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