Adapalene

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₂₈H₂₈O₃ 412.52

2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo [3.3.1.13,7]dec-1-ylphenyl)-;

6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid. CAS RN®: 106685-40-9; UNII: 1L4806J2QF.

1 DEFINITION

Adapalene contains NLT 98.0% and NMT 102.0% of adapalene (C₂₈H₂₈O₃), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

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

4 Procedure

Mobile phase: Acetonitrile, tetrahydrofuran, trifluoroacetic acid, and water (21:16:0.01:13)

Standard stock solution: 0.2 mg/mL of USP Adapalene RS in Mobile phase. Dissolve USP Adapalene RS in a minimal amount of tetrahydrofuran (about 1%–5% of the final volume), using sonication as needed, and dilute with Mobile phase to volume.

Standard solution: 40 μg/mL of USP Adapalene RS in Mobile phase from the Standard stock solution

Sample stock solution: 0.2 mg/mL of Adapalene in Mobile phase. Dissolve Adapalene in a minimal amount of tetrahydrofuran (about 1%–5% of the final volume), using sonication as needed, and dilute with Mobile phase to volume.

Sample solution: 40 μg/mL of Adapalene in Mobile phase from the Sample stock solution

4.1 Chromatographic system

Mode: LC

Detector: UV 235 nm

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

Flow rate: 1 mL/min

Injection volume: 20 μL

4.2 System suitability

Sample: Standard solution

4.3 Suitability requirements

Relative standard deviation: NMT 1.0%

4.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of adapalene (C H O ) in the portion of Adapalene 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 Adapalene RS in the Standard solution (μg/mL)

C_u = concentration of Adapalene in the Sample solution (μg/mL)

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

5 IMPURITIES

5.1 Residue on Ignition 〈281〉

NMT 0.20%

[Note - On the basis of the synthetic route, perform either Organic Impurities, Procedure 1 or Organic Impurities, Procedure 2.]

5.2 Organic Impurities, Procedure 1

Procedure 1 is recommended if adapalene related compounds A and B may be present.

Mobile phase: Proceed as directed in the Assay.

Standard stock solution: 0.2 mg/mL of USP Adapalene RS, 0.3 mg/mL of USP Adapalene Related Compound A RS, and 0.2 mg/mL of USP Adapalene Related Compound B RS in Mobile phase. Dissolve USP Adapalene RS, USP Adapalene Related Compound A RS, and USP Adapalene Related Compound B RS in a minimal amount of tetrahydrofuran (about 1%–5% of the final volume), using sonication as needed, and dilute with Mobile phase to volume.

Standard solution: 0.2 μg/mL of USP Adapalene RS, 0.3 μg/mL of USP Adapalene Related Compound A RS, and 0.2 μg/mL of USP Adapalene

Related Compound B RS in Mobile phase from the Standard stock solution

Sample solution: 0.2 mg/mL of Adapalene in Mobile phase. Dissolve Adapalene in a minimal amount of tetrahydrofuran (about 1%–5% of the final volume), using sonication as needed, and dilute with Mobile phase to volume.

Chromatographic system: Proceed as directed in the Assay, except use a run time of NLT two times the retention time of adapalene peak for Standard solution and NLT six times the retention time of adapalene peak for Sample solution.

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 3.0% for the adapalene peak

Column efficiency: NLT 3000 theoretical plates for the adapalene peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of adapalene related compounds A and B in the portion of Adapalene taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak area of each impurity from the Sample solution

r_s = peak area of corresponding adapalene related compound A or adapalene related compound B from the Standard solution

C_s = concentration of corresponding USP Adapalene Related Compound A RS or USP Adapalene Related Compound B RS in the Standard solution (mg/mL)

C_u = concentration of Adapalene in the Sample solution (mg/mL)

Calculate the percentage of each unspecified impurity in the portion of Adapalene taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak area of each unspecified impurity from the Sample solution

r_s = peak area of adapalene from the Standard solution

C_s = concentration of USP Adapalene RS in the Standard solution (mg/mL)

C_u = concentration of Adapalene in the Sample solution (mg/mL)

Acceptance criteria: See Table 1. Disregard any impurity peaks less than 0.05%.

Table 1

^a Methyl 6-bromo-2-naphthoate.

^b Methyl 6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoate.

5.3 Organic Impurities, Procedure 2

Procedure 2 is recommended if adapalene related compounds E, C, and D may be present.

Solution A: Glacial acetic acid and water (0.1:100)

Solution B: Acetonitrile and tetrahydrofuran (65:35)

Mobile phase: See Table 2.

Table 2

Diluent: Acetonitrile, tetrahydrofuran, and water (37:20:43)

Standard stock solution: 0.2 mg/mL of USP Adapalene RS in tetrahydrofuran

Standard solution: 2.0 μg/mL of USP Adapalene RS in Diluent from the Standard stock solution

System suitability solution: 0.2 mg/mL of USP Adapalene RS and 1.2 μg/mL each of USP Adapalene Related Compound C RS, USP

Adapalene Related Compound D RS, and USP Adapalene Related Compound E RS prepared by dissolving the standards in tetrahydrofuran equivalent to 50% of the final volume, and diluting with Diluent to volume

Sample solution: 2.0 mg/mL of Adapalene prepared by dissolving in tetrahydrofuran equivalent to 50% of the final volume, and diluting with Diluent to volume

Chromatographic system

Mode: LC

Detector: UV 270 nm

Column: 4.6-mm × 25-cm; 5-μm packing L11 with 7.5% carbon loading

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 25 μL

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 4.5 between the adapalene and adapalene related compound C peaks

Signal-to-noise ratio: NLT 10 for the adapalene related compound C peak

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_u/r_s) × (C_s/C_u) × (1/F) × 100

r_u = peak response of each impurity from the Sample solution

r_s = peak response of adapalene from the Standard solution

C_s = concentration of adapalene in the Standard solution (mg/mL)

C_u = concentration of Adapalene in the Sample solution (mg/mL)

F = relative response factor for each individual impurity (see Table 3)

Acceptance criteria: See Table 3. Disregard any impurity peaks less than 0.05%.

Table 3

^a 2,2’-Binaphthyl-6,6’-dicarboxylic acid.

^b 6-[3-(3-Hydroxyadamant-1-yl)-4-methoxyphenyl]-2-naphthoic acid.

^c 2-(Adamant-1-yl)methoxybenzene.

^d 4,4’-Dimethoxy-3,3’-di(adamant-1-yl)biphenyl.

5.4 Residual Solvent: Limit of Triethylamine

[Note - This test should be performed if triethylamine is used in the manufacturing process.]

Diluent: Dimethyl sulfoxide

Standard solution: 4.0 μg/mL of USP Triethylamine RS in Diluent. Transfer 4.0 mL of this solution to a 20-mL headspace vial, and add 1.0 mL of 1 N NaOH solution.

Sample solution: 50 mg/mL of Adapalene in Diluent. Transfer 4.0 mL of this solution to a 20-mL headspace vial, and add 1.0 mL of 1 N NaOH solution.

Chromatographic system

Mode: GC

Detector: Flame ionization

Column: 30-m × 0.53-mm; 3.0-μm coating of G27

Temperatures

Injection port: 250°

Detector: 300°

Column: See Table 4.

Table 4

Headspace operating parameters

[Note - Headspace operating parameters can be modified in order to optimize the performance.]

Equilibration temperature: 95°

Equilibration time: 15 min

Transfer line temperature: 125°

Pressurization time: 3 min

Carrier gas: Nitrogen

Flow rate: 4.8 mL/min

Injection volume: 1 mL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 15%

Analysis

Samples: Standard solution and Sample solution

Calculate the content, in ppm, of triethylamine in the portion of Adapalene taken:

Result = (r_u/r_s) × (C_s/C_u) × 10⁶

r_ur = peak response of triethylamine from the Sample solution

r_s = peak response of triethylamine from the Standard solution

C_s = concentration of triethylamine in the Standard solution (mg/mL)

C_u = concentration of Adapalene in the Sample solution (mg/mL)

Acceptance criteria: NMT 80 ppm

6 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry a sample at 105° for 4 h.

Acceptance criteria: NMT 0.6%

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers, and store at room temperature.

Labeling: If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.

USP Reference Standards 〈11〉

USP Adapalene RS

USP Adapalene Related Compound A RS

Methyl 6-bromo-2-naphthoate.

C₁₂H₉BrO₂   265.10

USP Adapalene Related Compound B RS

Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate.

C₂₉H₃₀O₃  426.55

USP Adapalene Related Compound C RS

2-(Adamant-1-yl)methoxybenzene.

C₁₇H₂₂O 242.36

USP Adapalene Related Compound D RS

4,4’-Dimethoxy-3,3’-di(adamant-1-yl)biphenyl.

C₃₄H₄₂O2 482.70

USP Adapalene Related Compound E RS

2,2’-Binaphthyl-6,6'-dicarboxylic acid.

C₂₂H₁₄O₄ 342.34

USP Triethylamine RS

Triethylamine.

C₆H₁₅N 101.19