Oxaliplatin for 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

Oxaliplatin for Injection is a sterile, lyophilized mixture of Oxaliplatin and Lactose Monohydrate. It contains NLT 90.0% and NMT 110.0% of the labeled amount of oxaliplatin (C₈H₁₄N₂O₄Pt).

2 IDENTIFICATION

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

Add the following:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 2S (USP41)

3 ASSAY

Change to read:

Procedure

[Note - Use vigorous shaking and very brief sonication to dissolve the substance to be examined. Inject the Sample solution within 20 min of preparation. Use polypropylene HPLC autosampler vials.]

Acidified water: Adjust water with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Acidified water (1:99)

System suitability solution: 0.1 mg/mL each of USP Oxaliplatin RS and USP Oxaliplatin System Suitability RS in water. [Note - USP Oxaliplatin System Suitability RS is [SP-4-2-(1R-trans)]-(1,2-cyclohexanediamine-N,N′) dichloridoplatinum(II).]

Standard solution: 0.1 mg/mL of USP Oxaliplatin RS in water

Sample solution: Nominally equivalent to 0.1 mg/mL of oxaliplatin obtained by constituting a suitable number of vials of Oxaliplatin for Injection with the appropriate amount of water

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm. For Identification B, use a diode array detector in the range of 200–400 nm. 2S (USP41)

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

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 20 μL

System suitability

Samples: System suitability solution and Standard solution

[Note - The relative retention times for [SP-4-2-(1R-trans)]-(1,2-cyclohexanediamine-N,N′) dichloridoplatinum(II) and oxaliplatin are about 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the peaks of [SP-4-2-(1R-trans)]-(1,2-cyclohexanediamine-N,N′) dichloridoplatinum(II) and oxaliplatin, System suitability solution

Tailing factor: NMT 2.0 for the oxaliplatin peak, System suitability solution

Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of oxaliplatin (C₈H₁₄N₂O₄Pt) in the portion of Oxaliplatin for Injection taken:

Result = (r_U/r_S) × (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 Oxaliplatin RS in the Standard solution (mg/mL)

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Uniformity of Dosage Units 〈905〉: Meets the requirements

5 IMPURITIES

Change to read:

5.1 Limit of Oxalic Acid

[Note - Use vigorous shaking and very brief sonication to dissolve the substance to be examined. Inject the Sample solution within 20 min of preparation. Use polypropylene HPLC autosampler vials.]

Buffer: Add 1.36 g of monobasic potassium phosphate 2S (USP41) to 10 mL of 10% tetrabutylammonium hydroxide in water, and dilute with water to 1000 mL. Adjust with phosphoric acid to a pH of 6.0.

Mobile phase: Acetonitrile and Buffer (1:4)

Standard stock solution: 0.06 mg/mL of USP Oxaliplatin Related Compound A RS in water. [Note - USP Oxaliplatin Related Compound A RS is available as oxalic acid dihydrate.]

Standard solution: 15 μg/mL of USP Oxaliplatin Related Compound A RS in water, from the Standard stock solution

System suitability stock solution: 0.05 mg/mL of sodium nitrate in water

System suitability solution: 1.0 μg/mL of sodium nitrate and 15 μg/mL of oxaliplatin related compound A in water, from the System suitability stock solution and Standard stock solution, respectively

Sensitivity solution: 1.5 μg/mL of USP Oxaliplatin Related Compound A RS in water, from the Standard solution 2S (USP41)

Sample solution: Nominally equivalent to 2.0 mg/mL of oxaliplatin in water from Oxaliplatin for Injection

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 205 nm

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

Column temperature: 40°

Flow rate: 2 mL/min

Injection volume: 20 μL

System suitability

Samples: Standard solution, System suitability solution, and Sensitivity solution

[Note - The relative retention times for the sodium nitrate and oxalic acid peaks are about 0.6 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the oxalic acid and sodium nitrate peaks, System suitability solution

Relative standard deviation: NMT 3.0% for the oxalic acid peak, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oxalic acid in the portion of Oxaliplatin for Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of oxalic acid from the Sample solution

r_S = peak response of oxalic acid from the Standard solution

C_S = concentration of USP Oxaliplatin Related Compound A RS in the Standard solution (mg/mL)

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

M_r1 = molecular weight of anhydrous oxalic acid, 90.03

M_r2 = molecular weight of USP Oxaliplatin Related Compound A RS, 126.07

Acceptance criteria: NMT 0.5%

Change to read:

5.2 Limit of (SP-4-2)-Diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum

[Note - Use vigorous shaking and very brief sonication to dissolve the substance to be examined. Inject the Sample solution within 20 min of preparation. Use polypropylene HPLC autosampler vials.]

Buffer: Dissolve 1.36 g of monobasic potassium phosphate 2S (USP41) and 1 g of sodium 1-heptanesufonate in 1 L of water. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (1:4)

System suitability solution: 2 mg/mL of USP Oxaliplatin RS in 0.005 M sodium hydroxide. Allow this solution to stand at room temperature for at least 5 days. [Note - Sonicate if necessary.] Transfer 5 mL of this solution into a 50-mL volumetric flask, and dilute with water to volume. [Note - The preparation of the System suitability solution forms diaquodiaminocyclohexaneplatinum dimer and (SP-4-2) diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum.]

Standard solution: 0.0125 mg/mL of USP Oxaliplatin Related Compound B RS prepared as follows. Transfer USP Oxaliplatin Related Compound B RS to a suitable volumetric flask, add 25% of the final volume of methanol, and sonicate for approximately 30 min to dissolve.

Allow to cool, if necessary, and dilute with water to volume. [Note - When preparing the solution, USP Oxaliplatin Related Compound B RS is converted to (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′] platinum.]

Sample solution: Use the Sample solution from the test for Limit of Oxalic Acid.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

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

Column temperature: 40°

Flow rate: 2 mL/min

Injection volume: 20 μL

System suitability

Samples: System suitability solution and Standard solution

[Note - The relative retention times for (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum and diaquodiaminocyclohexaneplatinum dimer are about 1.0 and 1.5, respectively.]

Suitability requirements

Resolution: NLT 2.0 between (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum and diaquodiaminocyclohexaneplatinum dimer, System suitability solution

Relative standard deviation: NMT 3.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum in the portion of Oxaliplatin for Injection

taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum from the Sample solution

r_S = peak response of (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum from the Standard solution

C_S = concentration of USP Oxaliplatin Related Compound B RS in the Standard solution (mg/mL)

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

M_r1 = molecular weight of (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum, 345.30

M_r2 = molecular weight of USP Oxaliplatin Related Compound B RS, 433.28

Acceptance criteria: NMT 0.5%

Change to read:

5.3 Limit of Related Compound C and Unspecified Impurities

[Note-Use vigorous shaking and very brief sonication to dissolve the substance to be examined. Inject the Sample solution within 20 min of preparation. Use polypropylene HPLC autosampler vials.]

Mobile phase: Prepare as directed in the Assay.

Standard stock solution: 0.1 mg/mL each of USP Oxaliplatin RS and USP Oxaliplatin Related Compound C RS in water

Standard solution: 0.01 mg/mL each of USP Oxaliplatin RS and USP Oxaliplatin Related Compound C RS in water, from the Standard stock solution

System suitability stock solution: 0.1 mg/mL of USP Oxaliplatin System Suitability RS in methanol. Sonicate for approximately 10 min to aid the dissolution.

System suitability solution: Transfer 10 mL each of the Standard stock solution and the System suitability stock solution into a 100-mL volumetric flask, and dilute with water to volume.

Sample solution: Use the Sample solution from the test for Limit of Oxalic Acid.

Chromatographic system: Proceed as directed in the Assay, except for the Injection volume.

Injection volume: 10 μL

System suitability

Samples: Standard solution and System suitability solution

Suitability requirements

Resolution: NLT 2.0 between [SP-4-2-(1R-trans)]-(1,2-cyclohexanediamine-N,N′) dichloridoplatinum(II) and oxaliplatin, System suitability solution

Tailing factor: NMT 2.0 for the oxaliplatin peak, System suitability solution

Relative standard deviation: NMT 3.0% each for the oxaliplatin and oxaliplatin related compound C peaks, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of oxaliplatin related compound C in the portion of Oxaliplatin for Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of oxaliplatin related compound C from the Sample solution

r_S = peak response of oxaliplatin related compound C from the Standard solution

C_S = concentration of USP Oxaliplatin Related Compound C RS in the Standard solution (mg/mL)

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

Calculate the percentage of each unspecified impurity in the portion of Oxaliplatin for Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of oxaliplatin from the Standard solution

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

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

Acceptance criteria: See Table 1.

Table 1

^a The relative retention time is included for system suitability purposes only.

^bIncludes oxalic acid, (SP-4-2)-diaqua[(1R,2R)-cyclohexane-1,2-diamine-N,N′]platinum, oxaliplatin related compound C, and the total of the individual unspecified impurities.

6 SPECIFIC TESTS

pH 〈791〉: 4.0–7.0 using a polymer combination electrode, determined in a solution constituted as directed in the labeling

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

Constituted Solution: At the time of use, it meets the requirements in Injections and Implanted Drug Products 〈1〉, Product Quality Tests Common to Parenteral Dosage Forms, Specific Tests, Completeness and Clarity of Solutions.

Bacterial Endotoxins Test 〈85〉: NMT 1.0 USP Endotoxin Unit/mg of oxaliplatin

Sterility Tests 〈71〉: Meets the requirements

Water Determination 〈921〉, Method I: NMT 4.0%

Other Requirements: It meets the requirements in Injections and Implanted Drug Products 〈1〉.

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve as described in Packaging and Storage Requirements 〈659〉, Injection Packaging, Packaging for Constitution. Store at controlled room temperature.

Labeling: Label it to indicate that it is to be diluted with a suitable parenteral vehicle before intravenous infusion.

Change to read:

USP Reference Standards 〈11〉  (CN 1-May-2018)

USP Oxaliplatin RS 2S (USP41)

USP Oxaliplatin Related Compound A RS

Oxalic acid dihydrate.

C₂H₂O₄ · 2H O 126.07

USP Oxaliplatin Related Compound B RS

[SP-4-2-(1R-trans)]-(1,2-Cyclohexanediamine-N,N′) dinitratoplatinum(II).

C₆H₁₄N₄O₆Pt 433.28

USP Oxaliplatin Related Compound C RS

[1R-trans-(1,2-Cyclohexanediamine-N,N′)]-trans-dihydroxido-[oxalato(2-)-O,O′]platinum(IV).

C₈H₁₆N₂O₆Pt 431.30

USP Oxaliplatin System Suitability RS

[SP-4-2-(1R-trans)]-(1,2-Cyclohexanediamine-N,N′) dichloridoplatinum(II).

C₆H₁₄Cl₂N₂Pt 380.17