Interim Revision AnnouncementOfficial January 1, 2017 Acitretin 1

. [NOTE—Exposure to the fluorescent light allows for theformation of two degradation products: acitretin re-Acitretin Capsules lated compound A and 6Z-isomer •.((2E,4E,6Z,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-DEFINITION dimethylnona-2,4,6,8-tetraenoic acid).• (IRA 1-Jan-2017)]Acitretin Capsules contain NLT 90.0% and NMT 110.0% of Sample solution: Nominally 0.1 mg/mL of acitretin inthe labeled amount of acitretin (C21H26O3). a mixture of Diluent and water (23:2). Open NLT 20[CAUTION—Acitretin is a teratogen. Great care should be Capsules, composite the Capsule fill, and mix well.taken when handling to avoid inhalation of dust or con- Transfer the Capsule fill to a volumetric flask, add watertact with skin.] equivalent to 8% of the final volume to wet the sam-[NOTE—Use low-actinic glassware and perform all tests ple, and sonicate for 5 min. Dilute with Diluent to vol-under yellow and subdued light. Make all injections ume, and sonicate for 5 min. Cool to room tempera-within 1 h of the Sample solution preparation.] ture, pass the suspension through a suitable filter of

0.5-µm pore size, and use the clear filtrate. [NOTE—IDENTIFICATIONInject the Sample solution within 1 h of preparation.]

Chromatographic systemDelete the following: (See Chromatography 〈621〉, System Suitability.)

Mode: LC•

.• A. THIN-LAYER CHROMATOGRAPHIC IDENTIFICATION TEST Detector: UV 365 nm. •.For Identification B, use a di-〈201〉 ode array detector in the range of 200–400 nm.• (IRA 1-Standard solution: 10 mg/mL of USP Acitretin RS in Jan-2017)tetrahydrofuran Column: 4.6-mm × 15-cm; 5-µm packing L1

Sample solution: Equivalent to 20 mg of acitretin from Flow rate: 1 mL/minCapsules. Grind to a fine powder, then triturate for 30 Injection volume: 25 µLs with 2 mL of tetrahydrofuran. Transfer the suspension System suitabilityto a 12-mL conical centrifuge tube, and centrifuge to Samples: Standard solution and System suitabilityobtain a clear supernatant. solution

Application volume: 10 µL •.[NOTE—The relative retention times for acitretin re-Developing solvent system: Chloroform and metha- lated compound A (2Z-isomer), acitretin, and the 6Z-nol (4:1) isomer are 0.84, 1.0, and 1.09, respectively.]• (IRA 1-Jan-

Analysis 2017)Samples: Standard solution and Sample solution Suitability requirementsProceed as directed in the chapter, and then air-dry. Resolution: NLT 3.0 between acitretin related com-Spray the plate with a saturated solution of antimony pound A and acitretin; NLT 1.8 between the 6Z-iso-trichloride in chloroform (250 mg/mL) followed by mer and acitretin, System suitability solutionconcentrated sulfuric acid, and then locate the spots. Relative standard deviation: NMT 2.0%, Standard• (IRA 1-Jan-2017) solution

AnalysisSamples: Standard solution and Sample solutionAdd the following: Calculate the percentage of the labeled amount of aci-tretin (C21H26O3) in the portion of Capsules taken:•

.• A. The retention time of the major peak of the Samplesolution corresponds to that of the Standard solution, as Result = (rU/rS) × (CS/CU) × 100obtained in the Assay.• (IRA 1-Jan-2017)

rU = peak response of acitretin from the SamplesolutionAdd the following: rS = peak response of acitretin from the Standardsolution•

.• B. The UV spectrum of the major peak of the Sample CS = concentration of USP Acitretin RS in thesolution corresponds to that of the Standard solution, as Standard solution (mg/mL)obtained in the Assay.• (IRA 1-Jan-2017) CU = nominal concentration of acitretin in theSample solution (mg/mL)ASSAY

Acceptance criteria: 90.0%–110.0%

PERFORMANCE TESTSChange to read:

• PROCEDURE Change to read:Diluent: Methanol and tetrahydrofuran (13:10)Mobile phase: Methanol, alcohol, glacial acetic acid, • DISSOLUTION 〈711〉and water (74: 5: 0.5: 21) Test 1Standard solution: 0.1 mg/mL of USP Acitretin RS in a Medium: 3% sodium lauryl sulfate in deaeratedmixture of Diluent and water (23:2). Dissolve USP Aci- water, pH 9.6–10.0; 900 mLtretin RS in Diluent equivalent to 80% of the final vol- Apparatus 1: 100 rpmume, sonicate for 5 min, add water equivalent to 8% Time: 30 minof the final volume, and dilute with Diluent to volume. Determine the amount of acitretin (C21H26O3) dissolvedSystem suitability solution: Transfer 2 mL of the Stan- using the following method.dard solution to a clear 4-mL glass vial. After sealing the Standard solution: Transfer about 14 mg of USP Aci-vial with a Teflon-lined silicone septum and cap, place tretin RS to a 500-mL volumetric flask. Dissolve inthe vial on its side in a light chamber, expose it to 400 50 mL of alcohol, and dilute with Medium to volume.foot-candles of fluorescent light for 5 min, and thencompletely wrap the vial with aluminum foil.

2016 The United States Pharmacopeial Convention All Rights Reserved.

C168530-M854-CHM32015, Rev. 0 20161118

Interim Revision Announcement2 Acitretin Official January 1, 2017

For Capsules labeled to contain 10 mg: Transfer Dissolution procedure: Perform the test using the20 mL of this solution to a 50-mL volumetric flask, conditions under Tier 1. In the presence of cross-link-and dilute with Medium to volume. ing repeat the test with new Capsules using the con-

Sample solution: Use portions of the solution under ditions under Tier 2 as follows. After •.15• (IRA 1-Jan-2017)test passed through a suitable filter of 0.45-µm pore min, stop the dissolution bath and timer (do not liftsize. the baskets), and add 450 mL of Medium B pre-equili-

Capsule shell solution: Dissolve 6 clean empty-shell brated at 37 ± 0.5°. Restart the timer and bath, andCapsules in 900 mL of Medium. after 5 min check the pH of the medium and adjust

Instrumental conditions with 1% sodium hydroxide to a range of 9.6–10.0.Mode: UV Continue dissolution for an additional •.10• (IRA 1-Jan-2017)Analytical wavelength: 347 nm min.Cell: 2 mm Chromatographic systemBlank: Medium (See Chromatography 〈621〉, System Suitability.)

Analysis Mode: LCSamples: Standard solution, Sample solution, and Detector: 360 nmCapsule shell solution Columns

Calculate the percentage of the labeled amount of Guard: 4-mm × 1-cm; 5-µm packing L1acitretin (C21H26O3) dissolved: Analytical: 4.6-mm × 5-cm; 5-µm packing L1

TemperaturesResult = [(AU − ACS)/AS] × (CS/L) × V × 100 Autosampler: 40°

Column: 35°AU = absorbance of the Sample solution Flow rate: 2.0 mL/minACS = Capsule shell correction, calculated as shown Injection volume: 10 µL

below System suitabilityAS = absorbance of the Standard solution Sample: Standard solutionCS = concentration of the appropriate Standard Suitability requirements

solution (mg/mL) Tailing factor: NMT 2.0L = label claim (mg/Capsule) Relative standard deviation: NMT 2.0%V = volume of Medium, 900 mL AnalysisThe Capsule shell correction, ACS, is calculated: Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount ofACS = ACSS/N acitretin (C21H26O3) dissolved:

ACSS = absorbance of the Capsule shell solution Result = (rU/rS) × (CS/L) × V × 100N = number of Capsule shells used to prepare theCapsule shell solution rU = peak response of acitretin from the Sample

Tolerances: NLT 85% (Q) of the labeled amount of solutionacitretin (C21H26O3) is dissolved. rS = peak response of acitretin from the Standard

Test 2: If the product complies with this test, the label- solutioning indicates that the product meets USP Dissolution CS = concentration of USP Acitretin RS in theTest 2. Standard solution (mg/mL)Tier 1 L = label claim (mg/Capsule)Medium: 3% sodium lauryl sulfate in deaerated V = volume of Medium, 900 mLwater, pH 9.6–10.0 (adjusted with 1 N sodium hy- Tolerances: NLT 85% (Q) of the labeled amount ofdroxide); 900 mL acitretin (C21H26O3) is dissolved.

Apparatus 1: 100 rpm • UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet theTime: 30 min requirements

Tier 2Medium A: Prepare a solution containing pancreatin IMPURITIESwith NMT •.2000• (IRA 1-Jan-2017) USP Units/L of prote-ase activity in deaerated water, pH 8.0 (adjusted Change to read:with 1% sodium hydroxide); 450 mL. Useimmediately.

• ORGANIC IMPURITIES: LIMIT OF DEGRADATION PRODUCTSMedium B: 6% sodium lauryl sulfate in deaeratedDiluent, Mobile phase, System suitability solution,water, pH 10.5 (adjusted with 1% sodium hydrox-Sample solution, Chromatographic system, and Sys-ide); 450 mLtem suitability: Proceed as directed in the Assay.Apparatus 1: 100 rpm

AnalysisTime: •.15• (IRA 1-Jan-2017) min, Medium A; •.15• (IRA 1-Jan- Sample: Sample solution2017) min, Medium A with the addition of Medium B Calculate the percentage of each degradation productDetermine the amount of acitretin (C21H26O3) dissolved in the portion of Capsules taken:using the following method.Mobile phase: Methanol, water, and glacial acetic Result = (rU/rT) × 100acid (750:250:1)Standard stock solution: 280 µg/mL of USP Acitretin rU = peak response of each individual impurityRS in absolute alcohol. Use sonication to dissolve. from the Sample solutionStandard solution: 20 µg/mL of USP Acitretin RS in rT = sum of the responses of all the peaks from theMedium under Tier 1, from Standard stock solution Sample solutionSample solution: Pass a portion of the solution under Acceptance criteria: See Table 1.test through a suitable glass filter with 1-µm poresize, discard the first few mL, and use the filtrate foranalysis.

2016 The United States Pharmacopeial Convention All Rights Reserved.

C168530-M854-CHM32015, Rev. 0 20161118

Interim Revision AnnouncementOfficial January 1, 2017 Acitretin 3

Table 1 • LABELING: When more than one Dissolution test is given,the labeling states the test used only if Test 1 is notRelative Acceptance used.Retention Criteria, • USP REFERENCE STANDARDS 〈11〉Name Time NMT (%) USP Acitretin RS

Acitretin relatedcompound A(2Z-isomer)a. 0.84 0.5

Acitretin 1.0 —•

.• (IRA 1-Jan-2017) •.• (IRA 1-Jan-2017) •.• (IRA 1-Jan-2017)Any unspecified

—impurity 0.4

Total unspecified—

impurities 0.8a

.(2Z,4E,6E,8E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid (C21H26O3 326.43).•

.• (IRA 1-Jan-2017)ADDITIONAL REQUIREMENTS• PACKAGING AND STORAGE: Preserve in well-closed, light-

resistant containers.

2016 The United States Pharmacopeial Convention All Rights Reserved.

C168530-M854-CHM32015, Rev. 0 20161118