Elsevier

Fluid Phase Equilibria

Volume 293, Issue 2, 25 June 2010, Pages 242-250
Fluid Phase Equilibria

Thermodynamic analysis of the solubility of ketoprofen in some propylene glycol + water cosolvent mixtures

https://doi.org/10.1016/j.fluid.2010.03.031Get rights and content

Abstract

By using the van’t Hoff and Gibbs equations the thermodynamic functions Gibbs energy, enthalpy, and entropy of solution, mixing, and solvation for ketoprofen in propylene glycol + water (PG + W) cosolvent mixtures, were evaluated from solubility data determined at several temperatures. The solubility was greater in pure PG and lower in W at all temperatures studied. By means of enthalpy–entropy compensation analysis, non-linear ΔHsoln° vs. ΔGsoln° plot with negative slope from pure water up to 0.50 in mass fraction of PG and positive beyond this PG proportion was obtained. Accordingly to this result, it follows that the driving mechanism for solubility of KTP in water-rich mixtures is the entropy, probably due to water-structure loosing around the drug non-polar moieties by PG, whereas, over 0.50 in mass fraction of PG the driving mechanism is the enthalpy probably due to KTP solvation increase by cosolvent molecules. On the other hand the Jouyban–Acree model was challenged in front to experimental KTP solubility values finding a predictive power within 30% of deviation.

Introduction

Ketoprofen (KTP, Fig. 1) is a non-steroidal anti-inflammatory drug (NSAID) derived from propionic acid used widely as analgesic and antipyretic, among other indications [1]. In the Colombian market it is commercially available as coated tablets and controlled release tablets for peroral administration, gel for topic use, and injectable solution for intramuscular administration [2]. Although KTP is used widely nowadays in therapeutics, the physicochemical information about properties such as solubility for this drug is not abundant. On the other hand, it is well known that injectable homogeneous liquid formulations supply relatively high doses of drug in small volumes. For this reason, some physicochemical properties, such as the solubility of drugs and other formulation components, are very important because they facilitate the design process of pharmaceutical dosage forms [3].

As has been already described, the solubility behavior of drugs in cosolvent mixtures is very important because cosolvent blends are frequently used in purification methods, preformulation studies, and pharmaceutical dosage forms design, among other applications [4], [5]. For these reasons it is important to determine systematically the solubility of drugs, in order to obtain complete information about physicochemical data of liquid pharmaceutical systems. Besides, temperature-solubility dependence allows us to carry out the respective thermodynamic analysis, which, on the other hand, also permits inside the molecular mechanisms, involved toward the solution processes [6].

The main objective of this study was to evaluate the effect of the cosolvent composition on solubility and solution thermodynamics of KTP in propylene glycol + water cosolvent mixtures based on van’t Hoff method, including the respective contributions by mixing and solvation of this drug toward the solution processes. Ethanol and propylene glycol are the cosolvents more widely used in the development of liquid pharmaceutical dosage forms [4], [5]. This report expands the information presented for this drug by Espitalier et al. [7], Singhai et al. [8], Kommury et al. [9], Perlovich et al. [10], and more recently, by Gantiva et al. [11].

Section snippets

Materials

Ketoprofen [2-(3-benzoyl-phenyl)propionic acid, CAS: 22071-15-4] and propylene glycol (PG) used were in agreement with the quality requirements indicated in the American Pharmacopeia, USP [12]. In similar way, cyclohexane A.R. Merck, distilled water (W) with conductivity <2 μS cm−1, molecular sieve Merck (numbers 3 and 4), and Millipore Corp. Swinnex®-13 filter units, were also used.

Cosolvent mixtures preparation

All PG + water cosolvent mixtures were prepared in quantities of 10.00 g by mass using an Ohaus Pioneer TM PA214

Results and discussion

It is important to keep in mind, that this drug acts in solution mainly as a Lewis acid in order to establish hydrogen bonds with proton-acceptor functional groups in the solvents (oxygen in –OH groups). On the other hand, KTP could also act as a proton-acceptor compound by means of its carbonyl and hydroxyl moieties (Fig. 1) [11].

Conclusions

From all topics discussed previously it can be concluded that the solution process of KTP (3) in PG (1) + water (2) mixtures is variable depending on the cosolvent composition. Non-linear enthalpy–entropy compensation was found for this drug in this cosolvent system. In this context, entropy driving was found for the solution processes in compositions from pure water to the mixture having 0.50 in mass fraction of PG; whereas, for cosolvent mixtures beyond this PG proportion, enthalpy-driving was

Acknowledgments

We thank the DIB of the Universidad Nacional de Colombia (UNC) for the financial support. Additionally we thank the Department of Pharmacy of UNC for facilitating the equipment and laboratories used.

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