Milrinone Lactate 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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1 DEFINITION

Milrinone Lactate Injection is a sterile aqueous solution of Milrinone and a suitable osmolality-adjusting substance in Water for Injection, prepared with the aid of Lactic Acid. It contains NLT 90.0% and NMT 110.0% of the labeled amount of milrinone (C₁₂H₉N₃O).

2 IDENTIFICATION

A. The retention time of the milrinone peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV absorption spectrum of the major peak of the Sample solution exhibits maxima and minima at the same wavelengths as those of the corresponding peak of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Buffer: Dissolve 3.3 g of dibasic potassium phosphate in 1 L of water and add 3 mL of triethylamine. Adjust with phosphoric acid to a pH of 7.5.

Mobile phase: Acetonitrile and Buffer (20:80)

Standard solution: 0.05 mg/mL of USP Milrinone RS in Mobile phase. Sonication may be necessary for complete dissolution.

Sample solution: Nominally equivalent to 0.05 mg/mL of milrinone prepared from a volume of Injection suitably diluted with Mobile phase

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 220 nm. For Identification B, use a diode array detector in the range of 200–400 nm.
• Column: 4.6-mm × 25-cm; 5-µm packing L7
• Flow rate: 1 mL/min
• Injection volume: 20 µL
• Run time: NLT 1.7 times the retention time of milrinone

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of milrinone (C₁₂H₉N₃O) in the portion of Injection taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of milrinone from the Sample solution

rₛ = peak response of milrinone from the Standard solution

Cₛ = concentration of USP Milrinone RS in the Standard solution (mg/mL)

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

Acceptance criteria: 90.0%–110.0%

4 IMPURITIES

Change to read:

4.1 Organic Impurities

Buffer and Mobile phase: Prepare as directed in the Assay.

System suitability solution: 0.5 µg/mL each of USP Milrinone RS and USP Milrinone Related Compound A RS in Mobile phase

Standard solution: 0.5 µg/mL of USP Milrinone RS in Mobile phase

Sensitivity solution: 0.1 µg/mL of USP Milrinone RS in Mobile phase from Standard solution

Sample solution: Nominally 500 µg/mL of milrinone from a volume of Injection in Mobile phase

Chromatographic system

Proceed as directed in the Assay, except for the Run times.

• Run times
• Standard solution: NLT 1.7 times the retention time of milrinone
• Sample solution: NLT 4 times the retention time of milrinone

System suitability

• Samples: System suitability solution, Standard solution, and Sensitivity solution
• Suitability requirements
• Resolution: NLT 5.0 between milrinone and milrinone related compound A, System suitability solution
• Relative standard deviation: NMT 5.0%, Standard solution
• Signal-to-noise ratio: NLT 20, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Injection taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of milrinone from the Standard solution

Cₛ = concentration of USP Milrinone RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of milrinone in the Sample solution (µg/mL)

Acceptance criteria: See Table 1. Disregard peaks below 0.01%.

Table 1

ᵃ Process-related impurity; 1,6-Dihydro-2-methyl-6-oxo(3,4′-bipyridine)-5-carboxamide.

ᵇ Total impurities include both process-related and degradation products.

5 SPECIFIC TESTS

5.1 Content of Lactic Acid

Mobile phase: Water adjusted with phosphoric acid to a pH of 2.1

Standard solution: 0.2 mg/mL of USP Sodium Lactate RS in Mobile phase

Sample solution: Nominally equivalent to 0.2 mg/mL of milrinone prepared as follows. Transfer a suitable volume of Injection into a suitable volumetric flask and add about 8% of the flask volume of 1.0 N sodium hydroxide solution. Shake well and keep for 10 min. Neutralize with an equal amount of 1.0 N sulfuric acid and dilute with Mobile phase to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Flow rate: 1 mL/min
• Injection volume: 20 µL
• Run times
• Standard solution: NLT 2.4 times the retention time of lactic acid
• Sample solution: NLT 4 times the retention time of lactic acid

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of lactic acid in the portion of Injection taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (M_r₁/M_r₂) × 100

rᵤ = peak response of lactic acid from the Sample solution

rₛ = peak response of lactic acid from the Standard solution

Cₛ = concentration of USP Sodium Lactate RS in the Standard solution (mg/mL)

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

M_r₁ = molecular weight of lactic acid, 90.08

M_r₂ = molecular weight of sodium lactate, 112.06

Acceptance criteria: 95.0%–129.0%

5.2 Bacterial Endotoxins Test 〈85〉

NMT 25 USP Endotoxin Units/mg of milrinone

5.3 Sterility Tests 〈71〉

Meets the requirements

5.4 pH 〈791〉

3.2–4.0

5.5 Particulate Matter in Injections 〈788〉

Meets the requirements for small-volume injections

5.6 Other Requirements

Meets the requirements in Injections and Implanted Drug Products 〈1〉

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in single-dose containers. Store at controlled room temperature.

Labeling: Label it to indicate that it is to be suitably diluted prior to administration.

USP Reference Standards 〈11〉

USP Milrinone RS

USP Milrinone Related Compound A RS

1,6-Dihydro-2-methyl-6-oxo(3,4′-bipyridine)-5-carboxamide.

C₁₂H₁₁N₃O₂ 229.24

USP Sodium Lactate RS

Sodium 2-hydroxypropanoate.

C₃H₅NaO₃ 112.06