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Analysis
Adapalene Samples: Standard solution and Sample solution
Calculate the percentage of adapalene (C28H28O3) in the
portion of Adapalene taken:

Result = (r U/r S) × (C S/C U) × 100

rU = peak response from the Sample solution

rS = peak response from the Standard solution
CS = concentration of USP Adapalene RS in the
Standard solution (µg/mL)
CU = concentration of Adapalene in the Sample
solution (µg/mL)

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

IMPURITIES
• RESIDUE ON IGNITION á281ñ: NMT 0.20%
[NOTE—On the basis of the synthetic route, perform either
Organic Impurities, Procedure 1 or Organic Impurities,
Procedure 2.]
• ORGANIC IMPURITIES, PROCEDURE 1
C28H28O3 412.52
Procedure 1 is recommended if adapalene related

al
2-Naphthalenecarboxylic acid, 6-(4-methoxy-3-tricyclo compounds A and B may be present.
[3.3.1.13,7]dec-1-ylphenyl)-; Mobile phase: Proceed as directed in the Assay.
6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid. Standard stock solution: 0.2 mg/mL of USP Adapalene RS,
[106685-40-9]. 0.3 mg/mL of USP Adapalene Related Compound A RS, and
DEFINITION
ci 0.2 mg/mL of USP Adapalene Related Compound B RS in
Adapalene contains NLT 98.0% and NMT 102.0% of Mobile phase. Dissolve USP Adapalene RS, USP Adapalene
adapalene (C28H28O3), calculated on the dried basis. Related Compound A RS, and USP Adapalene Related
Compound B RS in a minimal amount of tetrahydrofuran
IDENTIFICATION (about 1%–5% of the final volume), using sonication as
needed, and dilute with Mobile phase to volume.
Change to read:
ffi
Standard solution: 0.2 µg/mL of USP Adapalene RS, 0.3 µg/
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Infrared mL of USP Adapalene Related Compound A RS, and 0.2
Spectroscopy: 197K▲ (CN 1-May-2020) µg/mL of USP Adapalene Related Compound B RS in
• B. The retention time of the major peak of the Sample Mobile phase from the Standard stock solution
solution corresponds to that of the Standard solution, as Sample solution: 0.2 mg/mL of Adapalene in Mobile phase.
obtained in the Assay. Dissolve Adapalene in a minimal amount of tetrahydrofuran
O

(about 1%–5% of the final volume), using sonication as

ASSAY needed, and dilute with Mobile phase to volume.
• PROCEDURE Chromatographic system: Proceed as directed in the
Mobile phase: Acetonitrile, tetrahydrofuran, trifluoroacetic Assay, except use a run time of NLT two times the retention
acid, and water (21: 16: 0.01: 13) time of adapalene peak for Standard solution and NLT six
Standard stock solution: 0.2 mg/mL of USP Adapalene RS times the retention time of adapalene peak for Sample
in Mobile phase. Dissolve USP Adapalene RS in a minimal solution.
amount of tetrahydrofuran (about 1%–5% of the final System suitability
volume), using sonication as needed, and dilute with Sample: Standard solution
Mobile phase to volume. Suitability requirements
Standard solution: 40 µg/mL of USP Adapalene RS in Relative standard deviation: NMT 3.0% for the
Mobile phase from the Standard stock solution adapalene peak
Sample stock solution: 0.2 mg/mL of Adapalene in Column efficiency: NLT 3000 theoretical plates for the
Mobile phase. Dissolve Adapalene in a minimal amount of adapalene peak
tetrahydrofuran (about 1%–5% of the final volume), using Analysis
sonication as needed, and dilute with Mobile phase to Samples: Standard solution and Sample solution
volume. Calculate the percentage of adapalene related
Sample solution: 40 µg/mL of Adapalene in Mobile phase compounds A and B in the portion of Adapalene taken:
from the Sample stock solution
Chromatographic system Result = (r U/r S) × (C S/C U) × 100
(See Chromatography á621ñ, System Suitability.)
Mode: LC rU = peak area of each impurity from the Sample
Detector: UV 235 nm solution
Column: 4.6-mm × 25-cm; 5-µm packing L1 rS = peak area of corresponding adapalene related
Flow rate: 1 mL/min compound A or adapalene related compound B
Injection volume: 20 µL from the Standard solution
System suitability CS = concentration of corresponding USP Adapalene
Sample: Standard solution Related Compound A RS or USP Adapalene
Suitability requirements Related Compound B RS in the Standard solution
Relative standard deviation: NMT 1.0% (mg/mL)

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CU = concentration of Adapalene in the Sample Sample solution: 2.0 mg/mL of Adapalene prepared by
solution (mg/mL) dissolving in tetrahydrofuran equivalent to 50% of the final
volume, and diluting with Diluent to volume
Calculate the percentage of each unspecified impurity in Chromatographic system
the portion of Adapalene taken: (See Chromatography á621ñ, System Suitability.)
Mode: LC
Result = (r U/r S) × (C S/C U) × 100 Detector: UV 270 nm
Column: 4.6-mm × 25-cm; 5-µm packing L11 with 7.5%
rU = peak area of each unspecified impurity from the carbon loading
Sample solution Column temperature: 30°
rS = peak area of adapalene from the Standard solution Flow rate: 1.2 mL/min
CS = concentration of USP Adapalene RS in the Injection volume: 25 µL
Standard solution (mg/mL) System suitability
CU = concentration of Adapalene in the Sample Sample: System suitability solution
solution (mg/mL) Suitability requirements
Resolution: NLT 4.5 between the adapalene and
Acceptance criteria: See Table 1. Disregard any impurity adapalene related compound C peaks
peaks less than 0.05%. Signal-to-noise ratio: NLT 10 for the adapalene related
compound C peak
Table 1 Analysis
Relative Acceptance Samples: Standard solution and Sample solution
Retention Criteria, Calculate the percentage of each impurity in the portion of
Name Time NMT (%)

al
Adapalene taken:
Adapalene related compound Aa 0.52 0.10
Result = (r U/r S) × (C S/C U) × (1/F) × 100
Adapalene 1.0 —

Adapalene related compound Bb 1.57 0.10 rU = peak response of each impurity from the Sample
solution
Any individual unspecified impurity

Total impurities
—

—
ci
0.10

0.50
rS

CS
= peak response of adapalene from the Standard
solution
= concentration of adapalene in the Standard
a Methyl 6-bromo-2-naphthoate. solution (mg/mL)
b Methyl 6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoate. CU = concentration of Adapalene in the Sample
ffi
solution (mg/mL)
• ORGANIC IMPURITIES, PROCEDURE 2 F = relative response factor for each individual
Procedure 2 is recommended if adapalene related impurity (see Table 3)
compounds E, C, and D may be present.
Solution A: Glacial acetic acid and water (0.1: 100) Acceptance criteria: See Table 3. Disregard any impurity
Solution B: Acetonitrile and tetrahydrofuran (65:35) peaks less than 0.05%.
O

Mobile phase: See Table 2.

Table 3
Table 2 Relative Relative Acceptance
Time Solution A Solution B Retention Response Criteria,
(min) (%) (%) Name Time Factor NMT (%)

0 50 50 Adapalene related com-

pound Ea 0.3 1.4 0.3
2.5 50 50 b
Hydroxyadapalene 0.5 0.91 0.1
40 28 72
Adapalene related com-
42 28 72 pound Cc 0.9 0.14 0.1

42.1 50 50 Adapalene 1.0 — —

50 50 50 Adapalene related com-

pound Dd 1.9 0.71 0.2

Diluent: Acetonitrile, tetrahydrofuran, and water Any individual unspeci-

—
(37:20:43) fied impurity 1.0 0.1
Standard stock solution: 0.2 mg/mL of USP Adapalene RS Total impurities — — 0.5
in tetrahydrofuran
Standard solution: 2.0 µg/mL of USP Adapalene RS in a 2,2’-Binaphthyl-6,6’-dicarboxylic acid.
b 6-[3-(3-Hydroxyadamant-1-yl)-4-methoxyphenyl]-2-naphthoic acid.
Diluent from the Standard stock solution
c 2-(Adamant-1-yl)methoxybenzene.
System suitability solution: 0.2 mg/mL of USP
d 4,4’-Dimethoxy-3,3’-di(adamant-1-yl)biphenyl.
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 • RESIDUAL SOLVENT: LIMIT OF TRIETHYLAMINE
Compound E RS prepared by dissolving the standards in [NOTE—This test should be performed if triethylamine is
tetrahydrofuran equivalent to 50% of the final volume, and used in the manufacturing process.]
diluting with Diluent to volume Diluent: Dimethyl sulfoxide

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Standard solution: 4.0 µg/mL of USP Triethylamine RS in rS = peak response of triethylamine from the Standard
Diluent. Transfer 4.0 mL of this solution to a 20-mL solution
headspace vial, and add 1.0 mL of 1 N NaOH solution. CS = concentration of triethylamine in the Standard
Sample solution: 50 mg/mL of Adapalene in Diluent. solution (mg/mL)
Transfer 4.0 mL of this solution to a 20-mL headspace vial, CU = concentration of Adapalene in the Sample
and add 1.0 mL of 1 N NaOH solution. solution (mg/mL)
Chromatographic system
(See Chromatography á621ñ, System Suitability.) Acceptance criteria: NMT 80 ppm
Mode: GC
Detector: Flame ionization SPECIFIC TESTS
Column: 30-m × 0.53-mm; 3.0-µm coating of G27 • LOSS ON DRYING á731ñ
Temperatures Analysis: Dry a sample at 105° for 4 h.
Injection port: 250° Acceptance criteria: NMT 0.6%
Detector: 300° ADDITIONAL REQUIREMENTS
Column: See Table 4. • PACKAGING AND STORAGE: Preserve in tight, light-resistant
containers, and store at room temperature.
Table 4 • LABELING: If a test for Organic Impurities other than
Hold Time at Fi- Procedure 1 is used, the labeling states the test with which
Initial Temperature Final nal the article complies.
Temperature Ramp Temperature Temperature • USP REFERENCE STANDARDS á11ñ
(°) (°/min) (°) (min)
USP Adapalene RS
40 0 40 5 USP Adapalene Related Compound A RS

al
40 40 240 5
Methyl 6-bromo-2-naphthoate.
C12H9BrO2 265.10
USP Adapalene Related Compound B RS
Headspace operating parameters Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-
[NOTE—Headspace operating parameters can be naphthoate.
modified in order to optimize the performance.] C29H30O3 426.55
Equilibration temperature: 95°
Equilibration time: 15 min
Transfer line temperature: 125°
ci USP Adapalene Related Compound C RS
2-(Adamant-1-yl)methoxybenzene.
C17H22O 242.36
Pressurization time: 3 min
USP Adapalene Related Compound D RS
Carrier gas: Nitrogen 4,4’-Dimethoxy-3,3’-di(adamant-1-yl)biphenyl.
ffi
Flow rate: 4.8 mL/min C34H42O2 482.70
Injection volume: 1 mL
System suitability USP Adapalene Related Compound E RS
Sample: Standard solution 2,2’-Binaphthyl-6,6’-dicarboxylic acid.
Suitability requirements C22H14O4 342.34
Relative standard deviation: NMT 15% USP Triethylamine RS
O

Analysis Triethylamine.
Samples: Standard solution and Sample solution C6H15N 101.19
Calculate the content, in ppm, of triethylamine in the
portion of Adapalene taken:

Result = (r U/r S) × (C S/C U) × 106

rU = peak response of triethylamine from the Sample

solution

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