir and penciclovir [12], [13], [14]. The intermediate is 9-substituded with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxyl (a guanine) or hydrogen (a 2-aminopurine) [15]. 6-Chloroguanine is the most ubiquitous nitrogen-containing heterocycle in nature. However, the 6-chloroguanine solubility is very low in water [12], [16]. Cosolvency, pH adjustment, surfactant addition and complexation are the most used pharmaceutical approaches for solubilizing drug candidates with low aqueous solubility [1], [5]. Among them, the most effective and powerful tool for improving the solubility of poorly water soluble drugs is mixing a miscible and safe co-solvent with water [1], [2], [3], [5]. However, despite the usefulness of this intermediate, the information about physicochemical properties such as solubility in different solvents and solvent mixtures are very scarce. A thorough literature search shows that only the 6-chloroguanine solubility in some neat solvent at temperature range from 278.15 K to 333.15 K is available in literature [17]. However, the physicochemical property of 6-chloroguanine in solvent mixtures has not yet been systematically investigated. According to the literatures’ results, 6-chloroguanine is found to exhibit up to near 10²-10³-fold increase in mole fraction solubility in going from water to the solvents DMSO and DMF. The large increase in solubility strongly suggests the presence of preferential solvation of 6-chloroguanine in the co-solvent mixtures [10], [11]. This prompt us to conduct in-depth research about the 6-chloroguanine solubility in aqueous co-solvent mixtures of DMSO and DMF and analysis the solute-solvent and solvent-solvent interactions of 6-chloroguanine at different temperatures in the co-solvent mixtures.

For co-solvency approach, solvent selection is a essential process. Practicable solvents should be commercially available, noncorrosive, nontoxic (environmentally safe) and thermally stable. The commonly used co-solvents in the pharmaceutical fields are ethanol, isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), ethylene glycol (EG) and so forth [1], [3], [5], [6]. Isopropanol is a colourless and flammable compound with a strong odor. It is miscible with ethanol, water, ether and chloroform, and dissolves a wide range of non-polar compounds. Compared to alternative solvents, isopropanol is relatively non-toxic. It is used solely or in mixtures with other solvents for different purposes including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous applications [18], [19]. DMSO is an important polar aprotic solvent with immense biological importance and very low toxic [20]. It dissolves both nonpolar and polar compounds and is miscible in a wide range of organic solvents and water. It is chosen to obtain further broader insight about chemistry aqueous solutions for amino acid solvation. DMSO possesses two hydrophobic methyl groups with +I effect, and these hydrogen atoms of two CH₃- groups are of acidic character. Because of its aprotic and miscible with water, DMF is used as a co-solvent to investigate the interrelation between drug solubility and medium polarity [21]. The DMF-water solution has very strong non-ideal, so it can act in the solute‑solvation process through preferential solvation and hydrophobic interactions [22]. It is noteworthy that 1,4-dioxane are not employed in developing liquid medicine due to its high toxicity. Nevertheless 1,4-dioxane is completely miscible with water [23]. It is broadly employed as a model co-solvent. Even more, the Jouyban–Acree model has been used to correlate the solubility for lots of drugs in 1,4-dioxane (1) + water (2) mixed solvents [24].

Considering these points-of-view, the main objective of this work is to report the equilibrium solubility of 6-chloroguanine in aqueous co-solvent mixtures of DMF and DMSO as well as isopropanol and 1,4-dioxane at temperatures ranging from 278.15 K to 328.15 K under atmospheric conditions as well as evaluate the respective thermodynamic quantities of the solutions.