Acitretin
(a'' si tre' tin).
Click to View Image

C21H26O3 326.43
2,4,6,8-Nonatetraenoic acid, 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-, (all-E)-;    
(all-E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid     [55079-83-9].
DEFINITION
Acitretin contains NLT 98.0% and NMT 102.0% of C21H26O3, calculated on the dried basis.
[Caution—Acitretin is a teratogen. Great care should be taken when handling to avoid inhalation of dust or contact with skin. ]
[Note—Use low-actinic glassware and perform all tests under yellow and subdued light. ]
IDENTIFICATION
•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
[Note—Store the solutions at 4 before injection. ]
Mobile phase:  Alcohol, glacial acetic acid, and water (92:0.3:8)
System suitability stock solution:  0.01 mg/mL each of USP Acitretin RS and USP Tretinoin RS in alcohol. [Note—Dissolve in tetrahydrofuran before diluting with alcohol. ]
System suitability solution:  0.25 µg/mL each of USP Acitretin RS and USP Tretinoin RS in alcohol, from System suitability stock solution
Standard solution:  0.1 mg/mL of USP Acitretin RS in alcohol. [Note—Dissolve in tetrahydrofuran before diluting with alcohol. The final concentration of tetrahydrofuran in the preparation will be 2%. ]
Sample stock solution:  0.25 mg/mL of Acitretin in tetrahydrofuran and alcohol (1:19). [Note—Dissolve in tetrahydrofuran before diluting with alcohol. ]
Sample solution:  0.1 mg/mL of Acitretin in alcohol, from Sample stock solution
Chromatographic system 
Mode:  LC
Detector:  UV 360 nm
Column:  4-mm × 25-cm; packing L1
Flow rate:  0.6 mL/min
Injection size:  10 µL
System suitability 
Samples:  System suitability solution and Standard solution
[Note—The relative retention times for tretinoin and acitretin are 0.84 and 1.0, respectively. ]
Suitability requirements 
Resolution:  NLT 2.0 between tretinoin and acitretin, System suitability solution
Relative standard deviation:  NMT 1.0% of acitretin, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C21H26O3 in the portion of Acitretin taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Acitretin RS in the Standard solution (mg/mL)
CU== concentration of Acitretin in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the dried basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 20 ppm
Organic Impurities 
[Note—Store the solutions at 4 before injection. ]
•  Procedure
Mobile phase and Chromatographic system:  Proceed as directed in the Assay.
Standard solution:  0.8 µg/mL each of USP Acitretin RS, USP Acitretin Related Compound A RS, and USP Acitretin Related Compound B RS in alcohol. [Note—Dissolve in tetrahydrofuran before diluting with alcohol. ]
Sample solution:  0.25 mg/mL of Acitretin in tetrahydrofuran and alcohol (1:19). [Note—Dissolve in tetrahydrofuran before diluting with alcohol. ]
System suitability  
Sample:  Standard solution
Suitability requirements 
Resolution:  NLT 1.5 between acitretin related compound A and acitretin; NLT 1.5 between acitretin related compound B and acitretin
Relative standard deviation:  NMT 10.0% for acitretin related compound A and NMT 10.0% for acitretin related compound B
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of acitretin related compound A and acitretin related compound B in the portion of Acitretin taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the relevant impurity from the Sample solution
rS== peak response from the relevant impurity from the Standard solution
CS== concentration of USP Acitretin Related Compound A RS or USP Acitretin Related Compound B RS in the Standard solution (µg/mL)
CU== concentration of Acitretin in the Sample solution (µg/mL)
Calculate the percentage of impurities other than acitretin related compounds A and B in the portion of Acitretin taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of each individual unspecified impurity from the Sample solution
rS== peak response of USP Acitretin RS in the Standard solution
CS== concentration of USP Acitretin RS in the Standard solution (µg/mL)
CU== concentration of Acitretin in the Sample solution (µg/mL)
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 1.0%
Impurity Table 1
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Acitretin related compound A 0.78 0.3
Acitretin 1.0
Acitretin related compound B 1.61 0.3
Any unspecified impurity 0.1
Total unspecified impurities 0.4
SPECIFIC TESTS
•  Loss on Drying 731: Dry a sample in a vacuum at a pressure not exceeding 19 mm of mercury at 100 for 4 h: it loses NMT 0.2% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, protected from light. Store at controlled room temperature.
•  USP Reference Standards 11
USP Acitretin RS Click to View Structure
USP Acitretin Related Compound A RS
(2Z,4E,6E,8E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid.
    C21H26O3        326.43
USP Acitretin Related Compound B RS
Ethyl (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate.
    C23H30O3         354.48
USP Tretinoin RS Click to View Structure
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Pharmacopeial Forum: Volume No. 35(5) Page 1102