buffer systems

J. Chem. Thermodynamics 86 (2015) 180–187

Contents lists available at ScienceDirect

J. Chem. Thermodynamics journal homepage: www.elsevier.com/locate/jct

Thermodynamic study of the partitioning of methyl and propyl parabens in some organic solvent/buffer systems Zaira J. Cárdenas, Daniel M. Jiménez, Fleming Martínez ⇑ Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia, Cra. 30 No. 45-03, Bogotá D.C., Colombia

a r t i c l e

i n f o

Article history: Received 21 January 2015 Received in revised form 3 March 2015 Accepted 6 March 2015 Available online 16 March 2015 Keywords: Methyl paraben Propyl paraben Partition coefficient Organic solvents Thermodynamics of transfer

a b s t r a c t The thermodynamic quantities of partitioning of methyl paraben (MP) and propyl paraben (PP) were studied at five temperatures in several organic solvent/buffer systems, namely, 1-octanol (ROH/W), isopropyl myristate (IPM/W), chloroform (CLF/W) and cyclohexane (CH/W). In all cases, the values of the x ) were greater than unity; therefore, the standard Gibbs free enermole fraction partition coefficient (K o=w gies of transfer are negative indicating a high affinity of MP and PP for all the organic media evaluated. x values were approximately 470-fold and 1700-fold higher in the ROH/W system with respect The K o=w to the CH/W for MP and PP, thus indicating a high degree of hydrogen bonding contribution to partitionx values were in the orders of 0.48 or 0.30 of those ing. Otherwise, in the case of the IPM/W system, the K o=w x values were in the orders of 0.03 to observed in ROH/W, whereas, in the case of CLF/W system, the K o=w 0.04 of those observed in ROH/W. On the other hand, enthalpies and entropies of transfer of PP from water to organic solvents were all positive but in the case of MP the quantities were variable, negative or positive as well. These results could indicate some degree of participation of the hydrophobic hydration on the MP and PP partitioning processes. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Alkyl-parabens are a group of homologous series of esters of 4hydroxybenzoic acid (figure 1), only differing in the ester group length, which may be a methyl-, ethyl-, propyl- or butyl-group. They are widely used as antimicrobial preservatives in cosmetics, food products, and pharmaceutical formulations and they may be used either alone or in combination with others. The parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and moulds [1]. As a contribution to the generation and systematization of physicochemical information about pharmaceutical agents in aqueous and organic media, the thermodynamics of transfer of these compounds can be studied by measuring the mole fraction partition coefficient as a function of temperature by means of the van’t Hoff equation. Such data can be used for the prediction of absorption, membrane permeability, and in vivo distribution [2]. To understand properly the processes that happen at the biological barriers, the characterization of the behavior in simple systems, such as liquid/liquid systems is very useful in order to ⇑ Corresponding author. Fax: +57 1 3165060. E-mail address: [email protected] (F. Martínez). http://dx.doi.org/10.1016/j.jct.2015.03.006 0021-9614/Ó 2015 Elsevier Ltd. All rights reserved.

determine the relative lipophilicity of the compounds [3,4]. Also, semi-polar solvents have been found to yield better correlations with the partitioning of solutes obtained in model membranes compared to non-polar solvents such as cyclohexane (CH), which interacts only by non-specific forces (London interactions) [5]. Particularly, 1-octanol (ROH) is a useful solvent as reference for extra-thermodynamic studies in a variety of systems [6]. Isopropyl myristate (IPM) is useful for establishing hydrogen bonds with Lewis acid solutes since it acts mainly as a hydrogen acceptor and, also it simulates most closely the corneum stratum/water partition which is used especially for determining some drug hydrophobic constants [7]. Moreover, chloroform (CLF) acts mainly as a hydrogen donor. Thus, the effect of hydrogen bonding on partitioning would be studied in more details [8,9]. In this way, the main goal of this study was to compare the partitioning of methyl paraben (MP) and propyl paraben (PP) in different organic medium/buffer systems, namely: cyclohexane (CH/W), 1-octanol (ROH/W), isopropyl myristate (IPM/W), and chloroform (CLF/W), by employing a thermodynamic approach based on the mole fraction partitioning variation with temperature. With that purpose, an interpretation in terms of (solute + solvent) interactions based on the corresponding thermodynamic quantities of transfer was developed.

181

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

FIGURE 1. Molecular structure of parabens. (n = 1: methyl paraben and n = 3: propyl paraben).

property depends on all the partitioning data; whereas, in the traditional form, it depends solely on the value obtained at the specified temperature. The standard entropic change for the transfer process (Dw?oS°/J  K1  mol1) is obtained from the respective Dw?oH° and Dw?oG° values at Thm, by using:

Dw!o S ¼ 2. Theoretical background The following definitions of

Km o=w ,

K Co=w

and

x K o=w

imply that no

drug association or dissociation takes place in any of the respective phases, that is, the partitioning obeys the Nernst limit law. In this way, the molal partition coefficient (K m o=w ) for any solute between organic and aqueous phases is calculated by means of:

Km o=w

C1  C2 ¼ Ww ; C2W o

ð1Þ

where, Ww and Wo are the masses (usually in g) of aqueous and organic phases, respectively, and C1 and C2 are the solute aqueous concentrations (usually in lg  g1) before and after the transfer from the aqueous phase to the organic medium, respectively [8,9]. If the solutions are diluted, the molar partition coefficients (K Co=w ) are calculated as:

K Co=w ¼ K m o=w ðqo =qw Þ;

ð2Þ

where qo and qw are the densities of the organic and aqueous phases, respectively. In turn, the mole fraction partition coefficients x ) are calculated from K m (K o=w o=w values as: x K o=w ¼ Km o=w ðM o =M w Þ;

ð3Þ

where, Mo and Mw are the molar masses (g  mol1) of the organic and aqueous phases, respectively [8,9]. It is important to indicate that when very low solute concentrations are studied in both phases no partitioning dependence on concentration is observed because (solute + solute) interactions are normally not present [5,6]. On the other hand, the enthalpy change for the transfer of solutes from aqueous phases to organic systems may be obtained indirectly by means of the analysis of the temperature-dependence of partitioning. In this way, the classical van’t Hoff equation was applied to estimate the enthalpic change of transfer from aqueous media to organic systems (Dw?oH°/J  mol1), employing the pondered graphs based on the logarithm of partition coefficients as a function of the reciprocal of absolute temperature [8]. In this case, the mean harmonic temperature (Thm/K) was introduced into the van’t Hoff equation in order to facilitate the regression treatment. When temperature intervals from (298.15 to 318.15) K (varying in 5.00 K) are evaluated, the Thm value obtained is just 308.0 K. Thus the modified expression can be written as follows: x @ ln K o=w

@ð1=T  1=T hm Þ

! ¼ p

Dw!o H : R

ð4Þ

The standard Gibbs free energy change for the transfer process (Dw?oG°/J  mol1), considering the approach proposed by Krug et al. [10] is calculated at Thm by means of: 

Dw!o G ¼ RT hm  Intercept; in which, the intercept used is the one obtained from ln

ð5Þ x K o=w

vs.

1/T–1/Thm plots (equation (4)). The Dw?oG° value obtained by using the equation (5) is slightly different with respect to that calculated x as RT ln K o=w at T = 308.15 K, because in the former case, this

Dw!o H  Dw!o G : T hm

ð6Þ

The thermodynamic functions Dw?oH° and Dw?oS° represent the standard changes in enthalpy and entropy, respectively, when one mole of solute is transferred from the aqueous medium to the organic system, at infinite dilution and expressed in the mole fraction scale [2,11]. 3. Experimental 3.1. Chemicals The following chemicals were used: methyl paraben (Sigma– Aldrich, USA); propyl paraben (Sigma–Aldrich, USA); 1-octanol extra pure grade (Scharlau, Spain); isopropyl myristate for synthesis (Merck, Germany); chloroform A.R. (Mallinckrodt, USA); cyclohexane A.R. (Mallinckrodt, USA); potassium chloride A.R. (Merck, Germany); citric acid A.R. (Merck, Germany); sodium hydroxide A.R. (Merck, Germany); distilled water (conductivity <2 lS  cm1). The main properties of all these compounds are summarized in table 1. 3.2. Organic solvent/buffer partitioning Aqueous solutions of methyl paraben and propyl paraben at known concentrations were prepared in aqueous citrate buffers adjusted to pH 4.0 at ionic strength of 0.15 mol  L1, resembling maximum pH stability [12] and physiological ionic strength values [13]. Then, specific masses of organic solvents were added to specific masses of the aqueous solutions in glass flasks [14]. The employed masses of each phase and the concentrations are shown in table 2. All aliquots were weighted on a digital analytical balance (Ohaus Pioneer TM PA214, USA) whose sensitivity was ±0.1 mg.

TABLE 1 Provenance and mass fraction purity of the compounds used in this research. Compound

CAS

Formula

Molar mass/ g  mol–1

Source

Methyl paraben Propyl paraben 1-Octanol Isopropyl myristate Chloroform

99-76-3

C8H8O3

152.15

94-13-3

C10H12O3

180.20

111-87-5 110-27-0

C8H18O C17H34O2

130.23 270.45

Sigma-Aldrich, USA Sigma-Aldrich, USA Scharlau, Spain Merck, Germany

67-66-3

CHCl3

119.38

Cyclohexane

110-82-7

C6H12

84.16

Water

7732-18-5 H2O

18.02

5949-29-1 C6H8O7.H2O 210.14 Citric acid.H2O Sodium 1310-73-2 NaOH 40.00 hydroxide Potassium 7447-40-7 KCl 74.55 chloride

Purity in mass fraction 0.990 0.990 0.997 0.997

Mallinckrodt, 0.998 USA Mallinckrodt, 0.998 USA Obtained by >0.999 distillation Merck, Germany 0.998 Merck, Germany

0.997

Merck, Germany

0.999

182

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

TABLE 2 Partitioning conditions for parabens used in this research. Part. system

Methyl paraben Mass organic phase/g

Propyl paraben Aqueous phase

a

Mass organic phase/g –1b

Mass/g

T/K

Concentration/lg  g

Aqueous phase

a

Mass/g

T/K

Concentration/lg  g–1b

ROH/W

1.00

10.00

298.15 303.15 308.15 313.15 318.15

75.0 77.0 80.0 55.0 55.0

1.00

10.00

298.15 303.15 308.15 313.15 318.15

76.0 200.0 200.0 76.50 200.0

IPM/W

2.00

10.00

298.15 303.15 308.15 313.15 318.15

8.00 20.0 18.0 24.0 24.0

2.00

10.00

298.15 303.15 308.15 313.15 318.15

60.0 60.0 140.0 75.0 140.0

CLF/W

2.00

10.00

298.15 303.15 308.15 313.15 318.15

4.00 10.0 14.0 7.50 8.00

2.00

10.00

298.15 303.15 308.15 313.15 318.15

4.00 6.00 2.00 4.00 20.0

CH/W

2.00 2.00 2.00 3.00 3.50

10.00 10.00 10.00 15.00 10.00

298.15 303.15 308.15 313.15 318.15

4.00 4.00 4.00 9.00 9.00

3.00 2.00 2.00 3.00 3.50

10.00 10.00 10.00 15.00 15.00

298.15 303.15 308.15 313.15 318.15

10.0 10.0 10.0 12.5 13.0

a

The approximate composition of the used buffer with pH 4.0 and ionic strength is the following: citric acid: 1.34  105 mol  L1, monosodium citrate: 1.31  104 mol  L1, disodium citrate: 5.82  105 mol  L1, trisodium citrate: 1.19  106 mol  L1, potassium chloride: 0.1497 mol  L1. b Initial concentrations of paraben in the aqueous media before partitioning.

The procedures followed were similar to those reported in the literature [8,9,14–22]. In the case of CLF/W partitioning, the aqueous and organic solvents were mutually saturated before performing the experiments, whereas, for the other partitioning systems, only the organic solvent was saturated. After the preparation, samples were placed on thermostatic water baths (Julabo SW22 and SW23) at T = (298.15, 303.15, 308.15, 313.15 and 318.15) K (±0.05 K) at least for 96 h, a pre -established equilibrium time, with sporadic stirring in order to achieve the partitioning equilibrium, as previously reported [8,9,14,20–22]. After that, the aqueous phase was removed using a syringe followed by determining the solute concentration by means of UV absorbance measurement and interpolation on previously constructed calibration curves for methyl paraben and propyl paraben in a pH 4.0 buffer (Spectrophotometer UV/VIS BioMate 3 Thermo Electron Company, USA) through a validated methodology. The K m o=w values were calculated by using the equation 1 and x by using the equation 3 employing the folthen converted to K o=w lowing molar masses: 99.47 g  mol1 for water-saturated ROH (mole fraction of water = 0.2740 [23]); 263.72 g  mol1 for water-saturated IPM (mole fraction of water as determined by the Karl-Fischer method = 0.0266 [24]); 118.45 g  mol1 for water-saturated CLF (mole fraction of water = 9.20  103 [25]); 84.16 g  mol1 for water-saturated CH; 18.17 g  mol1 for (ROH, IPM or CH) organic solvents-saturated buffers; and 18.28 g  mol1 for CLF-saturated buffer (mole fraction of chloroform = 1.10  103 [25]).

4. Results and discussion 4.1. Physical and chemical properties of methyl and propyl parabens Some physicochemical properties of the solutes under study are summarized in table 3 [1,12,26,27]. The literature pKa value was corrected to an ionic strength value of 0.15 mol  dm3 by means of the extended Debye–Hückel equation [28]. The partitioning

TABLE 3 Some physicochemical properties of parabens.

a b c d

Compound

Methyl paraben

Propyl paraben

pKa a pH of maximum stability b Melting point/°C c Enthalpy of fusion/kJ  mol1d

8.4 at 22 °C 4 125–128 25.3 ± 0.7

8.4 at 22 °C 4 to 5 96–99 27.2 ± 0.8

From reference [1]. From reference [12]. From Ref. [26]. From reference [27].

was determined at pH 4.0, the maximum stability pH reported [12]. Such pH value was regulated with citrate buffer having b capacity of 0.010 mol  dm3 calculated by the Koppel–Spiro–Van Slyke equation [28] and curves of fractional distribution of the respective acid-base species [29], using the corrected pKa values. 4.2. Partition coefficients of methyl and propyl parabens Temperature-dependence of the molality, molarity and mole fraction partition coefficients of methyl and propyl parabens in all tested partitioning systems is summarized in tables 4–6. In all x cases the K o=w values are greater than unity. Yalkowsky et al. [30] studied the parabens solubility in 1-octanol and water, reporting the ratio between the two solubility values and concluding it was a good approximation to the partition coefficient values. For the other systems tested no partitioning values have been reported for these solutes. On the other hand, at all temperatures the drug partitioning decreases in the following order: ROH/W > IPM/W > CLF/W > CH/W. According to values in table 6, it can be observed there is a higher preference of the solutes for hydrogen-bonding organic solvents, namely ROH, CLF and IPM with respect to the hydrocarbon solvent, namely CH. This behavior is similar to that obtained for some drug molecules [8,9,21,22]. As has been previously described in the literature, ROH has a micro-heterogeneous structure on

183

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187 TABLE 4 Molality partition coefficient of parabens in different partitioning systems at several temperatures and pressure = 73.9 kPa.a Molality partition coefficient System

T = 298.15 K

303.15 K

308.15 K

313.15 K

318.15 K

Methyl paraben ROH/W IPM/W CLF/W CH/W

127 ± 6 22.9 ± 0.9 4.09 ± 0.17 0.320 ± 0.012

114 ± 3 19.1 ± 0.8 3.68 ± 0.13 0.382 ± 0.023

ROH/W IPM/W CLF/W CH/W

835 ± 31 93 ± 5 23.9 ± 1.1 0.58 ± 0.03

936 ± 16 150 ± 8 28.2 ± 1.8 0.89 ± 0.05

101 ± 4 17.4 ± 0.8 3.21 ± 0.09 0.440 ± 0.021

93 ± 4 15.1 ± 0.4 2.94 ± 0.14 0.55 ± 0.03

88 ± 3 12.4 ± 0.6 2.55 ± 0.10 0.73 ± 0.04

1066 ± 38 204 ± 10 35.0 ± 2.4 1.55 ± 0.10

1281 ± 71 296 ± 17 42.1 ± 2.5 2.51 ± 0.15

1510 ± 38 429 ± 28 61.3 ± 2.6 4.21 ± 0.27

Propyl paraben

a

The standard uncertainties are u(T) = 0.05 K and u(p) = 2.2 kPa. The expanded uncertainties in partition coefficients have 0.95 level of confidence.

TABLE 5 Molarity partition coefficient of parabens in different partitioning systems at several temperatures and pressure = 73.9 kPa.a Molarity partition coefficient System

T = 298.15 K

303.15 K

ROH/W IPM/W CLF/W CH/W

105 ± 5 19.3 ± 0.7 5.98 ± 0.24 0.247 ± 0.009

94 ± 3 16.1 ± 0.7 5.37 ± 0.19 0.293 ± 0.018

ROH/W IPM/W CLF/W CH/W

689 ± 25 79 ± 4 35.0 ± 1.6 0.447 ± 0.024

769 ± 16 126 ± 7 41.1 ± 2.7 0.69 ± 0.04

308.15 K

313.15 K

318.15 K

Methyl paraben 83 ± 3 14.6 ± 0.7 4.66 ± 0.13 0.336 ± 0.016

76 ± 3 12.7 ± 0.3 4.24 ± 0.20 0.422 ± 0.024

71.7 ± 2.1 10.4 ± 0.5 3.67 ± 0.14 0.56 ± 0.03

874 ± 31 172 ± 8 51 ± 3 1.19 ± 0.07

1049 ± 58 248 ± 14 61 ± 4 1.91 ± 0.11

1232 ± 31 358 ± 23 88 ± 4 3.20 ± 0.21

Propyl paraben

a

The standard uncertainties are u(T) = 0.05 K and u(p) = 2.2 kPa. The expanded uncertainties in partition coefficients have 0.95 level of confidence.

TABLE 6 Mole fraction partition coefficient of parabens in different partitioning systems at several temperatures and pressure = 73.9 kPa.a Mole fraction partition coefficient System

T = 298.15 K

303.15 K

308.15 K

313.15 K

318.15 K

Methyl paraben ROH/W IPM/W CLF/W CH/W

695 ± 32 332 ± 12 26.5 ± 1.1 1.48 ± 0.05

624 ± 20 277 ± 12 23.9 ± 0.9 1.77 ± 0.11

ROH/W IPM/W CLF/W CH/W

4573 ± 168 1356 ± 72 155 ± 7 2.69 ± 0.15

5122 ± 107 2172 ± 120 183 ± 12 4.14 ± 0.25

553 ± 20 252 ± 11 28.8 ± 0.6 2.04 ± 0.10

507 ± 20 219 ± 5 19.1 ± 0.9 2.57 ± 0.15

485 ± 14 180 ± 8 16.5 ± 0.6 3.39 ± 0.20

5835 ± 207 2961 ± 143 227 ± 15 7.2 ± 0.5

7013 ± 388 4289 ± 247 273 ± 17 11.6 ± 0.7

8266 ± 208 6220 ± 401 397 ± 17 19.5 ± 1.3

Propyl paraben

a

The standard uncertainties are u(T) = 0.05 K and u(p) = 2.2 kPa. The expanded uncertainties in partition coefficients have 0.95 level of confidence.

water saturation [6,31] that resembles inverted micelles. For this reason, ROH could interact with the parabens not only by hydrogen bonding through the hydroxyl, and ester groups present in these molecules, but also by weak interactions, such as London dispersion forces, which conduce to structural immobilization of the molecules near to the alkyl moieties of ROH.

and solvents should be considered for such an aim. However in a first approach, equation (7) is a good attempt to identifying the main (solute + solvent) interactions affecting the solute transfer: x x Dlog10 K ROH=CH ¼ log10 K xROH=W  log10 K CH=W   x x : ¼ log10 K ROH=W =K CH=W

ð7Þ

4.3. Seiler and other analogue parameters of methyl and propyl parabens

The above equation shows the hydrogen bonding nature of the interactions between the pharmaceutical agents and ROH with x greater than 0 indicates respect to CH. A value of Dlog10 K ROH=CH

As previously described [8], Seiler [32] proposed an equation analogous to equation (7) in order to compare partition coefficients of drugs in the ROH/W and CH/W systems. Equation (7) provides information related to contribution of hydrogen bonding for partitioning of solutes. In a more complete treatment, other considerations such as molecular geometry and steric effects of solutes

some contribution of hydrogen bonding to the molecule partitioning. Table 7 presents comprehensively the procedure followed in the calculation of these parameters while table 8 presents the values of Seiler and other analogous parameters for methyl and propyl parabens at the five temperatures studied, calculated from the different rational partition coefficients shown in table 6.

184

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

TABLE 7 Seiler [32] and other analogue parameters of parabens at T = 298.15 K.a

a b c

x log10 K o=w ðSyst:1Þ

x log10 K o=w ðSyst:2Þ

x Dlog10 K o1=o2

b

Parameter

System 1

System 2

x Dlog10 K ROH=CH

ROH/W

CH/W

Methyl paraben 2.84 ± 0.13

0.171 ± 0.006

2.67 ± 0.16

x Dlog10 K IPM=CH

IPM/W

CH/W

2.52 ± 0.09

0.171 ± 0.006

2.35 ± 0.12

x Dlog10 K CLF=CH

CLF/W

CH/W

1.42 ± 0.06

0.171 ± 0.006

1.25 ± 0.07

a c Dlog10 K x ROH=IPM

ROH/W

IPM/W

2.84 ± 0.13

2.52 ± 0.09

0.321 ± 0.019

c Dlog10 K xb ROH=CLF

ROH/W

CLF/W

2.84 ± 0.13

1.42 ± 0.06

1.42 ± 0.09

0.429 ± 0.023

3.23 ± 0.21

x Dlog10 K ROH=CH

ROH/W

CH/W

Propyl paraben 3.66 ± 0.13

x Dlog10 K IPM=CH

IPM/W

CH/W

3.13 ± 0.17

0.429 ± 0.023

2.70 ± 0.20

x Dlog10 K CLF=CH

CLF/W

CH/W

2.19 ± 0.10

0.429 ± 0.023

1.76 ± 0.12

a c Dlog10 K x ROH=IPM

ROH/W

IPM/W

3.66 ± 0.13

3.13 ± 0.17

0.53 ± 0.03

c Dlog10 K xb ROH=CLF

ROH/W

CLF/W

3.66 ± 0.13

2.19 ± 0.10

1.47 ± 0.08

The standard uncertainty in temperature is u(T) = 0.05 K. The expanded uncertainties in Seiler and analogue parameters have 0.95 level of confidence. x x x Dlog10 K o1=o2 = log10 K o=w ðSyst:1Þ – log10 K o=w ðSyst:2Þ. a and b indicate respectively the acidic or basic nature of the resultant difference between both organic solvents.

TABLE 8 Seiler [32] and other analogue parameters of parabens at different temperatures.a Parameter

T = 298.15 K

303.15 K

308.15 K

313.15 K

318.15 K

Methyl paraben x Dlog10 K ROH=CH

2.67 ± 0.16

2.55 ± 0.17

2.43 ± 0.15

2.30 ± 0.16

2.15 ± 0.14

x Dlog10 K IPM=CH

2.35 ± 0.12

2.20 ± 0.16

2.09 ± 0.14

1.93 ± 0.12

1.72 ± 0.13

x Dlog10 K CLF=CH

1.25 ± 0.07

1.13 ± 0.08

1.01 ± 0.06

0.87 ± 0.06

0.69 ± 0.05

a Dlog10 K x ROH=IPM

0.321 ± 0.019

0.353 ± 0.019

0.342 ± 0.020

0.364 ± 0.017

0.427 ± 0.023

Dlog10 K xb ROH=CLF

1.42 ± 0.09

1.42 ± 0.07

1.43 ± 0.07

1.43 ± 0.09

1.46 ± 0.07

x Dlog10 K ROH=CH

3.23 ± 0.21

3.09 ± 0.20

2.91 ± 0.21

2.78 ± 0.23

2.63 ± 0.18

x Dlog10 K IPM=CH

2.70 ± 0.20

2.72 ± 0.22

2.61 ± 0.21

2.57 ± 0.21

2.50 ± 0.23

x Dlog10 K CLF=CH

1.76 ± 0.12

1.64 ± 0.15

1.50 ± 0.14

1.37 ± 0.12

1.31 ± 0.10

a Dlog10 K x ROH=IPM

0.53 ± 0.03

0.373 ± 0.022

0.295 ± 0.018

0.214 ± 0.017

0.124 ± 0.009

Dlog10 K xb ROH=CLF

1.47 ± 0.08

1.45 ± 0.11

1.41 ± 0.11

1.41 ± 0.12

1.32 ± 0.07

Propyl paraben

a

The standard uncertainty in temperature is u(T) = 0.05 K. The expanded uncertainties in Seiler and analogue parameters have 0.95 level of confidence.

It is well known that CH is an aprotic solvent unable to form hydrogen bonds as donor or acceptor, and therefore acts only through non-specific interactions (London forces). However the hydroxyl group of ROH can be acceptor and/or donor of protons, and moreover, as was already expressed, its alkyl moieties allow the structural immobilization of solutes due to the tetrahedral microstructure adopted in saturation by this solvent in contrast x to the CH behavior [6,31]. Therefore, Dlog10 K ROH=CH includes contributions by hydrogen bonding and by structural immobilization to the partitioning (in this analysis it is assumed that the nonspecific interactions are similar for all organic solvents and the excipients). x On the other hand, Dlog10 K IPM=CH allows estimating the contribution of the organic solvent as hydrogen bonding acceptor in IPM/W rational partitioning. By comparison of the Seiler parameter x x ) with Dlog10 K IPM=CH it shows that ROH, besides con(Dlog10 K ROH=CH tributing to the excipient partitioning as a hydrogen-acceptor, may x value also contribute as a hydrogen-donor, therefore Dlog10 K IPM=CH is slightly smaller than the Seiler parameter (table 8). a A third parameter, namely Dlog10 K x ROH=IPM , was calculated by comparing the ROH/W and IPM/W partition coefficients, in order to establish the contribution of the organic solvent as a hydrogen-donor to the partitioning. Here, a indicates the acidic nature of the resultant difference between both organic solvents. This third parameter is relatively low, which apparently indicates that

this effect is negligible; nevertheless, this outcome indicates that any other structural solvent-effects should be considered in addition to hydrogen-bonding. On the other hand, as was already said, CLF acts mainly as a hydrogen-donor, and therefore, other two parameters were calculated to analyze the contribution of this kind of interaction on the partitioning of parabens. The term x Dlog10 K CLF=CH accounts for the possible contribution of CLF as a hydrogen-donor, while Dlog10 K xb ROH=CLF (obtained from ROH/W and CLF/W partitioning values) permits one to evaluate the behavior of ROH as a hydrogen-acceptor. Here, b indicates the basic nature of the resultant difference between both organic solvents. The acidic hydrogen atom in the parabens is the one present in the hydroxyl group; whereas, the basic groups (hydrogen-acceptors) in parabens are the hydroxyl oxygen itself and the ester groups present as substituents in the aromatic ring. Generally, the results show values slightly greater for x Dlog10 K o1=o2 when parabens act as a hydrogen-acceptor and the organic solvent (as the difference) acts as hydrogen-donor x a and Dlog10 K x (Dlog10 K CLF=CH ROH=IPM ) respect to those obtained when these molecules act as a hydrogen-donor and the organic solvent x and (as the difference) acts as hydrogen-acceptor (Dlog10 K IPM=CH

Dlog10 K xb ROH=CLF ). Thus, it could be said that parabens act mainly as Lewis acids. At this point, it is convenient to take into account that the previously analyses were performed considering only the effect of hydrogen bonding without considering other kind of

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

185

intermolecular interactions or geometric parameters, such as differences in molecular sizes.

4.4. Thermodynamics of partitioning of methyl and propyl parabens Figures 2 and 3 shows the modified van’t Hoff plots for partitioning of methyl paraben and propyl parabens in the systems studied. For all systems, linear models with regression determination coefficients (r2) > 0.96 were obtained. From the estimated slopes in the modified van’t Hoff plots, the respective standard enthalpic changes for transfer were calculated by means of equation 4 using methods of errors propagation [33]. Negatives slopes are observed when the partition coefficients increase when temperature arises, just as it happens with both parabens in CH/W system and with PP in all the partitioning systems. Then, the transfer enthalpies (Dw?oH°) were calculated as the product of slopes multiplied by R (that is, 8.314 J  K1  mol1) and are summarized in table 9. Additionally, values of the standard Gibbs free energy of transfer (Dw?oG°) of parabens from water to different organic systems (expressed in mole fraction at T = 308.0 K) are also presented in table 9. The Dw?oG° values were calculated by means of equation (5), based on all the partitioning data presented in table 6. From Dw?oH° and Dw?oG° values, the respective standard entropic changes of transfer (Dw?oS°) in mole fraction were calculated from equation (6). These values are also presented in table 9. From table 9 it can be observed that for all the systems under study the change of Gibbs free energy was negative meaning a favorable energy transfer from the aqueous phase to the organic media. According to the enthalpy values for propyl paraben the process is endothermic in all the partitioning systems whereas for methyl paraben the process is exothermic except for the cyclohexane system. In those systems where an endothermic transfer process is observed, energy has to be supplied in order to break or disrupt (solute + solvent) interactions in the aqueous media, to create a cavity in the organic phase that allows the transfer of the solute, and to break the structure or disrupt the water linked as hydrophobic hydration around the phenyl and alkyl moieties of the solutes. On the other hand, the exothermic process observed for methyl paraben in 1-octanol, isopropyl myristate, and chloroform suggests that the formation of hydrogen bonds and other interactions between the solute and these solvents liberates more energy than that required to break the interactions present in the aqueous media. Somehow, the two additional methylene groups in propyl paraben weakens the interactions between the solute and these

FIGURE 2. Modified van’t Hoff plot for the methyl paraben partitioning in the organic solvent/buffer systems. (s): ROH/W; (h): IPM/W; (}): CLF/W; (D): CH/W. x The ln K CH=W values are increased in 3.50.

FIGURE 3. Modified van’t Hoff plot for the propyl paraben partitioning in the organic solvent/buffer systems. (s): ROH/W; (h): IPM/W; (}): CLF/W; (D): CH/W. x values are increased in 5.00. The ln K CH=W

three solvents and/or strengthens the interactions in the aqueous media, especially those related to the hydrophobic hydration [34]. The entropy values are positive in all cases for propyl paraben because this solute has a longer alkyl chain and a greater amount of water can be structured around it forming hydrophobic hydration in water. During the transfer, the disorder produced from breaking the structure by water favors the transfer process as the overall molecular order is lower and the mechanical shaking of the system provides the energy required for the interactions between the solute and the organic phase. For methyl paraben the entropy values are positive for the 1-octanol and cyclohexane systems, because during the transfer of solute the disorder produced from breaking the structure of water is higher than the ordering increase produced in the organic media as a consequence of the weaker interactions between the solutes and these solvents: 1-octanol is a special case, because an additional molecular disorder is created as the solutes can replace an 1-octanol molecule from the tetrahedral microstructure created in water-saturated 1-octanol [31]. For chloroform and isopropyl myristate negative entropy values can be observed, indicating less randomness in these systems mixing, because the solutes can interact with these solvents through hydrogen bonds and in the case of isopropyl myristate, the solutes can be immobilized within the alkyl chain of this solvent. Equations (8) and (9) were used in order to evaluate the respective contributions of enthalpy and entropy, in absolute values, toward the standard Gibbs free energy of transfer and indeed to identify the dominant effect on transfer, that is, either energy changes or molecular organization changes. These equations have been introduced by Perlovich et al. [35] studying the naproxen solubility in several solvents and they have been used previously to evaluate the partitioning behavior of some analgesic drugs [8,14] and a beta-blocker drug [9], as well as some acetanilide derivatives [36]. The respective contributions for all the partitioning systems evaluated are also presented in table 9.

fH ¼

jDw!o H j ; jDw!o H j þ jT Dw!o S j

ð8Þ

fTS ¼

jT Dw!o S j : jDw!o H j þ jT Dw!o S j

ð9Þ

Table 9 shows that the enthalpy contribution to the Gibbs free energy for ROH/W, CLF/W and IPM/W for methyl paraben is higher than the entropy contribution, this indicates that the energetic factor has priority over the organizational factor, in other words in these solvents the change of Gibbs free energy would be mainly due to formation of bonds like hydrogen bonds and non-specific

186

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

TABLE 9 Apparent thermodynamic quantities of transfer of parabens from aqueous buffer to different organic solvents at 308.0 K.a System

a

Dw?oG°/kJ  mol1

Dw?oH°/kJ  mol1

Dw?oS°/J  K1  mol1

ROH/W IPM/W CLF/W CH/W

16.2 ± 0.6 14.1 ± 0.6 7.8 ± 0.3 1.97 ± 0.10

14.9 ± 1.1 23.0 ± 1.3 18.4 ± 1.0 31.9 ± 1.9

Methyl paraben 4.3 ± 0.3 28.7 ± 2.0 34.5 ± 2.4 110 ± 9

ROH/W IPM/W CLF/W CH/W

22.3 ± 0.8 20.5 ± 1.1 14.0 ± 0.8 5.0 ± 0.3

23.6 ± 1.2 58.8 ± 1.7 35.9 ± 2.3 78.8 ± 1.9

Propyl paraben 149 ± 9 257 ± 16 162 ± 14 272 ± 18

TDw?oS°/kJ  mol1

fH

fTS

1.31 ± 0.10 8.9 ± 0.6 10.6 ± 0.7 33.9 ± 2.7

0.919 0.722 0.634 0.485

0.081 0.278 0.366 0.515

45.9 ± 2.8 79 ± 5 50 ± 4 84 ± 5

0.340 0.426 0.419 0.485

0.660 0.574 0.581 0.515

The expanded uncertainties in thermodynamic quantities have 0.95 level of confidence.

TABLE 10 Fedor’s group contributions to interne energy and molar volume to estimate the Hildebrand solubility parameter of parabens. Group

Methyl paraben Number of groups

–CH3 –CH2– –Phenylene– –OH –COO– CED/kJ  cm3 d/MPa1/2 a

1 0 1 1 1 P

Propyl paraben

DU°/kJ  mol1a

V°/cm3  mol1a

4.71

33.5

31.9 29.8 18.0 84.41

52.4 10.0 18.0 113.9

741.1 27.2

Number of groups

DU° /kJ  mol1

V°/cm3  mol1

1 2 1 1 1 P

4.71 9.88 31.9 29.8 18.0 94.29

33.5 32.2 52.4 10.0 18.0 146.1

645.4 25.4

From references [37,38].

interactions. As expected, the greatest contribution for CH/W is due to the entropy. This occurs because cyclohexane cannot form hydrogen bonds, then the reason for the change in Gibbs free energy is given by organizational factors such as breaking the structure of water around the hydrophobic portions of the solute in the aqueous media. In terms of conduction of the process, in the case of ROH/W a double-driving is observed, indicating that the transfer process is enhanced by energetic as well as by organizational factors. For CLF/W and IPM/W enthalpic driving confirms the strong influence of the formation of hydrogen bonds on the overall processes. For CH/W, entropy-driving is also observed, confirming what was previously explained. In the case of propyl paraben, the entropic contribution to changes in the Gibbs free energy was higher than enthalpy contribution in all the systems studied, and also, the conduction of the processes is due to the entropic factor, indicating that organizational events are the predominant factor. As explained above, this result could be related to the increased disruption of water around hydrophobic sites since the alkyl portion is larger for propyl paraben in comparison with methyl paraben. Just as in co-solvency studies, where frequently a solute is more soluble in a mixture of solvents than in one solvent alone [28], it could be hypothesized that if a suitable mixture of solvents miscible between them but immiscible with water was employed to study the transfer processes of a solute, a partition coefficient-polarity profile could be obtained. The solubility parameter, defined as the square root of the cohesive energy density (CED) of a compound (d = (DU°/V°)1/2) [37,38], is a valuable quantity that describes some thermodynamic properties of non-polar or semi polar solutes in dilute solutions, and it was employed to construct a partition coefficient-polarity plot, where the following polarity correction was made: The volume fraction of water (fw) values are 0.045 and 2.1  103 for water-saturated 1-octanol and watersaturated chloroform, respectively. In the cases of isopropyl myristate and cyclohexane the fw values are lower than 104 [8], and therefore their d values are considered as the same of the pure

FIGURE 4. Logarithmic partition coefficients of parabens as a function of the Hildebrand solubility parameter of the organic phases. (s): methyl paraben; (h): propyl paraben.

organic solvents, i.e. (19.8 and 16.8) MPa1/2, respectively [8,38,39]. Thus, the d values for the organic phases are as follows: 22.3 MPa1/2 for water-saturated 1-octanol, 19.8 MPa1/2 for watersaturated isopropyl myristate, 19.1 MPa1/2 for water-saturated chloroform, and 16.8 MPa1/2 for water-saturated cyclohexane. The solubility parameter of the two solutes was estimated by means of the Fedor’s group contribution method [37,38], as can be seen in table 10. The plot showed in figure 4 appears to show a sigmoid curve, and the highest partition coefficient values were obtained in 1-octanol, the system with the closest polarity to that of the solutes, but it must be taken into account that each partition coefficient value plotted is related with a different kind of intermolecular interaction in each case. Anyway, with these results it is possible to confirm the ROH/W partition system as a good model of biophase and/or biological membrane as has been indicated previously in the literature [5,6].

Z.J. Cárdenas et al. / J. Chem. Thermodynamics 86 (2015) 180–187

5. Conclusions Based on this analysis, it could be concluded that these two parabens have an energetic-favorable transfer from the aqueous phase to the organic media, meaning that they are lipophilic in its molecular state. For both solutes, the largest magnitude of the partition coefficient for the ROH/W system can be explained by the formation of hydrogen bonding acceptor type and donor type, and because this solvent can immobilize the solute, indicating the crucial role of the hydrogen bonding on the partitioning of these solutes. For chloroform and isopropyl myristate systems there is an intermediate behavior as the solutes can create hydrogen bond only as donor or acceptor. However, the highest value in IPM/W shows the preferred behavior of the studied solutes as Lewis acid by their hydroxyl groups; this is also confirmed by the analysis of the original and modified Seiler parameter. The transfer from buffer to cyclohexane is due mainly by non-specific interactions. For methyl paraben, the enthalpy contribution to the free Gibbs free energy for ROH/W, CLF/W and IPM/W was higher indicating that the energetic factor has priority over the organizational factor for the partitioning. In terms of conduction of the methyl paraben partitioning process, in the case of ROH/W a double-driving is observed, indicating that the transfer process is enhanced by energetic as well as by organizational factors. For CLF/W and IPM/W enthalpic driving confirms the strong influence of the formation of hydrogen bonds on the overall process. For CH/W entropy-driving is also observed. In the case of propyl paraben, the entropic contribution in the free Gibbs free energies was higher in all the systems studied, and also, the conduction of the processes is due to the entropic factor, indicating that organizational events are the predominant factor. Disclosure statement No potential conflict of interest is reported by the authors. Acknowledgments We thank the Department of Pharmacy of the Universidad Nacional de Colombia for facilitating the equipment and laboratory facilities. References [1] R.C. Rowe, P.J. Sheskey, M.E. Quinn (Eds.), Handbook of Pharmaceutical Excipients, 6th ed., Pharmaceutical Press, London, 2009. [2] G.V. Betageri, A. Nayernama, M.J. Habib, Int. J. Pharm. Adv. 1 (1996) 310–319.

187

[3] P.D. Cratin, Ind. Eng. Chem. 60 (1968) 14–19. [4] N.K. Pandit, Introduction to the Pharmaceutical Sciences, Lippincott Williams & Wilkins, Baltimore MD, 2007. [5] A. Leo, C. Hansch, D. Elkins, Chem. Rev. 71 (1971) 525–616. [6] J. Sangster, Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry, John Wiley & Sons, Chichester, 1997. [7] M.H. Abraham, W.E. Acree Jr., Int. J. Pharm. 294 (2005) 121–128. [8] C.P. Mora, F. Martínez, J. Chem. Eng. Data 52 (2007) 1933–1940. [9] A.C. Reyes, M.T. Triana, A.F. Jimenez-Kairuz, R.H. Manzo, F. Martínez, J. Chem. Eng. Data 53 (2008) 2810–2815. [10] R.R. Krug, W.G. Hunter, R.A. Grieger, J. Phys. Chem. 80 (1976) 2341–2351. [11] J.M. Diamond, Y. Katz, J. Membrane Biol. 17 (1974) 121–154. [12] K.A. Connors, G.L. Amidon, V.J. Stella, Chemical Stability of Pharmaceuticals: A handbook for pharmacist, John Wiley & Sons, New Jersey, 1986. [13] G. Cevc, Lipid properties as basis for membrane modeling and rational liposome design, in: G. Gregoriadis (Ed.), Liposomes Technology, vol. 1, CRC Press, Boca Raton, 1993. [14] H.R. Lozano, F. Martínez, Rev. Bras. Cienc. Farm. 42 (2006) 601–613. [15] A.M.S. Ahmed, F.H. Farah, I.W. Kellaway, Pharm. Res. 2 (1985) 119–124. [16] G.V. Betageri, J.A. Rogers, Int. J. Pharm. 36 (1987) 165–173. [17] G.V. Betageri, S.R. Dipali, J. Pharm. Pharmacol. 45 (1993) 931–933. [18] M.L. Go, T.L. Ngiam, J.A. Rogers, Chem. Pharm. Bull. 43 (1995) 289–294. [19] M.L. Go, T.L. Ngiam, Chem. Pharm. Bull. 45 (1997) 2055–2060. [20] F. Martínez, A. Gómez, J. Phys. Org. Chem. 15 (2002) 874–880. [21] C.M. Ávila, F. Martínez, Chem. Pharm. Bull. 51 (2003) 237–240. [22] Y. Baena, J. Pinzón, H. Barbosa, F. Martínez, Rev. Bras. Cienc. Farm. 40 (2004) 413–420. [23] A. Dallos, J. Liszi, J. Chem. Thermodyn. 27 (1995) 447–448. [24] C.P. Mora, Estudio Termodinámico de la Transferencia de Naproxeno entre Medios Acuosos y Algunos Sistemas Orgánicos (M.Sc. thesis), Universidad Nacional de Colombia, Bogotá D.C., 2006. [25] A. Senol, Fluid Phase Equilib. 243 (2006) 51–56. [26] J.T. Doluisio, D.R. Bennett, J.V. Bergen, et al., US Pharmacopeia, 23rd ed., United States Pharmacopeial Convention, Rockville, MD, 1994. [27] F. Giordano, R. Bettini, C. Donini, A. Gazzaniga, M.R. Caira, G.G.Z. Zhang, D.J.W. Grant, J. Pharm. Sci. 88 (1999) 1210–1216. [28] A.N. Martin, P. Bustamante, A.H.C. Chun, Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences, 4th ed., Lea & Febiger, Philadelphia, 1993. [29] K.A. Connors, Thermodynamics of Pharmaceutical Systems: An Introduction for Students of Pharmacy, Wiley-Interscience, Hoboken, NJ, 2002. [30] S.H. Yalkowsky, S.C. Valvani, T.J. Roseman, J. Pharm. Sci. 72 (1983) 866–870. [31] C.P. Mora, H.R. Lozano, F. Martinez, Rev. Bras. Cienc. Farm. 41 (2005) 13–26. [32] P. Seiler, Eur. J. Med. Chem. Chim. Therap. 9 (1974) 473–479. [33] P.R. Bevington, Data Reduction and Error Analysis for the Physical Sciences, McGraw-Hill Book Co, New York, 1969. [34] C. Tanford, The Hydrophobic Effect: Formation of Micelles and Biological Membranes, John Wiley & Sons, New York, 1973. [35] G.L. Perlovich, S.V. Kurkov, A.N. Kinchin, A. Bauer-Brandl, Eur. J. Pharm. Biopharm. 57 (2004) 411–420. [36] Y. Baena, J. Pinzón, H. Barbosa, F. Martínez, Acta Pharm. 55 (2005) 195–205. [37] R.F. Fedors, Polym. Eng. Sci. 14 (1974) 147–154. [38] A. Barton, Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd ed., CRC Press, New York, 1991. [39] M.D. Contreras-Claramonte, F. Girela-Vilchez, A. Parera-Vialard, Thermochim. Acta 222 (1993) 219–229.

JCT 15-44