The effects of pH and mixed solvent systems on the solubility of oxytetracycline.
The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was studied. The effects of pH and cosolvent composition on the solubility and apparent dissociation constants (pKa') of OTC were determined by a solubility method. The pKa' values of OTC in each mixed solvent system were estimated and used to generate expressions for predicting drug solubility in each cosolvent as a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2-pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed increased solubility with increased cosolvent concentration, especially in 2-pyrrolidone solvent systems. These results also showed that cosolvents enhanced drug solubility through either their effects on polarity of the solvent medium or complex formation with OTC. Aqueous and mixed solvent systems at lower pH values resulted in higher OTC solubilization because the drug existed primarily in its cationic form. A mass balance equation including all ionic species of OTC allowed for estimation of the intrinsic solubilities and pKa' values in each solvent system. pKa' values and intrinsic solubility of the OTC zwitterion increased with increasing cosolvent content. These parameters allowed prediction of drug solubility within the pH range and cosolvent concentrations used in this study.
Tongaree
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Whitehall-Robins Healthcare, Richmond, Virginia 23220, USA. tongars@ahp.com
Flanagan
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DR
Poust
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RI
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D005990:Glycerol; D006863:Hydrogen-Ion Concentration; D008855:Microscopy, Electron, Scanning; D010118:Oxytetracycline / Q000737:chemistry*; D011409:Propylene Glycols; D011760:Pyrrolidinones; D012995:Solubility; D012997:Solvents
D000900:Anti-Bacterial Agents; D011409:Propylene Glycols; D011760:Pyrrolidinones; D012997:Solvents; C028537:2-pyrrolidone; D005990:Glycerol; D010118:Oxytetracycline