Imipenem and Cilastatin for Injectable Suspension

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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1 DEFINITION

Imipenem and Cilastatin for Injectable Suspension is a sterile mixture of Imipenem and Cilastatin Sodium. It contains NLT 90.0% and NMT 115.0% of the labeled amounts of imipenem (C₁₂H₁₇N₃O₄S) and cilastatin (C₁₆H₂₆N₂O₅S).

2 IDENTIFICATION

A. The retention times of the peaks for imipenem and cilastatin of the Sample solution correspond to those of Standard solution 1 and Standard solution 2, as obtained in the Assay.

3 ASSAY

Procedure

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 pore size.

Solution A:

0.1% solution of sodium bicarbonate in water

Mobile phase:

Dissolve 2.0 g of sodium 1-hexanesulfonate in 800 mL of 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 Buffer to make 1000 mL of solution. Pass this solution through a filter of 0.5-µm or finer pore size, and degas.

Standard solution 1:

0.5 mg/mL of imipenem from USP Imipenem Monohydrate RS prepared as follows. Transfer a suitable amount of USP Imipenem Monohydrate RS to a volumetric flask. Add saline TS, Solution A, and Buffer, using 20%, 2%, and 60% of the final volume, respectively. Dissolve by shaking and sonicating. The duration of sonication should not exceed 1 min. Dilute with Buffer to volume. Use this solution immediately.

Standard solution 2:

0.5 mg/mL of cilastatin from USP Cilastatin Ammonium Salt RS prepared as follows. Transfer a suitable amount of USP Cilastatin Ammonium Salt RS to a volumetric flask. Add saline TS, Solution A, and Buffer, using 20%, 2%, and 60% of the final volume, respectively. Dissolve by shaking and sonicating. The duration of sonication should not exceed 1 min. Dilute with Buffer to volume. Use this solution immediately.

Sample stock solution:

Nominally 2.5 mg/mL of imipenem prepared as follows. Constitute Imipenem and Cilastatin for Injectable Suspension in a volume of saline TS corresponding to the volume of solvent specified in the labeling. Withdraw all of the withdrawable contents, using a suitable hypodermic needle and syringe, and dilute with saline TS to final volume.

Sample solution:

Nominally 0.5 mg/mL each of imipenem and cilastatin from Sample stock solution in Buffer

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 30-cm; packing L1

Column temperature: 50 ± 1.0°

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Samples: Standard solution 1 and Standard solution 2

Suitability requirements

Column efficiency:

NLT 600 theoretical plates for the imipenem peak, Standard solution 1;

NLT 600 theoretical plates for the cilastatin peak, Standard solution 2.

Calculate as follows:

Result = 5.545 × (tᵣ / Wₕ/₂)²

tᵣ = retention time of the peak in Standard solution 1 or Standard solution 2

Wₕ/₂ = width of the peak at half-height in Standard solution 1 or Standard solution 2

Tailing factor:

NMT 1.5 for the imipenem peak, Standard solution 1;

NMT 1.5 for the cilastatin peak, Standard solution 2.

Calculate as follows:

Result = W₀.₁ / 2f

W₀.₁ = width of the peak at 10% height in Standard solution 1 or Standard solution 2

f = distance from the peak maximum to the leading edge of the peak at 5% of the peak height in Standard solution 1 or Standard solution 2

Relative standard deviation:

NMT 2.0% for the imipenem peak, Standard solution 1;

NMT 2.0% for the cilastatin peak, Standard solution 2

Analysis

Samples: Standard solution 1, Standard solution 2, and Sample solution

Calculate the percentage of the labeled amount of anhydrous imipenem (C₁₂H₁₇N₃O₄S) in the portion of Imipenem and Cilastatin for Injectable Suspension taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × P × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from Standard solution 1

Cₛ = concentration of imipenem in Standard solution 1 (mg/mL)

Cᵤ = nominal concentration of imipenem in the Sample solution (mg/mL)

P = potency of imipenem in USP Imipenem Monohydrate RS (mg/mg)

Calculate the percentage of the labeled amount of cilastatin (C₁₆H₂₆N₂O₅S) in the portion of Imipenem and Cilastatin for Injectable Suspension taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × P × F × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from Standard solution 2

Cₛ = concentration of cilastatin in Standard solution 2 (mg/mL)

Cᵤ = nominal concentration of cilastatin in the Sample solution (mg/mL)

P = potency of cilastatin in USP Cilastatin Ammonium Salt RS (µg/mg)

F = conversion factor, 0.001 mg/µg

Acceptance criteria: 90.0%–115.0% for each analyte

4 PERFORMANCE TESTS

Uniformity of Dosage Units 〈905〉: Meets the requirements

5 SPECIFIC TESTS

Bacterial Endotoxins Test 〈85〉:

NMT 0.23 USP Endotoxin Unit/mg of imipenem and

NMT 0.23 USP Endotoxin Unit/mg of cilastatin

pH 〈791〉

Sample solution: Constitute as directed in the labeling.

Acceptance criteria: 6.0–7.5

Sterility Tests 〈71〉

Sample solution: Dissolve the sample in Fluid A.

Acceptance criteria: Meets the requirements when tested as directed for Test for Sterility of the Product to Be Examined, Membrane Filtration

Loss on Drying 〈731〉

Sample: 100 mg

Analysis: Dry the Sample under vacuum at a pressure not exceeding 5 mm of mercury at 60° for 3 h.

Acceptance criteria: NMT 3.5%

6 ADDITIONAL REQUIREMENTS

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 the suspension obtained when constituted as directed in the labeling is for intramuscular injection only.

USP Reference Standards 〈11〉

USP Cilastatin Ammonium Salt RS

USP Imipenem Monohydrate RS