Norepinephrine Bitartrate 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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Norepinephrine Bitartrate Injection is a sterile solution of Norepinephrine Bitartrate in Water for Injection. It contains the equivalent of not less than 90.0 percent and not more than 115.0 percent of the labeled amount of norepinephrine (C₈H₁₁NO₃).

1 Packaging and storage

Preserve in single-dose, light-resistant containers, preferably of Type I glass.

2 Labeling

Label the Injection in terms of mg of norepinephrine per mL, and, where necessary, label it to indicate that it must be diluted prior to use. The label indicates that the Injection is not to be used if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

2.1 USP Reference standards 〈11〉

USP Norepinephrine Bitartrate RS

3 Color and clarity

Standard solution - Transfer 2.0 mL of 0.100 N iodine VS to a 500-mL volumetric flask, dilute with water to volume, and mix.

Procedure - Visually examine a portion of the Injection (Test solution) in a suitable clear glass test tube against a white background: it is not pinkish and it contains no precipitate. If any yellow color is observed in the Test solution, concomitantly determine the absorbances of the Test solution and the Standard solution in 1-cm cells with a suitable spectrophotometer set at 460 nm: the absorbance of the Test solution does not exceed that of the Standard solution.

4 Identification

A: It responds to Identification test B under Norepinephrine Bitartrate.

B: Dilute the Injection with water to a concentration of 1 mg in 5 mL. To 10 mL of the dilution add 2.0 mL of 0.10 N iodine, allow to stand for 5 minutes, then add 3.0 mL of 0.10 N sodium thiosulfate: the solution is colorless or has at most a slight pink or slight violet color (epinephrine and isoproterenol at the same pH, about 3.5, give a red-brown or violet color).

Bacterial Endotoxins Test 〈85〉- It contains not more than 83.4 USP Endotoxin Units per mg of norepinephrine.

pH 〈791〉: Between 3.0 and 4.5.

Particulate Matter in Injections 〈788〉: Meets the requirements for small-volume injections.

5 Other requirements

It meets the requirements under Injections and Implanted Drug Products 〈1〉.

6 Assay

Mobile phase - Dissolve 1.1 g of sodium 1-heptanesulfonate in 800 mL of water. Add 200 mL of methanol, and adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.1. Pass through a membrane filter. Make adjustments if necessary (see System Suitability under Chromatography 〈621〉).

Standard preparation - Dissolve an accurately weighed quantity of USP Norepinephrine Bitartrate RS in freshly prepared dilute acetic acid (1 in 25), and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.4 mg of norepinephrine bitartrate monohydrate per mL.

Assay preparation - Transfer an accurately measured volume of Injection, equivalent to about 5 mg of norepinephrine, to a 25-mL volumetric flask, add dilute acetic acid (1 in 25) to volume, and mix.

System suitability preparation - Dissolve a suitable quantity of isoproterenol hydrochloride in the Standard preparation to obtain a solution containing, in each mL, 0.4 mg of USP Norepinephrine Bitartrate RS and 0.4 mg of isoproterenol hydrochloride.

Chromatographic system (see Chromatography 〈621〉) - The liquid chromatograph is equipped with a 280-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 2 mL per minute. Chromatograph the Standard preparation and the System suitability preparation, and record the peak responses as directed under Procedure: the tailing factor for the analyte peak is not more than 2.5, the resolution, R, between the norepinephrine and isoproterenol peaks is not less than 4.0, and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure - Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of norepinephrine (C₈H₁₁NO₃) in each mL of the Injection taken by the formula:

(169.18/337.29)(25C/V)(rᵤ/rₛ)

in which 169.18 and 337.29 are the molecular weights of norepinephrine and norepinephrine bitartrate monohydrate, respectively; C is the concentration, in mg per mL, of USP Norepinephrine Bitartrate RS in the Standard preparation; V is the volume, in mL, of Injection taken; and rᵤ and rₛ are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.