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Comparison of The Octanol Water Partition Coefficients Calculated by ClogP, ACDlogP and KowWin To Experimental Values - 2
Comparison of The Octanol Water Partition Coefficients Calculated by ClogP, ACDlogP and KowWin To Experimental Values - 2
Abstract
The experimental octanol/water partition coefficient data, of 108 compounds from the data set [Rytting, E., Lentz, K.A.,
Chen, X., Qian, F., Venkatesh, S., 2004. A quantitative structureproperty relationship for predicting drug solubility in PEG
400/water cosolvent systems. Pharm. Res. 21, 237244] was compared to calculated values using the computer programs ClogP ,
ACD/logPdb and KowWin . It was found that all the three programs have a user friendly interface but ClogP appears to be
the more accurate predictor of log Kow .
2005 Elsevier B.V. All rights reserved.
Keywords: Comparison; Calculated; Octanol/water partition coefficient
1. Introduction
The octanol/water partition coefficient (Kow ) is
the ratio of a compounds concentration in octanol
to its concentration in water when the phases are at
equilibrium. Since partition coefficient values (Kow )
can range over many orders of magnitude they are
normally expressed in logarithmic form (log Kow ).
Corresponding author. Tel.: +1 520 626 4308;
fax: +1 520 626 4063.
E-mail address: machatha@pharmacy.arizona.edu
(S.G. Machatha).
0378-5173/$ see front matter 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2005.01.023
186
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
2. Method
2.1. Acquisition of data
In order to avoid any bias the compounds selected
by Rytting et al. (2004), are used as the evaluation set.
Fourteen of the 122 reported compounds were omitted due to lack of experimental values of log Kow . The
partition coefficients of the remaining 108 compounds
were determined using ClogP , ACD/logPdb , and
KowWin . The experimental log Kow values were
acquired from references listed in the ACD/logP
database. If more than one reference was listed
the average log Kow was taken as the experimental
value.
2.2. Statistical analysis
The average absolute error (AAE) was determined
using the relationship below:
|observed predicted|
AAE =
(1)
n
where n is the number of compounds studied.
t-Tests were performed on the logarithmic data using Microsoft Excel 1997 (Los Angeles, CA). The
P-value was determined using a paired t-test with
a two-tailed distribution. The significance level was
set at 0.05, hence, if the P-value is <0.05 than
the two data sets are considered to be significantly
different.
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
187
Table 1
Comparison between the three log Kow prediction programs
Name
1,2,3-Trichlorobenzene
2-Naphthol
5,5-Diphenylhydantoin
5-Aminosalicylic acida
5-Fluorocytosineb
Acetazolamidea
Adeninea
Adenosinea
Allopurinol
Aminopyrine
Ampicillina
Aspirin
Atropine
Azathioprinea
Baclofena
Benzamide
Benzocaine
Benzoic acid
Biphenyl
Bumetanidea
Butamben
Butylparaben
Caffeine
Camphor
Carbamazepine
Cephradineb
Chloramphenicol
Chlorthalidoneb
Chlorzoxazoneb
Cimetidine
Clofazimine
Corticosteronea
Cortisone
Cytosinea
Dapsone
Deoxycorticosterone
Dexamethasone
Diatrizoic acida
Diflunisal
Diosgeninb
Disopyramide
Diuron
Equilinb
Estradiol
Estriol
Estrone
Ethylparaben
Ethynylestradiol-17-alpha
Fenbufen
Flufenamic acid
MW
181.45
144.17
252.27
153.14
129.09
222.25
135.13
267.24
136.11
231.3
349.4
180.16
289.37
277.26
213.66
121.14
165.19
122.12
154.21
364.42
193.25
194.23
194.19
152.24
236.27
349.4
323.13
338.76
169.57
252.34
473.4
346.47
360.45
111.1
248.3
330.47
392.47
613.92
250.2
414.63
339.48
233.1
268.35
272.39
288.39
270.37
166.18
296.41
254.28
281.23
mp ( C)
52.6
122
296.5
280
296
258.5
110
234.5
350
108
200.5
135
115
243.5
207
130
89
122.4
70
230.5
58
68.5
238
179.8
191.5
151
225
191.75
142
211
145
222
175.5
141.5
263
210.5
205.5
94.75
158.5
239
176
282
255.3
116
143.5
186
125
KowWin
3.81
2.69
2.16
0.98
0.72
0.73
0.73
1.38
1.03
0.60
0.88
1.13
1.91
0.09
1.32
0.74
1.80
1.87
3.93
2.57
2.78
3.47
0.16
3.04
2.25
1.01
0.92
1.59
1.99
0.57
7.55
1.99
1.81
1.47
0.77
3.12
1.72
1.37
4.41
3.35
2.96
2.67
2.81
3.94
2.81
3.43
2.49
4.12
3.18
5.15
ACD
ClogP
4.27
2.70
2.52
0.46
1.78
0.26
0.03
1.02
1.33
0.76
1.35
1.20
1.50
0.90
1.56
0.70
1.95
1.90
3.98
2.78
3.60
3.50
0.13
2.10
2.70
0.98
1.00
0.74
2.29
0.40
7.50
1.80
1.20
1.71
0.90
3.40
2.10
0.45
4.30
4.04
2.65
2.08
1.06
1.65
1.25
0.29
2.27
0.88
0.57
1.20
1.02
1.32
0.01
0.62
0.65
1.92
1.88
4.03
3.36
2.98
3.57
0.06
2.18
1.98
1.53
1.28
0.45
1.87
0.35
6.69
2.32
1.30
1.85
0.89
3.25
1.75
0.73
4.39
2.90
2.80
3.53
4.10
2.90
3.70
2.40
4.52
3.00
5.60
2.58
2.68
2.90
3.78
3.20
3.38
2.51
4.61
3.14
4.88
Experimental value
Absolute error
KowWin
ACD
ClogP
4.09
2.78
2.38
0.16
0.28
0.09
0.22
1.14
0.18
0.08
0.14
0.62
0.05
0.13
0.30
1.22
0.26
0.11
1.12
0.55
0.90
0.81
1.25
1.82
0.10
0.96
0.65
1.97
1.87
3.91
0.30
3.02
3.57
0.07
2.38
2.32
0.47
0.62
0.26
0.48
0.30
0.07
0.12
0.09
0.19
0.36
0.09
0.17
0.00
0.02
2.87
0.24
0.10
0.23
0.66
0.07
0.00
0.08
0.10
0.78
0.14
2.16
0.05
0.32
0.80
2.52
0.05
0.02
0.03
0.07
3.08
0.58
0.07
0.06
0.28
0.38
0.99
0.18
1.15
0.33
0.33
0.39
0.23
0.50
0.09
0.34
0.00
0.05
0.01
0.12
3.66
0.04
0.00
0.01
0.20
0.34
1.14
0.22
0.14
0.14
0.47
7.48
1.94
1.47
1.73
0.97
2.88
1.89
1.05
3.56
0.10
0.07
0.05
0.34
0.26
0.20
0.24
0.17
2.42
0.85
0.07
0.02
0.14
0.27
0.02
0.07
0.52
0.21
1.50
0.74
0.12
0.79
0.38
0.17
0.12
0.08
0.37
0.14
1.78
0.83
2.65
2.68
0.31
0.01
0.25
0.12
0.07
0.00
3.86
2.45
2.95
2.47
3.67
3.20
4.32
0.08
0.36
0.48
0.02
0.45
0.02
0.83
0.24
0.45
0.75
0.07
0.85
0.20
1.28
0.08
0.75
0.43
0.04
0.94
0.06
0.56
188
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
Table 1 ( Continued )
Name
Fluorouracil
Flurbiprofen
Folic acidb
Glafenineb
Griseofulvin
Guaifenesinb
Guaninea
Haloperidol
Hydrochlorothiazide
Hydrocortisone
Hydroflumethiazide
Hyoscyamine
Ibuprofen
Indapamideb
Indoprofen
Iopanoic acidb
Ketoprofen
Khellinb
Linuron
Mefenamic acid
Methocarbamolb
Methylparaben
Metronidazole
Minoxidil
Nadolol
Nalidixic acid
Naphthalene
Naproxen
Nitrofurantoina
Norethisterone
Norfloxacina
p-Aminobenzoic acida
p-Aminosalicylic acida
Paracetamol
Perphenazine
Phenacetin
Phenolphthalein
Phenylbutazone
Praziquantelb
Prednisolonea
Primidone
Progesterone
Propylparaben
Pyrazinamide
Quinidine
Quinine
Salicylamide
Salicylic acid
Spironolactone
Strychnine
Sulfacetamide
MW
130.08
244.26
441.4
372.81
352.77
198.22
151.13
375.87
297.74
362.47
331.28
289.37
206.28
365.83
281.31
570.93
254.28
260.25
249.1
241.29
241.24
152.15
171.16
209.25
309.4
232.24
128.17
230.26
238.16
298.42
319.33
137.14
153.14
151.16
403.97
179.22
318.33
308.38
312.41
360.45
218.25
314.47
180.2
123.11
324.42
324.42
137.14
138.12
416.57
334.42
214.24
mp ( C)
282
110
169.5
220
78.75
148.7
274
218.5
272.5
108.5
76
161
213.5
156.1
94
154.5
93.5
230.5
93
131
159
248
125
229.5
80.2
153
203.5
220.5
187.75
150.5
169.75
97
134.5
260
105
137
281.5
126
96.5
190
174.5
177
140
158
134
280
183
KowWin
0.81
3.81
3.66
0.42
1.92
1.05
1.05
4.20
0.07
1.62
0.22
1.91
3.79
5.78
2.32
3.00
3.00
0.26
2.91
5.28
0.00
2.00
0.00
1.35
1.17
1.64
3.17
3.10
0.17
2.99
0.31
0.96
0.98
0.27
3.82
1.67
3.06
3.52
2.42
1.40
0.73
3.67
2.98
0.53
3.29
3.29
1.03
2.24
2.88
1.85
0.60
ACD
0.78
4.10
2.32
3.49
2.40
0.57
0.98
4.10
0.07
1.40
0.50
1.50
3.70
2.09
2.77
4.19
2.80
1.66
3.20
5.30
0.55
1.86
0.01
0.69
1.29
1.00
3.35
3.00
0.99
3.38
1.48
0.83
1.14
0.34
4.50
1.60
2.63
3.16
2.44
1.49
0.40
4.00
2.90
0.37
3.40
3.44
1.40
2.06
3.12
1.70
0.96
ClogP
0.58
3.75
2.17
3.04
1.75
0.10
1.28
3.85
0.40
1.70
0.25
1.32
3.68
2.94
2.74
4.89
2.76
2.57
3.00
4.94
0.15
1.99
0.46
0.48
0.38
1.32
3.32
2.82
0.47
2.78
0.99
0.98
1.06
0.49
4.32
1.77
2.63
3.38
3.36
1.38
0.88
3.77
3.04
0.71
2.79
2.79
1.28
2.19
2.25
1.66
0.98
Experimental value
Absolute error
KowWin
ACD
ClogP
0.85
4.16
0.04
0.35
0.07
0.06
0.27
0.41
2.18
0.26
0.22
0.43
0.94
4.29
0.07
1.65
0.36
1.83
3.50
0.11
0.09
0.00
0.03
0.14
0.08
0.29
0.04
0.19
0.00
0.25
0.14
0.33
0.20
0.34
0.44
0.33
0.05
0.61
0.51
0.18
2.77
0.45
0.00
0.03
3.12
0.12
0.32
0.36
3.16
4.29
0.25
0.99
0.04
1.01
0.16
0.65
1.96
0.02
1.33
0.71
1.50
3.30
3.26
0.47
2.97
1.26
0.73
0.91
0.48
4.20
1.57
2.41
3.23
0.04
0.02
0.02
0.46
0.14
0.13
0.16
0.30
0.02
0.95
0.23
0.07
0.21
0.38
0.10
0.65
0.29
0.10
0.01
0.64
0.58
0.50
0.05
0.26
0.52
0.41
2.74
0.10
0.23
0.14
0.30
0.03
0.22
0.07
0.03
0.44
0.85
0.33
0.18
0.02
0.44
0.00
0.19
0.27
0.25
0.15
0.01
0.12
0.20
0.22
0.15
1.59
0.91
3.87
3.04
0.60
2.36
2.36
1.28
2.24
2.26
1.93
0.96
0.19
0.18
0.20
0.06
0.07
0.93
0.93
0.25
0.00
0.62
0.08
0.36
0.10
0.51
0.13
0.14
0.23
1.04
1.08
0.12
0.18
0.86
0.23
0.00
0.21
0.03
0.10
0.00
0.11
0.43
0.43
0.00
0.05
0.01
0.27
0.02
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
189
Table 1 ( Continued )
Name
Sulfadiazine
Sulfamerazine
Sulfamethazine
Sulfamethoxazole
Sulfanilamide
Sulfathiazole
Sulindac
Sulpiridea
Tenoxicama
Terfenadine
Tetraethylthiuram disulfide
Theobromine
Theophyllinea
Thiamphenicol
Thyminea
Triamcinolone
Triamterene
Trimethoprim
Uracil
Uric acida
Xanthinea
a
b
MW
250.27
264.3
278.33
253.28
172.2
255.31
356.41
341.42
337.37
471.68
296.52
180.17
180.17
356.22
126.11
394.44
253.27
290.32
112.09
168.11
152.11
mp ( C)
252.5
236.5
176
171.5
165.5
202
183.5
179
211
147.5
70
357
272.5
165.3
270
201
201
335
KowWin
0.34
0.21
0.76
0.48
0.55
0.72
4.28
0.65
2.40
7.62
3.76
0.05
0.39
0.33
0.32
0.96
0.80
0.73
0.87
1.46
1.15
ACD
0.12
0.30
0.80
0.90
0.72
0.30
3.59
0.45
1.52
6.90
3.88
0.72
0.17
0.27
0.12
0.83
1.34
0.80
0.71
1.08
0.81
ClogP
0.09
0.57
1.07
0.55
0.57
0.72
3.16
1.11
1.61
6.09
3.88
0.69
0.06
0.10
0.56
0.67
1.31
0.88
1.06
1.46
0.70
Experimental value
0.07
0.14
0.28
0.89
0.70
0.05
3.24
0.42
0.81
5.69
3.88
0.77
0.02
0.27
0.62
1.16
0.98
0.91
1.06
2.66
0.73
Absolute error
KowWin
ACD
ClogP
0.27
0.07
0.48
0.41
0.15
0.67
1.04
0.23
1.59
1.93
0.12
0.72
0.37
0.06
0.30
0.20
0.18
0.18
0.19
1.20
0.42
0.05
0.16
0.52
0.01
0.02
0.25
0.35
0.03
0.71
1.21
0.00
0.05
0.15
0.00
0.50
0.33
0.36
0.11
0.35
1.58
0.08
0.02
0.43
0.79
0.34
0.13
0.67
0.08
0.69
0.80
0.40
0.00
0.08
0.04
0.17
0.06
0.49
0.33
0.03
0.00
1.20
0.03
other factors that should be considered. Table 5 compares the three programs on the basis of several criteria.
As can be seen from Table 5, these programs considered are similar in many respects. For example, they
each accept the common name and SMILES input
Fig. 1. Plots of experimental against predicted log Kow values for the three programs (KowWin , ACD/logP, ClogP ): () nontautomers/zwitterions and () zwitterions and tautomers.
190
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
Table 2
Fragmentation and calculation of the log Kow of sulindac using ClogP , ACD/logP and KowWin
Flouride
Sulfoxide
C aromatic
CH aromatic
CR aromatic
COOH aliphatic
CH2 aliphatic
CH3 aliphatic
Aliphatic isolating C
Connecting aromatic C
H on isolating carbons
CH (olefinic carbon)
Chain and cluster branches
Chain and alicyclic (net)
Allylic structure
Phenyl-fragment pair
Vinylic
Aliphatic
Aromatic
Type
KowWin
ACd/logP
ClogP
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Fragment
Branch
Bonds
Proximity
Proximity
Interaction
Interaction
Interaction
Interaction
Interaction
Interaction
0.2004
2.1103
0.294
0.6895
0.4911
0.5473
0.3836
0.5007
2.1284
0.370
2.12
0.3697
0.0793
1.1945
0.5314
0.9091
0.0840
0.2722
0.750
0.0678
0.1509
0.2750
0.0428
0.0722
0.130
1.070
0.195
0.227
0.130
0.540
0.200
0.150
Equation constant
0.2290
ACD/logP:
0.5007 2.1284 + 7(0.3697) 2(0.0793) 1.1945 + 0.5314 + 2(0.9091) + 2(0.084) + 0.2722 + 0.75 + 0.0678 + 0.1509 +
0.2750 0.0428 + 0.0722 = 3.59; KowWin : 0.2004 2.1103 + 12(0.294) 0.6895 + 0.4911 + 2(0.5473) + 4(0.3836) + 0.2290 = 4.28;
ClogP : 0.370 2.12 + 12(0.130) 1.070 + 7(0.195) + 16(0.227) + 0.200 + 0.15 3(0.13) 0.54 = 3.16.
Table 3
Average absolute errors and P-values
Group
All compounds
w/o Tautomers and zwitterions
Tautomers and zwitterions
a
na
108
85
23
AAE (P-values)
KowWin
ACD/logPdb
ClogP
0.358 (0.0032)
0.282 (0.0176)
0.638 (0.0658)
0.386 (0.0002)
0.281 (0.0086)
0.774 (0.0049)
0.329 (0.3035)
0.250 (0.6828)
0.623 (0.1357)
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192
191
Table 4
Average absolute errors and P-values without the five outliers
na
Group
All compounds
w/o Tautomers and zwitterions
Tautomers and zwitterions
a
AAE (P-values)
103
84
19
KowWin
ACD/logPdb
ClogP
0.282 (0.0441)
0.262 (0.0313)
0.371 (0.6921)
0.327 (0.0019)
0.270 (0.0153)
0.580 (0.0434)
0.265 (0.5524)
0.248 (0.5906)
0.341 (0.8004)
KowWin
ACD/logP
ClogP
Input
SMILES
CAS no.
Structure drawing
Batch
Online availability
Yes
Yes
N/Aa
Yes
Yes
Yes
N/A
Yes
Yes
Yes
Yes
Yes
N/Aa
Yes
Yes
Calculations
In database
13058
Distinguish enantiomers Yes
>12400
Yes
12800
N/A
Output
Details of calculation
Accuracy
References provided
Warnings
Yes
See Table 3
1
Yes
Yes
See Table 3
Many
Yes
Yes
See Table 3
1
Yes
Yesb
Yesc
Yesd
2895/995
2500/1500
4. Conclusion
As it has been demonstrated using an independent
data set, ClogP is a more accurate predictor of the
octanol/water partition coefficient than ACD/logPdb
and KowWin . All the three programs are similar in
many respects and they all have user friendly interfaces. It is the prerogative of the individual as to which
program they prefer to use.
References
Edward, J.T., Chubb, F.L., Sangster, J., 1997. Iron Chelators of
the pyridoxal isonicotinoyl hydrazone class. Relationship of the
192
S.G. Machatha, S.H. Yalkowsky / International Journal of Pharmaceutics 294 (2005) 185192