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COPYRIGHT 2006 Acedemia Colombiana de Ciencias Exactas, Fisicas y Naturales
Abstract
Based on van't Hoff and Gibbs equations the thermodynamic functions free energy, enthalpy, and entropy of solution, mixing and solvation of acetaminophen in ethanol + water cosolvent mixtures, were evaluated from solubility data determined at several temperatures. The solubility was greater at 90% m/m of ethanol at all temperatures studied. This result shows clearly the cosolvent effect present in this system. The solvation of this drug in the mixtures increases as the ethanol proportion is also increased. By means of enthalpy-entropy compensation analysis, a more complex behavior for solution was found with respect to that exposed previously in literature. From 0% up to 10% m/m of ethanol and from 90% up to 100% of ethanol, entropy driving was found, while from 20% up to 60% of ethanol, enthalpy driving was found. These facts would be explained in terms of a losing of water-structure in addition to a diminishing in the energy required for cavity formation in the solvent for mixtures from 20% up to 60% of ethanol. Nevertheless in the ethanol-rich mixtures the intermolecular mechanisms involved in the solution process should be more complex including other physicochemical considerations.
Key words: Acetaminophen, solubility, solution thermodynamics, solvation.
Resumen
A partir de valores de solubilidad a diferentes temperaturas mediante las ecuaciones de Gibbs y van't Hoff se calcularon las funciones termodinamicas, energia libre, entalpia y entropia, para los procesos de solucion, mezcla y solvatacion de acetaminofen (ACF) en mezclas cosolventes etanol + agua (EtOH + W). La solubilidad fue mas alta en mezclas del 90% de EtOH a todas las temperaturas estudiadas, lo que demuestra la importancia del efecto cosolvente en este sistema. La solvatacion del farmaco es mayor en la medida que se incrementa la proporcion de EtOH en las mezclas. Mediante analisis de compensacion entalpica-entropica se obtuvo un comportamiento mas complejo que el descrito previamente en la literatura. Desde el agua pura hasta el 10% m/m de EtOH y desde el 90% de EtOH hasta el etanol puro se encontro una conduccion entropica, mientras que en las otras mezclas se encontro conduccion entalpica. Estos hechos podrian explicarse en terminos de la perdida de estructura del agua y en una disminucion de la energia de cavidad en el solvente al incrementar la proporcion de EtOH. Sin embargo, en las mezclas ricas en EtOH los mecanismos intermoleculares involucrados en el proceso de solucion deben ser mas complejos involucrando a otras propiedades fisicoquimicas.
Palabras clave: Acetaminofen, solubilidad, termodinamica de soluciones, solvatacion.
Introduction
Acetaminophen is an analgesic and antipyretic drug widely used in modern therapeutics. This drug is specially indicated in the treatment of several minor diseases presented by pediatric patients (Lund W., 1994; Roberts II LJ & Morrow JD, 2001). In the Colombian market it is commercially available as tablets, syrups and concentrates, but it is not available as parenteral products (Rosenstein-Ster, E., 2004). The later products recently have been asked for by physicians and other care practitioners. Injectable homogeneous liquid formulations supply relatively high doses of drug in small volumes. For this reason, some physicochemical properties such as the solubility and the occupied volumes by the drugs and other components in the solution are very important because they facilitate the design process of pharmaceutical dosage forms (Lund W., 1994; Perez, C. et al., 2003).
The solubility behavior of drugs in cosolvent mixtutes is very important because cosolvent blends are frequently used in purification methods, preformulation studies, and pharmaceutical dosage forms design, among other applications (Rubino JC., 1988; Yaikowsky SH., 1999). Although several methods of calculating the solubility are available nowadays, these methods do not explain fully the mechanism of cosolvent action in mixtures. On the other hand, almost all of these methods in general do not consider the effect of temperature on this fundamental property. For these reasons it is important to determine systematically the solubility of drugs, in order to obtain complete information about physicochemical data for pharmaceutical systems. This information facilitates widely the labor of pharmacists associated to research and development of new products in pharmaceutical industry (Jimenez F. & Martinez F., 1995). Temperature-solubility dependence permits to realize the respective thermodynamic analysis, which, at its time, permits inside the molecular mechanisms, involved toward the solution processes (Garzon LC. & Martinez F., 2004).
The main objective of this study was to evaluate the effect of the cosolvent composition on solubility and solution thermodynamics of acetaminophen in ethanol + 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 (Rubino, JC., 1988). The present investigation is a continuation and expansion of those developed with this drug by Grant, DJW. et al. (1984), Etman MA. & Naggar VF. (1990), Bustamante P. et al. (1995, 1998), and Perez DC. et al. (2003), among others.
Experimental
Materials
Acetaminophen USP (ACP) (US Pharmacopeia, 1994): absolute ethanol A.R., Merck (EtOH); distilled water (W), conductivity < 2 [micro]S, Laboratory of Pharmaceutics of the Universidad Nacional de Colombia; molecular sicre Merck (numbers 3 and 4); Milliporc Corp. Swinnex[R]-13 filter units.
Solubility determinations
An excess of ACP was added to 20 mL of each cosolvent mixture evaluated in glass flasks. The cosolvent mixtures were prepared by mass in quantities close to 100.0 g varying in 10.00% m/m (Mettler Toledo PB302, sensitivity [+ or -] 0.01 g). The solid-liquid mixtures were then stirred in a (Wrist Action, Burrel, model 75) mechanical shaker for 1 hour. Samples were then allowed to stand in (Magni Whirl Blue M. Electric Company) water baths kept at the appropriate temperature [+ or -] 0.05[degrees]C. All samples were maintained at least for 48 hours to reach the equilibrium.
After this time the supernatant solutions were filtered (at isothermal conditions) to ensure that they were free of particulate matter before sampling. Drug concentrations were determined by measuring refractive indexes (Abbe Carlzeiss Jena refractive meter) after appropriate dilution and interpolation from previously constructed calibration curves for ACP in each cosolvent mixture (Perez DC., et al. 2003).
All the solubility experiments were repeated at least three times and the results were averaged. In order to permit conversion between molarity and mole fraction concentration scales, the density of the saturated solutions was determined with a digital density meter (DMA 45 Anton Paar, precision [+ or -] 0.0001 g [cm.sup.-3]).
Results and discussion
In Table 1, the molecular structure of ACP and some of their physicochemical properties are summarized. The melting point and enthalpy of fusion were reported by Bustamante P. et al. (1995) while the enthalpy of sublimation was reported by Williams D. et al. (2004). Accordingly to Romero S. et al. (1996) this drug act in solution mainly as...
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