Solubility modelling and preferential solvation of adenine in solvent mixtures of (N,N-dimethylformamide, N-methyl pyrrolidone, propylene glycol and dimethyl sulfoxide) plus water

Highlights

• Solubility of adenine in four cosolvent mixtures was determined and correlated.

• Solvent effect was explained in terms of solute–solvent and solvent–solvent interactions.

• Preferential solvation parameters were derived by IKBI method.

Abstract

The equilibrium solubility of adenine in solvent mixtures of N,N-dimethylformamide (DMF) + water, N-methyl pyrrolidone (NMP) + water, propylene glycol (PG) + water and dimethyl sulfoxide (DMSO) + water were determined experimentally by using shake-flask method within the temperature range from (278.15 to 318.15) K under atmospheric pressure (101.1 kPa). Linear solvation energy relationships concept was used to describe the variation in the solubility based on the solvent effect. The preferential solvation parameters were derived from their thermodynamic solution properties by means of the inverse Kirkwood–Buff integrals. The preferential solvation parameters (δx_1,3) for DMF, NMP, PG or DMSO were negative in the four solvent mixtures with water-rich compositions, which indicated that adenine was preferentially solvated by water. Temperature has little effect on the preferential solvation magnitudes. The higher solvation by water could be explained in terms of the higher acidic behavior of the solvents interacting with the Lewis basic groups of the adenine. Besides, the solubility of this drug was mathematically represented by using the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model obtaining average relative deviations lower than 1.23% for correlative studies. The standard dissolution enthalpies of adenine in the solvent mixtures were obtained. Positive values of the standard molar enthalpy demonstrated that the dissolution process of adenine was endothermic, and the entropy was driving force for the dissolution process.

Introduction

Aqueous solubility is an important physicochemical property that plays a significant role in various physical and biological processes. Poor aqueous solubility is likely to result in low bioavailability or increased formulation difficulties during clinical development [1], [2]. Evaluation of solubility at early stages of lead optimization and candidate selection is therefore necessary during the drug discovery process. The solubility of drugs in solvent mixtures as a function of composition and temperature is evaluated importantly 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 [3], [4]. Alternatively, temperature-dependence of the solubility allows performing a thermodynamic analysis to insight into the molecular mechanisms relating to the drug dissolution process. Moreover, drug solubility in solvent mixtures is employed to evaluate the preferential solvation of the solute by the solvent components in mixtures [5], [6]. This information provides a powerful tool in the understanding of molecular interactions relating to the drug dissolution process.

Accurate experimentally-determined values for the thermodynamic properties of aqueous nucleic acid bases at elevated temperatures are of great interest to hydrothermal biochemistry and geochemistry, and are necessary for our understanding of the biochemistry of extremophile metabolism and survival [7], [8], as well as the biogeochemical processes involved in the origin of life on earth [9]. Adenine (CAS Registry No. 73-24-5, chemical structure shown in Fig. S1 of Supporting material) is particularly important nucleic acid bases, as it is a fundamental unit of DNA and RNA that plays an important role in energy transfer and the processes of energy storage as well as in cell metabolism [10], and the nucleotides adenosine monophosphate, adenosine diphosphate and adenosine monophosphate are co-factors for biochemical regulation and serve as the energy currency for the cell. They are also key components of the Krebs citric acid cycle, which has been postulated to have arisen very early in the evolution of life [11]. The solubility and related thermodynamic parameters of the adenine like Gibbs energy of transfer are essential in exploring the mechanism of interactions between solvent molecules with bio-macromolecules [12]. In this way, the knowledge of the thermodynamic properties of adenine in different solutions is necessary. For a long time many researchers had drawn their attention to determine the solubility as well as various thermodynamic properties of adenine in neat water and aqueous mixtures [9], [13], [14], [15], [16], [17], [18], [19]. A thorough literature research reveals that a lot of solubility results of adenine in water, aqueous-organic and aqueous-electrolyte mixtures [13], [14], [15], [16], [17], [18], [19] are available, however a new addition in this area would definitely enrich the region which still remains to be explored. The physicochemical properties of adenine in aqueous-organic solutions have not been studied thoroughly in the previous works. So this work tries to give an idea about the thermodynamic properties of adenine in aqueous-organic mixtures with respect to water and the complex solute − solvent and solvent − solvent interactions therein.

Some theoretical and semiempirical models can be employed to predict drug solubilities in solvent mixtures, however the availability of experimental data is still fundamental for the pharmaceutical scientists [3], [20]. Although solvent mixtures has been widely used in pharmacies long ago [4], 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], [21]. PG and NMP are common co-solvents in pharmacy [22]. NMP is a very strong solubilizing agent and is an important solvent in extraction, purification, and crystallization of drugs [23]. DMF is a very interesting co-solvent to study the interrelation between drug solubility and medium polarity because it is aprotic and completely miscible with water [24]. Water‑DMF mixtures are strongly non ideal and can act in the solute‑solvation process via hydrophobic interactions and preferential solvation [25]. Solubility in dimethyl sulfoxide (DMSO) is one of the important parameters considered by pharmaceutical companies during early drug discovery [26]. In this way, the main goal of this work is to report the equilibrium solubility of adenine (component 3) in binary solvent mixtures of (DMF + water), (NMP + water), (PG + water) and (DMSO + water) at different temperatures in order to evaluate the respective thermodynamic quantities of the solution, as well as the preferential solvation of the drug by these organic solvents. This research expands the available solubility data about adenine [13], [14], [15], [16], [17], [18], [19] and also allows the thermodynamic analysis of the respective dissolution and specific solvation process.

The capacity of the solvent to dissolve the solute is defined as the polarity. Kamlet, Abboud and Taft put forward the solvatochromic comparison method to quantify the polarity in the terms of three parameters π∗, α and β to scale dipolarity/polarizability, hydrogen bonding acidity and hydrogen bonding basicity of the solvent, respectively [27], [28], [29]. In other words, π∗, α and β measure the relative ability of the solvent to make non-specific (dipole–dipole, dipole-induced dipole and dispersion), specific acceptor–donor hydrogen bonding and specific donor–acceptor hydrogen bonding interactions, respectively. Since, these parameters are derived directly from energy change measurement of the solute–solvent interactions, it is reasonable being a linear relationship between Gibbs free energy of solvent-dependent properties and these parameters. Kamlet, Abboud and Taft introduced the concept of linear solvation energy relationships, KAT-LSER, to generalize the solvent effect on the chemical phenomena [30]. The nature and the order of importance of various interactions can be evaluated from correlating the solvent-dependent properties with the solvent descriptors in the framework of KAT-LSER. This type of solvent effect treatment was employed in this work to describe the variation in the solubility of adenine in aqueous solutions of DMF, NMP, PG and DMSO.

Inverse Kirkwood–Buff integrals (IKBI) are widely used to evaluate the preferential solvation of non-electrolyte or non-dissociated weak electrolyte compounds in solvent mixtures, which describes the local solvent proportions around the solute with respect to the composition of the solvent mixtures [5], [6]. This treatment depends on the standard molar Gibbs energies of transfer of adenine (3) from neat solvent (2) to the solvent mixtures and also on the excess molar Gibbs energy of mixing for the solvent binary mixtures free of drug. Thus, the results are expressed in terms of the variation of preferential solvation parameter (δx_1,3) of the solute adenine (3) by the solvent molecules with the mixtures composition.