Imipenem and Cilastatin for Injection
»Imipenem and Cilastatin for Injection is a sterile mixture of Imipenem,Cilastatin Sodium,and Sodium Bicarbonate.It contains not less than 90.0percent and not more than 115.0percent of the labeled amounts of imipenem (C12H17N3O4S)and cilastatin (C16H26N2O5S).
Packaging and storage— Preserve in Containers for Sterile Solidsas described under Injections á1ñ,and store at controlled room temperature.
Labeling— Label it to indicate that after constitution it is to be solubilized in a suitable parenteral fluid prior to intravenous infusion.
Constituted solution— At the time of use,it meets the requirements for Constituted Solutionsunder Injections á1ñ.
Identification— The retention times of the peaks for imipenem and cilastatin in the chromatogram of the Assay preparationcorrespond to those in the chromatograms of the Imipenem standard preparationand the Cilastatin standard preparation,as obtained in the Assay.
Bacterial endotoxins á85ñ— It contains not more than 0.17USP Endotoxin Unit per mg of imipenem and not more than 0.17USP Endotoxin Unit per mg of cilastatin.
Sterility á71ñ— It meets the requirements when tested as directed for Membrane Filtrationunder Test for Sterility of the Product to be Examined,the specimen being dissolved in Fluid A.
pHá791ñ: between 6.5and 8.5,when constituted as directed in the labeling.
Loss on drying á731ñ— Dry about 100mg in vacuum at a pressure not exceeding 5mm of mercury at 60for 3hours:it loses not more than 3.5%of its weight.
Particulate matter á788ñ: meets the requirements for small-volume injections.
Assay—
pH6.8buffer— Dissolve 0.54g of monobasic potassium phosphate in 3600mLof water,adjust with 0.5Nsodium hydroxide or 0.5Mphosphoric acid to a pHof 6.8±0.1,dilute with water to make 4000mLof solution,and mix.Filter this solution through a filter of 0.5µm or finer porosity.
Mobile phase— Dissolve 2.0g of sodium 1-hexanesulfonate in 800mLof pH6.8buffer,adjust with 0.5Nsodium hydroxide or 0.5Mphosphoric acid to a pHof 6.8±0.1,and dilute with pH6.8bufferto make 1000mLof solution.Filter this solution through a filter of 0.5µm or finer porosity,and degas.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Imipenem standard preparation— Transfer about 13mg of USP Imipenem Monohydrate RS,accurately weighed,to a 25-mLvolumetric flask.Add 5mLof saline TS,0.5mLof a 0.1%solution of sodium bicarbonate,and about 15mLof pH6.8buffer,and dissolve by shaking and sonicating.[NOTE—The duration of sonication should not exceed 1minute.]Dilute with pH6.8bufferto volume,and mix.This solution contains the equivalent of about 500µg of anhydrous imipenem per mL.Use this solution immediately.
Cilastatin standard preparation— Transfer about 12.5mg of USP Cilastatin Ammonium Salt RS,accurately weighed,to a 25-mLvolumetric flask.Add 5mLof saline TS,0.5mLof a 0.1%solution of sodium bicarbonate,and about 15mLof pH6.8buffer,and dissolve by shaking and sonicating.[NOTE—The duration of sonication should not exceed 1minute.]Dilute with pH6.8bufferto volume,and mix.This solution contains the equivalent of about 500µg of cilastatin per mL.Use this solution immediately.
Assay preparation— Constitute Imipenem and Cilastatin for Injection in a volume of saline TS,accurately measured,corresponding to the volume of solvent specified in the labeling.Quantitatively transfer this suspension to a 100-mLvolumetric flask with the aid of pH6.8buffer,dilute with pH6.8bufferto volume,and mix.Dilute an accurately measured volume of this solution quantitatively with pH6.8bufferto obtain an Assay preparationhaving a concentration of about 500µg of imipenem per mL.
Chromatographic system (see Chromatography á621ñ)—The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm ×30-cm column that contains packing L1,and is maintained at a temperature of 50±1.0.The flow rate is about 2mLper minute.Chromatograph the Imipenem standard preparation,and record the peak responses as directed under Procedure:the column efficiency determined from the imipenem peak is not less than 600theoretical plates when calculated by the formula:
5.545(t/Wh/2)2,
the tailing factor for the imipenem peak is not more than 1.5when calculated by the formula:
W0.1/2f,
where W0.1is the width of the peak at 10%height,and the relative standard deviation for replicate injections is not more than 2.0%.Chromatograph the Cilastatin standard preparation,and record the peak responses as directed under Procedure:the column efficiency determined from the cilastatin peak is not less than 600theoretical plates when calculated by the formula:
5.545(t/Wh/2)2,
the tailing factor for the cilastatin peak is not more than 1.5when calculated by the formula:
W0.1/2f,
and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 10µL)of the Imipenem standard preparation,the Cilastatin standard preparation,and the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantities,in mg,of anhydrous imipenem (C12H17N3O4S)and cilastatin (C16H26N2O5S)in the container,taken by the same formula:
(CPL/D)(rU/rS),
in which Cis the concentration,in mg per mL,of USP Imipenem Monohydrate RSor USP Cilastatin Ammonium Salt RSin the appropriate Standard preparation,Pis the content,in µg per mg,of anhydrous imipenem (C12H17N3O4S)or cilastatin (C16H26N2O5S)in the relevant Reference Standard,Lis the labeled quantity,in mg,of imipenem or cilastatin in the container,Dis the concentration,in µg per mL,of imipenem or cilastatin in the Assay preparationbased on the labeled quantity in the container and the extent of dilution,and rUand rSare the peak responses of the corresponding analyte obtained from the Assay preparationand the appropriate Standard preparation,respectively.
Auxiliary Information— Staff Liaison:William W.Wright,Ph.D.,Scientific Fellow
Expert Committee:(PA7)Pharmaceutical Analysis 7
USP28–NF23Page 1001
Pharmacopeial Forum:Volume No.27(1)Page 1790
Phone Number:1-301-816-8335