ABSTRACT
In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using ß-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing ß-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott's method and statistical studies. The structure of the binary systems with ß-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect ß-cyclodextrin and N-acetylcysteine on the polymorph's chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the ß-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution.
ABSTRACT
Oxytetracycline hydrochloride, an antibiotic of the tetracycline family, is a polymorphic drug that evidences erratic absorption in oral administration. Additionally, poor solid state characterization of the polymorphs and diversity in the existing nomenclature impede the correct identification of the raw materials. In this work, oxytetracycline hydrochloride solid forms were prepared from isopropyl alcohol, ethanol and methanol through different crystallization techniques, and then their physicochemical and microbiological properties were evaluated. A combination of advanced techniques such as solid state nuclear magnetic resonance, powder X-ray diffraction, infrared spectroscopy, thermal analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy were used in the characterization of solid samples giving clear evidence of the existence of three stable and one metastable solid forms of the oxytetracycline hydrochloride. Solubility was determined in aqueous solution, simulated gastric fluid, and simulated intestinal fluid. In addition, microbiological studies were performed. The polymorphs showed similar antimicrobial activity against Escherichia coli and Staphylococcus aureus. Therefore, these solid forms of oxytetracycline hydrochloride constitute promising candidates to encourage studies for repositioning old and known antibiotic drugs in the developing strategies for new therapeutic alternatives.
