Valrubicin

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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C₃₄H₃₆F₃NO₁₃  723.64

(2S-cis)-2-[1,2,3,4,6,11-Hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-l-lyxohexopyranosyl]oxy]-2-naphthacenyl]-2-oxoethyl pentanoate;

(8S,10S)-8-Glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-10-[[2,3,6-trideoxy-3-(2,2,2-trifluoroacetamido)-α-l-lyxohexopyranosyl]oxy]-5,12-naphthacenedione 8²-valerate CAS RN®: 56124-62-0; UNII: 2C6NUM6878.

1 DEFINITION

Valrubicin contains NLT 98.0% and NMT 102.0% of C₃₄H₃₆F₃NO₁₃, calculated on the anhydrous and solvent-free basis.

[Caution-Great care should be taken to prevent inhaling particles of Valrubicin and exposing the skin to it.]

2 IDENTIFICATION

Change to read:

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

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

3.1 Procedure

Solution A: 3.4 mg/mL of monobasic potassium phosphate adjusted with phosphoric acid to a pH of 3.1

Mobile phase: Acetonitrile and Solution A (3:2)

Standard solution: 0.5 mg/mL of USP Valrubicin RS in acetonitrile

Sample solution: 0.5 mg/mL of Valrubicin in acetonitrile

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 254 nm
• Column: 4.6-mm × 5-cm; 1.8-µm packing L1
• Flow rate: 1.5 mL/min
• Column temperature: 40°
• Injection size: 10 µL

System suitability

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of C₃₄H₃₆F₃NO₁₃ in the portion of Valrubicin taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

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

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

Acceptance criteria: 98.0%–102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

Inorganic Impurities

4.1 Residue on Ignition 〈281〉: NMT 0.2%

Organic Impurities

4.2 Procedure

Solution A: Use Solution A as directed in the Assay.

Solution B: Acetonitrile

Mobile phase: See the gradient table below. [Note-Analysis time is 55 min. The steps that follow are for column washing and reequilibration.]

Solution C: Acetonitrile and water (1:1)

Stock standard solution: 2 mg/mL of USP Valrubicin RS in acetonitrile and water (1:1). [Note-Dissolve first in acetonitrile, using 50% of the final volume and dilute with water to volume.]

Standard solution: 0.01 mg/mL of valrubicin in Solution C

System suitability solution: 2 mg/mL of USP Valrubicin Resolution Mixture RS in acetonitrile and water (1:1). [Note-Dissolve first in acetonitrile, using 50% of the final volume and dilute with water to volume.]

Sample solution: 2 mg/mL of Valrubicin in acetonitrile and water (1:1). [Note-Dissolve first in acetonitrile, using 50% of the final volume and dilute with water to volume.]

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: 254 nm
• Column: 4.6-mm × 5-cm; 1.8-µm packing L1
• Flow rate: 1.5 mL/min
• Temperature
• Column: 40°
• Autosampler: 4°
• Injection size: 10 µL

System suitability

• Sample: System suitability solution
• [Note-Identify the peaks by the relative retention times listed in Impurity Table 1.]
• Suitability requirements
• Resolution: NLT 2.0 between doxorubicinone and daunorubicin

Analysis

Samples: Standard solution and Sample solution

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

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of valrubicin from the Standard solution

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

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

F = relative response factor as listed in Impurity Table 1

Acceptance criteria

[Note-Reporting level is 0.05%.]

Individual impurities: See Impurity Table 1.

Total impurities: NMT 1.0%

Impurity Table 1

ᵃ (8S,10S)-6,8,10,11-Tetrahydroxy-8-(hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

ᵇ (8S,10S)-10-[(3-Amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-8-(2-bromo-1,1-dimethoxyethyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

ᶜ 2-{(2S,4S)-4-[(3-Amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-oxoethyl pentanoate.

ᵈ 2-Oxo-2-[(2S,4S)-2,4,5,12-tetrahydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl]ethyl pentanoate.

ᵉ 2-(5,12-Dihydroxy-7-methoxy-6,11-dioxo-6,11-dihydrotetracen-2-yl)-2-oxoethyl pentanoate.

5 SPECIFIC TESTS

Water Determination, Method I 〈921〉: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Valrubicin RS

USP Valrubicin Resolution Mixture RS

This Reference Standard is a mixture of the following with their chemical names:

Doxorubicin: (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione.

Doxorubicin aglycone: (8S,10S)-6,8,10,11-tetrahydroxy-8-(hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

Daunorubicin: (8S,10S)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

Daunorubicin bromoketal: (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-8-(2-bromo-1,1-dimethoxyethyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione.

Doxorubicin valerate: 2-{(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-l-lyxo-hexopyranosyl)oxy]-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-oxoethyl pentanoate.

Doxorubicin aglycone valerate: 2-oxo-2-[(2S,4S)-2,4,5,12-tetrahydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl]ethyl pentanoate.

Valrubicin: (8S,10S)-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-10-[[2,3,6-trideoxy-3-(2,2,2-trifluoroacetamido)-α-l-lyxohexopyranosyl]oxy]-5,12-naphthacenedione 8²-valerate.

Dianhydrovalrubicin: 2-(5,12-dihydroxy-7-methoxy-6,11-dioxo-6,11-dihydrotetracen-2-yl)-2-oxoethyl pentanoate.