Drospirenone
(droe spye' re none).
Click to View Image

C24H30O3 366.49
(6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3¢,4¢,6,6a,7,8,9,10, 11,12,13,14,15,15a,16-Hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene-17,2¢(5¢H)-furan]-3,5¢(2H)-dione;    
17-Hydroxy-6,7:15,16-dimethylene-3-oxo-17 -pregn-4-ene-21-carboxylic acid, -lactone     [67392-87-4].
DEFINITION
Drospirenone contains NLT 98.0% and NMT 102.0% of C24H30O3, 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
Change to read:
•  Procedure
Solution A:  Water
Solution B:  Acetonitrile
Mobile phase:  See Table 1.
Table 1
Time
(min)
Solution A
(%)
Solution B
(%)
0 63 37
2.0 63 37
16.0 52 48
23.0 52 48
31.0 20 80
39.0 20 80
39.1 63 37
49.0 63 37
Diluent:  Acetonitrile and water (1:1)
System suitability solution:  60 µg/mL of USP Drospirenone RS and 60 µg/mL of USP Drospirenone Related Compound A RS in Diluent
Standard solution:  0.6 mg/mL of USP Drospirenone RS in Diluent
Sample solution:  0.6 mg/mL of Drospirenone in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 245 nm
Column:  4.6-mm × 25-cm; 3-µm packing L1
Column temperature:  35
Flow rate:  1 mL/min
Injection size:  10 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 5.0 between drospirenone and drospirenone related compound A, System suitability solution
Tailing factor:  Between 0.8 and 1.5, Standard solution
Relative standard deviation:  NMT 2.0%, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of the labeled quantity of drospirenone (C24H30O3) in the portion of Drospirenone 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 Drospirenone RS in the Standard solution (mg/mL)
CU== nominal concentration of drospirenone in the Sample solution (mg/mL)
USP35
Acceptance criteria:  NLT 98.0%–102.0% on the anhydrous and solvent-free basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
Organic Impurities 
•  Procedure 1: Limit of 1,2-Dimethoxyethane and Diisopropyl Ether (if present)
Standard solution:  0.1 mg/mL of 1,2-dimethoxyethane and 0.05 mg/mL of diisopropyl ether in dimethylformamide
Sample solution:  50 mg/mL of Drospirenone in dimethylformamide
Chromatographic system 
Mode:  GC
Detector:  Flame ionization
Column:  0.25-mm × 30-m; 1.4-µm coating of phase G43
Temperature 
Injector:  160
Detector:  250
Column:  See Table 2.
Table 2
Initial
Temperature
()
Temperature
Ramp
(/min)
Final
Temperature
()
Hold Time at
Final
Temperature
40 0 40 10
40 5 70 0
70 30 220 0
Carrier gas:  Helium
Flow rate:  32 ± 8 cm/s. [Note—For pressure-controlled systems, a column pressure of about 130 kPa is necessary. ]
Injector type:  Headspace
Sample volume:  2.0 mL/vial
Vial treatment:  Maintain at 80 for 60 min before injection.
System suitability 
Sample:  Standard solution
[Note—The relative retention times for diisopropyl ether and 1,2-dimethoxyethane are about 0.6 and 1.0, respectively. ]
Suitability requirements 
Relative standard deviation:  NMT 4.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of 1,2-dimethoxyethane and diisopropyl ether in the portion of Drospirenone taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of 1,2-dimethoxyethane or diisopropyl ether from the Sample solution
rS== peak response of 1,2-dimethoxyethane or diisopropyl ether from the Standard solution
CS== concentration of 1,2-dimethoxyethane or diisopropyl ether in the Standard solution (mg/mL)
CU== concentration of Drospirenone in the Sample solution (mg/mL)
Acceptance criteria 
Individual impurities:  NMT 0.2% of 1,2-dimethoxyethane and NMT 0.1% of diisopropyl ether
•  Procedure 2
Solution A:  Water
Solution B:  Acetonitrile
Mobile phase:  See Table 3.
Table 3
Time
(min)
Solution A
(%)
Solution B
(%)
0 63 37
2.0 63 37
16.0 52 48
23.0 52 48
31.0 20 80
39.0 20 80
39.1 63 37
49.0 63 37
Diluent:  Acetonitrile and water (1:1)
System suitability solution:  60 µg/mL of USP Drospirenone RS and 60 µg/mL of USP Drospirenone Related Compound A RS in Diluent
Standard solution:  0.6 µg/mL of USP Drospirenone RS in Diluent
Sample solution:  0.6 mg/mL of Drospirenone in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 195 nm and 245 nm
Column:  4.6-mm × 25-cm; 3-µm packing L1
Column temperature:  35 ± 5
Flow rate:  1 mL/min
Injection size:  10 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 5.0 between drospirenone and drospirenone related compound A, System suitability solution
Tailing factor:  Between 0.8 and 1.5, Standard solution
Relative standard deviation:  NMT 2.0%, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Drospirenone taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response of each individual impurity from the Sample solution
rS== peak response of drospirenone from the Standard solution
CS== concentration of USP Drospirenone RS in the Standard solution (µg/mL)
CU== concentration of Drospirenone in the Sample solution (µg/mL)
F== relative response factor for each individual impurity (see Table 4)
[Note—The percentage of hydroxydrospirenone is calculated at 195 nm. ]
Acceptance criteria 
[Note—Disregard any peaks that are less than 0.05% of the drospirenone peak. ]
Individual impurities:  See Table 4.
Table 4
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
7-Hydroxymethyl drospirenone at 245 nma 0.43 1.9 0.1
5-Hydroxydrospirenone at 195 nmb 0.57 0.57 0.1
17-Keto drospirenone at 245 nmc 0.77 1.2 0.1
Drospirenone at 245 and 195 nm 1.00
Drospirenone 6-ene at 245 nmd 1.04 0.30 0.1
Drospirenone related compound A at 245 nme 1.11 1.0 0.1
6,7-Epidrospirenone at 245 nmf 1.14 1.3 0.1
6,7-Desmethylene drospirenone at 245 nmg 1.18 2.2 0.1
15-Methyl drospirenone at 245 nmh 1.34 0.99 0.1
7-Chloromethyl drospirenone at 245 nmi 1.38 1.6 0.1
7-Chloromethyl 17-epidrospirenone at 245 nmj 1.51 1.9 0.1
7-Hydroxymethyl 3,5(6)-diene drospirenone at 245 nmk 1.55 1.4 0.1
Any unspecified impurity at 245 nm 1.0 0.1
Total impurities 0.4
a  17-Hydroxy-7-hydroxymethyl-15,16-methylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
b  5,17-Dihydroxy-6,7:15,16-dimethylene-17-pregnan-21-carboxylic acid, -lactone.
c  6,7:15,16-Dimethyleneandrost-4-ene-3,17-dione.
d  17-Hydroxy-15,16-methylene-3-oxo-17-pregn-4,6-diene-21-carboxylic acid, -lactone.
e  17-Hydroxy-6,7:15,16-dimethylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone; 17-epidrospirenone.
f  17-Hydroxy-6,7:15,16-dimethylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
g  17-Hydroxy-15,16-methylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
h  17-Hydroxy-15-methyl-6,7-methylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
i  17-Hydroxy-7-chloromethyl-15,16-methylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
j  17-Hydroxy-7-chloromethyl-15,16-methylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
k  17-Hydroxy-7-hydroxymethyl-15,16-methylene-17-pregn-3,5(6)-diene-21-carboxylic acid, -lactone.
SPECIFIC TESTS
•  Optical Rotation, Specific Rotation 781S
Sample solution:  10 mg/mL in methanol
Acceptance criteria:  187 to 193 at 20 on the anhydrous and solvent-free basis
•  Melting Range or Temperature, Class 1 741: 198–203. [Note—Dry over silica gel for NLT 24 h before testing. ]
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.
•  USP Reference Standards 11
USP Drospirenone RS Click to View Structure
USP Drospirenone Related Compound A RS
17-Hydroxy-6,7:15,16-dimethylene-3-oxo-17-pregn-4-ene-21-carboxylic acid, -lactone.
    C24H30O3        366.49
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