Solubility of Organic Compounds in Water/Octanol Systems. A Expanded Ensemble Molecular Dynamics Simulation Study of logPParameters (original) (raw)
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The Journal of Physical Chemistry B, 2001
The expanded ensemble method, developed to calculate solvation free energies, is applied to calculate octanol/ water partition coefficients P for some organic drug-related molecules and compared with experimental results. The experimental log P results were obtained by a miniaturized vial procedure using liquid chromatography with UV for quantification. The expanded ensemble technique, implemented within molecular dynamics scheme, is adapted to treat molecules of arbitrary size and type. For octanol, both all-atom and united atom models are evaluated. The solvation free energy of the organic solute molecules is found to be sensitive to the used sets of partial charges on the atoms in polar groups, particularly in water but also in the saturated octanol phase. Although this effect partially cancels out in the calculated partition coefficients, the charges obtained from ab initio Mulliken population analysis give consistently larger log P values than those obtained in simulations with the larger empirical atomic charges included in the CHARMM force field. In general, calculated log P turned out to be systematically higher than those measured experimentally. The possibility of improving potential models for the solutes in water and oil phase, respectively, is discussed.
Journal of Chemical Theory and Computation, 2009
The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1-Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C 1 -C 8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS-AA/TraPPE force field for the organic phase can give excellent predictions for n-alkanes up to C 8 with an absolute average deviation of 0.1 log P units to the experimental data.
Chemosphere, 1995
This study presents a thermodynamic analysis of the relationship between molecular size, hydrophobicity, aqueous solubility and octanol-water partitioning for several classes of hydrophobic organic compounds including chlorinated dibenzo-p-dioxins, PCBs, polynuclear aromatic hydrocarbons, alkylbenzenes, linear alcohols and alkanes. The purpose of the thermodynamic analysis is to explore the contribution of chemical-water and chemicalchemical interactions involved in the aqueous solution process. This is important for the development of relationships between the molecular structure and environmentally relevant properties of organic chemicals. The results show that the free energy of aqueous solvation is virtually independent on the molar volume of the solute for each of the congeneric series that was investigated. Within each congeneric series, congeners are therefore approximately equally "hydrophobic", and the relationship between the aqueous solubility of (subcooled) liquid hydrophobic chemicals and molecular volume predominantly reflects the dependence of chemical-chemical interactions on the molecular volume in the (subcooled) liquid phase, rather than chemical-water interactions as is usually assumed. The results indicate that improvements of quantitative structure-aqueous solubility relationships may be achieved by modelling chemical-chemical interactions in the pure (subcooled) liquid phase, rather than merely chemical-water interaction, and that within congeneric series of non-polar organic substances, an increase in octanol-water and environmental partition coefficients with increasing congener size is due to an increase in the congener's iipophilicity, not hydrophobicity.
AIChE Journal, 2012
In recent years molecular simulation has emerged as a useful tool to predict physical properties of complex chemical systems. A methodology to estimate the n-hexane/water and 1-octanol/water partition coefficients of environmentally relevant solutes, namely substituted alkyl-aromatic molecules, chlorobenzenes, polychlorinated biphenyls (PCBs) and polychlorinated diphenyl ethers (PCDEs) using molecular simulation is elucidated here. The partition coefficients are calculated based on the absolute solvation Gibbs energies in each phase which are estimated from molecular dynamics simulations employing the thermodynamic integration approach. Very encouraging results, with average absolute deviations of 0.4 log P units are presented. Consequently, this molecular-based approach with a strong physical background can provide reliable prediction of the partition coefficients in different solvent pairs without the a priori knowledge of experimental data.
The journal of physical chemistry. B, 2015
Octanol-water partition coefficient is an important physical-chemical characteristic widely used to describe hydrophobic/hydrophilic properties of chemical compounds. The partition coefficient is related to the transfer free energy of a compound from water to octanol. Here, we introduce a new protocol for prediction of the partition coefficient based on the statistical-mechanical, 3D-RISM-KH molecular theory of solvation. It was shown recently that with the compound-solvent correlation functions obtained from the 3D-RISM-KH molecular theory of solvation, the free energy functional supplemented with the correction linearly related to the partial molar volume obtained from the Kirkwood-Buff/3D-RISM theory, also called the "universal correction" (UC), provide accurate prediction of the hydration free energy of small compounds, compared to explicit solvent molecular dynamics [Palmer, D.S.; et al. J. Phys.: Condens. Matter 2010, 22, 492101]. Here we report that with the UC re-p...
European Journal of Pharmaceutics and Biopharmaceutics, 2019
In this review we will discuss how computational methods, and in particular classical molecular dynamics simulations, can be used to calculate solubility of pharmaceutically relevant molecules and systems. To the extent possible, we focus on the non-technical details of these calculations, and try to show also the added value of a more thorough and detailed understanding of the solubilization process obtained by using computational simulations. Although the main focus is on classical molecular dynamics simulations, we also provide the reader with some insights into other computational techniques, such as the COSMO-method, and also discuss Flory-Huggins theory and solubility parameters. We hope that this review will serve as a valuable starting point for any pharmaceutical researcher, who has not yet fully explored the possibilities offered by computational approaches to solubility calculations.
Solubility of drug-like molecules in pure organic solvents with the CPA EoS
Fluid Phase Equilibria, 2011
Solubility data in different solvents are an important issue for separation processes involving complex molecules such as natural products and pharmaceutical drugs. Nonetheless, solubility data are in general scarce and difficult to obtain, and so models are important tools to generate the necessary estimates. Different correlative, statistical and thermodynamic models have been proposed to evaluate solubilities. From these, the more theoretically sound thermodynamic models allow to generate estimates at broader temperature, pressure and composition conditions while using a smaller amount of experimental information. Among these, the Cubic-plus-Association equation of state that combines the simplicity and robustness of a cubic equation of state with the Wertheim's association contribution has been under attention. In this work, this EoS is for the first time proposed to model organic phase solubilities of drug-like molecules in a wide range of temperatures. Solubilities of acetanilide, acetylsalicylic acid, adipic acid, ascorbic acid, hydroquinone, ibuprofen, paracetamol and stearic acid were estimated in alcohols, ketones, alkanes, esters, acids, aromatics, chlorinated solvents, as well as in other common solvents. The hydrogen bonding behaviour was explicitly accounted for with each associating group being treated individually, as well as multiple group substitutions. Accurate correlations were obtained using a single binary interaction parameter (global AAD of 24.2%), while considering the complexity of the studied systems predictions were generally also satisfactory.
Solvation in octanol: parametrization of the continuum MST model
Journal of Computational Chemistry, 2001
This study reports the parametrization of the HF/6-31G(d) version of the MST continuum model for n-octanol. Following our previous studies related to the MST parametrization for water, chloroform, and carbon tetrachloride, a detailed exploration of the definition of the solute/solvent interface has been performed. To this end, we have exploited the results obtained from free energy calculations coupled to Monte Carlo simulations, and those derived from the QM/MM analysis of solvent-induced dipoles for selected solutes. The atomic hardness parameters have been determined by fitting to the experimental free energies of solvation in octanol. The final MST model is able to reproduce the experimental free energy of solvation for 62 compounds and the octanol/water partition coefficient (log P ow ) for 75 compounds with a root-mean-square deviation of 0.6 kcal/mol and 0.4 (in units of log P), respectively. The model has been further verified by calculating the octanol/water partition coefficient for a set of 27 drugs, which were not considered in the parametrization set. A good agreement is found between predicted and experimental values of log P o/w , as noted in a root-mean-square deviation of 0.75 units of log P.
Calculating the Solubilities of Drugs and Drug-Like Compounds in Octanol
Journal of Pharmaceutical Sciences, 2016
A modification of the Van't Hoff equation is used to predict the solubility of organic compounds in dry octanol. The new equation describes a linear relationship between the logarithm of the solubility of a solute in octanol to its melting temperature. More than 620 experimentally measured octanol solubilities, collected from the literature, are used to validate the equation without using any regression or fitting. The average absolute error of the prediction is 0.66 log units.