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Estimation of the Effect of NaCl on the Solubility of

Organic Compounds in Aqueous Solutions


NINA NI, MOHAMED M. EL-SAYED,* TAPAN SANGHVI, SAMUEL H. YALKOWSKY
College of Pharmacy, The University of Arizona, Tucson, Arizona 85721

Received 20 April 2000; revised 6 August 2000; accepted 7 August 2000

The Setschenow constant, Ksalt, of a nonelectrolyte in a NaCl solution is


shown to be related to the logarithm of its octanolwater partition coefficient, log Kow,
determined by Ksalt A log Kow + B, where Kow is the octanolwater partition coefficient of the solute and the coefficients A and B are constants. The values of A and B
were empirically determined from literature data for 62 organic compounds and validated for a test set of 15 compounds including several drugs. 2000 Wiley-Liss, Inc. and

ABSTRACT:

the American Pharmaceutical Association J Pharm Sci 89: 16201625, 2000

Keywords: Setschenow constant; nonelectrolyte; sodium chloride; partition coefficient; solubility

INTRODUCTION
Solubility data can be used to predict pharmaceutically important parameters such as dissolution
rate, absorption rate, and tissue distribution rate.
The presence of strong electrolyte salts can either
increase or decrease the solubility of organic compounds in water. The effect observed is dependent
on the polarity of both the solute and the salt.
Inorganic salts, such as NaCl, increase the polarity of water. As a result, they increase the
squeezing out effect of water on nonpolar solutes. This salting-out effect is frequently described by the Setschenow equation (eq. 1):1
log S S0 = KsaltCsalt

(1)

where S and S0 are the solubilities of the organic


solute in aqueous salt solution and in water respectively, Csalt is the molar concentration of electrolyte, and Ksalt is the empirical Setschenow constant.
*Present address: Department of Pharmaceutics, Faculty
of Pharmacy, Suez Canal University, Ismailia, Egypt
Correspondence to: S.H. Yalkowsky (Telephone: 520-6261289; Fax: 520-626-4063)
Journal of Pharmaceutical Sciences, Vol. 89, 16201625 (2000)
2000 Wiley-Liss, Inc. and the American Pharmaceutical Association

1620

Several attempts to quantitate the effect of


salts on the solubility of organic compounds have
been reported, including: (a) electrostatic Debye
MacAulay Theory (DMT) of Debye and MacAulay, 2 (b) ConwayDesnoyersSmith theory
(CDST) of Conway et al.,3 (c) internal pressure
theory (IPT) of McDevit and Long,4(d) scaled particle theory (SPT) of Masterton and Lee,5 and (e)
internal pressure theory (XIPT) modified by Xie
and Yang.6
Xie and Mackay,7 in reviewing the theories just
mentioned, showed that each method requires the
use of several parameters to calculate Ksalt and
the results are only fairly accurate. They also proposed that Setschenow constants can be simply
and more accurately determined by assuming
that they are related to the solute molar volume,
V, by Ksalt 0.0018V. The Xie and Mackay volume calculation (XMV) is based on the method of
Le Bas.8
In this paper, a simple relationship is proposed
for predicting the structural dependence of Ksalt
in NaCl from the octanolwater partition coefficient of the solute. Using new experimental data
and data from the literature, the results of this
relationship are compared with those of the six
methods just listed.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

EFFECT OF NaCl ON ORGANIC COMPOUNDS SOLUBILITY

THEORETICAL SECTION

Table 1. Log Kow and Experimental Ksalt Values for


Tested Compounds

It is well known that cosolvents increase the solubility of nonpolar compounds in aqueous solution.
The relationship between the drug solubility and
the cosolvent concentration can be described by
the log-linear model of Yalkowsky and coworkers;911 that is:
log S S0 = Ccosol

(2)

where S and S0 are the solubilities of solute in


cosolvent solution and in water, respectively,
Ccosol is the concentration of cosolvent and is the
empirical solubilizing power of the cosolvent for
the solute. The value of is related to both the
polarity of the solute by log Kow and the polarity of
the solvent:9/11
= S log Kow + T

(3)

where S and T are constants that characterize


each cosolvent. Combining eqs. 2 and 3 gives:
log S S0 = S log Kow + TCcosol

(4)

which describes both the solvating-out of polar


solutes as well as the solvating-in of nonpolar
solutes.
Cosolvents and salts mix completely with water to form homogenous solutions, but with different effects. Cosolvents decrease the polarity of the
water and reduce the ability of the aqueous system to squeeze out nonpolar solutes, which results in an increase of the solubility of nonelectrolytes. On the other hand, salts decrease the
solubility of nonelectrolytes by increasing the polarity of the water, thereby increasing the ability
of the aqueous system to squeeze out the nonpolar solutes. It can be seen that eqs. 1 and 2
describe a loglinear relationship between solute
solubility and the concentration of salt or cosolvent, respectively. By analogy, Ksalt can be expected to be correlated to log Kow by:
Ksalt = A log Kow + B

(5)

where A and B are constants that characterize


each salt. Combining eqs. 1 and 5 gives:
logS/S0 = A log Kow + B Csalt

1621

(6)

The objective of this investigation is to evaluate


the validity of the proposed eq. 5 in estimating the

Name

Log Kow

Ksalt

Reference

Ethylbenzene
Isopropylbenzene
1,2,4-Trimethylbenzene
1,2,3-Trimethylbenzene
1,3,5-Trimethylbenzene
Sec-Butylbenzene
Tert-Butylbenzene
1-Methylnaphthalene
1-Ethylnaphthalene
Biphenyl
Acenaphthene
Fluorene
Phenanthrene
Anthracene
2-Methylanthracene
1-Ethylanthracene
Pyrene
Fluroanthene
Chrysene
1,2-Benzanthracene
Benzo[a]-Pyrene
o-Dichlorobenzene
n-Pentane
n-Hexane
Cyclopentane
Cyclohexane
Cycloheptane
Methylcyclopentane
Methylcyclohexane
Phenol
o-Nitrophenol
m-Nitrophenol
p-Nitrophenol
p-Nitrotoluene
p-Toluidine
Benzoic acid
o-Chlorobenzoic acid
m-Chlorobenzoic acid
o-Hydroxylbenzoic acid
Phenylacetic acid
n-Hexanol
Cyclohexanone
Acetone
Ethylacetate
Phenylthiourea
Propanoic acid
Butanoic acid
Hexanoic acid
Septanoic acid
Acetic acid

3.17
3.57
3.59
3.54
3.64
4.10
3.97
3.81
4.34
4.03
3.77
4.08
4.49
4.49
4.99
5.52
4.95
4.95
5.66
5.66
6.12
3.45
3.34
3.87
2.79
3.35
3.91
3.31
3.87
1.47
1.85
1.85
1.85
2.38
1.41
1.88
2.00
2.70
2.19
1.41
1.88
0.86
0.21
0.71
0.75
0.33
0.79
1.92
2.45
0.17

0.234
0.316
0.293
0.321
0.318
0.288
0.243
0.200
0.273
0.276
0.238
0.267
0.272
0.326
0.336
0.313
0.320
0.339
0.336
0.354
0.328
0.247
0.221
0.276
0.182
0.277
0.343
0.273
0.274
0.111
0.136
0.147
0.165
0.163
0.170
0.177
0.182
0.180
0.172
0.190
0.232
0.202
0.110
0.172
0.184
0.132
0.166
0.220
0.242
0.064

12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
6
6
6
6

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

1622

NI ET AL.

Table 1. Continued
Name

Log Kow

Ksalt

Reference

Methane
Ethane
Ethene
Cystine
Tyrosine
Leucine
Glycine
Aniline
Phthalic acid
Benzyl amine
Piperidine
m-Cresol

1.09
1.81
1.13
4.46
2.22
1.67
3.21
0.91
0.73
1.09
0.66
1.97

0.127
0.162
0.127
0.068
0.048
0.114
0.002
0.136
0.178
0.112
0.156
0.182

5
5
5
14
14
14
14
14
15
15
15
16

Setschenow constant of NaCl for different nonelectrolyte solutes from their octanolwater partition coefficients.

EXPERIMENTAL SECTION

and 30% acetonitrile. The flow rate was 1 mL/min


and the injection volume was 100 L. The assay
was evaluated using phenytoin standard solutions at concentrations ranging from 15 to 105
g/mL.
Log Kow Values
All log Kow values were calculated by ClogP software (Pomona College). ClogP values were used
because they are easy to determine and reproducible, and because experimental values are not always available. In all cases where they are available, the calculated (ClogP) values and the measured (MlogP) values are in good agreement with
one another.
Training Set Data
The log Kow values were obtained by the ClogP
software and Ksalt values were obtained from the
literature. The log Kow and Ksalt values for the
62-compound training set are given in Table 1.

Materials
All chemicals were reagent grade , purchased
from Aldrich, and used as received.

Test Set Data


The log Kow and Ksalt values for the 15-compound
test set are given in Tables 25.

Solubility Determination
The solubilities of phenytoin, theophylline, and
cytosine were determined in different concentrations of NaCl in water. Excess amounts of each
drug were added directly into the different concentrations of NaCl solutions. Equilibrium was
reached by end-over-end rotation for a period of 3
days at room temperature. The saturated solutions were filtered through 0.45-m millipore
membranes and analyzed by Beckman DU 640,
UV-VIS spectrophotometry (theophylline at 220
nm and cytosine at 256 nm) or by highperformance liquid chromatography (HPLC; phenytoin). All experimental values are the average
of duplicate runs with a relative standard deviation of <3%.
HPLC Analysis
A Beckman Gold HPLC system, equipped with a
model no. 16 detector, was used at 254 nm. An
Econosphere C8 5U column (250 mm: 4.6 mm i.d.;
catalogue no. 70086, serial no. 080291l, Alltech)
was used with a mobile phase consisting of 70%
potassium dihydrogen phosphate (0.5%, pH 4.5)

RESULTS AND DISCUSSION


To validate eq. 5, we collected the Ksalt of NaCl for
62 different compounds from literature data and

Table 2. Experimental Setschenow Constants and


Partition Coefficients of Test Set Compoundsa
Solute

Exp

Log Kow

Benzene
Toluene
o-Xylene
m-Xylene
p-Xylene
Naphthalene
CB
1,3-DCB
1,4-DCB
1,2,4-TCB
2,4-DCP
2,4,6-TCP

0.195
0.228
0.227
0.248
0.251
0.220
0.198
0.226
0.240
0.250
0.218
0.228

2.14
2.64
3.09
3.14
3.14
3.32
2.86
3.57
3.57
4.16
2.96
3.37

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

References 7 and 13.

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EFFECT OF NaCl ON ORGANIC COMPOUNDS SOLUBILITY

Table 3. Summary of Ksalt Values for 12 Test Compounds in NaCl Solution by Different Estimation Methodsa
Method
Solute

DMT

CDST

IPT

SPD

XIPT

XMV

Proposed

Benzene
Toluene
o-Xylene
m-Xylene
p-Xylene
Naphthalene
CB
1,3-DCB
1,4-DCB
1,2,4-TCB
2,4-DCP
2,4,6-TCP

0.217
0.259
0.293
0.299
0.300
0.270
0.236
0.267
0.278
0.290
0.275
0.320

0.154
0.176
0.194
0.198
0.198
0.182
0.170
0.181
0.184
0.191
0.165
0.183

0.423
0.505
0.573
0.584
0.586
0.529
0.483
0.542
0.542
0.591
0.551
0.627

0.186
0.205
0.215
0.220
0.221
0.173
0.220
0.220
0.224
0.216
0.150
0.226

0.163
0.187
0.207
0.210
0.210
0.194
0.181
0.197
0.197
0.212
0.200
0.222

0.173
0.213
0.253
0.253
0.253
0.266
0.211
0.248
0.248
0.286
0.261
0.299

0.200
0.220
0.237
0.239
0.239
0.246
0.228
0.256
0.256
0.279
0.236
0.261

References 7, 12, and 13.

determined their log Kow values with ClogP software. Figure 1 shows the correlation between the
logarithm of the calculated octanolwater partition coefficient and the published Setschenow
constant in NaCl for the compounds listed in
Table 1. This relationship is described by:
Ksalt = 0.039 log Kow + 0.117 n = 62, r = 0.9257
(7)
Both the slope and the intercept are specific for
NaCl. Combining eqs. 1 and 7 gives:

log S S0 = 0.039 log Kow + 0.117Csalt

(8)

Equation 8 and Figure 1 show that if the ClogP


value of the solute is larger than zero, the Ksalt
value will be positive and NaCl will decrease its
solubility in water. If the ClogP value of the solute
is much less than zero (i.e., < (0.117/0.039), the
Ksalt value will be negative and NaCl will increase
its aqueous solubility.
Table 2 gives the octanolwater partition coefficients of the 12-solute test sets along with the

Table 4. Summary of Calculated Percentage Errorsa for 12 Test Compounds by Different Estimation Methods
Method
Solute

DMT

CDST

IPT

SPD

XIPT

XMV

Proposed

Benzene
Toluene
o-Xylene
m-Xylene
p-Xylene
Naphthalene
CB
1,3-DCB
1,4-DCB
1,2,4-TCB
2,4-DCP
2,4,6-TCP
Average errorb

11.2
13.6
29.0
20.5
19.5
22.7
19.1
18.1
15.8
16.0
26.1
40.3
21.0

21.0
22.8
14.5
20.1
21.1
17.2
14.1
19.9
23.3
23.6
24.3
19.7
20.1

116.9
121.4
152.4
135.4
133.4
140.4
143.9
139.8
125.8
136.4
152.7
175.0
139.5

4.62
10.09
5.29
11.29
11.95
21.36
11.11
2.65
6.67
13.60
31.19
0.88
10.89

16.41
17.98
8.81
15.32
16.33
11.82
8.58
12.83
17.92
15.20
8.26
2.63
12.68

11.38
6.68
11.33
1.90
0.68
20.76
6.56
9.73
3.33
14.40
19.72
31.14
11.47

2.80
3.53
4.63
3.44
4.60
12.04
15.42
13.38
6.76
11.70
8.41
14.40
8.43

a
b

Percentage error (predicated value experimental value) 100/experimental value.


Average error sum (ABS(percentage error))/12.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

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NI ET AL.

Figure 1. The Ksalt values of different compounds in


NaCl solution versus their log Kow values.

observed Setschenow constant for sodium chloride.


Table 3 shows the Setschenow Ksalt values predicted by the aforementioned theories and the experimental NaCl data on benzene, toluene, o-, m-,
and p-xylenes, naphthalene, chlorobenzene (CB),
1,3-dichlorobenzene (1,3-DCB), 1,4-dichlorobenzene (1,4-DCB), 1,2,4-trichlorobenzene (1,2,4TCB), 2,4-dichlorophenol (2,4-DCP), and 2,4,6trichlorophenol (2,4,6-TCP). The errors associated with the calculation of the Setschenow
constants by the various methods are given in
Table 4. The average errors predicted by the
aforementioned theories are given in the last line
of the table. It is obvious that the proposed
method is more accurate than the other theoretical and empirical methods.
Table 5 shows the data we obtained experimentally for phenytoin, theophylline, and cytosine in
NaCl solutions along with the data predicted by
the method of Xie and Mackay and by the proposed equation. (The theoretical methods were
not used because they require parameters that
could not be unambiguously determined.) In the

case of cytosine, the negative Ksalt value of the


experimental result indicates a salting-in effect.
But the Ksalt value is very small, showing that
there is no significant effect of NaCl on the solubility of cytosine as we predicted. Table 5 shows
that our data are much more accurate than the
XMV method because the XMV method is based
solely on volume, which cannot explain the solutesolute and solventsolute interactions. So,
the XMV method cannot be used to predict the
salting-in of polar compounds. Furthermore, it
cannot be used to distinguish among isomers or
among homomorphs that have the same molar
volume, but different polarity.
Of the theories listed in Tables 3 and 4, eqs.
68 are most comparable with scaled particle
theory (SPT), which treats the activity coefficient
of the nonelectrolyte as the sum of free energy
terms for cavity formation and interaction between the solute and solvent, like eqs. 24. SPT
can be used to explain how a cosolvent increases
the solubility of an organic compound in water.
Masterton and Lee applied the SPT to a system of
three components, giving a very complicated
equation. Our method, also based on SPT, uses
only three simple coefficients (log Kow, A, and B)
to more accurately predict the Ksalt value. The
partition coefficient reflects the effect of the interaction between the solute and water whereas the
constants A and B account for the effect of the salt
on the water.

CONCLUSIONS
A linear relationship between logarithm of octanolwater partition coefficient, log Kow and Setschenow constant, Ksalt, is proposed and applied
to 77 organic solutes. This relationship provides a
simple and accurate method to predict the effect
of NaCl on the aqueous solubility of organic compounds.

Table 5. Ksalt Values for Three Test Compounds by Equation 7


Solute

Experimental

VLe Basa

Log Kow

XMV

Proposed

Phenytoin
Theophylline
Cytosine

0.191
0.100
0.005

263.7
169.4
100.8

2.08
0.06
1.65

0.475
0.298
0.181

0.198
0.115
0.053

The calculated Le Bas molar volume is based on ref 8.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000

EFFECT OF NaCl ON ORGANIC COMPOUNDS SOLUBILITY

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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 12, DECEMBER 2000