Ixabepilone

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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C₂₇H₄₂N₂O₅S 506.70

17-Oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione, 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-,

(1S,3S,7S,10R,11S,12S,16R)-;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-

azabicyclo[14.1.0]heptadecane-5,9-dione. CAS RN®: 219989-84-1.

1 DEFINITION

Ixabepilone contains NLT 97.5% and NMT 102.0% of ixabepilone (C₂₇H₄₂N₂O₅S), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K (CN 1-May-2020)

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

Procedure

Buffer stock solution: 100 mM tris(hydroxymethyl)aminomethane in water prepared as follows. Dissolve 12.1 g of tris(hydroxymethyl)aminomethane in 1 L of water and adjust to a pH of 8.5.

Buffer: 5 mM tris(hydroxymethyl)aminomethane in water, from Buffer stock solution

Solution A: Acetonitrile and Buffer (10:90)

Solution B: Acetonitrile and Buffer (90:10)

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the system for 6 min.

Table 1

Standard solution: 1.0 mg/mL of USP Ixabepilone RS in acetonitrile. Sonicate to assist the dissolution.

Sample solution: 1.0 mg/mL of Ixabepilone in acetonitrile. Sonicate to assist the dissolution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Autosampler temperature: 4°

Flow rate: 1.8 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.8–1.5

Relative standard deviation: NMT 1.0% for six injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ixabepilone (C₂₇H₄₂N₂O₅S) in the portion of Ixabepilone taken:

Result = (r_U/r_S)x(C_S/C_U ) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Ixabepilone RS in the Standard solution (mg/mL)

C_U = concentration of Ixabepilone in the Sample solution (mg/mL)

Acceptance criteria: 97.5%–102.0% on the anhydrous basis

4 IMPURITIES

Organic Impurities

Mobile phase, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 1.0 mg/mL of USP Ixabepilone System Suitability Mixture RS in acetonitrile. Sonicate to assist the dissolution.

Sensitivity solution: 0.3 μg/mL of USP Ixabepilone RS in acetonitrile from Standard solution

System suitability

Samples: System suitability solution and Sensitivity solution

Suitability requirements

Resolution: NLT 1.0 between ixabepilone oxazine analog and desmethyl ixabepilone peaks, System suitability solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Sample: Sample solution

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

Result = r_U/{Σ[r_U× (1/F)] + r_T} × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

F = relative response factor for each individual impurity (see Table 2)

r_T = peak response of ixabepilone from the Sample solution

Acceptance criteria: See Table 2. Disregard any impurity peak less than 0.03%.

Table 2

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ic: NMT 0.2%

Bacterial Endotoxins Test 〈85〉: It contains NMT 0.32 USP Endotoxin Units/mg of ixabepilone.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Protect from light and store at 2°–8°.

USP Reference Standards 〈11〉

USP Endotoxin RS

USP Ixabepilone RS

USP Ixabepilone System Suitability Mixture RS

It contains ixabepilone and small amounts of:

Ixabepilone diol;

(4S,7R,8S,9S,13R,14R,16S)-4,8,13,14-Tetrahydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl]azacyclohexadecane-2,6- dione.

C₂₇H₄₄N₂O6S 524.72

Ixabepilone oxazine analog;

(1R,2R,6S,7S,8R,11S,15S)-2,7,11-Trihydroxy-2,6,8,10,10-pentamethyl-15-[(E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl]-17-oxa-14- azabicyclo[11.3.1]heptadec-13-en-9-one.

C₂₇H₄₂N₂O₅S 506.70

Desmethyl ixabepilone;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[(E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.

C₂₆H₄₀N₂O₅S 492.68

(Z)-Ixabepilone;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(Z)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.  

C₂₇H₄₂N₂O₅S 506.70

[Note—It may contain other impurities.]