Nicotine 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

Nicotine Transdermal System contains NLT 85% and NMT 115% of the labeled amount of nicotine (C₁₀H₁₄N₂).

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.

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

3 ASSAY

PROCEDURE

Solution A: Dissolve 1.1 g of monobasic potassium phosphate and 7.3 g of dibasic potassium phosphate in 1 L of water. [NOTE-The pH of this solution is between 7.5 and 7.6.]

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Extraction solvent: Methanol and tetrahydrofuran (90:10)

Standard stock solution: 3.0 mg/mL of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis (equivalent to about 1 mg/mL of nicotine) in Extraction solvent

Standard solution: 0.15 mg/mL of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis (equivalent to about 0.05 mg/mL of nicotine) in Solution A from the Standard stock solution

System suitability stock solution: 1 mg/mL each of USP Nicotine Related Compound E RS and USP Nicotine Related Compound D RS in Extraction solvent

System suitability solution: 0.15 mg/mL of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis and 0.1 mg/mL each of USP Nicotine Related Compound D RS and USP Nicotine Related Compound E RS in Solution A from the Standard stock solution and the System suitability stock solution

Sample stock solution: Nominally 1 mg/mL of nicotine from NLT 10 Transdermal System units prepared as follows. Transfer the required number of units to a suitable flask carefully ensuring that no adhesive contacts the walls. Add a suitable volume of Extraction solvent. Stopper the flask and seal to minimize the loss of the Extraction solvent. Shake the flask using a suitable shaker for 2 h.

Sample solution: Nominally 0.05 mg/mL of nicotine in Solution A from the Sample stock solution. Pass the solution through a suitable filter of 0.45-µm pore size.

Alternative sample preparation: If necessary, the Sample stock solution and the Sample solution may be prepared using the following alternative procedure.

Sample stock solution: Transfer one Transdermal System without the liner to a suitable 100-mL centrifuge tube with stopper. [NOTE-Cut Transdermal Systems larger than 2.5 cm² into 3-5-mm strips.] Add 10 mL of methylene chloride and a stirrer bar. Stopper the flask and stir the contents for NLT 4 h at room temperature. [NOTE-500 rpm for stirring speed is suitable.] Add 50 mL of 0.5% (v/v) phosphoric acid solution and continue extraction for another 1 h. Centrifuge at about 1000 rpm for NLT 5 min. Prepare separately the required number of extracts from the required number of Transdermal Systems following the same procedure described above. Combine equal volumes of the aqueous layer from each extract to obtain the Sample stock solution.

Sample solution: Nominally 0.03-0.05 mg/mL of nicotine from a suitable volume of the Sample stock solution and water

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing L1

Column temperature: 45 ± 2°

Flow rate: 1.0 mL/min

Injection volume: 80 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between nicotine related compound D and nicotine, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of nicotine (C₁₀H₁₄N₂) in the portion of Transdermal System taken:

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

r_U = peak response of nicotine from the Sample solution

r_S = peak response of nicotine from the Standard solution

C_S = concentration of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis in the Standard solution (mg/mL)

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

M_r1 = molecular weight of nicotine, 162.23

M_r2 = molecular weight of anhydrous nicotine bitartrate, 462.41 12

Acceptance criteria: 85%-115%

4 PERFORMANCE TESTS

4.1 DRUG RELEASE (724)

4.1.1 Test 1: If the product complies with this test, the labeling indicates that it meets USP Drug Release Test 1

Medium: Phosphoric acid solution (1 in 1000); 250 mL, in a tall-form beaker

Apparatus 7: Proceed as directed in the chapter, using the transdermal system holder-cylinder (see Drug Release (724), Figure 5b).

Sample solution: Center the Transdermal System onto a dry, unused 10-cm x 10-cm piece of Cuprophan dialysis membrane with the adhesive side against the membrane, taking care to eliminate air bubbles between the membrane and the release surface. Attach the membrane to the cylinder using two Parker O-rings, such that one of the borders of the Transdermal System is aligned to the groove and it is wrapped around the cylinder. The filled beakers are weighed and pre-equilibrated to 32.0 ± 0.3°, before immersing the test sample. Reciprocate at a frequency of about 30 cycles/min with an amplitude of 2.0 ± 0.1 cm. At the end of each time interval, transfer the test sample to a fresh beaker containing the appropriate volume of Medium, weighed and pre-equilibrated to 32.0 ± 0.3°. At the end of each release interval, allow the beakers to cool to room temperature, make up for evaporative losses by adding water to obtain the original weight, and mix.

Times: 2, 12, and 24 h

Mobile phase: Transfer 0.2 mL of N,N-dimethyloctylamine to a 1-L volumetric flask, add 220 mL of acetonitrile, and mix. Add 300 mL of water, 0.2 mL of glacial acetic acid, 0.20 g of anhydrous sodium acetate, and 0.55 g of sodium 1-dodecanesulfonate, and dilute with water to volume. Mix for 1 h until clear. [NOTE-Equilibration of the column may take as long as 3 h.]

Standard solution: 0.15 mg/mL of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis (or 0.05 mg/mL of nicotine as free base) in

Medium

System suitability solution: Transfer an amount of USP Nicotine Bitartrate Dihydrate RS equivalent to about 8 mg of nicotine to a 100-mL volumetric flask, and dissolve in 10 mL of acetonitrile. Add 5 mL of 30% Hydrogen peroxide, and allow 15 min to react. Dilute with Medium to volume, and mix. Transfer 20 mL of this solution to a 100-mL volumetric flask, and dilute with Standard solution to volume.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; packing L1

Flow rate: 1 mL/min

Injection volume: 50 µL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 1.1 between nicotine and any degradation peaks

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of nicotine (C₁₀H₁₄N₂) released at the times specified, conform to Acceptance Table 1.

4.1.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Drug Release Test 2

Buffer: 8 g/L of sodium chloride, 0.2 g/L of potassium chloride, 1.7 g/L of dibasic sodium phosphate, and 0.2 g/L of monobasic potassium phosphate in water

Medium: Buffer, 500 mL

Apparatus 6: 50 rpm, double-sided tape being used to attach the Transdermal System to the cylinder

Times: 6 and 24 h

Mobile phase: Acetonitrile, triethylamine, and water (300:1:700)

Standard solution: 0.6 mg/mL of USP Nicotine Bitartrate Dihydrate RS on the anhydrous basis (equivalent to about 0.2 mg/mL of nicotine) in Medium

Sample solution: At each of the test times, withdraw a 2-mL aliquot of the solution under test. Replace the aliquots withdrawn for analysis with fresh portions of Medium.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm x 12.5-cm; packing L1

Flow rate: 1 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of nicotine (C₁₀H₁₄N₂) released at the times specified, conform to Acceptance Table 1.

4.1.3 Test 3: If the product complies with this test, the labeling indicates that it meets USP Drug Release Test 3

Medium: Water: 900 mL

Apparatus 5: 50 rpm, the stainless steel disk assembly being replaced with a 5-cm watch glass for an 11-mg Transdermal System and an 8-cm watch glass for a 22-mg Transdermal System

Times: 1, 2, and 4 h

Standard solution: USP Nicotine Bitartrate Dihydrate RS in water having a known concentration of nicotine similar to that of the Sample solution.

Sample solution: At the specified times, withdraw a suitable volume of the solution under test.

Instrumental conditions

Mode: UV

Analytical wavelength: 259 nm

Blank: Water

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of nicotine (C₁₀H₁₄N₂) released at the times specified, conform to Table 5.

Table 5

4.1.4 Test 4: If the product complies with this test, the labeling indicates that it meets USP Drug Release Test 4

Medium: 0.025 N hydrochloric acid; 600 mL

Apparatus 5: 50 rpm, a convex screen being used to hold the Transdermal System in position during testing

Times: 4 and 16 h.

Standard solution: USP Nicotine Bitartrate Dihydrate RS in water having a known concentration of nicotine similar to that of the Sample solution

Sample solution: At the specified times, withdraw a suitable volume of the solution under test.

Instrumental conditions

Mode: UV

Analytical wavelength: 259 nm

Blank: Water

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 6.

Table 6

The percentages of the labeled amount of nicotine (C₁₀H₁₄N₂) released at the times specified, conform to Acceptance Table 1.

4.1.5 Test 5: If the product complies with this test, the labeling indicates that it meets USP Drug Release Test 5.

Buffer, Medium, and Apparatus 6: Proceed as directed in Test 2.

Times: 3, 6, and 24 h

Mobile phase, Standard solution, Sample solution, Chromatographic system, System suitability, and Analysis: Proceed as directed in Test 2, except to use an Injection volume of 30 µL.

Tolerances: See Table 7.

Table 7

The percentages of the labeled amount of nicotine (CHN) released at the times specified, conform to Acceptance Table 1.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meets the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

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

Diluent: Tetrahydrofuran, methanol, and Solution A (0.5: 4.5:95)

Sensitivity solution: 0.15 µg/mL of USP Nicotine Bitartrate Dihydrate RS (equivalent to about 0.05 µg/mL of nicotine) in Diluent from the Standard solution

System suitability

Samples: System suitability solution and Sensitivity solution

[NOTE-See Table & for the relative retention times. The 1R,2S isomer of nicotine related compound E is a small peak that precedes the 1S,2S isomer, which is the major peak.]

Suitability requirements

Resolution: NLT 3 between nicotine related compound D and nicotine, System suitability solution; NLT 1.2 between the (1R,2S) and (1S,2S) isomers of nicotine related compound E, System suitability solution

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

Analysis

Sample: Sample solution

                         Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_T = sum of all the peak responses from the Sample solution

F = relative response factor (see Table 8)

Acceptance criteria: See Table 8. Disregard peaks that are less than 0.05% of the nicotine peak.

Table 8

^a 3-Pyridine carboxylic acid.

^b Process impurity; controlled in drug substance and not to be included in total impurities.

^c (S)-3-(Pyrrolidin-2-yl)pyridine; also known as nornicotine.

^d (S)-1-Methyl-5-(pyridin-3-yl)pyrrolidin-2-one; also known as cotinine.

^e (S)-3-(Piperidin-2-yl)pyridine; also known as anabasine.

^f (S)-1,2,3,6-Tetrahydro-2,3'-bipyridine; also known as anatabine.

^g 3-(1-Methyl-1H-pyrrol-2-yl)pyridine; also known as nicotyrine.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in the hermetic, light-resistant, unit-dose pouch.

LABELING: The labeling indicates the Drug Release Test with which the product complies.

USP REFERENCE STANDARDS (11)

USP Nicotine Bitartrate Dihydrate RS

C₁₀H₁₄N₂O · C₂H₂O₄         498.44

USP Nicotine Related Compound D. RS

3-(4,5-Dihydro-3H-pyrrol-2-yl)pyridine fumarate;

Also known as Myosmine.

 C₉H₁₀N₂O · C₄H₄O₄       262.26

USP Nicotine Related Compound E.RS

(1RS,2S)-1-Methyl-2-(pyridin-3-yl)pyrrolidine 1-oxide oxalate;

Also known as Nicotine N-oxide.

[NOTE-This may be a mixture of (1R,2S) and (1S,2S) isomers.]

C₁₀H₁₄N₂O · C₂H₂O₄         268.27