Solubility and Solution Thermodynamics of SomeSulfonamides in 1-Propanol + Water Mixtures

Daniel R. Delgado • Fleming Martınez

Received: 28 October 2013 / Accepted: 23 January 2014 / Published online: 10 May 2014� Springer Science+Business Media New York 2014

Abstract The solubilities of sulfadiazine (SD), sulfamerazine (SMR) and sulfamethazine

(SMT) in some 1-propanol ? water co-solvent mixtures were measured at five temperatures

from 293.15 to 313.15 K over the polarity range provided by the aqueous solvent mixtures.

The mole fraction solubility of all these sulfonamides was maximal in the 0.80 mass fraction

of 1-propanol solvent mixture (dsolv = 28.3 MPa1/2) and minimal in water (d = 47.8 MPa1/2)

at all temperatures studied. The apparent thermodynamic functions Gibbs energy, enthalpy,

and entropy of solution were obtained from these solubility data by using the van’t Hoff

and Gibbs equations. Apparent thermodynamic quantities of mixing were also calculated

by using the ideal solubilities reported in the literature. Nonlinear enthalpy–entropy rela-

tionships were observed for these drugs in the plots of enthalpy versus Gibbs energy of

mixing. The plot of DmixH� versus DmixG� shows different trends according to the slopes

obtained when the mixture compositions change. Accordingly, the mechanism for the

solution process of SD and SMT in water-rich mixtures is enthalpy driven, whereas it is

entropy driven for SMR. In a different way, in 1-propanol-rich mixtures the mechanism is

enthalpy driven for SD and SMR and entropy driven for SMT. Ultimately, in almost all of

the intermediate compositions, the mechanism is enthalpy driven. Nevertheless, the

molecular events involved in the solution processes remain unclear.

Keywords Sulfonamides � 1-Propanol ? water mixtures � Solubility � Solution

thermodynamics � Activity coefficient

1 Introduction

The behavior of drugs in different co-solvent mixtures as function of temperature and

composition is studied for the main purposes of substances purification, design of liquid

D. R. Delgado � F. Martınez (&)Grupo de Investigaciones Farmaceutico-Fisicoquımicas, Departamento de Farmacia, UniversidadNacional de Colombia, A.A. 14490 Bogota D.C., Colombiae-mail: fmartinezr@unal.edu.co

123

J Solution Chem (2014) 43:836–852DOI 10.1007/s10953-014-0169-0

medicine formulations, and understanding the mechanisms involved in the physical and

chemical stabilization of dissolved pharmaceuticals [1, 2]. Therefore, the equilibrium

solubility of drugs is a very important physicochemical property to be considered during

the design of pharmaceutical products because it affects the drug efficacy by influencing

several biopharmaceutical and pharmacokinetic properties [3]. On the other hand, the

temperature dependence of the solubility allows a thermodynamic analysis in order to gain

insight into the molecular mechanisms involved in the drug dissolution processes [4].

Sulfadiazine (SD, molar mass 250.28 g�mol-1, Fig. 1), sulfamerazine (SMR, molar mass

264.31 g�mol-1, Fig. 1) and sulfamethazine (SMT, molar mass 278.33 g�mol-1, Fig. 1) are

sulfonamide drugs that are used as effective antimicrobial agents for the prevention and cure

of several kinds of bacterial infections in human and veterinary therapies [5].

Although SD, SMR and SMT have been widely used in therapeutics, solubility data for

these drugs in co-solvent mixtures is scarce in the literature [6]. Even though some theoretical

and semiempirical models have been developed to predict drug solubilities, the availability of

experimental data is still fundamental information for pharmaceutical scientists [7]. Because

the solubility of sulfonamides in neat water is so low [8, 9], co-solvent ? water mixtures have

been evaluated in order to increase the solubility of some of these compounds [10, 11]. These

studies have also been carried out to understand the molecular mechanisms involved in the

drug dissolution processes. In this regard, a complete physicochemical study has recently been

presented to contribute to the understanding of the mechanisms involved in the transfer of some

sulfonamides between aqueous and organic systems [12].

On the other hand, although 1-propanol is not widely used as co-solvent for design of

liquid medicines, it has been used as solvent in the pharmaceutical industry for resins and

cellulose esters [8]. This co-solvent is a hydrogen-donor and hydrogen-acceptor due to its

hydroxyl group, and thus it is miscible with water in all proportions [13].

The main goal of this work is thus to extend the database of experimental solubilities for

SD, SMR and SMT, and also to evaluate the effect of the co-solvent composition on

solubility and solution thermodynamics of these drugs in binary mixtures formed with

1-propanol and water, based on the van’t Hoff method, including the respective contri-

butions from mixing of these solvent compounds toward the solution processes, as has

been done with other sulfonamides in different co-solvent systems [14–17]. Therefore, this

thermodynamic study is very similar to the ones reported previously about the solubility of

SD, SMR and SMT in ethanol ? water mixtures [18, 19].

2 Experimental

2.1 Materials

Sulfadiazine (SD, component 3, CAS [68-35-9], 4-amino-N-pyrimidin-2-yl-benzene-

sulfonamide, with purity greater than 0.990 in mass fraction), sulfamerazine (SMR,

NH2

SNH

N

N

OO

R1

R2

Fig. 1 Molecular structure ofthe sulfonamides studied.Sulfadiazine: R1 and R2 = H;sulfamerazine: R1 = H,R2 = CH3; sulfamethazine: R1

and R2 = CH3

J Solution Chem (2014) 43:836–852 837

123

component 3, CAS [127-79-7], 4-amino-N-(4-methylpyrimidin-2-yl)benzenesulfonamide,

with purity greater than 0.990 in mass fraction) and sulfamethazine (SMT, component 3,

CAS [57-68-1], 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide, with purity

greater than 0.990 in mass fraction) from Sigma Chemical Company, 1-propanol A.R. from

Merck (component 1, with purity greater than 0.995 in mass fraction), and distilled water

(component 2) with conductivity \2 lS�cm-1, were used in this research. A molecular

sieve (Merck, number 3, pore size 0.3 nm) and Durapore� filters (0.45 lm, Millipore

Corp.) were also used. The source and purities of the compounds (expressed in mass

fractions) used in this work are summarized in Table 1.

2.2 Solvent Mixture Preparations

All 1-propanol ? water solvent mixtures were prepared by mass, using an Ohaus Pioneer

TM PA214 analytical balance with sensitivity ±0.1 mg, in quantities of 50.00 g. In order

to cover the entire composition range, the mass fractions of propanol, w1, of the nine binary

mixtures prepared was varied by 0.10 from 0.10 to 0.90.

2.3 Solubility Determinations

The procedures used in this research are similar to those employed previously in the study

of these sulfonamides in ethanol ? water mixtures [18, 19]. Briefly, an excess of SD, SMR

or SMT was added to approximately 10 g of each co-solvent mixture or neat solvents in

stoppered dark glass flasks. The flasks with the solid–liquid mixture were placed in an

ultrasonic bath (Elma� E60H Elmasonic, USA) for 15 min and later they were placed in

thermostatic mechanical shakers (Julabo SW23, Germany) kept at 303.15, 308.15, or

313.15 (±0.05) K, and also in re-circulating thermostatic baths (Neslab RTE 10 Digital

One Thermo Electron Company, USA) kept at 293.15 or 298.15 (±0.05) K, for at least

4 days to reach equilibrium. This equilibrium time was established by measuring the drug

concentrations in neat water at 293.15 K until they became constant. It is expected that the

equilibration times in the co-solvent mixtures will be smaller due to the greater drug

solubilities in these systems. After this time the supernatant solutions were filtered under

isothermal conditions (Millipore Corp. Swinnex�-13, USA) to ensure that they were free

of particulate matter before sampling.

Drug concentrations were determined after appropriate alcoholic dilution by measuring

the UV light absorbance at 268 nm for all drugs (UV/VIS BioMate 3 Thermo Electron

Company spectrophotometer, USA) and interpolation from previously constructed UV

spectrophotometric calibration curves. All the solubility experiments were run at least in

triplicate. In order to transform mole fractions to molar concentrations (mol�dm-3), the

density of the saturated solutions were determined by using a digital density meter (DMA

45 Anton Paar, Austria) connected to the same re-circulating thermostatic baths according

to procedures described in the literature [20].

3 Results and Discussion

Before proposing the possible intermolecular interactions present in the saturated solutions

of SD, SMR or SMT, it is important to keep in mind that these drugs in solution act mainly

as Lewis bases (due to their –NH2, –SO2–, and =N– groups) and as Lewis acids (due to

838 J Solution Chem (2014) 43:836–852

123

their –NH2 and[N–H groups) in order to establish hydrogen bonds with the –OH groups

in the solvents [18, 19, 21].

3.1 Experimental and Ideal Solubility

Tables 2 and 3 list the experimental solubilities (expressed in mole fraction and molarity,

respectively) of SD, SMR and SMT in 1-propanol ? water mixtures over the temperature

range studied, 293.15–313.15 K. In almost all cases the variation coefficients of the solubility

for all of the drugs were smaller than 2.0 %. Comparison of sulfonamide solubilities in neat

water with respect to values reported in the literature has been made previously [18, 19].

Some differences are found between data reported by Zhang et al. and data reported in

Table 2 for the mole fraction solubility of SD in neat 1-propanol at four of the temperatures

studied here, our values being almost three times lower than those reported previously (i.e.

1.243 9 10-4 at 298.15 K, 1.642 9 10-4 at 303.15 K, 2.085 9 10-4 at 308.15 K, and

2.446 9 10-4 at 313.15 K, respectively) [22]. Similarly, big differences are found between

data reported by Zhang et al. in another paper and data reported in Table 2 for the mole

fraction solubility of SMT in neat 1-propanol at all the temperatures studied here, with our

values being larger by almost two orders of magnitude than those reported previously (i.e.

2.746 9 10-6 at 293.15 K, 4.966 9 10-6 at 298.15 K, 8.314 9 10-6 at 303.15 K,

1.276 9 10-5 at 308.15 K, and 1.846 9 10-5 at 313.15 K, respectively) [23]. These

discrepancies could be due to different polymorphic solid states, different saturation times,

or different analytical techniques, among others, as has been described in the literature [6].

Finally, to the best of our knowledge, no solubility values have been published for SMR in

neat 1-propanol or for any these drugs in 1-propanol ? water mixtures, and therefore no

other comparison is possible.

The solubility increases with temperature in all cases indicating that the dissolution

process is endothermic. The highest mole fraction solubilities of SD, SMR and SMT were

obtained in the mixture with 0.80 in mass fraction of 1-propanol at T = 313.15 K, whereas

the lowest values are found in water at 293.15 K (Table 2). Nevertheless, if the molarity

(mol�dm-3) concentration scale is considered then the maximum solubilities are obtained

in the mixture 0.60 in mass fraction of 1-propanol for SD and 0.70 in mass fraction of

1-propanol for SMR and SMT (Table 3).

Table 2 also shows the ideal solubilities in mole fraction of the solutes (xid3 ) reported in

the literature [18, 19]. This table shows that the ideal solubilities of SD, SMR and SMT are

greater than the experimental solubilities obtained at all the temperatures studied. This

result could be explained as a consequence of the larger solvent–solvent and/or solute–

Table 1 Source and purities of the compounds used in this work

Compound CAS Formula Molar mass/g�mol-1

Source Purity in massfraction

Sulfadiazine 68-35-9 C10H10N4O2S 250.28 Sigma Chemical Co. 0.990

Sulfamerazine 127-79-7 C11H12N4O2S 264.31 Sigma Chemical Co. 0.990

Sulfamethazine 57-68-1 C12H14N4O2S 278.33 Sigma Chemical Co. 0.990

1-propanol 71-23-8 C3H8O 60.10 Merck 0.998

Water 7732-18-5 H2O 18.02 Obtained bydistillation

Conductivity\2 lS�cm-1

J Solution Chem (2014) 43:836–852 839

123

Table 2 Experimental solubility of sulfadiazine, sulfamerazine and sulfamethazine in 1-propanol ? watermixtures expressed in mole fraction (104 x3) including ideal solubility at several temperatures (±0.05 K)

w1a x1

a 104 x3

T = 293.15 K T = 298.15 K T = 303.15 K T = 308.15 K T = 313.15 K

Sulfadiazine

0.00b 0.0000 0.0380 ± 0.0001 0.0481 ± 0.0002 0.0649 ± 0.0004 0.087 ± 0.002 0.114 ± 0.001

0.10 0.0322 0.085 ± 0.001 0.115 ± 0.001 0.149 ± 0.001 0.198 ± 0.005 0.246 ± 0.006

0.20 0.0697 0.148 ± 0.002 0.200 ± 0.002 0.265 ± 0.001 0.324 ± 0.004 0.424 ± 0.001

0.30 0.1139 0.356 ± 0.001 0.459 ± 0.004 0.598 ± 0.007 0.788 ± 0.013 0.959 ± 0.022

0.40 0.1666 0.482 ± 0.005 0.609 ± 0.002 0.797 ± 0.001 1.016 ± 0.008 1.304 ± 0.011

0.50 0.2306 0.660 ± 0.008 0.808 ± 0.013 1.093 ± 0.014 1.364 ± 0.016 1.739 ± 0.036

0.60 0.3102 0.847 ± 0.002 1.050 ± 0.003 1.364 ± 0.018 1.782 ± 0.037 2.168 ± 0.005

0.70 0.4116 0.958 ± 0.003 1.192 ± 0.006 1.563 ± 0.021 1.871 ± 0.007 2.375 ± 0.028

0.80 0.5453 1.014 ± 0.012 1.233 ± 0.013 1.587 ± 0.014 1.916 ± 0.030 2.408 ± 0.043

0.90 0.7296 0.799 ± 0.007 0.946 ± 0.003 1.235 ± 0.018 1.508 ± 0.004 1.808 ± 0.023

1.00 1.0000 0.388 ± 0.004 0.471 ± 0.006 0.587 ± 0.010 0.721 ± 0.004 0.913 ± 0.012

Idealb 25.45 ± 0.10 30.14 ± 0.12 35.60 ± 0.14 41.92 ± 0.17 49.25 ± 0.20

Sulfamerazine

0.00c 0.0000 0.134 ± 0.002 0.171 ± 0.003 0.209 ± 0.001 0.258 ± 0.003 0.316 ± 0.004

0.10 0.0322 0.281 ± 0.003 0.352 ± 0.004 0.440 ± 0.008 0.545 ± 0.004 0.656 ± 0.012

0.20 0.0697 0.659 ± 0.002 0.864 ± 0.014 1.08 ± 0.01 1.31 ± 0.03 1.63 ± 0.01

0.30 0.1139 1.25 ± 0.02 1.59 ± 0.01 2.05 ± 0.00 2.53 ± 0.02 3.11 ± 0.02

0.40 0.1666 1.85 ± 0.03 2.32 ± 0.02 3.03 ± 0.04 3.68 ± 0.02 4.53 ± 0.06

0.50 0.2306 2.50 ± 0.04 3.24 ± 0.02 4.00 ± 0.06 4.99 ± 0.09 6.12 ± 0.03

0.60 0.3102 3.27 ± 0.01 3.97 ± 0.04 5.01 ± 0.05 6.04 ± 0.06 7.71 ± 0.06

0.70 0.4116 4.12 ± 0.04 4.87 ± 0.05 5.87 ± 0.05 7.12 ± 0.07 8.79 ± 0.27

0.80 0.5453 4.39 ± 0.03 5.11 ± 0.03 6.26 ± 0.05 7.30 ± 0.08 8.62 ± 0.05

0.90 0.7296 3.51 ± 0.01 4.23 ± 0.05 5.02 ± 0.02 5.94 ± 0.05 7.02 ± 0.10

1.00 1.0000 1.78 ± 0.02 2.15 ± 0.02 2.65 ± 0.01 3.07 ± 0.01 3.76 ± 0.00

Idealc 46.2 ± 1.1 54.5 ± 1.3 64.1 ± 1.5 75.3 ± 1.8 88.1 ± 2.1

Sulfamethazine

0.00c 0.0000 0.222 ± 0.001 0.281 ± 0.001 0.367 ± 0.003 0.433 ± 0.001 0.555 ± 0.004

0.10 0.0322 0.594 ± 0.005 0.737 ± 0.001 0.904 ± 0.009 1.12 ± 0.00 1.39 ± 0.01

0.20 0.0697 1.65 ± 0.02 2.01 ± 0.00 2.45 ± 0.03 3.07 ± 0.07 3.84 ± 0.06

0.30 0.1139 3.04 ± 0.09 3.89 ± 0.03 4.50 ± 0.11 5.50 ± 0.04 7.04 ± 0.07

0.40 0.1666 5.05 ± 0.11 5.88 ± 0.06 7.27 ± 0.15 8.42 ± 0.03 11.01 ± 0.15

0.50 0.2306 7.05 ± 0.12 8.41 ± 0.09 9.91 ± 0.03 12.08 ± 0.12 14.69 ± 0.10

0.60 0.3102 9.06 ± 0.13 10.55 ± 0.11 12.71 ± 0.17 15.33 ± 0.13 18.34 ± 0.11

0.70 0.4116 10.86 ± 0.02 12.45 ± 0.11 15.08 ± 0.11 18.43 ± 0.18 21.74 ± 0.20

0.80 0.5453 11.30 ± 0.07 13.73 ± 0.07 16.24 ± 0.16 19.13 ± 0.28 23.18 ± 0.11

0.90 0.7296 10.23 ± 0.30 11.98 ± 0.39 13.77 ± 0.33 17.07 ± 0.19 19.52 ± 0.27

1.00 1.0000 5.91 ± 0.14 6.48 ± 0.22 6.98 ± 0.05 8.40 ± 0.15 10.13 ± 0.13

840 J Solution Chem (2014) 43:836–852

123

solute interactions in comparison with the solvent–solute interactions as described later, in

particular in water-rich mixtures.

On the other hand, Fig. 2 shows the solubility profiles of the sulfonamides in 1-pro-

panol ? water and ethanol ? water [18, 19] mixtures as a function of the polarity of the

co-solvent mixtures, expressed by their solubility parameters (dmix), at T = 298.15 K. For

a binary mixture dsolv can be calculated as d1/1 ? d2(1 - /1) from the solubility

parameter of the neat solvents (d1 = 26.5 MPa1/2 for ethanol and 24.4 MPa1/2 for 1-pro-

panol and d2 = 47.8 MPa1/2 for water [24, 25] ) and the volume fraction /i of each

component in the mixture, which is calculated assuming additive volumes [26].

Considering the entire polarity region, all the solubility curves show a maximum at 0.80

mass fraction of 1-propanol (with dsolv = 28.3 MPa1/2), which is similar to that reported in

ethanol ? water mixtures where the maxima were obtained at 0.80 in mass fraction of

ethanol but with dsolv = 30.0 MPa1/2. According to the literature, solutes reach their

maximum solubility in solvents with the same solubility parameter [21] and, therefore, the

d3 values of SD, SMR and SMT should be 28.3 or 30.0 MPa1/2 depending on the co-

solvent considered in the mixtures, i.e. 1-propanol or ethanol, respectively. Nevertheless,

the solubility parameter of SD, SMR and SMT, estimated according to the group contri-

bution method proposed by Fedors [27], are d3 = 28.9 MPa1/2, 28.1 MPa1/2 and

27.4 MPa1/2, respectively [18, 19], which are close to the constant value of maximum

solubilities obtained in 1-propanol ? water mixtures (dsolv = 28.3 MPa1/2).

3.2 Activity Coefficients

Table 4 shows the activity coefficients, c3, of SD, SMR and SMT, calculated as xid3 /x3 from

the respective solubility values presented in Table 2. In almost all cases these values are

similar but slightly higher than the ones exhibited by the same sulfonamides in etha-

nol ? water mixtures [18, 19]. From the c3 values a rough estimate of solute–solvent

intermolecular interactions can be made by considering the following expression [28]:

ln c3 ¼ ðe11 þ e33 � 2e13ÞV3/

21

RTð1Þ

Here subscript 1 stands for the solvent (in the present case, the solvent mixture:

1-propanol ? water), e11, e33 and e13 represent the solvent–solvent, solute–solute and

solvent–solute interaction energies, respectively; V3 is the molar volume of the supercooled

liquid solute, and finally /1 is the volume fraction of the solvent. As a first approximation,

for compounds with low solubility x3, the term V3/12/RT may be considered constant, thus

c3 depends mainly on e11, e33 and e13 [28]. The e11 and e33 terms are unfavorable for

Table 2 continued

w1a x1

a 104 x3

T = 293.15 K T = 298.15 K T = 303.15 K T = 308.15 K T = 313.15 K

Idealc 88.6 ± 1.6 105.0 ± 1.9 124.1 ± 2.2 146.3 ± 2.6 172.0 ± 3.1

a w1 and x1 are the mass and mole fractions of 1-propanol in the co-solvent mixtures free of sulfadiazine,sulfamerazine or sulfamethazine, respectivelyb Values from Ref. [18]c Values from Ref. [19]

J Solution Chem (2014) 43:836–852 841

123

Table 3 Experimental solubility of sulfadiazine, sulfamerazine and sulfamethazine in 1-propanol ? watermixtures expressed in molarity (mol�dm-3) at several temperatures (±0.05 K)

w1a x1

a mol�dm-3 (9 103)

T = 293.15 K T = 298.15 K T = 303.15 K T = 308.15 K T = 313.15 K

Sulfadiazine

0.00b 0.0000 0.211 ± 0.001 0.266 ± 0.001 0.359 ± 0.002 0.479 ± 0.010 0.628 ± 0.008

0.10 0.0322 0.434 ± 0.004 0.581 ± 0.005 0.753 ± 0.003 1.002 ± 0.027 1.239 ± 0.030

0.20 0.0697 0.694 ± 0.012 0.934 ± 0.011 1.238 ± 0.006 1.507 ± 0.020 1.966 ± 0.006

0.30 0.1139 1.485 ± 0.004 1.910 ± 0.015 2.482 ± 0.028 3.263 ± 0.055 3.963 ± 0.089

0.40 0.1666 1.799 ± 0.021 2.273 ± 0.009 2.970 ± 0.003 3.759 ± 0.028 4.791 ± 0.040

0.50 0.2306 2.169 ± 0.025 2.651 ± 0.042 3.579 ± 0.044 4.440 ± 0.051 5.61 ± 0.12

0.60 0.3102 2.425 ± 0.004 2.988 ± 0.010 3.868 ± 0.053 5.03 ± 0.11 6.085 ± 0.013

0.70 0.4116 2.363 ± 0.007 2.916 ± 0.015 3.806 ± 0.051 4.529 ± 0.018 5.722 ± 0.067

0.80 0.5453 2.102 ± 0.025 2.541 ± 0.028 3.259 ± 0.030 3.915 ± 0.061 4.898 ± 0.087

0.90 0.7296 1.356 ± 0.011 1.597 ± 0.006 2.075 ± 0.030 2.521 ± 0.007 3.005 ± 0.038

1.00 1.0000 0.519 ± 0.005 0.628 ± 0.008 0.778 ± 0.013 0.951 ± 0.005 1.198 ± 0.015

Sulfamerazine

0.00c 0.0000 0.74 ± 0.01 0.95 ± 0.01 1.15 ± 0.01 1.42 ± 0.02 1.74 ± 0.02

0.10 0.0322 1.43 ± 0.02 1.79 ± 0.02 2.23 ± 0.04 2.75 ± 0.02 3.31 ± 0.06

0.20 0.0697 3.05 ± 0.01 3.99 ± 0.06 4.95 ± 0.06 6.01 ± 0.12 7.46 ± 0.06

0.30 0.1139 5.19 ± 0.07 6.61 ± 0.03 8.48 ± 0.02 10.48 ± 0.09 12.85 ± 0.07

0.40 0.1666 6.85 ± 0.10 8.58 ± 0.07 11.18 ± 0.16 13.51 ± 0.06 16.57 ± 0.21

0.50 0.2306 8.19 ± 0.13 10.57 ± 0.07 13.01 ± 0.18 16.14 ± 0.30 19.72 ± 0.08

0.60 0.3102 9.34 ± 0.03 11.29 ± 0.10 14.19 ± 0.13 17.00 ± 0.18 21.59 ± 0.16

0.70 0.4116 10.11 ± 0.10 11.91 ± 0.13 14.29 ± 0.13 17.23 ± 0.16 21.17 ± 0.64

0.80 0.5453 9.09 ± 0.06 10.51 ± 0.06 12.79 ± 0.10 14.86 ± 0.17 17.44 ± 0.10

0.90 0.7296 5.95 ± 0.02 7.13 ± 0.08 8.43 ± 0.04 9.93 ± 0.08 11.66 ± 0.16

1.00 1.0000 2.38 ± 0.03 2.87 ± 0.03 3.51 ± 0.01 4.05 ± 0.02 4.94 ± 0.00

Sulfamethazine

0.00c 0.0000 1.23 ± 0.01 1.56 ± 0.01 2.03 ± 0.02 2.39 ± 0.01 3.06 ± 0.02

0.10 0.0322 3.01 ± 0.02 3.74 ± 0.00 4.57 ± 0.05 5.64 ± 0.01 7.01 ± 0.05

0.20 0.0697 7.63 ± 0.09 9.25 ± 0.02 11.25 ± 0.14 14.09 ± 0.33 17.53 ± 0.27

0.30 0.1139 12.68 ± 0.37 16.15 ± 0.13 18.66 ± 0.43 22.70 ± 0.18 28.87 ± 0.30

0.40 0.1666 18.79 ± 0.39 21.80 ± 0.21 26.81 ± 0.53 30.94 ± 0.10 40.24 ± 0.54

0.50 0.2306 23.16 ± 0.38 27.46 ± 0.29 32.17 ± 0.09 39.04 ± 0.41 47.20 ± 0.33

0.60 0.3102 25.87 ± 0.38 29.97 ± 0.31 35.93 ± 0.47 43.07 ± 0.35 51.22 ± 0.29

0.70 0.4116 26.58 ± 0.04 30.29 ± 0.26 36.48 ± 0.26 44.31 ± 0.42 52.01 ± 0.46

0.80 0.5453 23.29 ± 0.14 28.14 ± 0.13 33.04 ± 0.31 38.64 ± 0.56 46.56 ± 0.22

0.90 0.7296 17.29 ± 0.51 20.13 ± 0.65 23.03 ± 0.55 28.36 ± 0.31 32.27 ± 0.45

1.00 1.0000 7.89 ± 0.18 8.62 ± 0.29 9.23 ± 0.07 11.06 ± 0.20 13.25 ± 0.17

a w1 and x1 are the mass and mole fractions of 1-propanol in the co-solvent mixtures free of sulfadiazine,sulfamerazine or sulfamethazine, respectivelyb Values from Ref. [18]c Values from Ref. [19]

842 J Solution Chem (2014) 43:836–852

123

solubility, whereas the e13 term favors the solution process. The contribution of the e33

term can be considered as constant in all the mixtures.

As was described previously for these sulfonamides in ethanol ? water mixtures [18,

19], in a qualitative approach the following analysis can be made based on the energetic

quantities and magnitudes described in Eq. 1. The term e11 is highest in neat water (Hil-

debrand solubility parameter d2 = 47.8 MPa1/2) and is smaller in 1-propanol

(d1 = 24.4 MPa1/2) [23, 24]. Water and water-rich mixtures having larger c3 values (higher

than 260, 150 and 140, for SD, SMR and SMT at 298.15 K for mixtures with w1 = 0.10)

would imply high e11 and low e13 values. On the other hand, in 1-propanol-rich mixtures

(exhibiting c3 values near to 7, 10 and 24 in mixtures with w1 = 0.80 for SD, SMR and

SMT, respectively), the e11 values are relatively low and the e13 values should be relatively

high. Accordingly, the solvation of SD, SMR and SMT should be higher in 1-propanol-rich

mixtures. In a similar way to that described for these compounds in ethanol ? water

mixtures [18, 19], in water and water-rich mixtures the c3 values are highly dependent on

temperature. In all cases the activity coefficients diminish as the temperature rises, giving

more ideal solution processes.

3.3 Apparent Thermodynamic Functions of Solution

The apparent standard enthalpy change of solution is obtained from the Eq. 2 by using the

mean harmonic temperature (Thm) [calculated as: Thm ¼ n=Pn

i¼1

ð1=TÞ], where n is the

number of temperatures studied [29]. Thus, in this case (from 293.15 to 313.15 K) the Thm

value obtained is 303.0 K. In all cases linear weighted regressions were used obtaining

determination coefficients (r2) greater than 0.995 [30].

olnx3

o 1=T � 1=303Kð Þ

� �

p

¼ �DsolnH�

Rð2Þ

The apparent standard Gibbs energy change for the solution process (DsolnG�), con-

sidering the approach proposed by Krug et al. [29], is calculated at 303.0 K by means of:

Fig. 2 Experimental solubility in mole fraction (x3) of sulfadiazine (circles), sulfamerazine (triangles), andsulfamethazine (squares), against the solubility parameter of the 1-propanol ? water (open symbols) andethanol ? water (filled symbols) co-solvent mixtures at 298.15 K

J Solution Chem (2014) 43:836–852 843

123

Table 4 Activity coefficients (c3) of sulfadiazine, sulfamerazine and sulfamethazine in 1-propanol ? watermixtures at several temperatures (±0.05 K)

w1a x1

a T = 293.15 K T = 298.15 K T = 303.15 K T = 308.15 K T = 313.15 K

Sulfadiazine

0.00b 0.0000 670 ± 6 627 ± 6 548 ± 7 483 ± 6 432 ± 7

0.10 0.0322 298 ± 4 263 ± 3 240 ± 2 212 ± 6 200 ± 3

0.20 0.0697 172 ± 3 151 ± 2 134 ± 2 129 ± 2 116 ± 2

0.30 0.1139 71.5 ± 0.7 65.6 ± 0.8 59.5 ± 0.8 53.2 ± 1.0 51.3 ± 0.8

0.40 0.1666 52.8 ± 0.8 49.5 ± 0.5 44.6 ± 0.4 41.3 ± 0.5 37.8 ± 0.6

0.50 0.2306 38.6 ± 0.6 37.3 ± 0.7 32.6 ± 0.5 30.7 ± 0.4 28.3 ± 0.4

0.60 0.3102 30.1 ± 0.3 28.7 ± 0.3 26.1 ± 0.4 23.5 ± 0.5 22.7 ± 0.4

0.70 0.4116 26.6 ± 0.2 25.3 ± 0.3 22.8 ± 0.4 22.4 ± 0.2 20.7 ± 0.3

0.80 0.5453 25.1 ± 0.4 24.4 ± 0.3 22.4 ± 0.3 21.9 ± 0.4 20.5 ± 0.3

0.90 0.7296 31.9 ± 0.4 31.9 ± 0.3 28.8 ± 0.5 27.8 ± 0.3 27.2 ± 0.4

1.00 1.0000 65.7 ± 0.9 64.0 ± 1.0 60.6 ± 1.2 58.1 ± 0.6 53.9 ± 0.8

Sulfamerazine

0.00c 0.0000 345 ± 10 319 ± 9 308 ± 8 292 ± 8 279 ± 7

0.10 0.0322 164 ± 4 154 ± 4 145 ± 4 138 ± 3 134 ± 4

0.20 0.0697 69.8 ± 1.7 62.8 ± 1.8 59.4 ± 1.6 57.3 ± 1.8 53.8 ± 1.3

0.30 0.1139 36.9 ± 1.0 34.1 ± 0.8 31.2 ± 0.7 29.6 ± 0.8 28.2 ± 0.7

0.40 0.1666 24.9 ± 0.7 23.4 ± 0.6 21.1 ± 0.6 20.4 ± 0.5 19.4 ± 0.5

0.50 0.2306 18.4 ± 0.5 16.8 ± 0.4 16.0 ± 0.4 15.0 ± 0.5 14.3 ± 0.3

0.60 0.3102 14.1 ± 0.3 13.7 ± 0.3 12.8 ± 0.3 12.4 ± 0.3 11.4 ± 0.3

0.70 0.4116 11.2 ± 0.3 11.2 ± 0.3 10.9 ± 0.3 10.5 ± 0.3 10.0 ± 0.4

0.80 0.5453 10.5 ± 0.3 10.6 ± 0.3 10.2 ± 0.3 10.3 ± 0.3 10.2 ± 0.2

0.90 0.7296 13.1 ± 0.3 12.9 ± 0.3 12.7 ± 0.3 12.6 ± 0.3 12.5 ± 0.3

1.00 1.0000 25.9 ± 0.7 25.3 ± 0.6 24.1 ± 0.6 24.4 ± 0.6 23.4 ± 0.6

Sulfamethazine

0.00c 0.0000 399 ± 8 373 ± 7 338 ± 7 338 ± 6 310 ± 6

0.10 0.0322 150 ± 3 143 ± 3 138 ± 3 131 ± 2 124 ± 2

0.20 0.0697 53.8 ± 1.2 52.5 ± 1.0 50.8 ± 1.1 47.7 ± 1.4 44.9 ± 1.1

0.30 0.1139 29.2 ± 1.0 27.1 ± 0.5 27.6 ± 0.8 26.6 ± 0.5 24.5 ± 0.5

0.40 0.1666 17.6 ± 0.5 17.9 ± 0.4 17.1 ± 0.5 17.4 ± 0.3 15.7 ± 0.4

0.50 0.2306 12.6 ± 0.3 12.5 ± 0.3 12.6 ± 0.2 12.1 ± 0.3 11.7 ± 0.2

0.60 0.3102 9.8 ± 0.2 10.0 ± 0.2 9.8 ± 0.2 9.6 ± 0.2 9.4 ± 0.2

0.70 0.4116 8.2 ± 0.1 8.5 ± 0.2 8.2 ± 0.2 8.0 ± 0.2 7.9 ± 0.2

0.80 0.5453 7.9 ± 0.1 7.7 ± 0.1 7.7 ± 0.2 7.7 ± 0.2 7.4 ± 0.1

0.90 0.7296 8.7 ± 0.3 8.8 ± 0.3 9.0 ± 0.3 8.6 ± 0.2 8.8 ± 0.2

1.00 1.0000 15.0 ± 0.4 16.2 ± 0.6 17.8 ± 0.3 17.5 ± 0.4 17.0 ± 0.4

a w1 and x1 are the mass and mole fractions of 1-propanol in the co-solvent mixtures free of sulfadiazine,sulfamerazine or sulfamethazine, respectivelyb Values from Ref. [18]c Values from Ref. [19]

844 J Solution Chem (2014) 43:836–852

123

DsolnG� ¼ �R� 303K� intercept ð3Þ

in which the intercept used is the one obtained in the analysis by treatment of ln x3 as a

function of 1/T - 1/Thm. Finally, the standard apparent entropic change for the solution

process (DsolnS�) is obtained from the respective DsolnH� and DsolnG� values at 303.0 K by

using:

DsolnS0 ¼ DsolnH� � DsolnG�ð Þ303K

ð4Þ

Table 5 presents the standard molar thermodynamic functions for dissolution of SD,

SMR and SMT in all of the 1-propanol ? water co-solvent mixtures, including those for

the neat solvents and the ideal solution processes. The propagation of uncertainties in the

thermodynamic quantities calculations was made according to the literature [30, 31].

The standard Gibbs energy of solution is positive in every case as also are the

enthalpy and entropy of solution. Therefore, the dissolution process is always endo-

thermic and entropy driven, according to the increase in entropy after the drug saturates

the solvents. Nevertheless, the thermodynamic function driving the drug’s solubility

increase or decrease according to the co-solvent mixture composition as is shown and

explained later.

In a different way to the behavior reported for SD and SMT in ethanol ? water mix-

tures [18, 19], in 1-propanol ? water mixtures the DsolnH� values of both sulfonamides

diminish from water to 1-propanol-rich mixtures, whereas the DsolnS� values follow a more

erratic behavior. Otherwise, the behavior exhibited by SMR in 1-propanol ? water mix-

tures is similar to the one reported in ethanol ? water mixtures [19]. For this sulfonamide

the DsolnH� and DsolnS� values increase from neat water to w1 = 0.40 or 0.50, but later they

diminish until reaching 1-propanol-rich mixtures.

The relative contributions by enthalpy (fH) and entropy (fTS) toward the solution pro-

cess are given by Eqs. 5 and 6 [32]:

fH ¼DsolnH�j j

DsolnH�j j þ TDsolnS�j j ð5Þ

fTS ¼TDsolnS�j j

DsolnH�j j þ TDsolnS�j j ð6Þ

In all cases the main contributor to the (positive) standard molar Gibbs energy of

solution of both drugs is the positive enthalpy change (fH [ 0.70 for all the sulfonamides),

indicating energetic predominance for the dissolution processes. On the other hand, in a

similar way to that reported in ethanol ? water mixtures [18, 19], the fH values for the

ideal solution processes are lower than the respective values obtained in all of the

experimental solution processes studied. Therefore, the entropy contributions (fTS) are

greater for the ideal dissolution processes, measuring in some way the extent of ran-

domness present in the entropy for the real dissolution processes.

The values of DsolnH� vary nonlinearly with the concentration of 1-propanol in the

aqueous mixtures (Table 5). The addition of 1-propanol to water tends to reduce the

DsolnH� values of SD and SMT solutions at almost all compositions, but it tends to increase

the DsolnH� values of SMR solutions to reach a maximum in the solvent mixture of 0.30 in

mass fraction of 1-propanol. As has been described in the literature, the co-solvent action

in ethanol ? water mixtures may be related to the breaking of the ordered structure of

water (hydrogen bonds) around the non-polar moieties of the drug that increases both the

J Solution Chem (2014) 43:836–852 845

123

Table 5 Apparent thermodynamic functions relative to solution process of sulfadiazine, sulfamerazine andsulfamethazine in 1-propanol ? water mixtures including ideal processes at 303.0 ± 0.05 K

w1a x1

a DsolnG�/kJ�mol-1

DsolnH�/kJ�mol-1

DsolnS�/J�mol-1�K-1

TDsolnS�/kJ�mol-1

fHb fTS

b

Sulfadiazine

0.00c 0.0000 30.0 ± 0.3 43.4 ± 1.1 44.0 ± 1.2 13.3 ± 0.4 0.765 0.235

0.10 0.0322 28.0 ± 0.4 40.7 ± 0.6 41.9 ± 0.9 12.7 ± 0.3 0.762 0.238

0.20 0.0697 26.6 ± 0.3 39.6 ± 0.6 42.6 ± 0.8 12.9 ± 0.3 0.754 0.246

0.30 0.1139 24.5 ± 0.3 38.5 ± 0.6 46.2 ± 0.9 14.0 ± 0.3 0.733 0.267

0.40 0.1666 23.8 ± 0.2 38.2 ± 0.4 47.5 ± 0.5 14.4 ± 0.2 0.726 0.274

0.50 0.2306 23.0 ± 0.3 37.6 ± 0.7 47.9 ± 1.1 14.5 ± 0.3 0.721 0.279

0.60 0.3102 22.4 ± 0.2 36.8 ± 0.6 47.3 ± 0.8 14.4 ± 0.3 0.719 0.281

0.70 0.4116 22.2 ± 0.2 34.6 ± 0.5 41.0 ± 0.7 12.4 ± 0.2 0.736 0.264

0.80 0.5453 22.1 ± 0.3 33.1 ± 0.5 36.4 ± 0.7 11.0 ± 0.2 0.750 0.250

0.90 0.7296 22.7 ± 0.2 32.1 ± 0.6 30.8 ± 0.7 9.3 ± 0.2 0.774 0.226

1.00 1.0000 24.5 ± 0.3 32.6 ± 0.5 26.8 ± 0.5 8.1 ± 0.2 0.801 0.199

Idealc 14.2 ± 0.06 25.2 ± 0.1 36.3 ± 0.3 11.0 ± 0.1 0.696 0.304

Sulfamerazine

0.00d 0.0000 27.2 ± 0.4 32.5 ± 0.4 17.5 ± 0.3 5.3 ± 0.1 0.859 0.141

0.10 0.0322 25.3 ± 0.3 32.6 ± 0.4 24.1 ± 0.4 7.3 ± 0.1 0.817 0.183

0.20 0.0697 23.1 ± 0.3 34.0 ± 0.5 36.0 ± 0.7 10.9 ± 0.2 0.757 0.243

0.30 0.1139 21.5 ± 0.2 35.0 ± 0.3 44.9 ± 0.5 13.6 ± 0.2 0.721 0.279

0.40 0.1666 20.5 ± 0.2 34.5 ± 0.5 46.2 ± 0.8 14.0 ± 0.3 0.711 0.289

0.50 0.2306 19.7 ± 0.2 34.0 ± 0.4 47.0 ± 0.8 14.2 ± 0.2 0.705 0.295

0.60 0.3102 19.2 ± 0.2 32.6 ± 0.5 44.4 ± 0.8 13.5 ± 0.2 0.708 0.292

0.70 0.4116 18.7 ± 0.3 28.9 ± 0.6 33.6 ± 0.9 10.2 ± 0.3 0.739 0.261

0.80 0.5453 18.6 ± 0.1 26.0 ± 0.4 24.4 ± 0.4 7.4 ± 0.1 0.779 0.221

0.90 0.7296 19.2 ± 0.2 26.4 ± 0.2 24.0 ± 0.3 7.3 ± 0.1 0.784 0.216

1.00 1.0000 20.8 ± 0.1 28.3 ± 0.4 24.7 ± 0.4 7.5 ± 0.1 0.791 0.209

Ideald 12.7 ± 0.3 24.6 ± 0.6 39.1 ± 1.3 11.9 ± 0.4 0.675 0.325

Sulfamethazine

0.00d 0.0000 25.8 ± 0.2 34.6 ± 0.6 28.9 ± 0.5 8.8 ± 0.2 0.798 0.202

0.10 0.0322 23.5 ± 0.1 32.4 ± 0.3 29.6 ± 0.3 9.0 ± 0.1 0.783 0.217

0.20 0.0697 20.9 ± 0.3 32.3 ± 0.6 37.5 ± 0.9 11.4 ± 0.3 0.739 0.261

0.30 0.1139 19.4 ± 0.3 30.9 ± 0.9 38.2 ± 1.2 11.6 ± 0.4 0.728 0.272

0.40 0.1666 18.2 ± 0.3 29.2 ± 1.0 36.4 ± 1.3 11.0 ± 0.4 0.726 0.274

0.50 0.2306 17.4 ± 0.2 27.9 ± 0.5 34.7 ± 0.7 10.5 ± 0.2 0.726 0.274

0.60 0.3102 16.8 ± 0.2 27.2 ± 0.5 34.5 ± 0.7 10.5 ± 0.2 0.723 0.277

0.70 0.4116 16.3 ± 0.1 27.1 ± 0.6 35.6 ± 0.8 10.8 ± 0.2 0.716 0.284

0.80 0.5453 16.2 ± 0.1 27.0 ± 0.3 35.7 ± 0.5 10.8 ± 0.2 0.714 0.286

0.90 0.7296 16.5 ± 0.4 25.1 ± 0.9 28.4 ± 1.2 8.6 ± 0.4 0.745 0.255

1.00 1.0000 18.2 ± 0.3 20.3 ± 1.3 7.2 ± 0.5 2.2 ± 0.2 0.903 0.097

846 J Solution Chem (2014) 43:836–852

123

enthalpy of and the entropy of the system [33]. This could be the case for SMR but not for

SD and SMT in 1-propanol ? water mixtures. Above the solvent mixture with 0.40 in

mass fraction of 1-propanol, the apparent enthalpy lowering is the driving force that

enhances the SMR solubility in these media. This behavior is similar to the ones described

previously for this drug in ethanol ? water mixtures [19].

These results indicate that for aqueous-1-propanol mixtures of SMR, two different

driving mechanisms, i.e. entropy or enthalpy, are dominant depending on the co-solvent

composition. At lower 1-propanol ratios (from the water up to the mixtures 0.40 or 0.50 in

mass fraction of 1-propanol the SMR solubility increase is entropy driven, whereas at

greater 1-propanol concentrations (0.50 B w1 B 0.80 or 0.90) the drug solubility

enhancement is enthalpy driven. On the other hand, in the cases of SD and SMT, the

solution process in water rich mixtures is driven by the enthalpy term but the reasons for

this result are unclear.

3.4 Apparent Thermodynamic Functions of Mixing

The dissolution process may be represented by the following hypothetic stages [34],

SoluteðsolidÞ ! SoluteðliquidÞat Tfus ! SoluteðliquidÞat Thm ! SoluteðsolutionÞ

where the dissolution stages are fusion of the solute, cooling of the liquid solute to the

harmonic mean temperature Thm (303.0 K), and the subsequent mixing of the hypothetical

supercooled liquid solute with the solvent at this temperature. This also allows the cal-

culation of the partial thermodynamic contributions to the overall dissolution process by

means of Eqs. 7 and 8, respectively.

DsolnH� ¼ DfusH303 þ DmixH� ð7Þ

DsolnS� ¼ DfusS303 þ DmixS� ð8Þ

where DfusH303 and DfusS

303 represent the thermodynamic functions of fusion of SD, SMR

or SMT and its cooling to the harmonic mean temperature. However, in this research the

DsolnH�-id and DsolnS�-id values for the ideal solution processes were used instead of

DfusH303 and DfusS

303 for reasons described previously in the literature [4]. The same

procedure was used with these sulfonamides in ethanol ? water co-solvent mixtures [18,

19]. Figure 3 summarizes the thermodynamic quantities of mixing of supercooled liquid

SD, SMR and SMT for all of the 1-propanol ? water co-solvent mixtures. The Gibbs

Table 5 continued

w1a x1

a DsolnG�/kJ�mol-1

DsolnH�/kJ�mol-1

DsolnS�/J�mol-1�K-1

TDsolnS�/kJ�mol-1

fHb fTS

b

Ideald 11.1 ± 0.2 25.3 ± 0.5 47.1 ± 1.2 14.3 ± 0.4 0.640 0.360

a w1 and x1 are the mass and mole fractions of 1-propanol in the co-solvent mixtures free of sulfadiazine,sulfamerazine or sulfamethazine, respectivelyb fH and fTS are the relative contributions by enthalpy and entropy towards the Gibbs energy of solution.These values were calculated by means of Eqs. 5 and 6, respectivelyc Values from Ref. [18]d Values from Ref. [19]

J Solution Chem (2014) 43:836–852 847

123

energy of mixing is positive in all cases, which is almost similar to that observed for these

sulfonamides in ethanol ? water mixtures [18, 19] and for sulfanilamide, sulfamethizole

and sulfapyridine in other aqueous alcoholic mixtures [14–17].

The ideal dissolution contributions (related to the solute fusion process) to the enthalpy

and entropy of dissolution of SD, SMR and SMT, DsolnH�-id and DsolnS�-id, are positive

(Table 5). In different way, the contributions of the mixing process toward the overall

dissolution processes are variable, i.e. DmixH� is positive for all drugs in almost all

compositions, except for SMR in 1-propanol rich mixtures, whereas, the entropy of mixing

(DmixS�) is positive for SD in compositions 0.00 B w1 B 0.80 and positive for SMR in

compositions 0.30 B w1 B 0.60 but negative in the other compositions. Finally, DmixS� is

negative for SMT in all the compositions.

According to Fig. 3, the molar DmixG� values diminish as the 1-propanol proportion

increases in the mixtures up to mixture with w1 = 0.80, and they increase in the mixture

with w1 = 0.90 and in neat 1-propanol. The behavior of DmixG� is similar to the one

exhibited by these sulfonamides in ethanol ? water co-solvent mixtures [18, 19]. In a

different way, for SD and SMT the general trend is a nonlinear decrease of DmixH� values

from water up to the mixtures with w1 = 0.90 or neat 1-propanol, respectively. The

enthalpy is responsible for increasing the solubility of SD and SMT in these solvent

mixtures; however, for SD the enthalpy increase from 0.90 mass fraction of 1-propanol up

to neat 1-propanol should corresponds to a decrease of solubility of SD. On the other hand,

the DmixS� values for SD decrease nonlinearly from water up to the mixture with

w1 = 0.10, which opposes the increase in solubility observed, and from this composition

up to 0.50 in mass fraction of 1-propanol the DmixS� increase favors the increase in

solubility of this sulfonamide (SD). With respect to SMR, this sulfonamide exhibits a

similar behavior to SD in the composition range from 0.10 mass fraction of 1-propanol up

to neat 1-propanol. Finally, SMT presents an interesting behavior, i.e. the entropy increases

in water-rich mixtures while the entropy decreases in the 1-propanol-rich mixtures.

However, in intermediate solvent mixtures (0.20 B w1 B 0.80) it remains practically

constant. In a general, the values of the mixing entropy tend to decrease with the increase

of number of methyl groups in the heterocyclic ring of the sulfonamide (SD = 0,

SMR = 1 and SMT = 2, Fig 1), these values being greater for SD and lower for SMT.

Finally, the general behaviors for enthalpy and entropy of mixing of SMR are similar to

those exhibited by the same drugs in ethanol ? water mixtures [18, 19].

As has been previously discussed [14–19], the net variation in DmixH� values (Fig. 3)

results from the contributions of several kinds of interactions. Thus, the enthalpy of cavity

formation (required for the solute accommodation) is endothermic because energy must be

supplied against the cohesive forces of the solvent. This process decreases the drug sol-

ubility, which is in agreement with the discussion of e11 and the solubility parameters of

water and 1-propanol made previously. On the other hand, the enthalpy of solvent–solute

interaction (corresponding to the energy e13) is exothermic and results mainly from van der

Waals and Lewis acid–base interactions. The association of water molecules around the

non-polar groups of the solutes (i.e. hydrophobic hydration) contributes to lowering of the

net DmixH� to small or even negative values in water-rich mixtures. This is not observed in

the case of SD, SMR and SMT in 1-propanol ? water mixtures, just as it was not observed

for the same sulfonamides in ethanol ? water mixtures [18, 19]. Nevertheless, this trend

was reported for sulfapyridine in water [17].

On the other hand, as was previously described [19], by considering the bigger

reduction in entropy obtained with SMR and SMT in neat water in comparison with SD

848 J Solution Chem (2014) 43:836–852

123

(Fig. 3), it is conjecturable that the hydrophobic hydration around the methyl-substituted

heterocyclic ring will be greater in SMR and SMT than in the heterocyclic ring of SD.

It is expected that the energy of cavity formation should be lower as the proportion of

1-propanol increases. This effect is well observed for both SMR and SMT in 1-propanol-

Fig. 3 Apparent thermodynamic quantities of mixing of sulfadiazine (open circle), sulfamerazine (opentriangle), and sulfamethazine (open square), in 1-propanol ? water mixtures at 303.0 K as a function of theco-solvent mixture composition

J Solution Chem (2014) 43:836–852 849

123

rich mixtures (w1 C 0.20 and w1 C 0.30, respectively), where the DmixH� values diminish

as the proportion of co-solvent increases. According to Romero et al. [33], in the initial

portion of the solubility curve the hydrogen bonding of the drug will increase with the co-

solvent concentration in the co-solvent mixtures. However, at large co-solvent proportions

this kind of interaction may become saturated, thus becoming a constant contribution.

Otherwise, nonspecific and cavity effects are not saturated and can vary with the co-solvent

concentration. Nevertheless, these results are observed only for SMR, whereas for SD and

SMT a continuous decrease in mixing enthalpy is observed from neat water up to the

mixture with 0.90 mass fraction of 1-propanol, but then increase slightly in neat 1-pro-

panol. Thus these results for the last two sulfonamides are different with respect to those

exhibited by the same drugs in ethanol ? water mixtures [18, 19]. Nevertheless, the rea-

sons for these behaviors are unclear but they could be associated to the higher hydrophobic

hydration of the propyl moiety of this co-solvent in comparison with ethanol.

3.5 Enthalpy–Entropy Compensation Analysis

There are some reports in the literature demonstrating non-enthalpy–entropy compensation

in the solubility of drugs in some aqueous co-solvent mixtures. These analyses have been

used in order to identify the mechanism of the co-solvent’s action. Thus, weighted fits of

DsolnH� as a function of DsolnG� or DmixH� as a function of DmixG� at the harmonic mean

temperature permit such an analysis [19, 35].

Figure 4 shows that SD, SMR and SMT in the 1-propanol ? water co-solvent system

present nonlinear DmixH� versus DmixG� curves with variable positive slope in the interval

from water up to the mixture with w1 = 0.80 for SD and SMT. Beyond this 1-propanol

proportion, up to w1 = 0.90 for SD and up to neat 1-propanol for SMT, negative slopes are

obtained for both. Otherwise, for SMR a variable but positive slope is observed from water

up to the mixture with w1 = 0.30. In the composition range 0.30 B w1 B 0.80, a variable

negative slope is found, and finally, in 1-propanol-rich mixtures negative slopes are also

observed. Accordingly, the mechanism for the dissolution of SMR in water-rich mixtures is

the entropy driven one, probably implying loosening of the water structure, whereas in the

Fig. 4 DmixH� versus DmixG� enthalpy–entropy compensation plot for dissolution process of sulfadiazine(open circle), sulfamerazine (open triangle), and sulfamethazine (open square), in 1-propanol ? water co-solvent mixtures at 303.0 K

850 J Solution Chem (2014) 43:836–852

123

cases with positive slopes the mechanisms is the enthalpy driven, probably due to better

solvation of the drugs by the 1-propanol molecules.

4 Conclusions

From all topics discussed here it can be concluded that the solution process of SD, SMR

and SMT in 1-propanol ? water mixtures depends strongly on the solvent composition as

was also observed for these drugs in ethanol ? water mixtures [18, 19] and for sulfanil-

amide, sulfamethizole and sulfapyridine in similar aqueous alcoholic solutions [14–17].

Nonlinear enthalpy–entropy compensations were found for these drugs in this co-solvent

system. In this context, the dissolution process in water-rich mixtures was found to be

entropy driven only for SMR, whereas for the other two drugs it is found to be enthalpy

driven in almost all of the mixtures. Ultimately, it can be said that the data presented in this

report amplify the physicochemical information about sulfonamide drugs in binary aque-

ous-co-solvent mixtures.

Acknowledgments We thank the Department of Pharmacy of the National University of Colombia forfacilitating us the equipment and laboratories used.

References

1. Rubino, J.T.: Cosolvents and cosolvency. In: Swarbrick, J., Boylan, J.C. (eds.) Encyclopedia of Phar-maceutical Technology, vol. 3. Marcel Dekker, New York (1988)

2. Yalkowsky, S.H.: Solubility and Solubilization in Aqueous Media. American Chemical Society andOxford University Press, New York (1999)

3. Avdeef, A.: Absorption and Drug Development, Solubility, Permeability and Charge State. Wiley-Interscience, Hoboken (2003)

4. Pacheco, D.P., Martınez, F.: Thermodynamic analysis of the solubility of naproxen in ethanol ? watercosolvent mixtures. Phys. Chem. Liq. 45, 581–595 (2007)

5. Gelone, S., O’Donell, J.A.: Anti-infectives. In: Gennaro, A.R. (ed.) Remington: The Science andPractice of Pharmacy, 21st edn. Lippincott Williams & Wilkins, Philadelphia (2005)

6. Jouyban, A.: Handbook of Solubility Data for Pharmaceuticals. CRC Press, Boca Raton (2010)7. Jouyban, A.: Review of the cosolvency models for predicting solubility of drugs in water–cosolvent

mixtures. J. Pharm. Pharmaceut. Sci. 11, 32–58 (2008)8. Yalkowsky, S.H., He, Y.: Handbook of Aqueous Solubility Data. CRC Press, Boca Raton (2003)9. Budavari, S., O’Neil, M.J., Smith, A., Heckelman, P.E., Obenchain Jr, J.R., Gallipeau, J.A.R.,

D’Arecea, M.A.: The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th edn.Merck, Whitehouse Station (2001)

10. Elworthy, P.H., Worthington, E.C.: The solubility of sulphadiazine in water–dimethylformamidemixtures. J. Pharm. Pharmacol. 20, 830–835 (1968)

11. Bustamante, P., Escalera, B., Martin, A., Selles, E.: A modification of the extended Hildebrandapproach to predict the solubility of structurally related drugs in solvent mixtures. J. Pharm. Pharmacol.45, 253–257 (1993)

12. Perlovich, G.L., Ryzhakov, A.M., Strakhova, N.N., Kazachenko, V.P., Schaper, K.-J., Raevsky, O.A.:Thermodynamic aspects of solubility and partitioning processes of some sulfonamides in the solventsmodeling biological media. J. Chem. Thermodyn. 69, 56–65 (2014)

13. Marcus, Y.: The Properties of Solvents. John Wiley & Sons, Chichester (1998)14. Delgado, D.R., Romdhani, A., Martınez, F.: Thermodynamics of sulfanilamide solubility in propylene

glycol ? water mixtures. Lat. Am. J. Pharm. 30, 2024–2030 (2011)15. Delgado, D.R., Romdhani, A., Martınez, F.: Solubility of sulfamethizole in some propylene gly-

col ? water mixtures at several temperatures. Fluid Phase Equilib. 322, 113–119 (2012)

J Solution Chem (2014) 43:836–852 851

123

16. Delgado, D.R., Rodrıguez, G.A., Holguın, A.R., Martınez, F., Jouyban, A.: Solubility of sulfapyridine inpropylene glycol ? water mixtures and correlation with the Jouyban–Acree model. Fluid Phase Equilib.341, 86–95 (2013)

17. Delgado, D.R., Rodrıguez, G.A., Martınez, F.: Thermodynamic study of the solubility of sulfapyridinein some ethanol ? water mixtures. J. Mol. Liq. 177, 156–161 (2013)

18. Delgado, D.R., Martınez, F.: Solution thermodynamics of sulfadiazine in ethanol ? water mixtures.J. Mol. Liq. 187, 99–105 (2013)

19. Delgado, D.R., Martınez, F.: Solubility and solution thermodynamics of sulfamerazine and sulfa-methazine in some ethanol ? water mixtures. Fluid Phase Equilib. 360, 88–96 (2013)

20. Rodrıguez, S.J., Cristancho, D.M., Neita, P.C., Vargas, E.F., Martınez, F.: Volumetric properties of theoctyl methoxycinnamate ? ethyl acetate solvent system at several temperatures. Phys. Chem. Liq. 48,638–647 (2010)

21. Martin, A.N., Bustamante, P., Chun, A.H.C.: Physical Pharmacy: Physical Chemical Principles in thePharmaceutical Sciences, 4th edn. Lea & Febiger, Philadelphia (1993)

22. Zhang, C.-L., Li, B.-Y., Wang, Y.: Solubilities of sulfadiazine in methanol, ethanol, 1-1-propanol, 2-1-propanol, acetone, and chloroform from (294.15 to 318.15) K. J. Chem. Eng. Data 55, 2338–2339(2010)

23. Zhang, C.-L., Zhao, F., Wang, Y.: Thermodynamics of the solubility of sulfamethazine in methanol,ethanol, 1-propanol, acetone, and chloroform from 293.15 to 333.15 K. J. Mol. Liq. 159, 170–172(2011)

24. Hansen, C.M.: Hansen Solubility Parameters, 2nd edn. Taylor & Francis Group, Boca Raton (2007)25. Barton, A.: Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd edn. CRC Press,

New York (1991)26. Connors, K.A.: Thermodynamics of Pharmaceutical Systems. Wiley Interscience, Hoboken (2002)27. Fedors, R.F.: A method for estimating both the solubility parameters and molar volumes of liquids.

Polym. Eng. Sci. 14, 147–154 (1974)28. Kristl, A., Vesnaver, G.: Thermodynamic investigation of the effect of octanol–water mutual miscibility

on the partitioning and solubility of some guanine derivatives. J. Chem. Soc. Faraday Trans. 91,995–998 (1995)

29. Krug, R.R., Hunter, W.G., Grieger, R.A.: Enthalpy–entropy compensation. 2. Separation of thechemical from the statistical effects. J. Phys. Chem. 80, 2341–2351 (1976)

30. Bevington, P.R.: Data Reduction and Error Analysis for the Physical Sciences. McGraw–Hill Book,Co., New York (1969)

31. Barrante, J.R.: Applied Mathematics for Physical Chemistry, 2nd edn. Prentice Hall Inc, Upper SaddleRiver (1998)

32. Perlovich, G.L., Kurkov, S.V., Kinchin, A.N., Bauer-Brandl, A.: Thermodynamics of solutions III:comparison of the solvation of (?)-naproxen with other NSAIDs. Eur. J. Pharm. Biopharm. 57, 411–420(2004)

33. Romero, S., Reillo, A., Escalera, B., Bustamante, P.: The behaviour of paracetamol in mixtures ofaprotic and amphiprotic-aprotic solvents. Relationship of solubility curves to specific and nonspecificinteractions. Chem. Pharm. Bull. 44, 1061–1066 (1996)

34. Holguın, A.R., Delgado, D.R., Martınez, F., Marcus, Y.: Solution thermodynamics and preferentialsolvation of meloxicam in propylene glycol ? water mixtures. J. Solution Chem. 40, 1987–1999 (2011)

35. Bustamante, P., Romero, S., Pena, A., Escalera, B., Reillo, A.: Nonlinear enthalpy–entropy compen-sation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide and nalidixic acid indioxane–water. J. Pharm. Sci. 87, 1590–1596 (1998)

852 J Solution Chem (2014) 43:836–852

123