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ABSTRACT:
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)
1620
THEORETICAL SECTION
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)
(3)
(4)
(5)
1621
(6)
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
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
Materials
All chemicals were reagent grade , purchased
from Aldrich, and used as received.
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)
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
1623
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
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:
(8)
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
1624
NI ET AL.
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.
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
REFERENCES
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Salzlosungen Auf Grund Ihres Verhaltens Zu
Kohlensaure. Z Physik Chem 4:117125.
2. Debye P, MacAulay IJ. 1925. Das Elektrische Feld
Der Ionen Und Die Neutralsalzwirking. Physik Z
26:2229.
3. Conway BE, Desnoyers JE, Smith AC. 1964. Hydration of simple ions and polyions. Philos Trans R
Soc 256:389437.
4. McDevitt WF, Long FA. 1952. The activity coefficient of benzene in aqueous salt solutions. J Am
Chem Soc 74:17731777.
5. Masterton WL, Lee TP. 1970. Salting coefficients
from scaled particle theory. J Phys Chem 74:1776.
6. Xie WH, Ji HW, Li WJ. 1985. The calculation
method of a modified equation of the internal pressure salt effect theory. Acta Physicochim Sin 1:304.
7. Xie WH, Su JZ, Xie XM. 1990. Studies on the activity coefficient of benzene and its derivatives in
aqueous salt solutions. Thermochim Acta 169:
271286.
8. Reid RC, Pransnitz JM, Poling BE. 1984. In: The
Properties of Gases and Liquids, 3rd edition. New
York:McGraw Hill.
9. Yalkowsky SH, Roseman TJ. 1981. Solubilization
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