Milrinone

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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C₁₂H₉N₃O  211.22

[3,4′-Bipyridine]-5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo-;

1,6-Dihydro-2-methyl-6-oxo[3,4′-bipyridine]-5-carbonitrile  CAS RN®: 78415-72-2; UNII: JU9YAX04C7.

1 DEFINITION

Milrinone contains NLT 98.0% and NMT 102.0% of milrinone (C₁₂H₉N₃O), calculated on the anhydrous basis.

[Caution-Milrinone is a cardiotonic agent.]

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

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

3 ASSAY

Change to read:

3.1 Procedure

Buffer: To 72.44 g of sodium tetraborate, anhydrous add 900 mL of water. Adjust with hydrochloric acid to a pH of 6.5. The solution should become nearly transparent after adjustment. Dilute with water to 1 L.

Mobile phase: Methanol, Buffer, and water (320:40:640)

Diluent: Methanol, water, and lactic acid (320:679:1.2)

Standard solution: 0.1 mg/mL of USP Milrinone RS in Diluent. Sonicate until dissolved.

Sample solution: 0.1 mg/mL of Milrinone in Diluent. Sonicate until dissolved.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 268 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Flow rate: 1 mL/min
• Injection volume: 20 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of milrinone (C₁₂H₉N₃O) in the portion of Milrinone 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 = concentration of Milrinone in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.2%

4.2 Organic Impurities

Buffer: To 2.7 g of dibasic potassium phosphate in 800 mL of water add 2.4 mL of triethylamine, and adjust with phosphoric acid to a pH of 7.5.

Mobile phase: Acetonitrile and Buffer (200:800)

System suitability stock solution: 0.2 mg/mL of USP Milrinone Related Compound A RS in Mobile phase. Heat in a water bath at approximately 80°, and/or sonicate if necessary to dissolve.

Standard stock solution: 2 mg/mL of USP Milrinone RS in Mobile phase. Heat in a water bath at approximately 80°, and/or sonicate if necessary to dissolve.

System suitability solution: 10.0 mL of System suitability stock solution and 1.0 mL of Standard stock solution in a 100-mL volumetric flask. Dilute with Mobile phase to volume.

Standard solution: 0.006 mg/mL of USP Milrinone RS, from the Standard stock solution, in Mobile phase

Sample solution: 2 mg/mL of Milrinone in Mobile phase. Heat in a water bath at approximately 80°, if necessary to dissolve.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 220 nm
• Column: 4.6-mm × 25-cm; packing L7
• Flow rate: 1 mL/min
• Injection volume: 20 µL

System suitability

Sample: System suitability solution

• [Note-The relative retention times for milrinone related compound A and milrinone are 0.6 and 1.0, respectively.]
• Suitability requirements
• Resolution: NLT 4.0 between milrinone related compound A and milrinone
• Relative standard deviation: NMT 5.0% from the milrinone peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Milrinone 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 (mg/mL)

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

Acceptance criteria

• Any individual impurity: NMT 0.3%
• Total impurities: NMT 1.0%

5 SPECIFIC TESTS

Water Determination, Method I 〈921〉: NMT 2.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

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  229.23