Prediction of pH-Dependent Aqueous Solubility of Druglike Molecules

Abstract

In the present work, the Henderson-Hasselbalch (HH) equation has been employed for the development of a tool for the prediction of pH-dependent aqueous solubility of drugs and drug candidates. A new prediction method for the intrinsic solubility was developed, based on artificial neural networks that have been trained on a druglike PHYSPROP subset of 4548 compounds. For the prediction of acid/base dissociation coefficients, the commercial tool Marvin has been used, following validation on a data set of 467 molecules from the PHYSPROP database. The best performing network for intrinsic solubility predictions has a cross-validated root mean square error (RMSE) of 0.70 log S-units, while the Marvin pKa plug-in has an RMSE of 0.71 pH-units. A data set of 27 drugs with experimentally determined pH-solubility curves was assembled from the literature for the validation of the combined pH-dependent model, giving a mean RMSE of 0.79 log S-units. Finally, the combined model has been applied on profiling the solubility space at low pH of five large vendor libraries.

Contrasting mechanisms of metoprolol uptake on kaolinite and talc

“…1) has a molecular weight of 267.364 g/mol and a pK a of 9.2 [2] [41]. An experimental and predicted solubility of log S 0 = À1.2 and À2.3, corresponding to 17 and 1.3 g/L, was reported [16]. The kaolinite used (KGa-2) is a poorly crystallized kaolinite obtained from the Clay Mineral Repository in Purdue University.…”

CO2-induced smart viscoelastic fluids based on mixtures of sodium erucate and triethylamine

“…When bubbling CO 2 , the pH of mixture solution experiences a drop from 12.30 to 10.00, indicating the ionization of TEA. According to Henderson-Hasselbalch equation [40] pK a ¼ pH À lgð½TEA=½TEA þ Þ ð1Þ 82% of TEA molecules have been transformed into quaternary ammonium salt, TEA + . Compared with the non-protonated TEA, this organic salt with positive charge cannot strengthen the basicity of the solution, but it can evidently enhance the solubility of NaOEr via ''salting-in'' effect [38,39].…”

Modelling, solubility and pKa of five sparingly soluble drugs

“…The CIM can interact with solvent and other drugs, especially with carboxyl group forming amorphous system of drugs with better solubility in water (Yamamura et al, 2000(Yamamura et al, , 2002Allesø et al, 2009). CIM is a model compound in many clinical experiments (Mostafavi and Foster, 2003;Ashiru et al, 2007) and in the prediction methods (Bergström et al, 2002;Ran et al, 2002;Hansen et al, 2006). PHBU is a non-steroidal antiinflammatory drug with analgesic and antipyretic properties and is used to treat fever, headache and pain associated with colds, influenza and arthritis.…”