pH—partition behavior of amino acid‐like β‐lactam antibiotics

The pH‐partition behavior of the ampholyte antibiotics ampicillin, cephalexin, and cephaloglycin, using n‐butanol or n‐octanol as the lipid phase and aqueous phosphate buffers, was determined at 37° over a pH range of 4.9–7.9. By comparing the pH‐partition behavior of these drugs with computer‐generated plots of the concentration of their various ionic species as a function of pH, the anion was found to be the major partitioning species. Minimum partitioning occurred in the isoelectric region, suggesting that the zwitterion did not partition to a significant extent. The pH‐partition behavior of L‐phenylalanine, as a model ampholyte, was studied over a pH range of 2.0–8.9; although the L‐phenylalanine cation partitioned into the lipid phase, the anion partitioned to a significantly greater extent, while the minimum partitioning in the isoelectric region indicated that the zwitterion was a poor partitioning species. Studies of surface activity as a function of antibiotic concentration in phosphate buffers showed that there is a relationship between the partitioning behavior of these antibiotics and either the reduction in surface tension or the resulting surface excess at the lipid‐water interface. To account for the difference in the pH‐partition behavior of the compounds employed in this study and the previously reported data for the tetracyclines, two general types of ampholytes capable of forming zwitterions should be considered, depending on whether or not significant amounts of uncharged species are present in the isoelectric region. Maximum partitioning into the lipid phase should occur if uncharged species is present in significant concentrations (e.g., tetracycline); the compounds in this study were of the other type and thus showed reduced partitioning in the isoelectric pH region.