Predicting the Octanol Solubility of Organic Compounds

doi:10.1002/jps.23561

Journal of Pharmaceutical Sciences

Volume 102, Issue 7, July 2013, Pages 2112-2119

https://doi.org/10.1002/jps.23561 Get rights and content

ABSTRACT

The molar octanol solubility of an organic nonelectrolytes can be reasonably predicted solely from its melting point provided that its liquid (or a hypothetical super-cooled liquid) form is miscible with octanol. The aim of this work is to develop criteria to determine if the real or hypothetical liquid form of a given compound will be miscible with octanol based on its molar volume and solubility parameter. Fortunately, most organic compounds (including most drugs) conform to the criteria for complete liquid miscibility, and therefore have solubilities that are proportional to their melting points. The results show that more than 95% of the octanol solubilities studied are predicted with an error of less than 1 logarithmic unit. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2112–2119, 2013

Section snippets

INTRODUCTION

The octanol–water partition coefficient, K_ow, 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, T_c, 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 T_c of a nonelectrolytes solute and octanol can be approximated by $T_{c} = \frac{(V_{o c t} + V_{u}) {(δ_{o c t} - δ_{u})}^{2}}{4 R}$ where 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

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Drug Discovery-Development InterfacePredicting the Octanol Solubility of Organic Compounds

ABSTRACT

Section snippets

INTRODUCTION

Upper Critical Solution Temperature

DATA COLLECTION

Miscibility of Liquids

DISCUSSION

CONCLUSIONS

Ecotoxicol Environ Saf

Water Res

Chemosphere

J mol Struct

Sci Total Environ

Fluid Phase Equilibria

J Chem Thermodyn

Int J Pharm

J Pharm Sci

J Pharm Sci

Water Res

J Pharm Sci

J Pharm Sci

Int J Pharm

Int J Pharm

J Pharm Sci

J Pharm Sci

Eur J Pharm Biopharm

Int J Pharm

Int J Pharm

J Pharm Sci

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

Drug Discovery-Development Interface
Predicting the Octanol Solubility of Organic Compounds