Vitae ISSN: 0121-4004 [email protected] Universidad de Antioquia Colombia BAENA A, Yolima; VARGAS E, Edgar F; MARTÍNEZ R, Fleming THERMODYNAMIC ASPECTS OF SOLVATION AND DILUTION FOR ACETANILIDE AND PHENACETIN IN SOME AQUEOUS AND ORGANIC SOLVENTS MUTUALLY SATURATED Vitae, vol. 15, núm. 1, enero, 2008, pp. 132-140 Universidad de Antioquia Medellín, Colombia Available in: http://www.redalyc.org/articulo.oa?id=169815394015 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative VITAE, REVISTA DE LA FACULTAD DE QUÍMICA FARMACÉUTICA ISSN 0121-4004 Volumen 15 número 1, año 2008. Universidad de Antioquia, Medellín, Colombia. págs. 132-140 THERMODYNAMIC ASPECTS OF SOLVATION AND DILUTION FOR ACETANILIDE AND PHENACETIN IN SOME AQUEOUS AND ORGANIC SOLVENTS MUTUALLY SATURATED ASPECTOS TERMODINÁMICOS DE LA SOLVATACIÓN Y LA DILUCIÓN DE ACETANILIDA Y FENACETINA EN ALGUNOS SOLVENTES ORGÁNICOS Y ACUOSOS MUTUAMENTE SATURADOS Yolima BAENA A.1, Edgar F. VARGAS E.2, Fleming MARTÍNEZ R.1* Recibido: Febrero 6 de 2008 Aceptado: Abril 22 de 2008 ABSTRACT Acetanilide (ACN) and phenacetin (PNC) are compounds structurally related with acetaminophen widely used as model drugs in pharmaceutical chemistry. Based on published thermodynamic quantities for dissolution, partitioning and sublimation of ACN and PNC, at 25.0 °C, thermodynamic quantities for drugs solvation in cyclohexane-saturated water (W(CH)) and water-saturated cyclohexane (CH(W)), chloroform-saturated water (W(CLF)) and water-saturated chloroform (CLF(W)), and isopropyl myristate- saturated water (W(IPM)) and water-saturated isopropyl myristate (IPM(W)), as well as the drugs dilution in the organic solvents were calculated. The Gibbs energies of solvation were favourable in all cases. Respective enthalpies and entropies were negative indicating an enthalpy-driving for the solvation process in all cases. Otherwise, the Gibbs energies of dilution were favourable for ACN and PNC in IPM(W) but unfavourable in the other organic solvents, whereas the respective enthalpies and entropies were negative for both drugs in all the organic solvents, except for PNC in CH(W) indicating enthalpy-driving for the dilution process in the former cases and entropy-driving for the later. From obtained values for the transfer processes, an interpretation based on solute-solute and solute-solvent interactions was developed. Keyword: Acetanilide, phenacetin, solvation, dilution, partition coefficient, organic solvents, solution thermodynamics RESUMEN La acetanilida (ACN) y la fenacetina (FNC) son dos compuestos estructuralmente relacionados con el acetaminofeno que son ampliamente utilizados en química farmacéutica como fármacos modelo. Con base en valores termodinámicos publicados para los procesos de disolución, reparto y sublimación de la ACN y la FNC, presentados a 25,0 °C, se calculan las funciones termodinámicas de solvatación de los dos fármacos en agua saturada de ciclohexano (W(CH)), ciclohexano saturado de agua (CH(W)), agua saturada de cloroformo (W(CLF)), cloroformo saturado de agua (CLF(W)), agua saturada de miristato de isopropilo (W(MIP)) y miristato de isopropilo saturado de agua (MIP(W)), así como las respectivas funciones 1 Sección de Farmacotecnia, Departamento de Farmacia, Universidad Nacional de Colombia, A.A. 14490, Bogotá D.C., Colombia. 2 Departamento de Química, Universidad de los Andes, Bogotá D.C., Colombia. * Autor a quien se debe dirigir la correspondencia: [email protected] THERMODYNAMIC ASPECTS OF SOLVATION AND DILUTION FOR ACETANILIDE AND PHENACETIN IN SOME AQUEOUS AND ORGANIC... 133 termodinámicas de los fármacos en los solventes orgánicos. Las energías libres de Gibbs de solvatación son favorables en todos los casos. Las respectivas entalpías y entropías son negativas indicando una conducción entálpica para el proceso de solvatación en todos los casos. De otro lado, las energías libres de dilución son favorables para ACN y PNC en MIP(W) pero desfavorables en los otros solventes orgánicos, mientras que las respectivas entalpías y entropías son negativas para los dos fármacos en todos los solventes orgánicos, excepto para PNC en CH(W), lo que indica que el proceso de dilución es conducido entálpicamente en los primeros casos y entrópicamente en el último. A partir de los valores termodinámicos obtenidos para los procesos de transferencia se desarrolla una interpretación en términos de interacciones soluto-soluto y soluto-solvente. Palabras clave: Acetanilida, fenacetina, solvatación, dilución, coeficiente de reparto, solventes orgánicos, termodinámica de soluciones. INTRODUCTION hydrogen bonding on partitioning would be studied completely. Phenacetin (PNC) was used as analgesic and As a contribution to systematization of physi- antipyretic drug long time ago but it was removed cochemical information about drugs’ transfer pro- from the market because it can induce nephropa- perties, the main goal of this study was to analyze thy and cancer. Otherwise, acetanilide (ACN) is the solvation and dilution behavior of ACN and mainly used as an intermediate in the synthesis of PNC in the cyclohexane/water (CH/W), chloro- some drugs and dyes (1). Both compounds have a form/water (CLF/W) and isopropyl myristate/water good molecular similarity between them as it can (IPM/W) systems by employing a thermodynamic be seen in Table 1. approach based on solubility (7), partitioning (8) On the other hand, as useful information in me- and sublimation processes (1). From the obtained dicinal chemistry, the thermodynamics of transfer values of the corresponding thermodynamic quan- of drug compounds can be studied by measuring tities of drugs’ transfer, an interpretation based on the partition coefficient and/or solubility as a func- solute-solvent and solvent-solvent interactions was tion of temperature. Such data can be used for the developed. prediction of absorption, membrane permeability, and in vivo drug distribution (2). Theoretical Semi-polar solvents have been found to yield The partition coefficient expressed in molality m better correlations with partitioning of solutes ( K o / w ), for any solute between organic and obtained in model membranes compared to non- aqueous phases is calculated by means of: polar solvents such as cyclohexane (CH), which C C interacts only by non-specific forces (London K m W 1 2 o / w w C W (1) interactions). In particular, octanol (ROH) has 2 o been found to be a useful solvent as the reference W W for extrathermodynamic studies in a variety of where, w and o are the masses (usually in g) of aqueous and organic phases, respectively, and C systems (3). Isopropyl myristate (IPM) has also 1 and C are aqueous concentrations of solute (usually been used acting as a hydrogen acceptor as well, 2 μ –1 and it has been used especially for determining in g mL ) before and after the transfer of solute drug hydrophobic constants since it simulates most from the aqueous phase to the organic medium, closely the corneum stratum/water partition. IPM is respectively (2). If the drug concentrations in both phases are lower than 10–4 mol Kg–1, the rational best related to skin/transdermal absorption because X partition coefficients ( K o / w , expressed in mole its polar/non-polar balance simulates the complex K m nature (polar/non-polar matrix) of the skin (4-6). fraction) are calculated from o / w values as: Moreover, chloroform (CLF) has also been used X m K o w K o w (M o / M w ) (2) in these kinds of studies since it acts mainly as a / / hydrogen donor for establishing hydrogen bonds where, Mo and Mw are the molar masses of the with Lewis basic solutes (7). Thus, the effect of organic and aqueous phases, respectively (9). 134 VITAE 0 X The standard change for Gibbs free energy of The thermodynamic functions ΔH w→o and 0 X transfer of a solute from an aqueous phase to an ΔS w→o represent the standard changes in enthalpy organic medium is calculated as follows: and entropy, respectively, when one mole of drug is transferred from the aqueous medium to the G 0 X RT ln K X (3) w o o / w organic system at infinite dilution expressed in the mole fraction scale (2). Otherwise, the enthalpy change for the transfer On the other hand, for the dissolution process may be obtained indirectly by means of the analysis of drugs some equations similar to 3, 4 and 5 have of the temperature-dependence for partitioning been used for calculating the respective thermo- by using the van’t Hoff method. This procedure dynamic functions. In this case, X is used instead permits to obtain the standard enthalpy change X 2 0 X of K o / w (7). ( ΔH w→o ) from: RESULTS AND DISCUSSION C K X S H 0 X D ln o / w T w o D T (4) All the experimental values of solubility, par- E (1/T) U R titioning and sublimation for the evaluated drugs P have been taken from the literature (1, 7, 8). The 0 X molecular structure and some physicochemical Therefore, ΔH w→o is determined from the slo- pe of a weighted linear plot of as a function properties of the drugs are summarized in Table of 1/T. The standard entropy change of transfer is 1 (1, 10). The solubility in water and the ROH/W obtained by means of: partitioning was determined at pH 7.4 (resembling the blood physiological value). At this pH value 0 X 0 X both compounds are present mainly in their mo- 0 X ΔH w→o − ΔGw→o ΔS = (5) lecular form without dissociation and therefore w→o T they have their lowest aqueous solubility and highest partitioning. Table 1. Some physicochemical properties of the drugs studied. (a) –1 (a) H –1 (b) T (b) Drug Molecular structure M / g mol Δ fus / kJ mol fus / K NH-CO-CH3 ACN 135.16 21.2 (0.5) 386.1 (0.2) NH-CO-CH3 PNC 179.21 31.3 407.2 O-CH2CH3 (a) From Budavari et al.