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Dutasteride
(doo tas' ter ide).
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C27H30F6N2O2 528.53
(5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide;    
,,,',','-Hexafluoro-3-oxo-4-aza-5-androst-1-ene-17-carboxy-2',5'-xylidide     [164656-23-9].
DEFINITION
Dutasteride contains NLT 97.0% and NMT 102.0% of dutasteride (C27H30F6N2O2), calculated on the anhydrous and solvent-free basis.
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
Diluent:  Acetonitrile and water (60:40)
Mobile phase:  Acetonitrile, water, and trifluoroacetic acid (52: 48: 0.025)
System suitability solution:  0.5 mg/mL of USP Dutasteride Resolution Mixture RS in Diluent. Sonicate to dissolve.
Standard solution:  0.5 mg/mL of USP Dutasteride RS in Diluent. Sonicate to dissolve.
Sample solution:  0.5 mg/mL of Dutasteride in Diluent. Sonicate to dissolve.
Chromatographic system 
(See Chromatography 621, System Suitability.)
Mode:  LC
Detector:  UV 220 nm
Column:  4.6-mm × 25-cm; 5-µm packing L1
Column temperature:  35
Flow rate:  1 mL/min
Injection volume:  10 µL
Run time:  1.5 times the retention time of dutasteride
System suitability 
Samples:  System suitability solution and Standard solution
[Note—See Table 3 for the relative retention times. ]
Suitability requirements 
Resolution:  NLT 1.5 between dutasteride 17-epimer and dutasteride, System Suitability solution
Relative standard deviation:  NMT 1.5%, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of dutasteride (C27H30F6N2O2) in the portion of Dutasteride 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 Dutasteride RS in the Standard solution (mg/mL)
CU== concentration of Dutasteride in the Sample solution (mg/mL)
Acceptance criteria:  97.0%–102.0% on the anhydrous and solvent-free basis
IMPURITIES
•  Residue on Ignition 281: NMT 0.1%
•  Limit of Platinum
[Note—Perform this test only if platinum is a known inorganic impurity of the manufacturing process. ]
Diluent:  Hydrochloric acid and dimethylsulfoxide (2:98). Prepare in a plastic volumetric flask.
Standard stock solution:  10 µg/mL of platinum in Diluent. Prepare by diluting (1:100) a 1000-µg/mL commercially available platinum standard.
Standard solution 1:  1.0 µg/mL of platinum in Diluent from the Standard stock solution
Standard solution 2:  0.1 µg/mL of platinum in Diluent from Standard solution 1
Sample solution:  0.01 g/mL of Dutasteride in Diluent. Sonicate to dissolve.
Instrumental conditions 
(See Plasma Spectrochemistry 730.)
Mode:  ICP–OES
Analytical wavelength:  306.471 nm
Spectrophotometer system:  Use an inductively coupled plasma–optical emission spectrophotometric system, and construct a calibration curve using the response from the Diluent, Standard solution 1, and Standard solution 2.
System suitability 
Samples:  Diluent, Standard solution 1, and Standard solution 2
Suitability requirements 
Limit of quantitation:  3 µg/g for platinum. Use the standard deviation, in µg/mL, of the platinum concentration obtained from the Diluent. Calculate the limit of quantitation from the Diluent:
Result = 10 × (SD/Cs)

SD== standard deviation of platinum from the Diluent (µg/mL)
CS== nominal concentration of platinum in the Sample solution (g/mL)
Correlation coefficient:  NLT 0.99 from the Diluent, Standard solution 1, and Standard solution 2
Analysis 
Samples:  Diluent, Standard solution 1, Standard solution 2, and Sample solution
Plot the responses of the Diluent, Standard solution 1, and Standard solution 2 versus their content (0, 0.1, and 1.0 µg/mL) of platinum. Determine the concentration, in µg/mL, of platinum in the Sample solution from the calibration curve.
Calculate the concentration, in µg/g, of platinum in the portion of Dutasteride taken:
Result = CS/CU

CS== concentration of platinum in the Sample solution (µg/mL)
CU== concentration of Dutasteride in the Sample solution (g/mL)
Acceptance criteria:  NMT 5 µg/g
•  Limit of Residual Solvents
Standard stock solution:  5 mg/mL each of acetonitrile, ethyl acetate, pyridine, toluene, dioxane, and n-heptane in dimethyl sulfoxide
Standard solution:  10 µg/mL each of acetonitrile, ethyl acetate, pyridine, toluene, dioxane, and n-heptane in dimethyl sulfoxide from the Standard stock solution
Sample solution:  10 mg/mL of Dutasteride in dimethyl sulfoxide
Chromatographic system 
(See Chromatography 621, System Suitability.)
Mode:  GC
Detector:  Flame ionization
Column:  0.32-mm × 30-m capillary column coated with 5-µm film of G1
Temperatures 
Column:  See Table 1.
Table 1
Initial
Temperature
() 		Temperature
Ramp
(/min) 		Final
Temperature
() 		Hold Time at Final
Temperature
(min)
50 — 50 3
50 10 200 2
Injection port:  180
Detector:  260
Carrier gas:  Helium
Flow rate:  Head pressure at 12 psi
Split flow:  10 mL/min
Septum purge:  2 mL/min
Injector type:  Headspace
Sample volume:  2 mL
Sample temperature:  85
Equilibration time:  1 min
Thermostating time:  15 min
Needle temperature:  100
Transfer line temperature:  110
System suitability 
Sample:  Standard solution
Suitability requirements 
Resolution:  NLT 1.2 between the n-heptane and dioxane peaks
Relative standard deviation:  NMT 5% for each solvent
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each solvent in the portion of Dutasteride taken:
Result = (rU/rS) × (CS/CU) × 100

rU== peak response for each solvent from the Sample solution
rS== peak response for each solvent from the Standard solution
CS== concentration of each solvent in the Standard solution (mg/mL)
CU== concentration of Dutasteride in the Sample solution (mg/mL)
Acceptance criteria:  See Table 2.
Table 2
Name Relative
Retention
Time 		Acceptance
Criteria,
NMT (%)
Acetonitrile 0.30 0.3
Ethyl acetate 0.60 0.2
Dioxane 0.83 0.1
n-Heptane 0.85 0.5
Pyridine 0.92 0.2
Toluene 1.0 0.2
•  Organic Impurities, Procedure 1
Diluent, Mobile phase, System suitability solution, Standard solution, Sample solution, and Chromatographic system:  Proceed as directed in the Assay.
System suitability 
Sample:  System suitability solution
[Note—See Table 3 for the relative retention times. ]
Suitability requirements 
Resolution:  NLT 1.5 between dutasteride 17-epimer and dutasteride
Analysis 
Sample:  Sample solution
Calculate the percentage of each impurity in the portion of Dutasteride taken:
Result = (rU/rT) × (1/F) × 100

rU== peak area for each impurity from the Sample solution
rT== total peak area from the Sample solution
F== relative response factor (see Table 3)
Acceptance criteria:  See Table 3.
Table 3
Name Relative
Retention
Time 		Relative
Response
Factor 		Acceptance
Criteria,
NMT (%)
Dutasteride acida 0.10 1.0 0.2
Dutasteride
dimethylamideb 		0.11 1.4 0.2
Dutasteride methyl
esterc 		0.28 1.0 0.15
Dutasteride ethyl
esterd 		0.39 1.0 0.2
Dutasteride 17-5-enee 0.90 1.0 0.2
Dutasteride 17-epimerf 0.93 1.0 0.3
Dutasteride 1.00 — —
Chlorodutasterideg 1.15 0.33 0.4
Dihydrodutasterideh 1.19 1.0 0.15
Dutasteride 5-enei 1.20 1.0 0.3
Any other individual impurity — — 0.1
a  (5,17)-3-Oxo-4-azaandrost-1-ene-17-carboxylic acid.
b  (5,17)-N,N-Dimethyl-3-oxo-4-azaandrost-1-ene-17-carboxamide.
c  Methyl (5,17)-3-oxo-4-azaandrost-1-ene-17-carboxylate.
d  Ethyl (5,17)-3-oxo-4-azaandrost-1-ene-17-carboxylate.
e  (17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1,5(6)-diene-17-carboxamide.
f  (5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide.
g  (1,5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-1-chloro-3-oxo-4-azaandrostane-17-carboxamide.
h  (5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-17-carboxamide.
i  (17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1,5(6)-diene-17-carboxamide.
•  Organic Impurities, Procedure 2
Diluent:  Acetonitrile and water (60:40)
Mobile phase:  Acetonitrile and water (80:20)
System suitability solution:  0.5 mg/mL of USP Dutasteride Resolution Mixture RS in Diluent. Sonicate to dissolve.
Sample solution:  0.5 mg/mL of Dutasteride in Diluent. Sonicate to dissolve.
Chromatographic system 
(See Chromatography 621, System Suitability.)
Mode:  LC
Detector:  UV 220 nm
Column:  4.6-mm × 15-cm; 5-µm packing L11
Flow rate:  1 mL/min
Injection volume:  10 µL
Run time:  5 times the retention time of dutasteride
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 2.0 between the dutasteride -dimer and dutasteride -dimer peaks
Analysis 
Sample:  Sample solution
Integrate the dutasteride peak and all drug-related peaks eluting after the dutasteride peak.
Calculate the percentage of each impurity in the portion of Dutasteride taken:
Result = (rU/rT) × 100

rU== peak area for each impurity from the Sample solution
rT== total peak area from the Sample solution
Acceptance criteria:  See Table 4.
Table 4
Name Relative
Retention
Time 		Acceptance
Criteria,
NMT (%)
Dutasteride 1.0 —
Dutasteride -dimera 3.7 0.3
Dutasteride -dimerb 4.3 0.5
Any other individual impurity — 0.1
Total impuritiesc — 2.0
a  {[(5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide-]4-yl}{[(5,17)-3-oxo-4-azaandrost-1-ene]-17-yl}methanone.
b  {[(5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide-]4-yl}{[(5,17)-3-oxo-4-azaandrost-1-ene]-17-yl}methanone.
c  Sum of impurities from Tables 3 and Table 4.
SPECIFIC TESTS
•  Water Determination, Method Ic 921
Sample:  100 mg
Analysis:  Heat at 180 for 4 min.
Acceptance criteria:  NMT 0.50%
•  Optical Rotation, Specific Rotation 781S
Sample solution:  10 mg/mL in chloroform and alcohol (98:2)
Acceptance criteria:  +15.0 to +25.0
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, and store below 30.
•  USP Reference Standards 11
USP Dutasteride RS Click to View Structure
USP Dutasteride Resolution Mixture RS Click to View Structure
The mixture contains the following impurities (other impurities may also be present):
Dutasteride 17-epimer: (5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide.
    C27H30F6N2O2         528.53
Dutasteride -dimer: {[(5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide-]4-yl}{[(5,17)-3-oxo-4-azaandrost-1-ene]-17-yl}methanone.
    C46H55F6N3O4         827.94
Dutasteride -dimer: {[(5,17)-N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide-]4-yl}{[(5,17)-3-oxo-4-azaandrost-1-ene]-17-yl}methanone.
    C46H55F6N3O4         827.94
USP38
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Monograph Domenick Vicchio, Ph.D.
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USP38–NF33 Page 3247
Pharmacopeial Forum: Volume No. 39(2)