Physics and Chemistry of Liquids, 2015

Vol. 53, No. 6, 763–775, http://dx.doi.org/10.1080/00319104.2015.1048247

Extended Hildebrand solubility approach applied to some

sulphonamides in propylene glycol + water mixtures
Zaira J. Cárdenasa, Daniel M. Jiméneza, Daniel R. Delgadob, María Á. Peñac
and Fleming Martínez a*
a
Grupo de Investigaciones Farmacéutico Fisicoquímicas, Departamento de Farmacia, Facultad de
Ciencias, Universidad Nacional de Colombia, Cra. 30 No. 45-03, Bogotá DC, Colombia;
b
Programa de Ingeniería Industrial, Facultad de Ingeniería, Universidad Cooperativa de
Colombia, Neiva, Colombia; cDepartamento de Ciencias Biomédicas, Facultad de Farmacia,
Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
(Received 16 March 2015; accepted 1 May 2015)

Extended Hildebrand solubility approach (EHSA) was applied to evaluate the

solubility of sulphanilamide, sulphapyridine and sulphamethizole in some propylene
glycol + water mixtures at 298.15 K. Reported experimental solubility and some
properties of fusion of this drug were used for the calculations. In particular, a good
predictive character of EHSA has been found by using a regular polynomial in order
five of the interaction parameter W as a function of the solubility parameter of solvent
mixtures free of drug. Nevertheless, the predictive character of EHSA is the same as
the one obtained by direct correlation between drug solubilities and the same descriptor
of polarity of the co-solvent mixtures.
Keywords: sulphonamides; propylene glycol; binary mixtures; extended Hildebrand
solubility approach; solubility parameter

1. Introduction
Sulphonamides are drugs extensively used for the treatment of certain infections caused
by Gram-positive and Gram-negative microorganisms, some fungi and certain protozoa.
Although the advent of the antibiotics has diminished the usefulness of sulphonamides,
these drugs still occupy an important place in the therapeutic resources of physicians and
veterinarians.[1,2] Despite the usefulness of these drugs, their physicochemical properties
in aqueous solution have not yet studied completely.[3] In particular, it is well known that
their solubilities in neat aqueous media are very low.[4] It is noteworthy that co-solvency
is the best technique used in pharmacy for increasing drugs solubility.[5,6] On the other
hand, it is clear that predictive methods of physicochemical properties of drugs, in
particular the ones intended to estimate solubilities, are very important for industrial
pharmacists because they allow optimising several design processes.[4,7–10]
For this reason, this work presents a physicochemical study about the solubility
prediction of three structurally related sulphonamides, namely, sulphanilamide (SA),
sulphapyridine (SP) and sulphamethizole (SMT), in binary mixtures conformed by
propylene glycol (PG) and water at 298.15 K. The study was done based on the
extended Hildebrand solubility approach (EHSA) [7,11] by using experimental

*Corresponding author. Email: fmartinezr@unal.edu.co

© 2015 Taylor & Francis

764 Z.J. Cárdenas et al.

solubility values and some properties relative to the fusion of these drugs taken from
the literature.[12–15] Thus, this work is a continuation of those developed previously
for other drugs in the same co-solvent mixtures.[16–19] It is important to keep in
mind that EHSA method has been widely used to study the solubility of a lot of
pharmaceutical compounds as has been recently exposed in the literature.[18]
Furthermore, it is still employed to evaluate the behaviour of drugs in several co-
solvent mixtures.[20–23] On the other hand, it is remarkable that PG is one of the
more employed co-solvent to develop liquid pharmaceutical dosage forms because of
its solubilising and antimicrobial properties.[24,25]

2. Theoretical background
The ideal solubility (X2id ) of a solid solute is calculated by means of the expression
     
ΔHfus ðTfus  T Þ ΔCp Tfus  T T
log X2id ¼ þ þ ln (1)
2:303RTfus T 2:303R T Tfus

where ΔHfus is the molar enthalpy of fusion of the pure solute (at the melting point), Tfus is
the absolute melting point, T is the absolute solution temperature, R is the gas constant
(8.314 J mol–1 K–1) and ΔCp is the difference between the molar heat capacity of the
crystalline form and the molar heat capacity of the hypothetical supercooled liquid form,
both at the solution temperature. Since ΔCp cannot be easy experimentally determined,
this property may be approximated to the entropy of fusion, ΔSfus. Ideal solubility depends
only on the physicochemical properties of the solid compound without considering the
properties of the solvent. For this reason, the ideal solubility would be higher as the
solute–solute interactions are lower.[26] Accordingly, compounds with high values of
melting point and enthalpy of fusion have lower ideal solubilities.
On the other hand, the real solubility (X2) of a solid solute in a liquid solution is
calculated by means of the expression

 log X2 ¼  log X2id þ log γ2 (2)

where log γ2 is the non-ideality term, being γ2 the solute activity coefficient, which is
determined experimentally. Nevertheless, one method of calculating γ2 in the case of
hydrocarbon compounds is the referent to regular solutions obtained from

V2 ϕ21
 log X2 ¼  log X2id þ ðδ1  δ2 Þ2 (3)
2:303RT

where V2 is the partial molar volume of the solute, ϕ1 is the volume fraction of the solvent
in the saturated solution and δ1 and δ2 are the solubility parameters of solvent and solute,
respectively. It is important to note that in this case, solvent 1 corresponds to the binary
PG + water mixtures. ϕ1 is calculated as

V1 ð1  X2 Þ
ϕ1 ¼ (4)
V1 ð1  X2 Þ þ V2 X2

where V1 is the molar volume of solvent.

 Physics and Chemistry of Liquids 765

Nevertheless, all the pharmaceutical dissolutions deviate of predicted by the regular

solutions theory. For this reason, Martin et al. developed the EHSA method.[27–33] Thus,
if A term (defined as V2 ϕ21 =ð2:303RT Þ) is introduced in Equation (3), the real solubility of
drugs can be calculated from the expression


 log X2 ¼  log X2id þ A δ21 þ δ22  2W (5)

where W term is equal to 2Kδ1δ2 (where K is the Walker parameter [9]). The W factor can
be calculated from experimental data by means of,
 
log γ2
W ¼ 0:5  δ21 þ δ22  (6)
A

where γ2 is the activity coefficient of the solute in the saturated solution, and it is
calculated as, X2id =X2 . The experimental values of the W parameter can be correlated by
means of regression analysis by using regular polynomials as a function of δ1, as follows:

W ¼ C0 þ C1 δ1 þ C2 δ21 þ C3 δ31 . . . :: þ Cn δn1 (7)

These empiric models can be used to estimate the drug solubility by means of back-
calculation resolving this property from the specific W value obtained in the respective
polynomial regression.

3. Results and discussion

The required properties about the sulphonamides studied, like ideal solubility, molar
volume and Hildebrand solubility parameter, are presented in Table 1,[3,12–14,34]
whereas the volumetric behaviour and polarity of PG + water mixtures, as a function
of the composition, are shown in Table 2.[18] Volume fractions and Hildebrand
solubility parameters were calculated assuming additive behaviour.[7,35] Table 2
also summarises the experimental solubility of the sulphonamides expressed in
molarity and mole fraction reported in the literature.[12–14] In all cases, the standard
deviations in solubility were lower than 2.0%.[12–14] It is important to note that
according to the literature,[12–14] these sulphonamides exhibit negative deviations in
aqueous-rich mixtures but positive deviations in PG-rich mixtures in front to the log-
linear model proposed by Yalkowsky and Roseman.[36] Furthermore, by using the
inverse Kirkwood–Buff integrals,[37–39] the preferential solvation parameters were
calculated for these compounds observing that they are preferentially solvated by
water in water-rich mixtures and by PG in PG-rich mixtures.[34] These results were
interpreted as a consequence of hydrophobic hydration of the non-polar moieties of
the sulphonamides in aqueous-rich mixtures and by polarity effects in the co-solvent-
rich mixtures.
Figure 1 shows the ideal and experimental solubility, as well as the calculated
solubility by using the regular solution model, i.e. Equation (3), as a function of the
solubility parameter of solvent mixtures, from 30.2 to 47.8 MPa1/2. In order to use
Equation (3), the molar volume and Hildebrand solubility parameter of the sulphonamides
are required. These values were taken from the literature and are shown in Table 1.[34] It
766 Z.J. Cárdenas et al.

Table 1. Molecular structure and some properties of the sulphonamides considered.

Molar
mass CAS V2 δ2/
Sulphonamide Abbreviation (g mol–1)a number a
Substituentb X2id (cm3 mol–1)c (MPa1/2)c

Sulphanilamide SA 172.20 63-74-1 –H 8.74E–02d 110.3 27.4

N
Sulphapyridine SP 249.29 144-83-2 9.83E–03e 158.5 27.3

CH3
S
Sulphamethizole SMZ 270.33 144-82-1 3.91E–03f 151.7 29.7
N
N
Notes: aFrom [3].
b
Substituent group on the basic structure of sulphanilamide:

H2N SO2 NHR

c
From [34].
d
From [12].
e
From [13]
f
From [14].

Table 2. Propylene glycol + water solvent mixtures composition, Hildebrand solubility parameter
of mixtures and solubility of sulphonamides expressed in molarity and mole fraction at 298.15 K.

Mixtures compositiona Sulphanilamideb Sulphapyridinec Sulphamethizoled

δ1
w1 f1 (MPa1/2) Mol L–1 X2 Mol L–1 X2 Mol L–1 X2

0.0000 0.0000 47.80 7.86E–02 1.43E–03 1.48E–03 2.67E–05 1.83E–03 3.30E–05

0.1000 0.0969 46.10 1.01E–01 1.98E–03 1.56E–03 3.02E–05 2.50E–03 4.85E–05
0.2000 0.1944 44.38 1.27E–01 2.70E–03 2.04E–03 4.28E–05 3.80E–03 7.96E–05
0.3000 0.2926 42.65 1.90E–01 4.43E–03 3.04E–03 6.93E–05 6.73E–03 1.54E–04
0.4000 0.3916 40.91 2.52E–01 6.51E–03 5.21E–03 1.31E–04 1.13E–02 2.84E–04
0.5000 0.4912 39.16 3.48E–01 1.01E–02 7.99E–03 2.23E–04 2.02E–02 5.66E–04
0.6000 0.5915 37.39 4.58E–01 1.53E–02 1.22E–02 3.86E–04 3.34E–02 1.06E–03
0.7000 0.6925 35.61 5.79E–01 2.26E–02 1.59E–02 5.82E–04 4.83E–02 1.78E–03
0.8000 0.7943 33.82 6.27E–01 2.90E–02 1.96E–02 8.53E–04 6.45E–02 2.83E–03
0.9000 0.8968 32.02 7.33E–01 4.21E–02 2.39E–02 1.29E–03 7.38E–02 3.99E–03
1.0000 1.0000 30.20 8.02E–01 5.95E–02 2.74E–02 1.92E–03 8.21E–02 5.80E–03

Notes: aw1 and f1 are the mass and volume fraction of propylene glycol in the co-solvent mixtures free of
sulphonamide.
b
Data from [12].
c
Data from [13].
d
Data from [14].

is important to keep in mind that according to regular solutions model, the maximum
solubility value corresponds to the ideal solubility and it is obtained just when both
solubility parameters of drug and solvent mixture are coincident, like it is shown in
Figure 1. On the other hand, according to the literature, the maximum experimental
solubility values are found when the solubility parameters of both solute and solvent
are also coincident.[7,11] Nevertheless, in the present case, the experimental drug solu-
bilities are lower than the calculated according to Equation (3) in all the compositions for
 Physics and Chemistry of Liquids 767

Figure 1. Ideal solubility (–), experimental solubility (○) and calculated solubility according to the
regular solutions model of Hildebrand (□) of sulphonamides as a function of the solubility parameter
in propylene glycol + water mixtures at 298.15 K.

all the sulphonamides, except SMT in the mixture with w1 = 0.90 and neat PG. Otherwise,
in all the next calculations, the δ2 values used were those obtained according to Fedors
method as reported in Table 1.[40]
768 Z.J. Cárdenas et al.

The ϕ1 values calculated according to Equation (4) for SP and SMT are almost equal to
1.000 because the solubility of these sulphonamides is very low in all the solvent system
considered. Oppositely, the ϕ1 values for SA vary from 0.91 to 0.95 in PG-rich mixtures due
to its high solubility (Table 3). Otherwise, the activity coefficients of these sulphonamides
expressed as decimal logarithm are also presented in Table 3. This table also summarises the
parameters A, K and W for the sulphonamides in PG + water mixtures. In this way, if Walker
K parameter is higher than 1, the solubility is greater than the solubility predicted by the
equation of Hildebrand due to increase of solute-solvent interactions, whereas if it is lower
than 1 the predominant interactions are the solute–solute or solvent–solvent ones. The results
for the three drugs studied indicate that the values of K are smaller than unity which indicates
some interactions that oppose to the solubility.

Table 3. Volume fraction of solvent, sulphonamide activity coefficients, A, K, and W experimental

parameters of sulphonamides in propylene glycol + water mixtures at 298.15 K.

δ1/MPa1/2 ϕ1 log γ2 100 A (cm3 J–1) K W (J cm–3)a

Sulphanilamide
47.80 0.9913 1.785 1.89870 0.561491 1470.791
46.10 0.9906 1.644 1.89595 0.552015 1394.396
44.38 0.9895 1.510 1.89177 0.542850 1320.174
42.65 0.9855 1.296 1.87632 0.534975 1250.339
40.91 0.9815 1.128 1.86127 0.527181 1181.826
39.16 0.9747 0.936 1.83555 0.520318 1116.450
37.39 0.9661 0.758 1.80322 0.514093 1053.349
35.61 0.9549 0.588 1.76167 0.508722 992.770
33.82 0.9472 0.479 1.73355 0.503666 933.473
32.02 0.9300 0.317 1.67119 0.500664 878.422
30.20 0.9090 0.167 1.59663 0.499211 826.174
Sulphapyridine
47.80 0.9998 2.565 2.77515 0.562803 1468.848
46.10 0.9998 2.513 2.77530 0.552194 1389.757
44.38 0.9998 2.361 2.77512 0.542629 1314.819
42.65 0.9997 2.152 2.77462 0.533938 1243.361
40.91 0.9995 1.876 2.77346 0.526311 1175.571
39.16 0.9992 1.643 2.77194 0.519004 1109.565
37.39 0.9987 1.406 2.76949 0.512498 1046.249
35.61 0.9983 1.227 2.76696 0.506358 984.551
33.82 0.9977 1.061 2.76380 0.501113 925.352
32.02 0.9968 0.883 2.75896 0.497205 869.170
30.20 0.9956 0.708 2.75230 0.494749 815.802
Sulphamethizole
47.80 0.9997 2.073 2.65587 0.543947 1544.441
46.10 0.9997 1.906 2.65564 0.535982 1467.546
44.38 0.9996 1.691 2.65506 0.528787 1393.921
42.65 0.9993 1.405 2.65361 0.522645 1324.057
40.91 0.9989 1.138 2.65137 0.517015 1256.327
39.16 0.9980 0.839 2.64686 0.512409 1191.770
37.39 0.9967 0.566 2.63982 0.508487 1129.319
35.61 0.9950 0.342 2.63088 0.505191 1068.637
33.82 0.9928 0.140 2.61909 0.502895 1010.282
32.02 0.9906 −0.010 2.60788 0.501510 953.767
30.20 0.9875 −0.172 2.59121 0.501918 900.381

Note: a1 J cm–3 = 1 MPa.

 Physics and Chemistry of Liquids 769

Figure 2. W parameter of sulphonamides in propylene glycol + water mixtures as a function of the

solubility parameter of the solvent mixtures at 298.15 K. (○): Sulphanilamide; (□): sulphapyridine;
(Δ): sulphamethizole.

Figure 2 shows that the variation of the W parameter with respect to the solubility
parameter of solvent mixtures presents deviation from linear behaviour in all sulphona-
mides, just as it is expectable because the W term implies the summation of two quadratic
(δ21 and δ22 ) and one non-constant-quotient (–log γ2/A) terms, as Equation (6) shows.
W values were adjusted to regular polynomials in orders from 2 to 5 (Equation (7)).
[41] Linear equation was also considered just as comparison. Table 4 summarises the
coefficients obtained in all the regular polynomials for the three sulphonamides. The
significant figures in the coefficients and uncertainties were defined according to the
criterion 3–30, when that was possible.[42] Briefly, this criterion establishes that the
numeric quantity in uncertainty should be placed between 3 and 29, without consider
decimal positions, except if they are integers greater than 30. In this way, the number of
decimal places for the coefficients is defined according to the decimal places of the
respective uncertainties.
In the same way as was previously made,[18,20,21] since we are searching for the
best adjust, the first criterion used to define the best polynomial order of W term as
function of δ1 was the fitting standard uncertainties obtained (Table 4). As another
comparison criterion, beside the calculated solubility values, Table 5 also summarises
the difference percentages between the experimental solubilities and those calculated by
using EHSA.
It is found that as more complex the polynomial used is, better the agreement found
between experimental and calculated solubility also is. Accordingly, the most important
increment in concordance is obtained passing from order 1 to order 2. The concordances
also increase in good way from order 2 to 3 and from order 3 to 4. In the last case, the
mean uncertainties obtained are in the same order or lower than those reported experi-
mentally.[12–14] It is important to keep in mind that for pharmaceutical purposes,
uncertainties lower than 5% are useful for practical purposes, but for academic purposes,
best agreements are required. In this way, although an additional improves is obtained by
passing from orders 4 to 5, this result is not relevant because the mean uncertainties are
lower in comparison with those reported for experimental values.[12–14]
770 Z.J. Cárdenas et al.

Table 4. Coefficients and statistical parameters of regular polynomials in several orders of W as a

function of solubility parameters of co-solvent mixtures free of sulphonamide (Equation (7)) in
propylene glycol + water mixtures at 298.15 K.

Polynomial ordera
Coefficient or
parameter 1 2 3 4 5

Sulphanilamide
C0 –302 (31) 423 (10) 299 (76) 1617 (431) 4785 (3938)
C1 36.6 (0.8) –1.4 (0.5) 8 (6) –130 (45) –547 (517)
C2 – 0.486 (0.007) 0.23 (0.15) 5.7 (1.8) 27 (27)
C3 – – 2.2 (1.3) E–03 –9 (3) E–02 –0.7 (0.7)
C4 – – – 6.0 (1.9) E–04 8 (9) E–03
C5 – – – – –4 (5) E–05
Adj. R2b 0.9947 1.0000 1.0000 1.0000 1.0000
Fit. Err.c 14.72 0.6217 0.5638 0.3789 0.3902
Sulphapyridine
C0 –323 (32) 417 (20) 40 (97) 2125 (213) 2427 (2066)
C1 37.0 (0.8) –1.8 (1.0) 28 (8) –192 (22) –213 (271)
C2 – 0.496 (0.013) –0.27 (0.20) 8.3 (0.9) 10 (14)
C3 – – 6.6 (1.7) E–03 –0.141 (0.015) –0.2 (0.4)
C4 – – – 9.5 (1.0) E–04 2 (5) E–03
C5 – – – – 0.4 (2.4) E–05
Adj. R2b 0.9945 1.0000 1.0000 1.0000 1.0000
Fit. Err.c 15.06 1.2038 0.7194 0.1873 0.2047
Sulphamethizole
C0 –222 (30) 476 (19) 83 (59) 1267 (228) 4494 (1676)
C1 36.5 (0.8) –0.1 (1.0) 31 (5) –94 (24) –518 (220)
C2 – 0.468 (0.012) –0.34 (0.12) 4.5 (0.9) 27 (11)
C3 – – 6.9 (1.0) E–03 –7.7 (1.6) E–02 –0.7 (0.3)
C4 – – – 5.4 (1.0) E–04 8 (4) E–03
C5 – – – – –3.8 (2.0) E–05
Adj. R2b 0.9950 1.0000 1.0000 1.0000 1.0000
Fit. Err.c 14.20 1.1197 0.4378 0.2006 0.1661
Notes: aValues in parentheses are the respective uncertainties.
b
Adj. R2 are adjusted coefficients of determination.
c
Fit. Err. are fitting errors or residuals.

As has been previously described, a very important consideration about the usefulness
of the EHSA method is the one referent to justify the complex calculations involving
any other experimental variables of solute and solvents, instead of the simple empiric
regression of the experimental solubility as a function of the solubility parameters of
solvent mixtures as shown in Figure 3. For this reason, Table 6 shows the coefficients of
regular polynomials in order 4 of log X2 as a function of δ1 values (Equation (8)).[41] The
significant figures in the coefficients and uncertainties were also defined according to
criterion 3–30.[42]

log X2 ¼ C0 þ C1 δ1 þ C2 δ21 þ C3 δ31 þ C4 δ41 (8)

On the other hand, Table 7 shows the calculated values of solubility by using Equation (8)
and also the respective difference percentages in front the experimental ones.
 Physics and Chemistry of Liquids 771

Table 5. Calculated solubility of sulphonamides in propylene glycol + water mixtures by using the
W parameters obtained from regression models in orders 1, 2, 3, 4 and 5, and standard deviations
with respect to the experimental values, at 298.15 K.
a
X2 calculated % dev.

δ1 (MPa1/2) 1 2 3 4 5 1 2 3 4 5

Sulphanilamide
47.80 1.89E–04 1.35E–03 1.40E–03 1.45E–03 1.44E–03 87 6.1 2.6 1.05 0.39
46.10 8.91E–04 2.00E–03 1.99E–03 1.92E–03 1.95E–03 55 1.0 0.4 3.07 1.78
44.38 3.27E–03 2.97E–03 2.90E–03 2.79E–03 2.80E–03 21 10.1 7.3 3.40 3.71
42.65 9.44E–03 4.46E–03 4.34E–03 4.31E–03 4.27E–03 113 0.9 1.9 2.72 3.51
40.91 2.08E–02 6.63E–03 6.51E–03 6.66E–03 6.60E–03 219 1.9 0.0 2.25 1.35
39.16 3.52E–02 9.87E–03 9.86E–03 1.02E–02 1.02E–02 248 2.6 2.7 0.72 0.65
37.39 4.57E–02 1.46E–02 1.48E–02 1.52E–02 1.53E–02 200 4.5 3.0 0.64 0.17
35.61 4.57E–02 2.13E–02 2.19E–02 2.18E–02 2.20E–02 103 5.6 3.1 3.46 2.62
33.82 3.53E–02 3.03E–02 3.11E–02 3.01E–02 3.00E–02 22 4.3 7.0 3.58 3.44
32.02 2.18E–02 4.30E–02 4.33E–02 4.19E–02 4.14E–02 48 2.0 2.8 0.57 1.73
30.20 1.11E–02 5.95E–02 5.77E–02 5.94E–02 5.98E–02 81 0.1 3.2 0.20 0.34
Mean valueb 109 3.6 3.1 1.97 1.79
Standard deviationb 79 3.0 2.3 1.34 1.35
Sulphapyridine
47.80 1.13E–06 2.10E–05 2.47E–05 2.69E–05 2.69E–05 96 21.6 7.5 0.67 0.58
46.10 9.87E–06 3.31E–05 3.22E–05 2.97E–05 2.98E–05 67 9.7 6.6 1.57 1.38
44.38 6.05E–05 5.24E–05 4.65E–05 4.28E–05 4.28E–05 41 22.4 8.8 0.05 0.00
42.65 2.56E–04 8.29E–05 7.30E–05 7.16E–05 7.16E–05 270 19.6 5.3 3.34 3.23
40.91 7.47E–04 1.31E–04 1.21E–04 1.28E–04 1.27E–04 472 0.6 7.3 2.36 2.47
39.16 1.48E–03 2.08E–04 2.07E–04 2.25E–04 2.25E–04 564 6.7 7.2 0.86 0.86
37.39 1.99E–03 3.31E–04 3.56E–04 3.78E–04 3.78E–04 415 14.3 7.8 2.15 2.02
35.61 1.79E–03 5.25E–04 5.95E–04 5.90E–04 5.91E–04 207 9.9 2.2 1.29 1.43
33.82 1.07E–03 8.33E–04 9.43E–04 8.69E–04 8.69E–04 25 2.3 10.5 1.88 1.87
32.02 4.23E–04 1.32E–03 1.37E–03 1.26E–03 1.26E–03 67 2.9 6.9 1.97 2.14
30.20 1.10E–04 2.10E–03 1.78E–03 1.94E–03 1.94E–03 94 9.1 7.4 0.55 0.65
Mean valueb 211 10.8 7.1 1.52 1.51
Standard deviationb 192 7.8 2.1 0.95 0.95
Sulphamethizole
47.80 1.93E–06 2.70E–05 3.18E–05 3.33E–05 3.30E–05 94 18.3 3.6 0.95 0.02
46.10 1.71E–05 5.11E–05 4.96E–05 4.75E–05 4.84E–05 65 5.2 2.3 2.08 0.23
44.38 1.08E–04 9.49E–05 8.43E–05 8.05E–05 8.09E–05 36 19.2 6.0 1.19 1.61
42.65 4.80E–04 1.73E–04 1.52E–04 1.51E–04 1.49E–04 212 12.7 0.8 1.76 2.92
40.91 1.49E–03 3.10E–04 2.86E–04 2.94E–04 2.90E–04 423 9.2 0.7 3.54 2.20
39.16 3.19E–03 5.44E–04 5.41E–04 5.66E–04 5.66E–04 463 3.9 4.4 0.01 0.10
37.39 4.69E–03 9.37E–04 1.01E–03 1.04E–03 1.05E–03 342 11.7 5.1 2.03 0.85
35.61 4.72E–03 1.58E–03 1.78E–03 1.78E–03 1.80E–03 166 11.4 0.3 0.16 1.16
33.82 3.23E–03 2.59E–03 2.92E–03 2.80E–03 2.79E–03 14 8.5 3.4 1.06 1.28
32.02 1.50E–03 4.14E–03 4.30E–03 4.10E–03 4.03E–03 62 3.7 7.6 2.72 0.80
30.20 4.72E–04 6.45E–03 5.49E–03 5.74E–03 5.79E–03 92 11.2 5.3 1.07 0.18
Mean valueb 179 10.5 3.6 1.51 1.03
Standard deviationb 160 5.2 2.4 1.05 0.93
Notes: aCalculated as 100 ×│X2 expt – X2 calc│/X2 expt.
b
Calculated considering the obtained values in the neat solvents and the nine binary mixtures.

Based on mean deviation percentages presented in Tables 5 and 7, it follows that no

significant difference is found between the values obtained by using both methods. These
results would show a non-significant usefulness of EHSA method for practical and
772 Z.J. Cárdenas et al.

Figure 3. Logarithmic solubility of sulphonamides in propylene glycol + water mixtures as a

function of the solubility parameter of the solvent mixtures at 298.15 K. Dotted lines are the additive
log-solubility behaviour. (○): Sulphanilamide; (□): sulphapyridine; (Δ): sulphamethizole.

Table 6. Coefficients and statistical parameters of regular polynomials in fourth degree of log X2 as
a function of solubility parameters of co-solvent mixtures free of sulphonamide (Equation (8)) in
propylene glycol + water mixtures.

Coefficient or parameter Sulphanilamidea Sulphapyridinea Sulphamethizolea

C0 44 (17) 95 (12) 41 (12)

C1 –4.8 (1.8) –10.6 (1.2) –4.9 (1.3)
C2 0.19 (0.07) 0.43 (0.05) 0.21 (0.05)
C3 –3.4 (1.2) E–03 –7.9 (0.8) E–03 –4.1 (0.9) E–03
C4 2.3 (0.8) E–05 5.3 (0.5) E–05 2.8 (0.6) E–06
Adj. R2b 0.9991 0.9997 0.9998
Fit. Err.c 0.0152 0.0104 0.0107
Notes: a Values in parentheses are the respective uncertainties.
b
Adj. R2 are adjusted coefficients of determination.
c
Fit. Err. are fitting errors or residuals.

academic purposes in the case of the sulphonamides studied. Nevertheless, it is necessary

keep in mind that this correlative method considers the drug solubility from a systematic
physicochemical point of view. These results are similar to those previously described for
other drugs.[20–22] Moreover, it would just be necessary to find an effective method to
calculate the Walker K parameter in order to calculate the W term according to the
expression W = 2Kδ1δ2, because the δ1 and δ2 terms would be known, and thus, the
drug experimental solubility could be calculated in any mixture.[11]

4. Conclusions
In this investigation. the EHSA has been adequately used to study the solubility of SA, SP
and SMT in PG + water mixtures at 298.15 K. In particular, a good predictive character
has been found by using a regular polynomial in order 5 of the interaction parameter W
as a function of the solubility parameter of solvent mixtures free of drug. Nevertheless, the
 Physics and Chemistry of Liquids 773

Table 7. Calculated solubility of sulphonamides in propylene glycol + water mixtures by using the
equations of log X2 vs. δ1 as regression models in order 4, and standard deviations with respect to
the experimental values, at 298.15 K.

X2 calculated % dev.a

δ1 (MPa1/2) SA SP SMT SA SP SMT

47.80 1.45E–03 2.69E–05 3.33E–05 1.09 0.63 0.96

46.10 1.92E–03 2.97E–05 4.75E–05 3.24 1.62 2.10
44.38 2.80E–03 4.27E–05 8.05E–05 3.70 0.09 1.18
42.65 4.29E–03 7.16E–05 1.51E–04 3.01 3.32 1.76
40.91 6.67E–03 1.28E–04 2.94E–04 2.43 2.39 3.57
39.16 1.02E–02 2.25E–04 5.66E–04 0.74 0.84 0.00
37.39 1.52E–02 3.77E–04 1.04E–03 0.71 2.20 2.08
35.61 2.17E–02 5.90E–04 1.78E–03 3.84 1.27 0.18
33.82 3.02E–02 8.69E–04 2.80E–03 4.15 1.88 1.04
32.02 4.18E–02 1.26E–03 4.10E–03 0.79 2.01 2.76
30.20 5.94E–02 1.93E–03 5.74E–03 0.21 0.54 1.10
Mean valueb 2.17 1.53 1.52
Standard deviationb 1.48 0.96 1.07
Notes: aCalculated as 100 ×│X2 expt – X2 calc│/X2 expt.
b
Calculated considering the obtained values in the neat solvents and the nine binary mixtures.

predictive character of EHSA is the same as the one obtained by direct correlation
between sulphonamides solubility and the same descriptor of polarity of the co-solvent
mixtures. Finally, it is noteworthy that this research expands the previous analysis
developed based on classical thermodynamic properties and preferential solvation of the
drugs by the solvent components present in the mixtures.[12–14,34]

Disclosure statement
No potential conflict of interest was reported by the authors.

ORCID
Fleming Martínez http://orcid.org/0000-0002-4008-7273

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