Drospirenone
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This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
(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-6β,7β:15β,16β-dimethylene-3-oxo-17 α-pregn-4-ene-21-carboxylic acid, γ-lactone CAS RN®: 67392-87-4; UNII: N295J34A25.
1 DEFINITION
Drospirenone contains NLT 98.0% and NMT 102.0% of C24H30O3, calculated on the anhydrous and solvent-free basis.
2 IDENTIFICATION
Change to read:
A.SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197M
B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
3 ASSAY
PROCEDURE
Solution A: Water
Solution B: Acetonitrile
Mobile phase: See 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
(See Chromatography (621), System Suitability)
Mode: LC
Detector: UV 245 mm
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 drospirenone C24H30O3 in the portion of Drospirenone taken:
Result = (rU/(rS) × (CS /CU) x 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) C
CU = concentration of drospirenone in the Sample solution (mg/mL)
Acceptance criteria: 98.0%-102.0%
4 IMPURITIES
INORGANIC IMPURITIES
RESIDUE ON IGNITION (281): NMT 0.1%
ORGANIC INPURITIES
PROCEDURE 1: LIMIT OF 1,2-DIMETHOXYETHANE AND DUSOPROPYL 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
(See Chromatography (621). Svatem Suitability.)
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
| Initial Temperature (°) | Temperature Ramp (° / min ) | Final Temperature (°) | Hold Time at Final Temperature (min) |
| 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) x 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.
| 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 |
| 31.0 | 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 BS in Diluent
Sample solution: 0.6 mg/ml of Drospirenone in Diluent
Chromatographic system
(See Chromatography (621), System Suitability.)
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 15.0%, Standard solution
Analysis
Samples: Standard solution and Sample solution
USP-NF Drospirenone
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 (ug/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.
| Name | Relative Retention Time | Relative Response Factor | Acceptance Criteria, NMT (%) |
| 7-Hydroxymethyl drospirenone at 245 nma | 0.43 | 1.9 | 0.1 |
| 5-Hydroxydros pirenone 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 mme | 1.11 | 1.0 | 0.1 |
| 6,7-Epidrospirenone at 245 nmf | 1.14 | 1.3 | 0.1 |
| 6,7-Desmethylene drospirenone at 245nmg | 1.18 | 2.2 | 0.1 |
| 15-Methyl drospirenone at 245 nmh | 1.34 | 0.99 | 0.1 |
| 7-Chloromethyl drospirenone at 245nmi | 1.38 | 1.6 | 0.1 |
| 7-Chloromethyl 17-epidrospirenone at 245 nmi | 1.51 | 1.9 | 0.1 |
| 7-Hydroxymethyl 3,5(6)-diene drospirenone at 245 mmk | 1.55 | 1.4 | 0.1 |
| Any unspecified impurity at 245 nm | - | 1.0 | 0.1 |
| Total impurities | - | - | 0.4 |
a 17-Hydroxy-7β-hydroxymethyl-15β,16β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone.
b 5β,17-Dihydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregnan-21-carboxylic acid, γ-lactone.
c 6β,7β:15β,16β-Dimethyleneandrost-4-ene-3,17-dione.
d 17-Hydroxy-15β,16β-methylene-3-oxo-17α-pregn-4,6-diene-21-carboxylic acid, γ-lactone.
e 17-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17β-pregn-4-ene-21-carboxylic acid, γ-lactone; 17-epidrospirenone.
f 17-Hydroxy-6α,7α:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone.
g 17-Hydroxy-15β,16β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone.
h 17-Hydroxy-15β-methyl-6β,7β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone.
i 17-Hydroxy-7β-chloromethyl-15β,16β-methylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone.
j 17-Hydroxy-7β-chloromethyl-15β,16β-methylene-3-oxo-17β-pregn-4-ene-21-carboxylic acid, γ-lactone.
k 17-Hydroxy-7β-hydroxymethyl-15β,16β-methylene-17α-pregn-3,5(6)-diene-21-carboxylic acid, γ-lactone.
5 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.]
Water Determination, Method I (921): NMT 0.2%
6 ADDITIONAL REQUIREMENTS
Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.
