Predicting aqueous solubility

Delaney,. S. Predicting aqueous solubility from structure. Drug Discov. Today 2005, 10, 289-295. 

Lande, S. S., Baneijee, S. (1981) Predicting aqueous solubility of organic nonelectrolytes from molar volume. Chemosphere 10,751-759. 

Wang, L., Zhao, Y., Hong, G. (1992) Predicting aqueous solubility and octanol/water partition coefficients of organic chemicals from molar volume. Environ. Chem. 11, 55-70. 

It is difficult to accurately predict aqueous solubility from chemical structure, because it involves disruption of the crystal lattice as well as solvation of the compound. Simple methods based on log P and melting temperature have been widely used [113, 114]. Recently, various prediction methods have been reported [115-125] that are able to predict aqueous solubility to within ca. 0.5 log units (roughly a factor of 3 in concentration). Although these predictors may not be precise or robust enough to select final compounds, they can be used as rough filters for narrowing the list of candidates. 

Yaeee, D., Cohen, Y., Espinosa, G., Arenas, A., and Giealt, E. A fuzzy ARTMAP based on quantitative structure-property relationships (QSPRs) for predicting aqueous solubility of organic compounds. 

Besides the counts of fragments or atom types, a lot of theoretical descriptors have been successfully applied in predicting aqueous solubility. Mitchell and Jurs... 

Physico-chemical properties and evaluation of potential safety liabilities are important aspects of the library design process. Predicted properties like hERG liability (45), compound aqueous solubility, etc. (46-48) have been extensively studied and included in various library design strategies (49, 50) as a part of multiple constraints optimisation. We have therefore further extended the ProSAR concept to take the library property profile into account in the design process. Several in-house calculated properties are considered these include a compound novelty check (that checks in in-house and external compound databases to see if the compound is novel), predicted aqueous solubility... 

Solubility of racemic praziquantel was determined in MeOH and 2-PrOH in the temperature range between 0 °C and 40 °C. A ternary phase diagram of praziquantel enantiomers and the MeOH system was also determined (06CH259). The solubility phase and binary melting-point phase diagrams were determined. Experimental and predicted aqueous solubility of praziquantel was reported (07CPB669,08SQE191). Dissolution of praziquantel... 

Select only those compounds with predicted aqueous solubility >1 mM... 

The ChemBridge collection of 5213 compounds was rationally selected from their EXPRESS-Pick Collection,181 utilizing Astex s rule of three considerations (MW < 300, HBD<3, HBA<3, CLogP<3)[12] and measures of diversity. ChemBridge has used a predicted aqueous solubility of greater than 3 mM for all selected compounds and can be... 

Figure 11. Observed and predicted aqueous solubilities of nonelectrolytes (o) and weak electrolytes ( ). The solid line is the theoretical line described by Equation 22. The dashed line is the regression line of the experimental data. (Reproduced with permission from Ref. 38. Copyright 1983 American Pharmaceutical Association.)...

Programs such as QMPRPlus (SimulationPlus, Inc.) and WSKOWIN (EPISUITE available from the Environmental Protection Agency website, Syracuse Research Corporation, Inc.) can be used to predict aqueous solubility directly (see Chapters 3 and 4). As log Kow inversely correlates reasonably well with aqueous solubility for many compounds, programs that are available to predict log Kow may also be useful in preliminary screens for aqueous solubility. 

Duffythe group contribution approach of Klopman and the neural network model of Huuskonen. " The PCCHEM program used at the US Environmental Protection Agency (EPA) incorporates three different equations. All of them are similar to GSE but have different coefficients to predict aqueous solubility depending on the range of log P values. " Meylan and Howard used a database of 817 (RMSE = 0.62) compounds to derive a heuristic equation ... 

Water solubilities of environmentally important chemicals can also be calculated from the mobile order of thermodynamics [64]. The predicted aqueous solubility of 35 PCDE congeners at 25 °C have been in good agreement with the values from HPLC data [64]. 

In spite of the great importance of aqueous solubility in pharmaceutical chemistry, it is a very poorly understood phenomenon. Several attempts at predicting aqueous solubility from the chemical structure have been made [98.99] however, it is a quite complex process. The first step involves the removal of a molecule from the solid phase. The second step involves the creation of a hole or cavity in the solvent large enough to accept the molecule. The last step is the accommodation of the solute molecules in the cavity of the solvent. So we have to be able to estimate the entropy of mixing, the solute-water interactions and the interactions associated with lattice energy of crystalline solutes. The... 

Table 5.1 Experimental aqueous solubilities, boiling points, surface areas and predicted aqueous solubilities" ...

A number of methods to predict aqueous solubility of molecules use other experimental values, which can be more easily measured. The appearance of such methods is not surprising considering limited availability and low quality of experimental measurements for aqueous solubility. The melting point and lipophilicity are the two most frequently used parameters in such equations. 

Methods Using 3D Descriptors Advances in quantum-chemical calculations and the increasing power of personal computers have made a great impact on the development of methods to predict aqueous solubility directly from the 3D structures of molecules. Monte Carlo statistical mechanics simulations by Jorgensen and Duffy [45] were used to predict the solubility of 150 compounds (MAE = 0.56) using the equation... 

Thompson JD, Cramer CJ, Truhlar DG. Predicting aqueous solubilities from aqueous free energies of solvation and experimental or calculated vapor pressures of pure substances. J Chem Phys 2003 119 1661-70. 

Among the recent reviews, the most comprehensive one is by Dearden [15]. In his review, he discusses the fundamentals of aqueous solubility, which lead to the Yalkowsky equation. Dearden also reviews the oldest approaches of predicting aqueous solubility, from a very simple fragment-based approach of 1924 to the numerous approaches post-1990, for which he made an extensive tabular comparison. 

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