Short communicationStability and degradation kinetics of meropenem in powder for injection and reconstituted sample
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.
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2021, International Journal of PharmaceuticsCitation Excerpt :Also, solid-state stability studies showed that carbapenems such as MER and tebipenem are also unstable at 40 °C after 5 h and undergo thermolysis, which could also produce toxic degradation products (Cielecka-Piontek et al., 2013; Talaczyńska et al., 2016). This chemical instability coupled with fast renal elimination (i.e. short half-life of around 1 h) necessitates short-term intravenous bolus injections (typically 5 min) after dosage preparation (<1.0 h) (Craig, 1997; Mendez et al., 2006). These challenges demand frequent administration of MER with other healthcare facilities such as temperature-controlled environment to minimize MER degradation, and pharmacy and nursing staff for frequent preparation and administration of MER, respectively.
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2020, International Journal of Antimicrobial AgentsCitation Excerpt :Stability of meropenem was tested using liquid chromatography/tandem mass spectrometry (LC-MS/MS) (see Supplementary Methods for details) and the rate of its disappearance was determined by linear regression of data (limited to situations with <20% loss from the original concentration) with calculation of the 95% confidence interval. As proposed previously [6,11–13], meropenem was considered as staying stable as long as its content remained ≥90% of the original value. Dissolution studies mimicking the approved bolus administration of meropenem consisted of dissolving 0.5 g in 10 mL of water (as per the instructions for use in the corresponding Summary of Product Characteristics [3]).
Self-assembled cyclodextrin-based nanoparticles for meropenem stabilization
2018, Journal of Drug Delivery Science and TechnologyCitation Excerpt :Thus, meropenem is marketed as powder for preparation of parenteral solution. The t90 for this antibiotic was determined to be 4.78 h at 25 °C for the re-constituted commercial product [9]. The storage conditions for the IV samples are strict, the vials re-constituted with sterile water may be stored for maximum 3 h at room temperature and 13 h at 5 °C.
Measurement and correlation of solubility of meropenem trihydrate in binary (water + acetone/tetrahydrofuran) solvent mixtures
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