Permeability prediction for zwitterions via chromatographic indexes and classification into 'certain' and 'uncertain'.

The development of zwitterions to a drug is likely to be more challenging than compounds of other charge types. Two chromatographic indexes (log k'80 PLRP-S and log K) can be successfully used as permeability classifiers of ampholytes. Moreover, a pragmatic classification into ordinary ampholytes; zwitterions 'certain' (i.e., the zwitterionic species is dominant in the physiological pH range); and zwitterions 'uncertain' (multiple species are present in the physiological pH range) enables to study the permeability of ampholytic compounds in relation to species distribution. Potentiometry (pK), reversed-phase (RP)-chromatography, tri-layer parallel artificial membrane permeability assays, quantitative structure-property relationships (QSPR) and block relevance (BR) analysis, receiver operating characteristic (ROC) curves. Structures considered as poorly permeable like zwitterions can be integrated in drug discovery programs by applying experimental and computational tools.