Rotigotine

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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C₁₉H₂₅NOS 315.48 (CN 1-Aug-2024)

1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino-(6S)-;

(–)-(S)-5,6,7,8-Tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol;

(6S)-6-[Propyl(2-(2-thienyl)ethyl)amino]-5,6,7,8-tetrahydro-1-naphthalenol  CAS RN^®: 99755-59-6.

1 DEFINITION

Rotigotine contains NLT 98.0% and NMT 102.0% of rotigotine (C₁₉H₂₅NOS).

2 IDENTIFICATION

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

Standard: USP Rotigotine RS

Acceptance criteria: Meets the requirements

B. The retention time of the major peak of the Identification solution corresponds to the rotigotine–S isomer peak of the System suitability solution, as obtained in the Limit of Rotigotine R-Enantiomer test.

3 ASSAY

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3.1 Procedure

Solution A: 0.3 mL of trifluoroacetic acid in 1 L of water

Solution B: 0.2 mL of trifluoroacetic acid in 1 L of acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent A: 1 mL of trifluoroacetic acid in 1 L of water

Diluent B: 1 mL of trifluoroacetic acid in 1 L of acetonitrile

Standard stock solution: 1.3 mg/mL of USP Rotigotine Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Rotigotine Hydrochloride RS to a suitable volumetric flask. Add 5% of the flask volume of Diluent B and 40% of the flask volume of Diluent A. Sonicate to promote dissolution.

[Note—A sonication time of NLT 20 min with shaking at 5-min intervals may be suitable.]

Dilute with Diluent A to volume.

Standard solution: 650 µg/mL of USP Rotigotine Hydrochloride RS from Standard stock solution in Diluent A

System suitability solution: 0.005 mg/mL each of USP Rotigotine Related Compound G RS and USP Rotigotine Related Compound H RS in Standard solution

Sample solution: 600 µg/mL of Rotigotine in Diluent A prepared as follows. Transfer a suitable amount of Rotigotine to a suitable volumetric flask. Add 5% of the flask volume of Diluent B followed by 40% of the flask volume of Diluent A. Sonicate to promote dissolution.

[Note—A sonication time of NLT 20 min with shaking at 5-min intervals may be suitable.]

Dilute with Diluent A to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Column temperature: 40°

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 1.2 between rotigotine related compound G and rotigotine related compound H

Tailing factor: NMT 3.0 for rotigotine

Relative standard deviation: NMT 0.73% for rotigotine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of rotigotine (C₁₉H₂₅NOS) in the portion of Rotigotine taken:

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

M_r1 = molecular weight of rotigotine, 315.48 (CN 1-Aug-2024)

M_r2 = molecular weight of rotigotine hydrochloride, 351.93

Acceptance criteria: 98.0%–102.0%

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.1%

4.2 Limit of Rotigotine R-Enantiomer

Diluent A: Absolute alcohol, methanol, and 2-propanol (90:5:5)

Diluent B: 1 mL of diethylamine in 1 L of Diluent A

Mobile phase: Heptane, Diluent A, and diethylamine (98:2:0.1)

System suitability solution: 0.1 mg/mL of USP Rotigotine Racemate RS in Diluent B

Sample solution: 2 mg/mL of Rotigotine in Diluent B

Identification solution: 0.05 mg/mL of Rotigotine from the Sample solution in Diluent B

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 25-cm; 10-µm packing L40

[Note—A 4.6-mm × 5-cm guard column with L40 packing may be used.]

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: About 1.5 times the retention time of rotigotine

System suitability

Sample: System suitability solution

[Note—The relative retention times for rotigotine R-isomer and rotigotine are 0.9 and 1.0, respectively. Use the chromatogram from the Identification solution for Identification B.]

Suitability requirements

Resolution: NLT 1.5 between rotigotine R-isomer and rotigotine

Tailing factor: NMT 2.0 for rotigotine

Analysis

Samples: Sample solution and Identification solution

Calculate the percentage of rotigotine R-isomer in the portion of Rotigotine taken:

Result = (r_U/r_T) × 100

r_U = peak response of rotigotine R-isomer from the Sample solution

r_T = sum of the peak responses of rotigotine R-isomer and rotigotine from the Sample solution

Acceptance criteria: NMT 0.15% of rotigotine R-isomer

Change to read:

4.3 Organic Impurities

Mobile phase, Diluent A, Diluent B, Standard stock solution, System suitability solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.65 µg/mL of USP Rotigotine Hydrochloride RS from Standard stock solution and Diluent A

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 1.2 between rotigotine related compound G and rotigotine related compound H, System suitability solution

Tailing factor: NMT 2.0 for rotigotine, Standard solution

Relative standard deviation: NMT 5.0% for rotigotine, Standard solution

Analysis

Samples: Sample solution and Standard solution

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

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response from the Standard solution

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

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

M_r1 = molecular weight of rotigotine, 315.48 (CN 1-Aug-2024)

M_r2 = molecular weight of rotigotine hydrochloride, 351.93

Acceptance criteria: See Table 2.

Table 2

ᵃ (S)-6-(Propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol.

ᵇ (S)-6-{[2-(Thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol.

ᶜ (S)-6-{Ethyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol.

ᵈ (6S)-6-[Propyl[2-(thiophen-2-yl)ethyl]amino]-5,6,7,8-tetrahydronaphthalen-1-yl acetate.

ᵉ Included for System suitability evaluation only.

ᶠ (S)-6-{Propyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-yl 4-methylbenzenesulfonate.

ᵍ (S)-N-Propyl-5-[2-(thiophen-2-yl)ethoxy]-N-[2-(thiophen-2-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-amine.

5 SPECIFIC TESTS

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

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at room temperature.

Change to read:

USP Reference Standards 〈11〉

USP Rotigotine RS

USP Rotigotine Hydrochloride RS

(6S)-6-[Propyl(2-(2-thienyl)ethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol hydrochloride.

C₁₉H₂₅NOS · HCl 351.93

USP Rotigotine Related Compound G RS

(S)-6-{Bis[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol hydrochloride.

C₂₂H₂₅NOS₂ · HCl 420.03

USP Rotigotine Related Compound H RS

(S)-5-Methoxy-N-propyl-N-[2-(thiophen-2-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-amine.

C₂₀H₂₇NOS 329.50

USP Rotigotine Racemate RS

(RS)-6-{Propyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol.

C₁₉H₂₅NOS  315.48 (CN 1-Aug-2024)