Meropenem exists in equilibrium with a carbon dioxide adduct in bicarbonate solution.
Evidence is provided for the existence of a second discrete chemical form of meropenem at clinically relevant concentrations prepared from the marketed formulation of the drug. Proton and carbon-13 NMR spectra in D2O, coupled with tandem mass spectroscopy (MS/MS) and cross polarization/magic angle spinning (CP-MAS) NMR experiments, allow structural assignment of the compound as a covalent carbon dioxide adduct of meropenem. This carbon dioxide adduct exists in equilibrium with the free drug in solution and can be observed in the solid state following lyophilization. The equilibrium constant of formation of the adduct (Keq = 20 +/- 8 M-1) was estimated in D2O at 25 degreesC.
Almarsson
O
O
Pharmaceutical Research and Development, Merck Research Laboratories, and Analytical Methods and Support, Merck Manufacturing Division, West Point, Pennsylvania 19486, USA. orn_almarsson@merck.com
Kaufman
M J
MJ
Stong
J D
JD
Wu
Y
Y
Mayr
S M
SM
Petrich
M A
MA
Williams
J M
JM
D001639:Bicarbonates; D002245:Carbon Dioxide / Q000737:chemistry*; D005612:Freeze Drying; D009682:Magnetic Resonance Spectroscopy; D000077731:Meropenem; D012996:Solutions; D013845:Thienamycins / Q000737:chemistry*
D001639:Bicarbonates; D012996:Solutions; D013845:Thienamycins; D002245:Carbon Dioxide; D000077731:Meropenem