The Interaction Between Oxytetracycline and Divalent Metal Ions in Aqueous and Mixed Solvent Systems

Abstract

The effects of pH, mixed solvent systems, and divalent metal ions on oxytetracycline (OTC) solubility and the interactions between OTC and metal ions in aqueous and mixed solvent systems were investigated. OTC solubility profiles were obtained for pH 4-9. The cosolvents studied were glycerin, propylene glycol, PEG 400, and 2-pyrrolidone with the following metal ions: magnesium, calcium, and zinc. OTC and its interactions with these metal ions were evaluated by solubility, NMR, circular dichroism (CD), and electron diffraction (ED) methods. At pH 5.6, no complexation occurred with these metal ions, but OTC zwitterion formed aggregates in aqueous solutions as shown by NMR spectra. The hydration of the metal ions was observed to affect OTC aggregation, with Mg+2 causing the greatest OTC aggregation. At pH 7.5, OTC aggregation and metal-OTC complexation were observed in solutions with Ca+2 and Mg+2. Zinc ion was found to decrease OTC solubility because of zincate formation, which caused anionic OTC to precipitate. Electron diffraction revealed a relationship between OTC and metal-OTC complex crystallinity and solubility behavior. The zinc-OTC complex exhibited the highest crystallinity and lowest solubility at pH 8.0. Various cosolvents generally enhanced OTC solubility, with 2-pyrrolidone having the best solubility power. In OTC-metal-2-pyrrolidone and OTC-Zn(+2)-PEG 400 systems, circular dichroism provided evidence for the formation of soluble ternary complexes.

Optimization and Characterization of a Sphingomyelin/Cholesterol Liposome Formulation of Vinorelbine with Promising Antitumor Activity

“…The rationale for this was initially unclear; however, further examination of empty and drug-loaded liposomes revealed the presence of electron dense intravesicular regions within the drug-loaded liposomes, which were not observed in the empty liposomes, suggesting the presence of an amorphous drug precipitate or gel within these liposomes. Several drugs, including anthracyclines (e.g., doxorubicin, daunorubicin), 45,46 anthracenediones (e.g., mitoxantrone), 47 antibiotics, 48,49 and camptothecins, 50 have been shown to form ordered, crystalline precipitates in the presence of di-and trivalent metal ions. In liposomes, these precipitates typically lead to the formation of ovaloid vesicles with defined linear structures that run along the long axis of the vesicles, giving the vesicles an appear- The data indicate the amount of intact VRL (n ¼ 4), % drug retention (n ¼ 4), and typical particle sizes after 1 year.…”

Oxytetracycline in intensive aquaculture: water quality during and after its administration, environmental fate, toxicity and bacterial resistance

“…In this form, OTC is able to establish intermolecular interactions, forming aggregates in aqueous solution (Tongaree et al . ). The structural groups mainly affected by those pH variations are the tricarbonyl system—C1 to C3 (pKa 1 ), the phenolic diketone—C10 to C12 (pKa 2 ) and the dimethylamine group—at C4 (pKa 3 ) (Kulshrestha et al .…”

Biomarker analysis of combined oxytetracycline and zinc pollution in earthworms (Eisenia fetida)

“…3). Tongaree et al (1999) also observed OTC aggregation and metal-OTC complexation in solutions with Ca 2+ and Mg 2+ at pH 7.5. Additionally, zinc ions reduce the solubility of OTC because of zincate formation, which causes anionic OTC to precipitate.…”

“…Additionally, zinc ions reduce the solubility of OTC because of zincate formation, which causes anionic OTC to precipitate. The zinc-OTC complex exhibited the highest crystallinity and lowest solubility at pH 8.0 (Tongaree et al, 1999).…”