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Stability and degradation kinetics of meropenem in powder for injection and reconstituted sample

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Abstract

The stability of broad-spectrum antibiotic meropenem was studied in order to investigate the kinetics of degradation of this drug in powder for injection and reconstituted sample. Carbapenem was submitted to conditions of accelerated thermal decomposition. Degradation of meropenem was adequately modeled by specific equations for order rate kinetics. The analyses of the degraded samples were performed by high-performance liquid chromatographic (HPLC) method and microbiological assay. At higher temperatures, the decomposition reactions of meropenem in powder for injection could be described by first-order kinetics. The higher rate of degradation was observed in meropenem reconstituted in 0.9% sodium chloride, and the thermal decomposition obeyed also first-order kinetics. The results obtained confirm the reliability of chromatographic method for determining the kinetics run of meropenem in the presence of its degradation products. The present study reveals the thermal lability of the drug, especially as reconstituted sample. Thus, appropriate thermal protection is recommended during the storage and handling.

Introduction

Meropenem (Fig. 1) is a parenteral carbapenem antibiotic with a very broad spectrum of antibacterial activity against the majority of gram-positive and gram-negative pathogens [1], [2]. This antibiotic is stable to ring opening by human renal dehydropeptidase I (DHP-I) and consequently does not require concomitant administration of a DHP-1 inhibitor. Meropenem has shown clinical efficacy in the treatment of a wide range of serious infections such as intra-abdominal infections, urinary tract infections and lower respiratory tract infections [3], [4].

Literature survey reveals several analytical methods reported for the quantitative estimation of meropenem in pharmaceutical dosage form, including high-performance liquid chromatography (HPLC) [5], [6], [7], ultraviolet spectrophotometry [6] and microbiological assay [8]. The quantitation of meropenem in the presence of its degradation products has been studied. Recently, in preliminary forced thermal testing, a liquid chromatographic method and a microbiological assay were performed for quantitative determination of this antibiotic in reconstituted sample submitted to thermal degradation [8]. In another work, a chromatographic method for determination of polymerized impurities in meropenem was proposed [9]. The separation of these impurities was carried out by gel filtration chromatography. Some investigators have reported the stability of meropenem under various conditions [10], [11], [12]. Patel and Cook [10] studied the stability of meropenem in 0.9% sodium chloride injection. The stability of commonly used meropenem concentrations in both PVC containers and a frequently used elastomeric infusion device was determined in a recent study [11]. In a solid state formulation for injection, meropenem was found to be stable at room temperature [13]. However, the formulation must be prepared under a controlled relative humidity of less than 40%.

Considering the few publications concerning kinetic studies of meropenem, the purpose of this paper was to establish the effect of temperature on the decomposition of this antibiotic in powder for injection and reconstituted sample, to determine the kinetics of degradation describing the concentration changes of meropenem as a function of time, and to determine the kinetics run parameters. The analysis of the degraded samples was performed by stability-indicating HPLC method [6] and microbiological assay [8], developed and validated in our laboratory in compliance with ICH guidelines.

Section snippets

Chemicals

Meropenem reference standard was kindly supplied by Sumitomo Pharmaceuticals Co. Ltd. (Osaka, Japan) and AstraZeneca (São Paulo, Brazil). Pharmaceutical dosage form (Meronem®) containing meropenem was obtained commercially and was claimed to contain 500 mg (as anhydrous base) of the drug and 104 mg of the anhydrous sodium carbonate as excipient. Acetonitrile for chromatography LiChrosolv®, potassium dihydrogenphosphate p.a., orthophosphoric acid p.a., Grove Randall number 11 agar and Grove

Results and discussion

In this study, thermal stability of meropenem was carried out through employment of stress conditions. The thermal degradation profile of meropenem was studied at different temperatures for different time periods. For reconstituted sample, the drug was found to degrade extensively after reconstitution in saline solution. Almost 80% drug degradation was observed on exposure to heating at 45 °C for 36 h. A yellowish color developed thereupon exposure of the meropenem reconstituted sample at heat.

Conclusions

The above results showed reliability of HPLC method and microbiological assay for thermal decomposition kinetic study of meropenem. Degradation of this antibiotic during thermal processing is found to follow first-order reaction kinetics. The kinetic parameters of degradation rate constant, t1/2 and t90 can be predicted. In this study, extensive thermal decomposition was observed for meropenem in saline solution. Consequently, an appropriate thermal protection is recommended during the storage

Acknowledgements

The authors are grateful to Sumitomo Pharmaceuticals (Osaka, Japan) and AstraZeneca (São Paulo, Brazil) for providing the meropenem referende standard. Authors are also thankful to LCQFar, LEPCQ and CNPq program.

References (13)

  • M.A. Pfaller et al.

    Diagn. Microbiol. Infect. Dis.

    (1997)
  • J.L. Blumer

    Int. J. Antimicrob. Agents

    (1997)
  • A.S.L. Mendez et al.

    J. Pharm. Biomed. Anal.

    (2003)
  • A.S.L. Mendez et al.

    J. Pharm. Biomed. Anal.

    (2005)
  • S.-Y. Cai et al.

    J. Pharm. Biomed. Anal.

    (2005)
  • L.R. Wiseman et al.

    Drugs

    (1995)
There are more references available in the full text version of this article.

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