Solubility of doxycycline in aqueous solution.

The solubility of doxycyline monohydrate and doxycycline hydrochloride dihydrate was investigated in aqueous solution. The hydrochloride dihydrate salt was isolated and identified from solutions initially containing doxycycline hyclate in water. The pKa' = 3.09 (mu = 0.1 and 25 degrees) for protonation of doxycycline was determined spectrophotometrically. The pH-solubility profiles were determined for doxycycline monohydrate in water and in 1.0 M NaNO3-HNO3 and NaCl-HCl. The pH-solubility profile at 25 degrees for doxycycline in aqueous hydrochloric acid without added salt reached a sharp maximum fo 50 mg/ml at pH 2.16. Added chloride ion strongly suppressed the solubility of the hydrochloride dihydrate salt. The apparent solubility product was not constant but decreased as the concentration of added salt increased. A theoretical model was developed involving dimerization of doxycycline and applied to the experimental data. The dimerization constant, Kd = 24 M-1, and true solubility product, K0sp = 1.8 X 10(-3) M2, were calculated. The effect of concentration on NMR and visible spectra indicated that dimerization resulted from intermolecular hydrogen bonding of the phenolic beta-diketone portion of the molecule.