Determination of imipenem and cilastatin sodium in Primaxin by first order derivative ultraviolet spectrophotometry.

A UV-spectrophotometric assay to measure the concentrations of the active drug components (imipenem and cilastatin) or Primaxin for routine release testing is described. The assay is based on the use of first order derivative spectrophotometry. The trough amplitudes in the first derivative spectrophotometric spectra at 243 and 318 nm were selected to determine cilastatin and imipenem, respectively. A linear relationship (R > 0.99) between the trough amplitudes and concentrations was demonstrated over the range 14-42 micrograms ml-1 for both drug components. Commercial IV formulations and laboratory prepared mixtures containing both drugs in different proportions were assayed using the developed method with good recoveries (ave. 100.6%). The method is rapid, precise, accurate and was shown to be equivalent to the more time consuming LC method; which is currently used for routine release testing. The specificity and stability indicating properties of the method will also be addressed.

First- and second-derivative spectrophotometric determination of imipenem and cilastatin in injections.

First- and second-derivative spectrophotometry has been used for the quantitation of mixtures of imipenem and cilastatin sodium, compounds that have closely overlapping spectral bands. Beer's law was obeyed at concentrations up to 100 micrograms ml-1 of imipenem in both the first- and second-derivative modes and up to 75 micrograms ml-1 of cilastatin in the first-derivative mode. Detection limits at the P = 0.05 level of significance were calculated to be 0.40 and 0.52 micrograms ml-1 of imipenem and cilastatin sodium, respectively, in the first-derivative mode, and in a range from 0.45 to 0.68 micrograms ml-1 for imipenem in the second-derivative mode. The method, which is rapid, simple and does not require a separation step, has been successfully applied to the assay of commercial injections.

High-performance liquid chromatographic determination of cilastatin and its major metabolite N-acetylcilastatin in rat plasma, urine and bile.

A new high-performance liquid chromatographic method coupled with solid-phase (C8) sample extraction has been developed for the simultaneous quantification of cilastatin and its major metabolite N-acetylcilastatin in rat plasma, urine and bile. The method is linear, reproducible and reliable with a detection limit of 1 microgram/ml in all three fluids. Plasma concentrations of cilastatin and N-acetylcilastatin at selected time intervals and biliary and urinary recoveries of cilastatin and N-acetylcilastatin following an intravenous dose of 10 mg/kg cilastatin are presented.

Stability of imipenem and cilastatin sodium in total parenteral nutrient solution.

The chemical stability and compatibility of imipenem-cilastatin sodium (Primaxin) in two different total parenteral nutrient (TPN) solutions was determined. TPN solutions consisted of 4.25% and 5% amino acids with 25% and 35% dextrose, respectively. Imipenem-cilastatin sodium was constituted with 10 ml of sterile water and admixed with 90 ml of TPN solution for a final concentration of 5 mg/ml of each drug. The final solutions were assayed at times 0 (immediately after admixture), 15 min, 30 min, 1, 4, 8, and 24 hr by a stability-indicating high-performance liquid chromatographic assay. Concurrently, test TPN solutions were monitored for pH changes, color changes, and precipitate formation. The potential effect of imipenem-cilastatin sodium on the stability of amino acids and other TPN additives was not evaluated. Imipenem and cilastatin sodium was stable (greater than or equal to 90% recovered) in each TPN solution at 15 min. A significant (greater than or equal to 10%) and steady decrease of imipenem recovery occurred at subsequent sampling times. Cilastatin appeared more stable than imipenem in both TPN solutions. A physical color change from colorless to dark orange appeared in each TPN solution over the 24-hr study period. Imipenem-cilastatin sodium is stable for 15 min in the TPN solutions studied; however, until the stability of the amino acids can be determined, the antibiotic should be administered through a separate line or Y-site while the TPN infusion is interrupted.

Comparative neurotoxicity of benzylpenicillin, imipenem/cilastatin and FCE 22101, a new injectible penem.

Rabbits were given benzylpenicillin, imipenem/cilastatin and a penem beta-lactam, FCE 22101, as constant intravenous infusions with intervals of greater than or equal to 7 days between doses. Neurotoxicity was defined as epileptogenic electroencephalographic (EEG) activity. Mean doses precipitating neurotoxicity were 486 mg/kg of benzylpenicillin, 86 mg/kg of imipenem and 102 mg/kg of FCE 22101 leading to mean serum concentrations of 606, 55 and 30 mg/l, respectively. Doses and serum concentrations of benzylpenicillin were significantly (P less than 0.001) higher than those of imipenem or FCE 22101. Neurotoxicity was seen at significantly (P less than 0.02) higher serum concentrations of imipenem than of FCE 22101. Neurotoxicity seemed to be related to antibiotic concentrations in brain tissue fluid (BTF) rather than to CSF concentrations which were less than 0.2 mg/l in 10 of 11 animals tested after administration of imipenem or FCE 22101. In BTF, significantly (P less than 0.001) higher concentrations of benzylpenicillin than of imipenem or FCE 22101 were found. When related to concurrent serum concentrations, BTF penetration of benzylpenicillin and FCE 22101 did not differ significantly but both these antibiotics penetrated significantly better than imipenem. In conclusion, imipenem/cilastatin and FCE 22101 were more neurotoxic in rabbits than benzylpenicillin but did not show major differences from each other.