Most drugs are ionizable in aqueous solutions: their solubility is pH-dependent. Ideally, prediction of solubility of new drug entities involves training sets consisting of INTRINSIC solubility, i.e., the solubility of the uncharged form of the drug substance. Searches of the literature suggest that hundreds, maybe thousands, of solubility values are reported ONLY for the SALT form of the ionizable drug in distilled water. In order to be rationally added to the prediction training set, theses salt values first need to be converted into intrinsic values. If the pKa(s) of the drug and the counterion are known, how can the intrinsic solubility be calculated? Has anyone published in this area? Any help would be much appreciated. Maybe Professor Sam Yalkowsky can help.
If the solubility of the drug in the salt form has a pH associated with it, I would use the textbook formula S=S0(1+10pKa-pH) for a base, correcting the pKa for ionic strength. If the pH is not known, and the drug has low solubility (that I assume is the case), use the pH of the DI water.
The objective is to calculate S0, not S. Suppose that prazosin oxalate 1:1 salt has the solubility of 0.16 mg/mL in distilled water. We want to determine (if possible) the intrinsic solubility value (S0). Let's say we know that the pKas of oxalic acid are 3.83 and 0.09, and that the pKa of prazosin is 6.92. Is that enough information? Would it help if I know that the saturated solution of the salt has the pH 4.96? How does one calculate (if possible) the S0 with this information?
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