Drug Discovery-Development InterfacePredicting the Octanol Solubility of Organic Compounds
Section snippets
INTRODUCTION
The octanol–water partition coefficient, Kow, is commonly used to model the interface between various biological tissues and water. Raevsky et al.1 and Anliker and Moser2 suggest that “the solubility in pure octanol is an indicator of the maximum storage capacity of a chemical in natural lipids and in some cases should be preferred to the widespread use of the octanol–water partition coefficient.” Anliker and Moser2 found good correspondence between the solubilities of some organic compounds in
Upper Critical Solution Temperature
The upper critical solution temperature, Tc, is the highest temperature at which a two component regular system exists as two phases. Above the critical solution temperature, they will be miscible in all proportions. A regular solution is one in which the entropy of mixing is ideal, the volume of mixing is zero, and the heat of mixing is positive. According to Hildebrand et al.,7 Tc of a nonelectrolytes solute and octanol can be approximated bywhere V and δ are molar
DATA COLLECTION
The reported octanol solubilities and melting points of 224 compounds were taken from the literature (see Table S1).1., 9., 12., 13., 14., 15., 16., 17., 18., 19., 20., 21., 22., 23., 24., 25., 26., 27., 28., 29., 30., 31., 32., 33., 34., 35. The molar volumes and solubility parameters were taken from literature36., 37., 38., 39., 40., 41., 42., 43., 44., 45., 46., 47., 48., 49., 50. or calculated using Fedors' group contribution method.51 For compounds with multiple octanol solubility or
Miscibility of Liquids
The curves in Figure 1 represent the upper and lower limits of solubility parameters (J/cm3)0.5 as a function of solute molar volumes (cm3/mol), which correspond to complete miscibility at 298.15 K. The solid curves, dashed curves and dotted curves correspond to the solubility parameters calculated from (5), (6), (7), respectively. The three sets of curves are nearly identical for compounds with molar volumes greater than 200 cm3/mol. However, the curves differ increasingly as the solute molar
DISCUSSION
Compounds that fall between the sets of curves of Figure 1 have octanol solubilities that are well predicted by Eq. 13. The AAE of 0.33 is quite reasonable in view of the experimental error in determining solubility parameters as well as octanol solubilities. It is also clear that for all models there is a somewhat greater accuracy when the predictions are based on grams per liter rather than moles per liter. Equation 13 is somewhat more accurate than Eq. 12 because complete miscibility is more
CONCLUSIONS
The solubilities of an organic nonelectrolyte in octanol can be calculated as a function of its crystallinity (as reflected by its melting point) and whether or not its liquid (or hypothetical super-cooled liquid) form is miscible with octanol.
Three regular solution based models are presented to describe the dependence of the miscibility of the liquid solute with octanol. All three models indicate that miscibility of a solute with octanol is dependent on the product of its molar volume and the
REFERENCES (52)
- et al.
The limits of bioaccumulation of organic pigments in fish: Their relation to the partition coefficient and the solubility in water and octanol
Ecotoxicol Environ Saf
(1987) Solubility of organic chemicals in octanol, triolein and cod liver oil and relationships between solubility and partition coefficients
Water Res
(1991)- et al.
Fat solubility—A property of environmental relevance?
Chemosphere
(1983) - et al.
Solubility of simvastatin: A theoretical and experimental study
J mol Struct
(2011) - et al.
Measuring the saturation limit of low-volatility organic compounds in soils Implications for estimates of dermal absorption
Sci Total Environ
(2010) - et al.
Experimental solid-liquid phase equilibria of {cholesterol plus binary solvent mixture: 1-Alcohol (C-4-C-10) +cyclohexane}
Fluid Phase Equilibria
(2010) - et al.
Solubility and pK(a) of select pharmaceuticals in water, ethanol, and 1-octanol
J Chem Thermodyn
(2010) - et al.
Modelling, solubility and pK(a) of five sparingly soluble drugs
Int J Pharm
(2011) - et al.
Dissolution and partition thermodynamic functions of some nonsteroidal anti-inflammatory drugs
J Pharm Sci
(1986) - et al.
A novel method for measuring membrane-water partition-coefficients of hydrophobic organic-chemicals—Comparison with 1-octanol-water partitioning
J Pharm Sci
(1988)
Solubility of organic-chemicals in octanol, triolein and cod liver oil and relationships between solubility and partition-coefficients
Water Res
Towards an understanding of the molecular mechanism of solvation of drug molecules: A thermodynamic approach by crystal lattice energy, sublimation, and solubility exemplified by paracetamol, acetanilide, and phenacetin
J Pharm Sci
Synthesis, pharmacology, crystal properties, and quantitative solvation studies from a drug transport perspective for three new 1,2,4-thiadiazoles
J Pharm Sci
The use of solubility parameters in pharmaceutical dosage form design
Int J Pharm
Investigations on the predictability of the formation of glassy solid solutions of drugs in sugar alcohols
Int J Pharm
Expanded solubility parameter approach. 2. Para-hydroxybenzoic acid and methyl para-hydroxybenzoate in individual solvents
J Pharm Sci
Extended hildebrand solubility approach—Sulfonamides in binary and ternary solvents
J Pharm Sci
Solubility parameter and oral absorption
Eur J Pharm Biopharm
Prediction of solubility of sulfonamides in water and organic-solvents based on the extended regular solution theory
Int J Pharm
Comparison of the solubility of polycyclic aromatic-hydrocarbons in nonassociated and associated solvents—The hydrophobic effect
Int J Pharm
Solubility parameter of selected sulfonamides
J Pharm Sci
Effect of physicochemical properties of adhesive on the release, skin permeation and adhesiveness of adhesive-type transdermal drug delivery systems (a-tdd) containing silicone-based pressure-sensitive adhesives
Int J Pharm
Physicochemical properties/descriptors governing the solubility and partitioning of chemicals in water-solvent-gas systems. Part 2. Solubility in 1-octanol
SAR QSAR Environ Res
Solubility and partitioning VI: Octanol solubility and octanol–water partition coefficients
J Pharm Sci
Relationships between aqueous solubility and octanol–water partition coefficients
Chemosphere
The solubility of non-electrolytes
Cited by (14)
Calculating the Solubilities of Drugs and Drug-Like Compounds in Octanol
2016, Journal of Pharmaceutical SciencesEstimating the Aqueous Solubility of Pharmaceutical Hydrates
2016, Journal of Pharmaceutical SciencesCitation Excerpt :Predictive models for the estimation of solubility provide the researcher with vital information of the compound to aid in experimental design and minimize expenses. As such, the development of models to predict solute solubility in both aqueous and organic solvents, as well as the effects cosolvents, surfactants, and pH have on solubility have been investigated for decades.1-11 Computational models for solubility based on lipophilicity, solvation interactions, and substructure components can be found throughout the literature.12-18
Unified physicochemical property estimation relationships (UPPER)
2014, Journal of Pharmaceutical SciencesCitation Excerpt :These hydrocarbons represent the backbones of organic compounds and cover a wide range of molecular shape and size. The experimentally measured property values were taken from the NIST, Aquasol, Merck Index252523, EPA database, and other references.5,25-32 A total of 4633 experimental data points were included in the current study that enable us to clearly determine the role of symmetry, flexibility, and eccentricity on entropies as well as the group contribution values of some of the most common molecular fragments of organic compounds.
The solubility of liquid and solid compounds in dry octan-1-ol
2014, ChemosphereCitation Excerpt :We suggest that if the necessary descriptors are available then Eq. (13) is the preferred equation for estimations of log Soct (M), with an SD of 0.47 log units. If the descriptors are not available, then Eq. (1) will provide an estimate of log Soct (M) with an SD of 0.71 log units (Admire and Yalkowsky, 2013). Both of these equations require a knowledge of the compound melting point.