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Meropenem exists in equilibrium with a carbon dioxide adduct in bicarbonate solution
O Almarsson1, M J Kaufman, J D Stong
1Pharmaceutical Research and Development, Merck Research Laboratories, and Analytical Methods and Support, Merck Manufacturing Division, West Point, Pennsylvania 19486, USA. orn_almarsson@merck.com
Journal of Pharmaceutical Sciences
|May 20, 1998
Summary
A new chemical form of meropenem, a carbon dioxide adduct, exists in equilibrium with the free drug. This discovery impacts understanding meropenem stability and formulation.
Area of Science:
- Pharmaceutical Chemistry
- Chemical Analysis
- Drug Stability
Background:
- Meropenem is a broad-spectrum carbapenem antibiotic.
- Understanding the chemical forms of meropenem in solution is crucial for its effective use.
- The marketed formulation of meropenem may contain uncharacterized species.
Purpose of the Study:
- To identify and characterize any additional chemical forms of meropenem present in clinically relevant solutions.
- To elucidate the structure of any novel meropenem species.
- To determine the equilibrium dynamics between different meropenem forms.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy (proton and carbon-13) in D2O.
- Tandem mass spectrometry (MS/MS) for structural analysis.
- Cross-polarization/magic angle spinning (CP-MAS) NMR for solid-state characterization.
Main Results:
- Identification of a second discrete chemical form of meropenem.
- Structural assignment of this form as a covalent carbon dioxide adduct of meropenem.
- Observation of an equilibrium between the meropenem-CO2 adduct and free meropenem in solution and solid states.
Conclusions:
- The existence of a meropenem-CO2 adduct is demonstrated at clinically relevant concentrations.
- This adduct formation is a reversible equilibrium process.
- Findings are critical for meropenem formulation, stability studies, and pharmacokinetic understanding.