Equilibrium solubility, dissolution thermodynamics and preferential solvation of adenosine in aqueous solutions of N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and propylene glycol

https://doi.org/10.1016/j.jct.2017.07.023Get rights and content

Highlights

  • Solubility of adenosine in four (co-solvent + water) mixtures were determined.

  • The solubility data were correlated by using three thermodynamic models.

  • Preferential solvation parameters were derived by IKBI method.

  • Adenosine was preferentially solvated by water in water-rich mixtures.

Abstract

The equilibrium solubility of adenosine in co-solvent mixtures of {(N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and propylene glycol) + water} were determined experimentally by the isothermal dissolution equilibrium method in the temperature range of (278.15–323.15) K under atmospheric pressure of 101.0 kPa. The maximum solubility was observed in neat N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide or propylene glycol. The mole fraction solubility of adenosine increased with increasing temperature and mass fraction of co-solvent in each binary system. At the same temperature and mass fraction of the organic solvent, the solubility of adenosine was greater in (N-methyl-2-pyrrolidone + water) than in the other three mixed solvents. The Jouyban-Acree model, Van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model were employed to correlate the measured solubility data. The largest values of relative average deviation and root-mean-square deviation were 4.87 × 10−2 and 3.52 × 10−4, respectively. Positive values of the dissolution enthalpy illustrated that the dissolution process of adenosine in these mixed solvents was endothermic. Moreover, the preferential solvation parameters were derived from their thermodynamic solution properties by using the inverse Kirkwood–Buff integrals. For the four co-solvent mixtures with intermediate composition and co-solvent-rich mixtures, adenosine is preferentially solvated neither by organic solvent nor by water. However, adenosine is preferentially solvated by water in water-rich mixtures. Adenosine could act mainly as a Lewis base interacting with acidic hydrogen atoms of water.

Introduction

Solid-liquid equilibrium data is one of the most important thermodynamic properties because it can provide necessary information for the design, analysis and optimization of the separation and purification processes in various fields e.g. pharmaceutical, chemical, food, petrochemical and material [1]. The solubility behaviour of drugs in solvent mixtures as a function of composition and temperature is evaluated 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 [2], [3]. In addition, solvent mixing with temperature alteration is a common way to vary the solubility of compounds in crystallization investigations. Furthermore, the solubility data enables us to look for the most suitable solvent system to purify drugs by way of solvent crystallization. For these reasons, it is very important to systematically determine drug solubilities in different aqueous and organic solvent mixtures [2], [3], [4]. Although solvent mixing as a solubilization technique has been widely employed in pharmacy and chemistry, recently the mechanisms involved in increasing or decreasing drugs' solubility have started to be investigated by analysis of the preferential solvation of the solutes by the solvent components in the saturated solutions [4], [5], [6].

Adenosine (C10H13N5O4, CAS R.N. 58-61-7, chemical structure shown in Fig. S1 of Supporting material) is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a β-N9-glycosidic bond [7], [8], [9], [10]. Adenosine is widely found in nature and plays an important role in biochemical processes, such as energy transfer—as adenosine triphosphate (ATP) [11] and adenosine diphosphate (ADP) [12]—as well as in signal transduction as cyclic adenosine monophosphate (cAMP) [13]. It is also a neuromodulator, believed to play a role in promoting sleep and suppressing arousal. Adenosine also plays a role in regulation of blood flow to various organs through vasodilation [14], [15], [16], [17]. In addition to adenosine's endogenous forms, it is also used as a medication, specifically, as an antiarrhythmic agent to treat a number of forms of supraventricular tachycardia that do not improve with vagal manoeuvers [7], [8], [9], [10]. In recent years, various medical values of adenosine have gradually drawn people's attention so as to urge increasing demand both synthetic intermediates and pharmacological fields. In order to extend the drug’s use in various fields, it is necessary to determine systematically their solubilities for liquid pharmaceutical systems. The solubility of adenosine in water has been widely studied in the literatures [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Nevertheless, despite the usefulness of this drug, the study on physicochemical properties of adenosine in aqueous solutions has not been made up to yet.

Some theoretical and semi-empirical models have been employed to predict drug solubilities in solvent mixtures, however the availability of experimental data is still fundamental for the pharmaceutical scientists [2], [28], [29]. Because the solubility of adenosine in neat water is too low, some aqueous and non-aqueous mixtures may be employed to increase the solubility of this drug. Based on the considerations mentioned above, the main purpose of this work is to determine the equilibrium solubility of adenosine (3) in binary mixtures of {N,N-dimethylformamide (DMF) (1) + water (2)}, {N-methyl-2-pyrrolidone (NMP) (1) + water (2)}, {dimethylsulfoxide (DMSO) (1) + water (2)} and {propylene glycol (PG) (1) + water (2)} at various temperatures ranging from (278.15 to 323.15) K under atmospheric pressure in order to evaluate the respective thermodynamic quantities of the solution, as well as the preferential solvation of the drug by these organic solvents. In this way, this research expands the available solubility data about drug in neat organic solvents and solvent mixtures [2] and also allows the thermodynamic analysis of the respective dissolution and specific solvation process.

It is noteworthy that PG and NMP are common co-solvents in pharmacy [30]. NMP is a very strong solubilizing agent [31] and is an important solvent in extraction, purification, and crystallization of drugs [32]. 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 [33]. Water‑DMF mixtures are strongly non ideal and can act in the solute-solvation process via hydrophobic interactions and preferential solvation [34], [35]. Solubility in dimethyl sulfoxide (DMSO) is one of the important parameters considered by pharmaceutical companies during early drug discovery [36], [37].

Section snippets

Materials, reagents and apparatus

Adenosine was purchased from Dalian Meilun Biological Technology Co., Ltd. with a mass fraction of 0.983. It was purified three times via crystallization in methanol. The final content of adenosine employed for solubility determination was 0.996 in mass fraction confirmed by using a high-performance liquid chromatography (HPLC). In this work, all solvents {DMF, NMP, DMSO and PG (racemic mixture)} were of analytical grade, which were provided by Sinopharm Chemical Reagent Co., Ltd., China. The

X-ray powder diffraction analysis

In order to demonstrate the existence of the polymorph transformation or solvate formation of adenosine during the solubility determination, the equilibrium solid phase is collected and analysed by XPRD. The patterns of the raw material and the solids crystallized in neat solvents and solvent mixtures are plotted in Fig. S3 of Supporting material. It is confirmed by XPRD pattern that all the XPRD patterns of solid phase of adenosine in equilibrium with its solution have the same characteristic

Conclusions

The equilibrium solubility of adenosine in binary mixed solvents of (DMF, NMP, DMSO and PG) + water with various composition were acquired experimentally via the isothermal dissolution equilibrium method in the temperature range of (278.15–323.15) K under about 101.0 kPa. For all solvent mixtures, the mole fraction solubility of adenosine increased with increasing temperature and mass fraction of DMF, NMP, DMSO and PG for the binary systems of (DMF, NMP, DMSO and PG) + water, and the maximum

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