Imipenem and Cilastatin for Injection

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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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 90.0 percent and not more than 115.0 percent of the labeled amounts of imipenem (C₁₂H₁₇N₃O₄S) and cilastatin (C₁₆H₂₆N₂O₅S).

Packaging and storage—

Preserve as described in Packaging and Storage Requirements 〈659〉, Injection Packaging, Packaging for constitution, 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.

USP Reference standards 〈11〉—

USP Cilastatin Ammonium Salt RS

USP Imipenem Monohydrate RS

Constituted solution—

At the time of use, it meets the requirements for Injections and Implanted Drug Products 〈1〉, Specific Tests, Completeness and clarity of solutions.

1 Identification—

The retention times of the peaks for imipenem and cilastatin in the chromatogram of the Assay preparation correspond to those in the chromatograms of the Imipenem standard preparation and the Cilastatin standard preparation, as obtained in the Assay.

Bacterial Endotoxins Test 〈85〉 —

It contains not more than 0.17 USP Endotoxin Unit per mg of imipenem and not more than 0.17 USP Endotoxin Unit per mg of cilastatin.

Sterility Tests 〈71〉 —

It meets the requirements when tested as directed for Membrane Filtration under Test for Sterility of the Product to be Examined, the specimen being dissolved in Fluid A.

pH 〈791〉:

between 6.5 and 8.5, when constituted as directed in the labeling.

Uniformity of dosage units 〈905〉:

meets the requirements.

Loss on drying 〈731〉—

Dry about 100 mg in vacuum at a pressure not exceeding 5 mm of mercury at 60° for 3 hours: it loses not more than 3.5% of its weight.

Particulate Matter in Injections 〈788〉:

meets the requirements for small-volume injections.

2 Assay—

pH 6.8 Buffer—

Dissolve 0.54 g of monobasic potassium phosphate in 3600 mL of water, adjust with 0.5 N sodium hydroxide or 0.5 M phosphoric acid to a pH of 6.8 ± 0.1, dilute with water to make 4000 mL of solution, and mix. Pass this solution through a filter of 0.5-µm or finer porosity.

Mobile phase—

Dissolve 2.0 g of sodium 1-hexanesulfonate in 800 mL of pH 6.8 Buffer, adjust with 0.5 N sodium hydroxide or 0.5 M phosphoric acid to a pH of 6.8 ± 0.1, and dilute with pH 6.8 Buffer to make 1000 mL of solution. Pass this solution through a filter of 0.5-µm or finer porosity, and degas. Make adjustments if necessary (see System Suitability under Chromatography 〈621〉).

Imipenem standard preparation—

Transfer about 13 mg of USP Imipenem Monohydrate RS, accurately weighed, to a 25-mL volumetric flask. Add 5 mL of saline TS, 0.5 mL of a 0.1% solution of sodium bicarbonate, and about 15 mL of pH 6.8 Buffer, and dissolve by shaking and sonicating.

[Note—The duration of sonication should not exceed 1 minute.]

Dilute with pH 6.8 Buffer to volume, and mix. This solution contains the equivalent of about 500 µg of anhydrous imipenem per mL. Use this solution immediately.

Cilastatin standard preparation—

Transfer about 12.5 mg of USP Cilastatin Ammonium Salt RS, accurately weighed, to a 25-mL volumetric flask. Add 5 mL of saline TS, 0.5 mL of a 0.1% solution of sodium bicarbonate, and about 15 mL of pH 6.8 Buffer, and dissolve by shaking and sonicating.

[Note—The duration of sonication should not exceed 1 minute.]

Dilute with pH 6.8 Buffer to volume, and mix. This solution contains the equivalent of about 500 µg 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-mL volumetric flask with the aid of pH 6.8 Buffer, dilute with pH 6.8 Buffer to volume, and mix. Dilute an accurately measured volume of this solution quantitatively with pH 6.8 Buffer to obtain an Assay preparation having a concentration of about 500 µg of imipenem per mL.

Chromatographic system (see Chromatography 〈621〉)—

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 2 mL per minute.

Chromatograph the Imipenem standard preparation, and record the peak responses as directed for Procedure:

the column efficiency determined from the imipenem peak is not less than 600 theoretical plates when calculated by the formula:

5.545(tᵣ/Wₕ/₂)²

the tailing factor for the imipenem peak is not more than 1.5 when calculated by the formula:

W₀.₁ / 2f

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 for Procedure:

the column efficiency determined from the cilastatin peak is not less than 600 theoretical plates when calculated by the formula:

5.545(tᵣ/Wₕ/₂)²

the tailing factor for the cilastatin peak is not more than 1.5 when calculated by the formula:

W₀.₁ / 2f

the relative standard deviation for replicate injections is not more than 2.0%.

Procedure—

Separately inject equal volumes (about 10 µL) of the Imipenem standard preparation, the Cilastatin standard preparation, and the Assay preparation into 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

C = concentration, in mg per mL, of USP Imipenem Monohydrate RS or USP Cilastatin Ammonium Salt RS in the appropriate Standard preparation;

P = content, in µg per mg, of anhydrous imipenem (C₁₂H₁₇N₃O₄S) or cilastatin (C₁₆H₂₆N₂O₅S) in the relevant Reference Standard;

L = labeled quantity, in mg, of imipenem or cilastatin in the container;

D = concentration, in µg per mL, of imipenem or cilastatin in the Assay preparation based on the labeled quantity in the container and the extent of dilution;

rᵤ and rₛ = peak responses of the corresponding analyte obtained from the Assay preparation and the appropriate Standard preparation, respectively.