|
Sepassi K, Yalkowsky SH.
Solubility Prediction in Octanol: A Technical Note. AAPS PharmSciTech.
2006; 7(1): Article 26. DOI:
10.1208/pt070126
Kia Sepassi1 and Samuel H. Yalkowsky1
1 College of Pharmacy, University of Arizona, Tucson, AZ
Correspondence to:
Kia Sepassi
Tel: (520) 626-4309
Fax: (520) 626-4063
Email: sepassi@pharmacy.arizona.edu
Received: July 21, 2005;
Accepted: December 29, 2005;
Published: March 24, 2006
Keywords: octanol solubility, activity coefficient, solubility parameter
The purpose of this work was to derive an equation for the rapid estimation of octanol solubilities of organic compounds. Solubilities ranging over 4 orders of magnitude were predicted with an average absolute error of 0.39 logarithmic units using melting point alone. The greatest error in prediction occurred for strongly bonded compounds.
The octanol solubility of environmental and pharmaceutically relevant compounds plays an important role in determining their partitioning and absorption behavior. The accurate prediction of octanol solubility will allow for better modeling and understanding the fate of environmental and pharmaceutically prevalent compounds. Quantitative structure-property relationship (QSPR) schemes for the prediction of the octanol solubility may be attempted; however, their applications are limited to specific classes of compounds.1 To date, no simple method has been established for the prediction of the octanol solubility and a more general approach is needed.
According to Liu et al, the solubility of a solid solute is not only dependent on the activity coefficient of the solute in the solvent but also on its crystallinity.2 The mole fraction solubility of a solute in octanol (Xoct) can be described by
|
log X
oct
=
−
ΔH
m
(
T
m
−
T
)
2
.3
⋅
R
⋅
T
⋅
T
m
−
log γ
oct
|
(1) |
ΔHm and R denote the enthalpy of melting and ideal gas constant. Tm and T denote the melting point and reference temperature in Kelvin. It should be noted that Equation 1 assumes the heat capacity change on melting is negligible. The first part of the equation accounts for the crystal contribution to solubility and γoct represents the activity coefficient of the solute in octanol. In the case of liquid solutes, there is no crystallinity and the above equation is simplified to
|
log
X
o
c
t
L
=
−
log
γ
o
c
t
|
(2) |
in which the solubility of a liquid solute is limited only by the activity coefficient of the solute in octanol.
The Scatchard-Hildebrand equation can be used for the estimation of the activity coefficient of a solute in octanol. This equation assumes mixing is random, interaction forces are additive, interaction is between the centers of molecules, and the constant pressure change of volume on mixing is zero.3 While these assumptions are generally useful, they are not applicable to strongly hydrogen-bonded compounds such as water. Using octanol, a weakly hydrogen-bonded liquid, the Scatchard-Hildebrand activity coefficient of the solute is
|
log γ
oct
=
V
2
φ
oct
2
(
δ
oct
-δ
2
)
2
2.3
⋅
R
⋅
T
|
(3) |
where V2 and δ2 are the molar volume and solubility parameters of the solute, respectively, and δoct and φoct are the solubility parameter and volume fraction of octanol, respectively. Although this equation is intended for nonpolar solutes, numerous variations that account for hydrogen bonding are available. However, as a first approximation, the use of this equation for polar solutes in octanol is reasonable. Combining Equations 2 and 3 leads to Equation 4:
|
log X
oct
L
=
−
V
2
φ
o
c
t
2
(
δ
oct
−
δ
2
)
2
2.3
⋅
R
⋅
T
|
(4) |
In order to estimate the solubility of liquid solutes in octanol, the following generalization is made. Complete miscibility of liquid solutes in octanol is given a mole fraction solubility value of 0.5 (
X
o
c
t
L
). The upper critical solution temperature of 2 liquids (X1 and X2) occurs when X1 = X2 = 0.5.4 This assumption was used by Hildebrand et al in the determination of the upper critical solution temperature.4 Therefore, assuming that complete miscibility corresponds to a mole fraction solute solubility of 0.5, the volume fraction of octanol (Φoct) must also be 0.5. For complete miscibility (ie, X2 ≥ 0.5) and a reference temperature of 298 K, Equation 4 becomes
|
log
(
0
.5
)
=
−
V
2
⋅
(
0
.5
)
2
(
21
.1
−
δ
2
)
2
5709
|
(5) |
where 21.1 (J/cm3)0.5 is the solubility parameter of octanol. This equation is further simplified to
|
82
.9
≥
V
2
⋅
|
21
.1
−
δ
2
|
|
(6) |
Thus, from the molar volume of a liquid solute its range of complete miscibility with octanol can be obtained. For liquid solutes having solubility parameters outside the calculated range, phase separation will occur upon mixing with octanol. Table 1 depicts several hypothetical liquid molar volumes along with their corresponding ranges of complete miscibility with octanol obtained from Equation 6. As the molar volumes increase in Table 1, the range of complete miscibility decreases.
|
Table 1. Liquid Molar Volumes and Corresponding Ranges of Complete Miscibility With Octanol
|
|
|
|
Liquid Molar Volume
(cm3/mol) |
Range of Complete Miscibility
(J/cm3)0.5 |
|
| 50 |
9.4 - 32.8 |
| 100 |
12.8 - 29.4 |
| 200 |
15.2 - 27.0 |
| 300 |
16.3 - 25.9 |
| 400 |
17.0 - 25.2 |
| 500 |
17.4 - 24.8 |
|
If a liquid solute has a molar volume near that of octanol (ie, 158 cm3/mol), Equation 6 is simplified to
|
6
.60
≥
|
21
.1
−
δ
2
|
|
(7) |
This leads to a solubility parameter range of 15 to 28 (J/cm3)0.5 for liquid solutes that are completely miscible with octanol at 298 K.
Interestingly, the solubility parameters of most common environmental and pharmaceutical compounds fall within this range of complete miscibility with octanol.
Since the molarity of pure dry octanol is 6.33 mol/L, a mole-fraction solubility of 0.50 corresponds to a molar solubility of 3.17 mol/L. Coincidentally, the logarithm of 3.17 is 0.50. Thus, if a liquid solute has a solubility parameter value in the above range of complete miscibility, the solubility in octanol (
S
o
c
t
L
) can be approximated on a molar scale by
The first part of Equation 1 accounts for the ideal crystalline solubility (Xi), which is a measure of the crystal contribution to solubility in an ideal solution. The ideal crystalline solubility is also called the crystal-liquid solubility ratio and is given by
|
log X
i
=
−
ΔH
m
(
T
m
−
T
)
2
.3
⋅
R
⋅
T
⋅
T
m
|
(9) |
Equation 9 is further simplified by use of Walden’s rule.5 Walden’s rule states that the entropy of melting (
Δ
S
m
=
Δ
H
m
/
T
m
) for coal tar derivatives (which are primarily rigid organic compounds) can be approximated by a constant value of 56.5 J/mol·K.5 If the experimental temperature of interest is 298 K, Equation 9 is simplified to
|
log X
i
=
−
56
.5
⋅
(
T
m
−
298
)
5709
=
−
0
.01
⋅
(
MP
−
25
)
|
(10) |
where MP denotes the melting point of a compound in Celsius and 25°C represents the experimental temperature of interest. Thus, MP − 25 is used in place of Tm − 298, since melting point data are normally reported in Celsius.
The solubility of a crystalline solute in octanol can be determined from the product of the solubility it would have if it were a liquid and its ideal crystalline solubility. This expression is given by
|
S
oct
C
=
S
oct
L
⋅
X
i
|
(11) |
where (
S
o
c
t
C
) is the molar solubility of a crystalline solute in octanol. Taking the logarithm of both sides and substituting Equations 8 and 10 into the above equation leads to
|
log S
oct
C
=
0
.5
−
0
.01
⋅
(
MP
−
25
)
|
(12) |
Thus, for crystalline solutes having solubility parameters in the range of 15 to 28 (J/cm3)0.5, the molar octanol solubility can be predicted by the melting point alone. It should be noted that the term in the parentheses cannot be less than zero. Therefore, for all compounds that melt below ambient temperature, the melting point is set to 25°C.
The miscibility of 32 common organic liquids with octanol was determined by mixing equal volumes and visually evaluating for phase separation over a 3-day period. All liquid solutes were of high purity (>98%) and used as received without further modification or purification from the following companies: Sigma-Aldrich, St Louis, MO; Burdick and Jackson, Morristown, NJ; and AAPER Alcohol and Chemical Co, Shelbyville, KY.
The reported octanol solubilities of 123 compounds were taken from the literature.6-16 The melting points ranged from below room temperature to 485°C and included environmentally prevalent compounds such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and polychlorinated benzenes, as well as steroids and nonsteroidal anti-inflammatory drugs. Multiple solubility values obtained for several compounds from various sources were used independently without averaging. The molar volumes and solubility parameters of the liquid solutes were determined by the Bondi group contribution method described by Barton.17
Table 2 depicts the observed and predicted miscibility data of 32 common organic liquids with octanol. Predicted miscibility data were obtained by use of Equation 6. It can be seen that complete miscibility occurs with solutes having solubility parameters ranging from 14 to 32 (J/cm3)0.5. This range includes the range of 15 to 28 (J/cm3) 0.5, which is based on the assumption that a liquid solute has a molar volume near that of octanol.
|
Table 2. Miscibility Data of 32 Common Organic Liquid Solutes in Octanol*
|
|
|
|
|
|
|
| Liquid Solute |
Molar Volume
(cm3/mol) |
Solubility Parameter
(J/cm3)0.5 |
Miscibility |
| Obs |
Pred |
|
| Butane |
101 |
14.7 |
Y |
Y |
| Hexane |
130 |
14.9 |
Y |
Y |
| Acetonitrile |
52 |
15.2 |
Y |
Y |
| Octane |
162 |
15.6 |
Y |
Y |
| Ether |
105 |
15.7 |
Y |
Y |
| Hexadecane |
131 |
15.7 |
Y |
Y |
| Cyclohexane |
108 |
16.8 |
Y |
Y |
| p-Xylene |
123 |
17.3 |
Y |
Y |
| Isopropyl Myristate |
319 |
17.5 |
Y |
Y |
| Carbon tetrachloride |
96 |
17.8 |
Y |
Y |
| Toluene |
106 |
18.2 |
Y |
Y |
| Ethyl acetate |
99 |
18.2 |
Y |
Y |
| Benzene |
89 |
18.6 |
Y |
Y |
| Chloroform |
81 |
18.7 |
Y |
Y |
| Acetone |
73 |
20.1 |
Y |
Y |
| Methylene chloride |
65 |
20.2 |
Y |
Y |
| Acetic acid |
58 |
21.4 |
Y |
Y |
| Nitrobenzene |
102 |
22.3 |
Y |
Y |
| PEG 600 |
350 |
22.5 |
Y |
Y |
| Butanol |
91 |
23.1 |
Y |
Y |
| PEG 400 |
525 |
23.1 |
Y |
Y |
| Benzyl alcohol |
104 |
23.8 |
Y |
Y |
| Propanol |
75 |
24.6 |
Y |
Y |
| PEG 200 |
175 |
26.1 |
Y |
Y |
| DMSO |
73 |
26.6 |
Y |
Y |
| Ethanol |
58 |
26.6 |
Y |
Y |
| Methanol |
40 |
29.7 |
Y |
Y |
| Propylene glycol |
74 |
30.7 |
Y |
Y |
| Ethylene glycol |
56 |
32.7 |
Y |
Y |
| Glycerin |
73 |
36.1 |
N |
N |
| Formamide |
40 |
36.7 |
N |
N |
| Water |
18 |
48.0 |
N |
N |
|
Glycerin, formamide, and water have solubility parameters outside their calculated ranges of complete miscibility and are thus predicted not to be completely miscible with octanol. This was validated by the presence of 2 phases when equal volumes of these solutes were mixed with octanol.
Table 3 depicts the melting points and the experimental and predicted molar solubilities of 123 compounds reported in literature.6-16 The predicted values were obtained by use of Equation 12.
|
Table 3. Predicted Molar Solubilities Obtained With Equation 12 for 123 Reported Octanol Solubilities*
|
|
|
|
|
|
|
| Compound |
MP
(°C) |
Exp log Soct |
Est log Soct |
Abs Error |
|
| 1,2,3,5-Tetrachlorobenzene |
55 |
0.15 |
0.21 |
0.06 |
| 1,2,3-Trichlorobenzene |
53 |
0.09 |
0.22 |
0.13 |
| 1,2,3-Trichlorobenzene |
53 |
0.18 |
0.22 |
0.04 |
| 1,2,4,5-Tetrabromobenzene |
182 |
–1.32 |
–1.07 |
0.25 |
| 1,2,4,5-Tetrachlorobenzene |
139 |
–1.08 |
–0.64 |
0.44 |
| 1,2,4,5-Tetrachlorobenzene |
139 |
–0.92 |
–0.64 |
0.28 |
| 1,2,4-Tribromobenzene |
43 |
–0.15 |
0.32 |
0.47 |
| 1,3,5-Tribromobenzene |
124 |
–0.90 |
–0.49 |
0.41 |
| 1,3,5-Trichlorobenzene |
65 |
–0.16 |
0.10 |
0.26 |
| 1,4-Dibromobenzene |
87 |
–0.30 |
–0.12 |
0.18 |
| 1,4-Dichlorobenzene |
53 |
0.11 |
0.22 |
0.11 |
| 1,4-Dichlorobenzene |
53 |
0.25 |
0.22 |
0.03 |
| 1,4-Dichlorobenzene |
53 |
0.20 |
0.22 |
0.02 |
| 1-Methylfluorene |
85 |
–0.56 |
–0.10 |
0.46 |
| 2,3,4-Trichloronitrobenzene |
56 |
–0.29 |
0.20 |
0.49 |
| 2,3,5,6-Tetrachloronitrobenezne |
100 |
–0.68 |
–0.25 |
0.43 |
| 2,3-Benzanthracene |
341 |
–2.28 |
–2.66 |
0.38 |
| 2,3-Benzofluorene |
208 |
–1.75 |
–1.33 |
0.42 |
| 2,4,6-Trichlorophenol |
70 |
0.22 |
0.06 |
0.17 |
| 2,4-Dichlorophenol |
45 |
0.36 |
0.30 |
0.06 |
| 2-Methyl-4-nitroimidazole |
252 |
–1.77 |
–1.77 |
0.00 |
| 3,4-Dichloronitrobenzene |
41 |
–0.08 |
0.34 |
0.42 |
| Acenaphthene |
94 |
–0.59 |
–0.19 |
0.40 |
| Acetanilide |
114 |
–0.12 |
–0.39 |
0.27 |
| Acetylsalicyclic acid |
135 |
–0.69 |
–0.60 |
0.09 |
| Anthracene |
216 |
–1.91 |
–1.41 |
0.50 |
| Anthracene |
216 |
–1.78 |
–1.41 |
0.37 |
| Antipyrene |
111 |
–0.19 |
–0.36 |
0.17 |
| Atrazine |
175 |
–1.32 |
–1.00 |
0.32 |
| Barbital |
190 |
–0.92 |
–1.15 |
0.23 |
| Benzil |
95 |
–0.89 |
–0.20 |
0.69 |
| Benzo[a]pyrene |
179 |
–1.60 |
–1.04 |
0.56 |
| Benzoic acid |
122 |
–0.95 |
–0.47 |
0.48 |
| Benzoic acid |
122 |
–0.06 |
–0.47 |
0.41 |
| beta-Carotene |
180 |
–0.75 |
–1.05 |
0.30 |
| Bibenzyl |
52 |
–0.35 |
0.23 |
0.58 |
| Biphenyl |
69 |
–0.13 |
0.06 |
0.19 |
| Butyl p-aminobenzoate |
58 |
0.13 |
0.17 |
0.04 |
| Butyl p-hydroxybenzoate |
69 |
0.34 |
0.06 |
0.28 |
| Caffeine |
238 |
–1.72 |
–1.63 |
0.09 |
| Chrysene |
258 |
–2.60 |
–1.83 |
0.77 |
| Chrysene |
258 |
–2.51 |
–1.83 |
0.68 |
| Coronene |
438 |
–3.41 |
–3.63 |
0.22 |
| Cortisone |
222 |
–1.97 |
–1.47 |
0.50 |
| Decachlorobiphenyl |
306 |
–2.77 |
–2.31 |
0.46 |
| Deoxycorticosterone |
142 |
–0.71 |
–0.67 |
0.04 |
| Dibenz[a,h]anthracene |
270 |
–3.03 |
–1.95 |
1.08 |
| Dibenzofuran |
82 |
–0.27 |
–0.07 |
0.20 |
| Dieldrin |
175 |
–0.97 |
–1.00 |
0.03 |
| Dimetridazole |
140 |
–1.11 |
–0.65 |
0.46 |
| Diphenylamine |
52 |
0.03 |
0.23 |
0.20 |
| Diphenylethane |
25 |
–0.66 |
0.50 |
1.16 |
| Diuron |
159 |
–1.14 |
–0.84 |
0.31 |
| Endrin |
200 |
–0.94 |
–1.25 |
0.31 |
| Ethyl p-aminobenzoate |
89 |
–0.31 |
–0.14 |
0.17 |
| Ethyl p-hydroxybenzoate |
116 |
0.04 |
–0.41 |
0.45 |
| Fenchlorphos |
35 |
–0.16 |
0.40 |
0.56 |
| Fenuron |
134 |
–0.77 |
–0.59 |
0.19 |
| Fenuron |
134 |
–0.77 |
–0.59 |
0.19 |
| Fluoranthene |
108 |
–0.76 |
–0.33 |
0.43 |
| Fluorene |
112 |
–0.62 |
–0.37 |
0.25 |
| Fluorodifen |
94 |
–1.52 |
–0.19 |
1.33 |
| Flurbiprofen |
111 |
–0.20 |
–0.36 |
0.16 |
| Gentisic acid |
205 |
–0.13 |
–1.30 |
1.17 |
| Heptachlor |
95 |
–0.63 |
–0.20 |
0.43 |
| Hexachlorobenzene |
230 |
–1.86 |
–1.55 |
0.31 |
| Hexachlorobenzene |
230 |
–1.82 |
–1.55 |
0.27 |
| Hexachloroethane |
187 |
–0.28 |
–1.12 |
0.84 |
| Hexamethylbenzene |
164 |
–0.89 |
–0.89 |
0.00 |
| Ibuprofen |
76 |
0.18 |
–0.01 |
0.19 |
| Ipronidazole |
61 |
–0.06 |
0.14 |
0.20 |
| Isazophos |
25 |
0.50 |
0.50 |
0.00 |
| Ketoprofen |
94 |
–0.26 |
–0.19 |
0.07 |
| Ketoprofen |
94 |
–0.10 |
–0.19 |
0.09 |
| Lindane |
113 |
–0.74 |
–0.38 |
0.36 |
| m-Bromobenzoic acid |
157 |
–0.07 |
–0.82 |
0.75 |
| Metalaxyl |
72 |
–0.33 |
0.03 |
0.36 |
| Methyl p-aminobenzoate |
114 |
–0.53 |
–0.39 |
0.14 |
| Methyl p-hydroxybenzoate |
131 |
–0.08 |
–0.56 |
0.48 |
| Methyltestosterone |
163 |
–0.45 |
–0.88 |
0.43 |
| Metolachlor |
25 |
0.47 |
0.50 |
0.03 |
| Metoxuron |
127 |
–1.06 |
–0.52 |
0.55 |
| Metronidazole |
160 |
–1.53 |
–0.85 |
0.68 |
| Mirex |
485 |
–0.51 |
–4.10 |
3.59 |
| Monuron |
172 |
–1.04 |
–0.97 |
0.07 |
| Naphthalene |
80 |
–0.36 |
–0.05 |
0.31 |
| Naphthalene |
80 |
–0.15 |
–0.05 |
0.10 |
| Naproxen |
153 |
–0.89 |
–0.78 |
0.11 |
| o,p′-DDT |
75 |
–0.49 |
0.01 |
0.50 |
| o-Bromobenzoic acid |
146 |
–0.12 |
–0.71 |
0.59 |
| p,p-DDT |
109 |
–0.98 |
–0.34 |
0.65 |
| p,p-DDT |
109 |
–0.79 |
–0.34 |
0.46 |
| p-Aminobenzoic acid |
189 |
–0.80 |
–1.14 |
0.34 |
| p-Aminobenzoic acid |
189 |
–1.68 |
–1.14 |
0.54 |
| p-Bromobenzoic acid |
252 |
–1.11 |
–1.77 |
0.66 |
| PCB-15 |
149 |
–0.89 |
–0.74 |
0.15 |
| PCB-29 |
76 |
–0.75 |
–0.01 |
0.74 |
| PCB-3 |
78 |
–0.22 |
–0.03 |
0.19 |
| PCB-52 |
87 |
–0.63 |
–0.12 |
0.52 |
| PCB-61 |
91 |
–0.85 |
–0.16 |
0.70 |
| Pentachlorobenzene |
86 |
–0.63 |
–0.11 |
0.52 |
| Pentachlorobenzene |
86 |
–0.56 |
–0.11 |
0.45 |
| Pentachlorophenol |
174 |
–0.11 |
–0.99 |
0.88 |
| Perlyene |
277 |
–2.52 |
–2.02 |
0.50 |
| Phenacetin |
135 |
–0.84 |
–0.60 |
0.24 |
| Phenanthracene |
99 |
–0.53 |
–0.24 |
0.29 |
| Phenanthracene |
99 |
–0.45 |
–0.24 |
0.21 |
| Phenobarbital |
176 |
–1.09 |
–1.01 |
0.08 |
| Phenol |
41 |
0.94 |
0.34 |
0.60 |
| Prednisolone |
240 |
–1.62 |
–1.65 |
0.03 |
| Profluralin |
32 |
–0.20 |
0.43 |
0.63 |
| Progesterone |
131 |
–0.71 |
–0.56 |
0.15 |
| Propyl p-hydroxybenzoate |
96 |
0.36 |
–0.21 |
0.57 |
| p-Toluic acid |
180 |
–0.32 |
–1.05 |
0.73 |
| Pyrene |
156 |
–0.95 |
–0.81 |
0.14 |
| Pyrene |
156 |
–0.90 |
–0.81 |
0.09 |
| Salicylic acid |
158 |
0.15 |
–0.83 |
0.98 |
| Terbutyrne |
105 |
–0.27 |
–0.30 |
0.03 |
| Testosterone |
155 |
–0.49 |
–0.80 |
0.31 |
| Theophylline |
272 |
–1.99 |
–1.97 |
0.02 |
| trans-Stilbene |
125 |
–1.10 |
–0.50 |
0.60 |
| Triazolam |
224 |
–2.05 |
–1.49 |
0.56 |
| Triphenylene |
199 |
–1.77 |
–1.24 |
0.53 |
|
Figure 1 represents the relationship between the experimental molar solubilities in octanol and melting point (MP – 25°C). The figure shows that melting point is the primary determinant of octanol solubility. As the melting point increases, a corresponding decrease in octanol solubility occurs. The line in the figure is the theoretical relationship described by Equation 12.
 |
|
Figure 1. Dependence of octanol solubility on melting points.
|
Linear regression analysis was performed with SPSS Version 10.0 (SPSS Inc, Chicago, IL). Regression analysis was based on 149 solubilities, corresponding to 123 reported solubilities and 26 miscible liquid solutes from Table 2 that lie in the theoretical range of complete miscibility. Mirex, the square point in Figure 1 was deemed a statistical outlier and not included in the regression analysis.
Linear regression analysis results in
log S
oct
C
=
0
.378
−
0
.0099
⋅
(
MP
−
25
)
, which is in agreement with those of Equation 12. The average absolute error for the predictions for the entire data set was determined to be 0.39 logarithmic units.
The accuracy in predicting octanol solubility will be limited to the availability of reliable experimental data and the compounds having solubility parameters in the range of complete miscibility. The equation also does not account for the self-association of solutes in octanol.
The estimation of octanol solubility with the proposed equation uses Walden’s rule for the entropy of melting. A literature search of entropies of melting resulted in 68 experimental entropies of melting taken from the work of Jain et al.18 For comparison, octanol solubilities were estimated from Equation 12 and from the experimental entropies of melting. These values are presented in Table 4.
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Table 4. Octanol Solubilities Estimated From Using 56.5 J/mol·K and Experimental Entropies of Melting*
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| Compound |
MP
(°C) |
Exp
logSoct |
Est
logSoct† |
ΔSm‡ |
Est
logSoct§ |
Abs
Error|| |
Abs
Errorĥ |
|
| 1,2,3,5-Tetrachlorobenzene |
55 |
0.15 |
0.21 |
58.7 |
0.20 |
0.06 |
0.05 |
| 1,2,3-Trichlorobenzene |
53 |
0.09 |
0.22 |
62.7 |
0.20 |
0.13 |
0.11 |
| 1,2,3-Trichlorobenzene |
53 |
0.18 |
0.22 |
62.7 |
0.20 |
0.04 |
0.02 |
| 1,2,4,5-Tetrabromobenzene |
182 |
–1.32 |
–1.07 |
62.3 |
–1.21 |
0.25 |
0.11 |
| 1,2,4,5-Tetrachlorobenzene |
139 |
–1.08 |
–0.64 |
57.2 |
–0.64 |
0.44 |
0.44 |
| 1,2,4,5-Tetrachlorobenzene |
139 |
–0.92 |
–0.64 |
57.2 |
–0.64 |
0.28 |
0.28 |
| 1,3,5-Trichlorobenzene |
65 |
–0.16 |
0.10 |
54.1 |
0.12 |
0.26 |
0.28 |
| 1,4-Dibromobenzene |
87 |
–0.30 |
–0.12 |
55.7 |
–0.11 |
0.18 |
0.19 |
| 1,4-Dichlorobenzene |
53 |
0.11 |
0.22 |
55.7 |
0.23 |
0.11 |
0.12 |
| 1,4-Dichlorobenzene |
53 |
0.25 |
0.22 |
55.7 |
0.23 |
0.03 |
0.02 |
| 1,4-Dichlorobenzene |
53 |
0.20 |
0.22 |
55.7 |
0.23 |
0.02 |
0.03 |
| 2,3-Benzofluorene |
208 |
–1.75 |
–1.33 |
47.8 |
–1.03 |
0.42 |
0.72 |
| 2,4-Dichlorophenol |
45 |
0.36 |
0.30 |
63.2 |
0.28 |
0.06 |
0.08 |
| Acenaphthene |
94 |
–0.59 |
–0.19 |
42.4 |
–0.01 |
0.40 |
0.58 |
| Acetylsalicyclic acid |
135 |
–0.69 |
–0.60 |
56.4 |
–0.59 |
0.09 |
0.10 |
| Anthracene |
216 |
–1.91 |
–1.41 |
60.1 |
–1.51 |
0.50 |
0.40 |
| Anthracene |
216 |
–1.78 |
–1.41 |
60.1 |
–1.51 |
0.37 |
0.27 |
| Barbital |
190 |
–0.92 |
–1.15 |
54.0 |
–1.06 |
0.23 |
0.14 |
| Benzil |
95 |
–0.89 |
–0.20 |
64.5 |
–0.29 |
0.69 |
0.60 |
| Benzo[a]Pyrene |
179 |
–1.60 |
–1.04 |
59.9 |
–1.12 |
0.56 |
0.48 |
| Benzoic acid |
122 |
–0.95 |
–0.47 |
45.5 |
–0.27 |
0.48 |
0.68 |
| Benzoic acid |
122 |
–0.06 |
–0.47 |
45.5 |
–0.27 |
0.41 |
0.21 |
| Biphenyl |
69 |
–0.13 |
0.06 |
54.6 |
0.08 |
0.19 |
0.21 |
| Butyl p-Aminobenzoate |
58 |
0.13 |
0.17 |
61.8 |
0.14 |
0.04 |
0.01 |
| Caffeine |
238 |
–1.72 |
–1.63 |
47.6 |
–1.28 |
0.09 |
0.44 |
| Chrysene |
258 |
–2.60 |
–1.83 |
55.3 |
–1.76 |
0.77 |
0.84 |
| Chrysene |
258 |
–2.51 |
–1.83 |
55.3 |
–1.76 |
0.68 |
0.75 |
| Coronene |
438 |
–3.41 |
–3.63 |
27.0 |
–1.45 |
0.22 |
1.96 |
| Cortisone |
222 |
–1.97 |
–1.47 |
74.5 |
–2.07 |
0.50 |
0.10 |
| Decachlorobiphenyl |
306 |
–2.77 |
–2.31 |
68.1 |
–2.85 |
0.46 |
0.08 |
| Deoxycorticosterone |
142 |
–0.71 |
–0.67 |
67.6 |
–0.89 |
0.04 |
0.18 |
| Dibenz[a,h]anthracene |
270 |
–3.03 |
–1.95 |
57.3 |
–1.96 |
1.08 |
1.07 |
| Dibenzofuran |
82 |
–0.27 |
–0.07 |
52.3 |
–0.02 |
0.20 |
0.25 |
| Diphenylamine |
52 |
0.03 |
0.23 |
54.8 |
0.24 |
0.20 |
0.21 |
| Ethyl p-Aminobenzoate |
89 |
–0.31 |
–0.14 |
61.4 |
–0.19 |
0.17 |
0.12 |
| Fluoranthene |
108 |
–0.76 |
–0.33 |
48.9 |
–0.21 |
0.43 |
0.55 |
| Fluorene |
112 |
–0.62 |
–0.37 |
50.5 |
–0.27 |
0.25 |
0.35 |
| Fluorodifen |
94 |
–1.52 |
–0.19 |
50.6 |
–0.11 |
1.33 |
1.41 |
| Hexachlorobenzene |
230 |
–1.86 |
–1.55 |
47.2 |
–1.20 |
0.31 |
0.66 |
| Hexachlorobenzene |
230 |
–1.82 |
–1.55 |
47.2 |
–1.20 |
0.27 |
0.62 |
| Hexachloroethane |
187 |
–0.28 |
–1.12 |
53.2 |
–1.01 |
0.84 |
0.73 |
| Hexamethylbenzene |
164 |
–0.89 |
–0.89 |
51.0 |
–0.74 |
0.00 |
0.15 |
| Methyl p-Aminobenzoate |
114 |
–0.53 |
–0.39 |
58.6 |
–0.41 |
0.14 |
0.12 |
| Naphthalene |
80 |
–0.36 |
–0.05 |
54.1 |
–0.02 |
0.31 |
0.34 |
| Naphthalene |
80 |
–0.15 |
–0.05 |
54.1 |
–0.02 |
0.10 |
0.13 |
| Naproxen |
153 |
–0.89 |
–0.78 |
67.0 |
–1.00 |
0.11 |
0.11 |
| o,p′-DDT |
75 |
–0.49 |
0.01 |
66.8 |
–0.08 |
0.50 |
0.41 |
| p-Aminobenzoic acid |
189 |
–0.80 |
–1.14 |
45.3 |
–0.80 |
0.34 |
0.00 |
| p-Aminobenzoic acid |
189 |
–1.68 |
–1.14 |
45.3 |
–0.80 |
0.54 |
0.88 |
| PCB-29 |
76 |
–0.75 |
–0.01 |
65.2 |
–0.09 |
0.74 |
0.67 |
| PCB-3 |
78 |
–0.22 |
–0.03 |
38.2 |
0.15 |
0.19 |
0.36 |
| PCB-61 |
91 |
–0.85 |
–0.16 |
69.3 |
–0.30 |
0.70 |
0.56 |
| Pentachlorobenzene |
86 |
–0.63 |
–0.11 |
57.6 |
–0.12 |
0.52 |
0.51 |
| Pentachlorobenzene |
86 |
–0.56 |
–0.11 |
57.6 |
–0.12 |
0.45 |
0.44 |
| pentachlorophenol |
174 |
–0.11 |
–0.99 |
37.1 |
–0.47 |
0.88 |
0.36 |
| Phenanthracene |
99 |
–0.53 |
–0.24 |
44.8 |
–0.08 |
0.29 |
0.45 |
| Phenanthracene |
99 |
–0.45 |
–0.24 |
44.8 |
–0.08 |
0.21 |
0.37 |
| Phenol |
41 |
0.94 |
0.34 |
36.7 |
0.40 |
0.60 |
0.54 |
| Prednisolone |
240 |
–1.62 |
–1.65 |
75.8 |
–2.35 |
0.03 |
0.73 |
| Progesterone |
131 |
–0.71 |
–0.56 |
66.8 |
–0.74 |
0.15 |
0.03 |
| p-Toluic acid |
180 |
–0.32 |
–1.05 |
50.2 |
–0.86 |
0.73 |
0.54 |
| Pyrene |
156 |
–0.95 |
–0.81 |
43.4 |
–0.49 |
0.14 |
0.46 |
| Pyrene |
156 |
–0.90 |
–0.81 |
43.4 |
–0.49 |
0.09 |
0.41 |
| Salicylic acid |
158 |
0.15 |
–0.83 |
57.0 |
–0.83 |
0.98 |
0.98 |
| Testosterone |
155 |
–0.49 |
–0.80 |
68.8 |
–1.07 |
0.31 |
0.58 |
| Theophylline |
272 |
–1.99 |
–1.97 |
51.8 |
–1.74 |
0.02 |
0.25 |
| trans-Stilbene |
125 |
–1.10 |
–0.50 |
68.8 |
–0.71 |
0.60 |
0.39 |
| Triphenylene |
199 |
–1.77 |
–1.24 |
52.5 |
–1.10 |
0.53 |
0.67 |
|
The use of experimental entropies of melting resulted in an average absolute error of 0.36 logarithmic units as compared with 0.41, which was obtained by using 56.5 J/mol·K as the entropy of melting. Interestingly, for the compounds in Table 4 the entropies of melting values are close to the value estimated by Walden’s rule.
A theoretical range of complete miscibility of liquid solutes with octanol was derived from the Scatchard-Hildebrand equation and validated with a group of common organic solvents. Molar octanol solubilities ranging over 4 orders of magnitude were predicted with a nonregression-based equation using melting point as the only molecular descriptor. The use of experimental entropies of melting resulted in only a slight improvement in predicting octanol solubilities for 68 compounds having melting points above ambient temperature. The equation in its current form is unable to account for strongly hydrogen-bonded compounds.
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