Abstract
d-cycloserine is a broad-spectrum antibiotic that is currently being used as a secondary choice in the treatment of tuberculosis. In recent years, it has become more popular, due to its effect on the nervous system. In this current study, we provide evidence that The International Pharmacopoeia HPLC–UV method for d-cycloserine impurity profiling is not repeatable due to the variable response of cycloserine dimer, one of d-cycloserine impurities. Therefore, we introduced the DOSY (diffusion ordered spectroscopy) NMR (nuclear magnetic resonance) technique to determine the levels of d-cycloserine impurities in pharmaceutical dosage forms. The DOSY NMR technique allowed separation of d-cycloserine, its degradation products, and key process impurities in concentrations below pharmacopoeial specification limits. The proposed DOSY NMR method allowed accurate identification and quantification of the cycloserine dimer, which was not possible through the use of the pharmacopoeial HPLC method. The current method has the potential for practical use in analytical laboratories of the pharmaceutical industry.
Highlights
Introduction dCycloserine is a broad-spectrum antibiotic, which can be biosynthesized by Streptomyces garyphalus, Streptomyces orchidaceous, and Streptomyces lavendulae, but can be obtained by synthesis.It was first isolated in 1955 and in vitro tested against M. tuberculosis in 1966 [1]
Relative standard deviation (RSD) for the area of d-cycloserine peaks obtained from all ten injections was calculated to be 0.58%, which proved the repeatability of the analytical system for determination of d-cycloserine
The method failed to show the repeatability of the chromatographic peak areas corresponding to the cycloserine dimer—one of the known d-cycloserine impurities—and was, not considered to be suitable for its quantification
Summary
Standard d-cycloserine in concentration of 0.0015 mg mL−1 was injected ten times in sequence. Relative standard deviation (RSD) for the area of d-cycloserine peaks obtained from all ten injections was calculated to be 0.58%, which proved the repeatability of the analytical system for determination of d-cycloserine. Retention times of d-cycloserine were repeatable as well. For determination of LOQ, five different concentrations of d-cycloserine in the range of 0.001% to. 0.05%, relative to its concentration in the sample were prepared and the peak signal to noise ratio (S/N). The concentration at 0.05% (S/N = 52.5) was determined as LOQ At this level, the peak was integrable, while the concentration was still below the specification limit (no more than (NMT) 0.15% in active pharmaceutical ingredient and NMT 0.4% in final dosage form [10,11])
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