pH-Partition Behavior of Tetracyclines

The apparent partition coefficients between n-octyl alcohol and aqueous buffers (ranging from pH 2.1 to 8.5) were determined for several tetracyclines. Using the previously suggested microscopic dissociation constants for tetracycline, the relative amounts of each microscopic ionic form of tetracycline theoretically present at each pH were calculated. The zwitterionic form, −0+ (tricarbonyl methane system ionized, phenolic diketone moiety unionized, dimethylammonium cation postively charged), which was present in highest concentration in the pH range from 4 to 7, appeared to be the most lipid soluble form, its reduced polarity possibly resulting from an intramolecular type of ion-pair formation. Possible relationships between the biological activity of the various tetracycline analogs and their pH-octanol solubility profiles have been discussed.