Elsevier

Fluid Phase Equilibria

Volume 299, Issue 2, 25 December 2010, Pages 259-265
Fluid Phase Equilibria

Solubility and preferential solvation of indomethacin in 1,4-dioxane + water solvent mixtures

https://doi.org/10.1016/j.fluid.2010.09.027Get rights and content

Abstract

The solubilities of indomethacin (IMC) in 1,4-dioxane + water cosolvent mixtures were determined at several temperatures, 293.15–313.15 K. The thermodynamic functions: Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these data by using the van’t Hoff and Gibbs equations. The solubility was maximal in 0.95 mass fraction of 1,4-dioxane and very low in pure water at all the temperatures. A non-linear plot of ΔHsoln ° vs. ΔGsoln ° with negative slope from pure water up to 0.60 mass fraction of 1,4-dioxane and positive beyond this up to 0.95 mass fraction of 1,4-dioxane was obtained. Accordingly, the driving mechanism for IMC solubility in water-rich mixtures is the entropy, probably due to water-structure loss around the drug non-polar moieties by 1,4-dioxane, whereas, above 0.60 mass fraction of 1,4-dioxane the driving mechanism is the enthalpy, probably due to IMC solvation increase by the co-solvent molecules. The preferential solvation of IMC by the components of the solvent was estimated by means of the quasi-lattice quasi-chemical method, whereas the inverse Kirkwood-Buff integral method could not be applied because of divergence of the integrals in intermediate compositions.

Introduction

Indomethacin (IMC, Fig. 1) is a non-steroidal anti-inflammatory drug used as analgesic and antipyretic, among other indications [1]. Although IMC is used in therapeutics, the physicochemical information about its solubility is not abundant.

Its solubility in water is very low [2], [3], but water-co-solvent mixtures have been used widely in pharmacy, in order to increase the solubility of drugs poorly soluble in water for the design of homogeneous pharmaceutical dosage forms, such as syrups and elixirs, among others. 1,2-propanediol and ethanol are the cosolvents most widely used in medicine design, especially those intended for peroral and parenteral administration [2], [3]. Several examples of pharmaceutical formulations using these cosolvents have been presented by Rubino [2]. 1,2-propanediol and ethanol are hydrogen-donor and hydrogen-acceptor solvents, and have relatively large dielectric constants (24 and 32 at 293.15 K [4]). Therefore, mixtures with low polarities could not be studied by using these two solvents blended with water.

On the other hand, 1,4-dioxane is miscible with water in all possible compositions, although it has a low dielectric constant (2.2 at 293.15 K [4]). This solvent, when is blended with water, therefore allows to study polarities from 2 to 80 at room temperature. Contrary to 1,2-propanediol and ethanol that act as both Lewis donors and acceptors, 1,4-dioxane acts only as a Lewis base in aqueous media. Although it is a toxic solvent, it has been widely used as a model co-solvent for solubility studies of drugs by several authors [5], [6], [7], [8].

Since drugs are frequently used in solvent mixture for purification, pre-formulation studies, and pharmaceutical dosage design [2], [3], it is important to determine systematically their solubility, in order to obtain complete physicochemical data of liquid pharmaceutical systems. The temperature dependence of the solubility allows a thermodynamic analysis that permits insight into the molecular mechanisms involved in the solution processes [9]. Another way to obtain such insights is to estimate the preferential solvation of the drug by the components of the solvent mixture. This can be done in suitable cases by the application of the quasi-lattice quasi-chemical (QLQC) and the inverse Kirkwood-Buff integral (IKBI) methods [10], [11], [12] to solubility data.

The objective of this study was to evaluate the effect of the solvent mixture composition on solubility and solution thermodynamics of IMC in aqueous 1,4-dioxane mixtures as well as its preferential solvation by the components of the solvent mixture.

Section snippets

Materials

The indomethacin [1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, CAS: 53-86-1, purity at least 0.998 in mass fraction] that was used conformed to the quality requirements of the British Pharmacopoeia, BP [13]. So did the 1,4-dioxane (A.R. Scharlau, solvent component 1, purity at least 0.998 in mass fraction), the distilled water with conductivity <2 μS cm−1 (the solvent component 2), and the filter units (Millipore Corp. Swinnex®-13).

Solvent mixtures preparation

All 1,4-dioxane + water solvent mixtures were

Ideal and experimental solubility of IMC

The ideal solubility of a crystalline solute (3) in a liquid solvent can be calculated by Eq. (1):lnx3id=ΔHfus(TfusT)RTfusT+ΔCpRTfusTT+lnTTfusHere x3id is the mole fraction ideal solubility of the solute, ΔHfus is the molar enthalpy of fusion of the pure solute (at the fusion point), Tfus is the absolute fusion temperature, T is the absolute solution temperature, R is the gas constant (8.314 J mol−1 K−1), and ΔCp is the difference between the molar heat capacity of the crystalline form and

Discussion

In order to propose the possible intermolecular interactions present in the saturated solutions of IMC, it is important to keep in mind that IMC acts in solution mainly as a Lewis acid (due to its –OH group) in order to establish hydrogen bonds with proton-acceptor functional groups in the solvents (oxygen atoms in –OH and –O-groups). On the other hand, IMC can also act as a proton-acceptor compound by means of its carbonyl, methoxyl, and hydroxyl moieties (Fig. 1).

It is well known that the net

Conclusions

From all topics discussed here it can be concluded that the solution process of IMC (3) in 1,4-dioxane (1) + water (2) mixtures depends strongly on the solvent composition. Hydrogen bonding of the carboxylate group of IMC to the more basic solvent component, 1,4-dioxane, causes the latter to solvate the drug molecules preferentially. This is a part of the cause for its higher solubility in the 1,4-dioxane-rich mixtures, the other being the strong self-interaction of the water molecules that

Acknowledgments

We thank the DIB of the National University of Colombia (NUC) for the financial support. Additionally we thank the Department of Pharmacy of NUC for facilitating the equipment and laboratories used.

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