Solubility of sulfamethizole in some propylene glycol + water mixtures at several temperatures

doi:10.1016/j.fluid.2012.03.014

Fluid Phase Equilibria

Volumes 322–323, 25 May 2012, Pages 113-119

https://doi.org/10.1016/j.fluid.2012.03.014 Get rights and content

Abstract

The solubility of sulfamethizole (SMZ) in propylene glycol + water cosolvent mixtures was determined at temperatures from 293.15 to 313.15 K. The solubility was maximal in pure propylene glycol and very low in pure water at all the temperatures. The thermodynamic functions: Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data by using the van’t Hoff and Gibbs equations. Thermodynamic quantities of mixing were also calculated by using calorimetric values related to drug fusion process. A nonlinear enthalpy–entropy relationship was observed from a plot of enthalpy vs. Gibbs energy of solution. The plot of Δ_solnH° vs. Δ_solnG° shows two different trends, one with negative slope from pure water up to 0.20 mass fraction of propylene glycol and the other one positive beyond this composition up to pure propylene glycol. Accordingly, the driving mechanism for SMZ solubility in water-rich mixtures is the entropy, probably due to water-structure loss around the drug non-polar moieties by effect of propylene glycol, whereas, above 0.20 mass fraction of propylene glycol the driving mechanism is the enthalpy, probably due to SMZ solvation increase by the co-solvent molecules. This behavior is similar to the one exhibited by sulfanilamide and other drugs in the same co-solvent mixtures.

Highlights

► The sulfamethizole solubility was maximal in pure propylene glycol and minimal in pure water. ► Thermodynamic quantities of solution and mixing were obtained for sulfamethizole. ► A non-linear plot of Δ_solnH° vs. Δ_solnG° compensation is found for sulfamethizole at 303.0 K.

Introduction

The behavior of drugs in different kinds of solvent mixtures is commonly evaluated for the purposes of purification, pre-formulation studies, and liquid pharmaceutical dosage forms design [1]. Hence, it is important to determine systematically their solubilities in order to obtain complete physicochemical data about liquid pharmaceutical and chemical systems. The temperature dependence of the solubility allows a thermodynamic analysis that permits insight into the molecular mechanisms involved in the drug dissolution processes [2]. This knowledge is also important for several biopharmaceutical applications.

Sulfamethizole (SMZ, Fig. 1) is a sulfonamide-derived drug extensively employed as effective antimicrobial agent for the prevention and cure of several bacterial infections in humans and animals [3].

Although SMZ has been widely used in therapeutics the physicochemical information about its solubility in aqueous media is not abundant, although is known that its solubility in neat water is too low [4]. In this way, some water + co-solvent mixtures have been evaluated in order to increase drugs solubility and also to permit molecular understanding of solution phenomena and development of homogeneous liquid pharmaceutical products. According to the literature, ethanol and propylene glycol (1,2-propanediol) have been studied in particular as possible co-solvents in the design of several medicines intended for oral and parenteral administration [1]. Moreover, propylene glycol has also been used as an evaporation regulator and antimicrobial agent in several liquids formulations [5]. Both co-solvents are hydrogen-donor and hydrogen-acceptor compounds, and thus, they are miscible with water in all proportions [6].

For all these reasons, the main objective of this study was to evaluate the effect of the co-solvent composition on solubility and solution thermodynamics of SMZ in binary mixtures conformed by propylene glycol and water, based on the van’t Hoff method, including the respective contributions by mixing of this compound toward the solution processes. Thus, this research is a continuation of the one developed with sulfanilamide in the same solvent mixtures [7].

Section snippets

Reagents

The solute sulfamethizole (compound 3, 4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide, CAS [144-82-1], purity >0.995 in mass fraction), the propylene glycol (compound 1, purity >0.998 in mass fraction) and the distilled water (compound 2) with conductivity <2 μS cm⁻¹ were used conformed to the quality requirements of the American Pharmacopeia, USP [8].

Solvent mixtures preparation

All propylene glycol (1) + water (2) solvent mixtures were prepared by mass, using an Ohaus Pioneer TM PA214 analytical balance with

Results and discussion

In order to propose the possible intermolecular interactions present in the saturated solutions of SMZ (3), it is important to keep in mind that this drug acts in solution mainly as a Lewis base (due to its aromatic single bond NH₂ and/or SO₂, double bond N and S groups) and as a Lewis acid (due to its NH₂ and 2 bonds on the lefthand side NH groups) in order to establish hydrogen bonds with proton-acceptor functional groups in the solvents (oxygen atoms in OH and O groups). In addition, some effects due to weak London dispersive forces could be

Conclusions

From all topics discussed here it can be concluded that the solution process of SMZ (3) in propylene glycol (1) + water (2) mixtures depends strongly on the solvent composition as was also observed for sulfanilamide [7]. Hydrogen bonding of the sulfonamide and amine groups of SMZ (3) to the more basic solvent component, propylene glycol (1), could to cause the latter to solvate the drug molecules preferentially [22]. This is just a part of the cause for its higher solubility in the propylene

Acknowledgments

We thank the Department of Pharmacy of the National University of Colombia for facilitating us the equipment and laboratories used. We also thank Mr. R.G. Sotomayor for collaborating us with the DSC analysis.

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Citation Excerpt :
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Solubility of sulfamethizole in some propylene glycol + water mixtures at several temperatures

Abstract

Highlights

Introduction

Section snippets

Reagents

Solvent mixtures preparation

Results and discussion

Conclusions

Acknowledgments

J. Pharm. Sci.

J. Chem. Thermodyn.

Eur. J. Pharm. Biopharm.

Fluid Phase Equilib.

Fluid Phase Equilib.

Fluid Phase Equilib.

J. Pharm. Sci.

Phys. Chem. Liq.

The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals

The Science of Dosage Forms Design

Solubilization in Aqueous Media

Lat. Am. J. Pharm.