Solubility temperature dependence and preferential solvation of sulfadiazine in 1,4-dioxane + water co-solvent mixtures
Graphical abstract
Introduction
The cosolvency as a solubilizing technique has been widely employed in pharmaceutical dosage design; nonetheless it has been just recently that the mechanisms involved in the modification of drug solubility started to be approached from a thermodynamic point of view, including the evaluation of the preferential solvation of the solute by the solvents in the mixtures [1], [2]. Additionally, the experimental drug behavior in co-solvent mixtures is frequently evaluated as a function of composition and temperature for the purification of raw materials, preformulation studies, and understanding of the molecular mechanisms involved in the physical and chemical stability of pharmaceutical dissolutions [3]. And also, the solubility of active ingredients is a crucial property to be considered because it affects several biopharmaceutical and pharmacokinetic properties [4], [5]. Moreover, the preferential solvation of the solute by the solvent components in the mixtures provides a powerful tool in the understanding of molecular interactions involved in the drug dissolution processes [6].
Sulfadiazine (SD, 4-amino-N-2-pyrimidinylbenzenesulfonamide, Fig. 1) is an extensively employed sulfonamide drug with a wide spectrum against most gram-positive and gram-negative organisms as it inhibits multiplication of bacteria by acting as competitive inhibitors of p-aminobenzoic acid in the folic acid metabolism cycle [7]. In spite of its solubility data in co-solvent mixtures is not yet complete [3], [8].
Although some theoretical and semiempirical models can be used to predict drug solubilities in solvent mixtures, the availability of experimental data is still fundamental for the pharmaceutical scientists [9]. Because the solubility of sulfonamides in neat water is too low [8], [10], some co-solvent + water mixtures have been evaluated in order to increase the solubility of SD [11], [12], [13], [14]. These researches have also been developed to understand the molecular mechanisms involved in the drug dissolution processes.
According to the literature, despite of its toxicity, 1,4-dioxane has been widely studied as model co-solvent in solubility studies because it is miscible with water in entire range of proportions although its polarity is very low (its dielectric constant is 2.21 at 298.15 K) [15], [16]. This co-solvent also allows studying molecular interactions since it is only a hydrogen-acceptor compound due to its two cyclic ether groups. On the other hand, aqueous 1,4-dioxane mixtures could be employed for purification of drugs by using recrystallization procedures.
For the reasons set out above, the main goal of this work is to expand the database on experimental solubility for SD, and also to evaluate the effect of the co-solvent composition on the solubility, solution thermodynamics, and preferential solvation of this drug in some binary mixtures conformed by 1,4-dioxane and water. The respective contributions by mixing of this compound toward the solution processes is also analyzed, as has been made previously for this drug in methanol + water, ethanol + water and 1-propanol + water co-solvent mixtures [12], [13], [14], as well as with other sulfonamides in other co-solvent systems [17], [18], [19], [20], [21].
Section snippets
Materials
The source and purities of the compounds (expressed in mass fractions) used in this work are summarized in Table 1. In the case of the solute sulfadiazine (SD, component 3), it was in agreement with the quality requirements of the United States Pharmacopeia, USP [22]. 1,4-Dioxane A.R. (component 1) from Scharlau (Spain), and distilled water (component 2) with conductivity <2 μS cm−1, were also used. Molecular sieve (Merck, Germany, number 3, pore size 0.3 nm) and Durapore® filters (0.45 μm,
Results and discussion
In order to put forward the possible intermolecular interactions existing in the saturated solutions of SD (3) that can explain the thermodynamic behavior and in order to establish hydrogen bonds with the OH groups in the solvents, it is important to keep in mind that this drug acts in solution mainly as a Lewis acid (due to its NH2 and NH groups) and as a Lewis base (due to its NH2, SO2, and N groups) [12], [15].
Conclusions
It can be concluded that the solution process of SD (3) in 1,4-dioxane (1) + water (2) mixtures depends strongly on the solvent composition as was also observed for this drug in other co-solvent binary mixtures [12], [13], [14]. Non-linear enthalpy–entropy compensation was found for this drug in this co-solvent system. In this context, enthalpy-driving was found for transfer processes in almost all the mixtures. Otherwise, this drug is preferentially solvated by water in water-rich and
Acknowledgment
We thank the Department of Pharmacy of the National University of Colombia for facilitating us the equipment and laboratories used.
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