Rotigotine Transdermal System

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

Rotigotine Transdermal System contains NLT 90.0% and NMT 110.0% of the labeled amount of rotigotine (C₁₉H₂₅NOS).

2 IDENTIFICATION

A. The UV spectrum of the rotigotine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

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

Change to read:

3.1 Procedure

Extraction solvent: Prepare a mixture of 2-propanol and tert-butylmethylether (80:20). Add 1 mL of methanesulfonic acid to 1 L of the solvent mixture.

Solution A: 0.5 mL of methanesulfonic acid in 1 L of water

Solution B: 0.5 mL of methanesulfonic acid in 1 L of acetonitrile

Mobile phase: Solution A and Solution B (65:35)

Diluent: 1 mL of methanesulfonic acid in 1 L of water

Standard stock solution: 0.5 mg/mL of USP Rotigotine Hydrochloride RS in Extraction solvent.

[Note—Sonication in a cooled ultrasonic bath may be used to aid in dissolution.]

Standard solution: Mix 3 mL of the Standard stock solution with 7 mL of Diluent.

Sample stock solution: Nominally 0.45 mg/mL of rotigotine from NLT 10 Transdermal Systems prepared as follows. Transfer the required number of Transdermal Systems without the release liner to a suitable flask containing N mL of Extraction solvent, where N is the total area of the Transdermal Systems taken. Close the flask and sonicate the solution for NLT 10 min in a sonicator maintained at 20°, shaking the flask intermittently to ensure the silicone matrix is completely dissolved.

[Note—Sonication time may be extended if needed to enable complete dissolution of the silicone matrix.]

Sample solution: Mix 3 mL of Sample stock solution with 7 mL of Diluent. Centrifuge the solution and use the clear supernatant.

[Note—A centrifuge speed of NLT 4000 rpm for NLT 15 min may be used.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 272 nm. For Identification A, use a diode array detector in the range of 200–400 nm.

Column: 4.0-mm × 7.5-cm; 4-µm packing L7

Column temperature: 30°

Flow rate: 2 mL/min

Injection volume: 10 µL

Run time: NLT 4 times the retention time of rotigotine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.2

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of rotigotine (C₁₉H₂₅NOS) in each Transdermal System taken:

Result = (r_U/r_S) × C_S × (V/N) × (M_r1/M_r2) × (1/L) × 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 stock solution (mg/mL)

V = volume of the Sample stock solution (mL)

N = number of Transdermal System units used to prepare the Sample stock solution

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

M_r2 = molecular weight of rotigotine hydrochloride, 351.93

L = label claim (nominal content) of rotigotine in each Transdermal System (mg/unit)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 Drug Release 〈724〉

Medium: Dissolve 6.9 g of monobasic sodium phosphate in 1 L of water. Adjust with a suitable concentration of sodium hydroxide or phosphoric acid to a pH of 4.5; 900 mL, deaerated.

Apparatus 5: 50 rpm; Transdermal System on metal disk

Times: 15, 30, 60, and 180 min

Solution A, Solution B, and Mobile phase: Prepare as directed in the Assay.

Standard solution: (L/800) mg/mL of USP Rotigotine Hydrochloride RS in Medium, where L is the label claim in mg/unit

Sample solution: Withdraw 2 mL from the vessel at the specified times.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 272 nm

Column: 4.0-mm × 7.5-cm; 4-µm packing L7

Column temperature: 30°

Flow rate: 2 mL/min

Injection volume: 50 µL

Run time: NLT 2.5 times the retention time of rotigotine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.2 for rotigotine

Relative standard deviation: NMT 2.0% for rotigotine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount (nominal content) of rotigotine (C₁₉H₂₅NOS) released at each time point i:

Result = (r_U/r_S) × C_S × V × (1/L) × (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 (mg/mL)

V = volume of the Medium, 900 mL

L = label claim (nominal content) of rotigotine in the Transdermal System (mg/unit)

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 1.

Table 1

The percentages of the labeled amount of rotigotine (C₁₉H₂₅NOS) released at the times specified conform to Drug Release 〈724〉, Acceptance Table 1.

4.2 Uniformity of Dosage Units 〈905〉: Meets the requirements

5 IMPURITIES

5.1 Organic Impurities

Extraction solvent, Solution A, Solution B, Diluent, and Standard stock solution: Prepare as directed in the Assay.

Mobile phase: See Table 2.

Table 2

Impurities stock solution: 0.1 mg/mL each of USP Rotigotine Related Compound C RS and USP Rotigotine Related Compound K RS in 2-propanol

System suitability stock solution: 0.15 mg/mL of USP Rotigotine Hydrochloride RS and 0.0025 mg/mL each of USP Rotigotine Related Compound C RS and USP Rotigotine Related Compound K RS from suitable volumes of Standard stock solution and Impurities stock solution in Extraction solvent

System suitability solution: Mix 3 mL of System suitability stock solution with 7 mL of Diluent.

Sensitivity stock solution: 0.25 µg/mL of USP Rotigotine Hydrochloride RS from Standard stock solution in Extraction solvent

Sensitivity solution: Mix 3 mL of Sensitivity stock solution with 7 mL of Diluent.

Sample stock solution:

[Note—Lacquer removal is recommended to minimize the interferences from the lacquer with the degradation product peaks as follows. Remove the lacquer from the backing foil of each Transdermal System with 4% (v/v) glacial acetic acid in methanol. Dry the lacquer-removed Transdermal Systems for NLT 1 h at room temperature.]

Nominally 0.45 mg/mL of rotigotine from NLT 3 Transdermal Systems prepared as follows. Transfer the required number of (lacquer removed, if necessary) Transdermal Systems without the release liner to a suitable flask containing n mL of Extraction solvent, where n is the total area (cm²) of the Transdermal Systems taken. Close the flask and sonicate the solution for NLT 10 min in a sonicator maintained at 20°, shaking the flask intermittently to ensure the silicone matrix is completely dissolved.

[Note—Sonication time may be extended if needed to enable complete dissolution of the silicone matrix.]

Sample solution: Mix 3 mL of Sample stock solution with 7 mL of Diluent. Centrifuge the solution and use the clear supernatant.

[Note—A centrifuge speed of NLT 4000 rpm for NLT 15 min may be used.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 12.5-cm; 5-µm packing L10.

[Note—A guard column with dimensions 4-mm × 1-cm with 5-µm L3 packing is recommended to minimize interference from the adhesive.]

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 80 µL

System suitability

Samples: System suitability solution and Sensitivity solution

[Note—See Table 3 for relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between rotigotine related compound K and rotigotine related compound C, System suitability solution

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

Analysis

Sample: Sample solution

Calculate the percentage of each specified or unspecified degradation product in the portion of the Transdermal System taken:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each specified or unspecified degradation product from the Sample solution

r_T = sum of all the peak responses (including the rotigotine peak) from the Sample solution

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3.

Table 3

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

6 ADDITIONAL REQUIREMENTS

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

Labeling: The label states the total amount of rotigotine in the Transdermal System and the release rate, in mg/day, for the duration of the application of one system.

USP Reference Standards 〈11〉

USP Rotigotine Hydrochloride RS

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

C₁₉H₂₅NOS · HCl 351.93

USP Rotigotine Related Compound C RS

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

C₁₆H₁₉NOS 273.39

USP Rotigotine Related Compound K RS

7,8-Dihydronaphthalen-1-ol.

C₁₀H₁₀O 146.19