1. The tetracyclines are amphoteric compounds, forming salts with either acids or bases. In neutral solutions, these substances exist mainly as zwitterions. The acid salts, which are formed through protonation of the enol group on C-2, exist as crystalline compounds that are very soluble in water. These amphoteric antibiotics will crystallize out of aqueous solutions of their salts, however, unless stabilized by an excess of acid.

2. The hydrochloride salts are used most commonly for oral administration and usually are encapsulated because they are bitter. Water-soluble salts may be obtained also from bases, such as sodium or potassium hydroxides, but they are not stable in aqueous solutions. Water-insoluble salts are formed with divalent and polyvalent metals. The unusual structural groupings in the tetracyclines produce three cidity constants in aqueous solutions of the acid salts (Table 8.7).

5. An interesting property of the tetracyclines is their ability to undergo epimerization at C-4 in solutions of intermediate pH range.