Palonosetron Hydrochloride

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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C₁₉H₂₄N₂O·HCI 332.87

1H-Benzo[de]isoquinoline-1-one,2,3,3a,4,5,6-hexahydro-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl], (S)-, hydrochloride;

(S)-2-[(3S)-Quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride CAS RN^®: 135729-62-3; UNII: 23310D4119.

1 DEFINITION

Palonosetron Hydrochloride contains NLT 98.0% and NMT 102.0% of palonosetron hydrochloride (C₁₉H₂₄N₂O·HCI), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A or 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.

C. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Chloride: Meets the requirements

3 ASSAY

3.1 PROCEDURE

Mobile phase: Acetonitrile, water, and trifluoroacetic acid (280:720:0.67)

Standard stock solution: 0.7 mg/mL of USP Palonosetron Hydrochloride RS in methanol. Sonicate to dissolve, if necessary.

Standard solution: 0.014 mg/mL of USP Palonosetron Hydrochloride RS from the Standard stock solution, in Mobile phase

Sample stock solution: 0.7 mg/mL of Palonosetron Hydrochloride in methanol. Sonicate to dissolve, if necessary.

Sample solution: 0.014 mg/mL of Palonosetron Hydrochloride from the Sample stock solution, in Mobile phase

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Flow rate: 1 mL/min

Injection volume: 80 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of palonosetron hydrochloride (C₁₉H₂₄N₂O·HCI) in the portion of Palonosetron Hydrochloride taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of palonosetron from the Sample solution

r_S = peak response of palonosetron from the Standard solution

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

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

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 LIMIT OF SPECIFIED IMPURITIES

Mobile phase: n-Hexane, dehydrated alcohol, methanol, diethylamine, and trifluoroacetic acid (85:7.5:7.5:0.2:0.05)

System suitability stock solution 1: 0.05 mg/mL of each USP Palonosetron Related Compound B RS, USP Palonosetron Related Compound C RS, and USP Palonosetron Enantiomer RS in Mobile phase. Sonicate to dissolve, if necessary.

System suitability stock solution 2: 0.05 mg/mL USP Palonosetron Related Compound E RS in Mobile phase. Sonicate to dissolve, if necessary.

System suitability stock solution 3: 0.05 mg/mL USP Palonosetron Related Compound D RS in Mobile phase. Sonicate to dissolve, if necessary.

System suitability solution: 0.5 µg/mL each of USP Palonosetron Related Compound B RS, USP Palonosetron Related Compound C RS, and USP Palonosetron Enantiomer RS from System suitability stock solution 1; 2.5 µg/mL of USP Palonosetron Related Compound E RS from System suitability stock solution 2; 1.5 µg/mL of USP Palonosetron Related Compound D RS from System suitability stock solution 3; and 0.5 mg/mL of USP Palonosetron Hydrochloride RS in Mobile phase

Sensitivity solution: 0.25 µg/mL of USP Palonosetron Hydrochloride RS from Standard solution, in Mobile phase

Standard solution: 0.5 µg/mL of USP Palonosetron Hydrochloride RS in Mobile phase. Sonicate to dissolve, if necessary.

Sample solution: 500 µg/mL of Palonosetron Hydrochloride in Mobile phase. Sonicate to dissolve, if necessary.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 25-cm; 5-µm packing L40

Temperatures

Autosampler: 10°

Column: 20°

Flow rate: 0.5 mL/min

Injection volume: 20 µL

Run time: NLT 3 times the retention time of

System suitability

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

[NOTE-See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.4 between palonosetron related compound C and palonosetron; NLT 2.5 between palonosetron and palonosetron related compound E, System suitability solution

Tailing factor: NLT 0.8 and NMT 2.0, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Palonosetron Hydrochloride taken:

Result = (r_U/r_S) x (C_S/C_U) x (1/F) x 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of palonosetron from the Standard solution

C_S = concentration of USP Palonosetron Hydrochloride RS in the Standard solution (µg/mL)

C_U = concentration of Palonosetron Hydrochloride in the Sample solution (µg/mL)

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

Table 1

4.3 LIMIT OF PALONOSETRON RELATED COMPOUND A

Buffer: 13 mL/L of 70% perchloric acid in water. Add 4 g of sodium hydroxide and adjust with dilute sodium hydroxide to a pH of 2.3.

Solution A: Acetonitrile and Buffer (20:80)

Solution B: Acetonitrile and Buffer (80:20)

Mobile phase: See Table 2.

Table 2

Diluent: Acetonitrile and water (50:50)

System suitability stock solution: 0.0225 mg/mL of USP Palonosetron Related Compound A RS in Diluent. Sonicate to dissolve, if necessary.

System suitability solution: 0.225 µg/mL of USP Palonosetron Related Compound A RS from System suitability stock solution and 0.15 mg/mL of USP Palonosetron Hydrochloride RS in Diluent. Sonicate to dissolve, if necessary.

Sensitivity solution: 0.075 µg/mL of USP Palonosetron Hydrochloride RS from Standard solution in Diluent

Standard solution: 0.15 µg/mL of USP Palonosetron Hydrochloride RS in Diluent. Sonicate to dissolve, if necessary.

Sample solution: 150 µg/mL of Palonosetron Hydrochloride in Diluent. Sonicate to dissolve, if necessary.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 15-cm; 3-µm packing L26

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution [NOTE-The relative retention time for palonosetron related compound A is 1.05.]

Suitability requirements

Resolution: NLT 2.0 between palonosetron and palonosetron related compound A, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of palonosetron related compound A in the portion of Palonosetron Hydrochloride taken:

Result = (r_U/r_S) x (C_S/C_U) x (1/F) x 100

r_U = peak response of palonosetron related compound A from the Sample solution

r_S = peak response of palonosetron from the Standard solution

C_S = concentration of USP Palonosetron Hydrochloride RS in the Standard solution (µg/mL)

C_U = concentration of Palonosetron Hydrochloride in the Sample solution (µg/mL)

F = relative response factor, 0.94

Acceptance criteria: NMT 0.1%. The reporting threshold is 0.05%.

Change to read:

4.4 LIMIT OF UNSPECIFIED IMPURITIES

Mobile phase, Standard stock solution, (ERR 1-Jan-2023) and Chromatographic system: Proceed as directed in the Assay.

Peak identification stock solution: 0.07 mg/mL each of USP Palonosetron Related Compound A RS, USP Palonosetron Related Compound B RS, USP Palonosetron Related Compound D RS, and USP Palonosetron Related Compound E RS in methanol. Sonicate to dissolve, if necessary.

Peak identification solution: 0.07 µg/mL each of USP Palonosetron Related Compound A RS, USP Palonosetron Related Compound B RS, USP Palonosetron Related Compound D RS, and USP Palonosetron Related Compound E RS from the Peak identification stock solution, and 3.5 µg/mL of USP Palonosetron Hydrochloride RS from the Standard stock solution, in Mobile phase

Sensitivity solution: 0.0175 µg/mL of USP Palonosetron Hydrochloride RS in Mobile phase

Sample stock solution: 0.175 mg/mL of Palonosetron Hydrochloride in methanol. Sonicate to dissolve, if necessary.

Sample solution: 0.035 mg/mL of Palonosetron Hydrochloride from the Sample stock solution, in Mobile phase

System suitability

[NOTE-See Table 3 for relative retention times.]

Sample: Sensitivity solution

Suitability requirements

Signal-to-noise ratio: NLT 10

Analysis

Sample: Sample solution

Calculate the percentage of each unspecified impurity in the portion of Palonosetron Hydrochloride taken:

Result = (r_U/r_T) x 100

r_U = peak response of each unspecified impurity from the Sample solution

r_T = sum of all peak responses from the Sample solution

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3

^a These impurities are controlled in the test for Limit of Specified Impurities and are not to be reported here.

^b This impurity is controlled in the test for Limit of Palonosetron Related Compound A and is not to be reported here.

^c Total impurities include impurities controlled in the test for Limit of Specified Impurities and in the test for Limit of Unspecified Impurities.

5 SPECIFIC TESTS

5.1 PH (791)

Sample solution: 10 mg/mL in water

Acceptance criteria: 5.0-6.0

5.2 LOSS ON DRYING (731)

Analysis: Dry under vacuum at 80° for 3 h.

Acceptance criteria: NMT 1.0%

5.3 MICROBIAL ENUMERATION TESTS (61) and TESTS FOR SPECIFIED MICROORGANISMS (62)

The total aerobic microbial count does not exceed 10² cfu/g, and the total combined molds and yeasts count does not exceed 10 cfu/g.

5.4 BACTERIAL ENDOTOXINS TEST (85)

Where the label states that Palonosetron Hydrochloride must be sterile or subjected to further processing during the preparation of injectable dosage forms, the level of bacterial endotoxins are such that the requirement under the relevant dosage form monograph(s) in which Palonosetron Hydrochloride is used can be met.

5.5 STERILITY TESTS (71)

Meets the requirements where the label states that Palonosetron Hydrochloride is sterile

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers. Store at controlled room temperature, protected from light.

6.2 LABELING

Where Palonosetron Hydrochloride must be sterile or subjected to further processing during the preparation of injectable dosage forms to ensure acceptable levels of bacterial endotoxins, it is so labeled.

6.3 USP REFERENCE STANDARDS (11)

USP Palonosetron Enantiomer RS

(R)-2-[(3R)-Quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride.

C₁₉H₂₄N₂O·HCI 332.87

USP Palonosetron Hydrochloride RS

USP Palonosetron Related Compound A RS

Palonosetron N-oxide;

(S)-1-Oxo-2-[(3S)-quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinoline 1-oxide.

C₁₉H₂₄N₂O₂ 312.41

USP Palonosetron Related Compound B RS

Palonosetron-3-ene N-oxide;

(3S)-3-(1-Oxo-5,6-dihydro-1H-benzo[de]isoquinolin-2(4H)-yl) quinuclidine 1-oxide.

C₁₉H₂₂N₂O₂ 310.39

USP Palonosetron Related Compound C RS

Palonosetron S,R-diastereomer;

(S)-2-[(3R)-Quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride.

C₁₉H₂₄N₂O·HCI 332.87

USP Palonosetron Related Compound D RS

Palonosetron R,S-diastereomer or palonosetron 3a-epimer;

(R)-2-[(3S)-Quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride.

C₁₉H₂₄N₂O·HCI 332.87

USP Palonosetron Related Compound E RS

Palonosetron-3-ene;

2-[(3S)-Quinuclidin-3-yl]-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-1-one hydrochloride.

C₁₉H₂₂N₂O·HCI 330.85