Venlafaxine Hydrochloride
(ven'' la fax' een hye'' droe klor' ide).
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C17H27NO2·HCl 313.86
Cyclohexanol, 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-, hydrochloride;     
(±)-1-[-[(Dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol hydrochloride     [99300-78-4].
DEFINITION
Venlafaxine Hydrochloride contains NLT 98.0% and NMT 102.0% of C17H27NO2·HCl, calculated on the dried basis.
IDENTIFICATION
•  A. Infrared Absorption 197K
[Note—If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the Reference Standard separately in methanol or 2-propanol, evaporate to dryness, and record new spectra of the residues. ]
•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
•  C. Identification Tests—General, Chloride 191: Meets the requirements
ASSAY
•  Procedure
Solution A:  Phosphoric acid and water (1:10)
Buffer:  3.4 g of monobasic potassium phosphate in 700 mL of water. Adjust with Solution A to a pH of 3.0.
Diluent:  Acetonitrile and water (1:1)
Mobile phase:  Acetonitrile and Buffer (3:7)
Standard solution:  0.04 mg/mL of USP Venlafaxine Hydrochloride RS in Diluent
Sample solution:  0.04 mg/mL of Venlafaxine Hydrochloride in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 225 nm
Column:  4.6-mm × 25-cm; 5-µm packing L7
Flow rate:  1.5 mL/min
Column temperature  30 ± 2
Injection size:  20 µL
Run time:  2 times the retention time of the venlafaxine peak
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
Calculate the percentage of C17H27NO2·HCl in the portion of Venlafaxine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of venlafaxine from the Sample solution
rS== peak response of venlafaxine from the Standard solution
CS== concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Venlafaxine Hydrochloride 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%
Organic Impurities 
•  Procedure
Buffer and Mobile phase:  Proceed as directed in the Assay.
System suitability solution:  0.5 mg/mL of USP Venlafaxine Hydrochloride RS and 1.5 µg/mL of USP Venlafaxine Related Compound A RS in Mobile phase
Standard solution:  1 µg/mL of USP Venlafaxine Hydrochloride RS in Mobile phase
Sample solution:  1 mg/mL of Venlafaxine Hydrochloride in Mobile phase
Chromatographic system  
Mode:  LC
Detector:  UV 225 nm
Column:  4.6-mm × 25-cm; 5-µm packing L7
Column temperature:  30 ± 2
Flow rate:  0.7 mL/min
Injection size:  10 µL
Run time:  7 times the retention time of the venlafaxine peak
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 1.5 between venlafaxine and venlafaxine related compound A
Relative standard deviation:  NMT 2.0% for the venlafaxine peak
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Venlafaxine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response of individual impurity from the Sample solution
rS== peak response of venlafaxine from the Standard solution
CS== concentration of USP Venlafaxine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Venlafaxine Hydrochloride in the Sample solution (mg/mL)
F== relative response factor for the corresponding impurity peak (see Impurity Table 1)
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 0.5%
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Descyclohexanol venlafaxinea 0.6 0.8 0.15
Didesmethyl venlafaxineb 0.8 1.0 0.15
Venlafaxine related compound Ac 0.9 1.0 0.15
Venlafaxine 1.0
Deoxy venlafaxined 3.1 0.75 0.15
Any unknown
individual
impurity
1.0 0.10
a  2-(4-Methoxyphenyl)-N,N-dimethylethylamine.
b  1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol.
c  1-(1-(4-Methoxyphenyl)-2-(methylamino)ethyl)cyclohexanol.
d  2-Cyclohexyl-2-(4-methoxyphenyl)-N,N-dimethylethylamine.
SPECIFIC TESTS
•  Loss on Drying 731: Dry a sample in vacuum at 105 for 3 h: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers and store at controlled room temperature.
•  USP Reference Standards 11
USP Venlafaxine Hydrochloride RS Click to View Structure
USP Venlafaxine Related Compound A RS
1-(1-(4-methoxyphenyl)-2-(methylamino)ethyl)cyclohexanol.
    C16H25NO2        263.38
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Topic/Question Contact Expert Committee
Monograph Hariram Ramanathan, M.S.
Associate Scientific Liaison
1-301-816-8313
(SM42010) Monographs - Small Molecules 4
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 5008
Pharmacopeial Forum: Volume No. 35(6) Page 1482