Drospirenone and Ethinyl Estradiol Tablets

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Drospirenone and Ethinyl Estradiol Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of drospirenone (C₂₄H₃₀O₃) and NLT 90.0% and NMT 110.0% of the labeled amount of ethinyl estradiol (C₂₄H₃₀O₂).

2 IDENTIFICATION

A. The retention times of the drospirenone and ethinyl estradiol peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Solution A: Dissolve 132 g of dibasic ammonium phosphate in 0.8 L of water, adjust with phosphoric acid to a pH of 6.8, and dilute to 1 L

Solution B: Solution A and water (1:24)

Mobile phase: Acetonitrile and Solution B (1:1). Adjust with phosphoric acid to a pH of 6.8.

Standard solution: (L/25) mg/mL of USP Drospirenone RS and USP Ethinyl Estradiol RS in Mobile phase, where L is the Tablet label claim, in mg/Tablet, of each compound

Sample solution: Transfer 10 Tablets to a 250-ml, volumetric flask, add 230 mL of Mobile phase, and sonicate with intermittent shaking for NLT 10 min, or until the Tablets are completely dispersed. Equilibrate to room temperature. Dilute with Mobile phase to volume, and centrifuge the sample until a clear supernatant is obtained. Use the supernatant,

Chromatographic system

(See Chromatography (621) System Suitability)

Mode: LC

Detector 1: UV 270 nm for drospirenone

Detector 2: Fluorescence, excitation wavelength at 285 nm, emission wavelength at 315 nm for ethinyl estradiol, Nors-Detector 1 and Detector 2 are connected in series.]

Column: 4.0-mm x 12.5-cm; 3-µm packing L

OFFIC

Column temperature: 25±3°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: Between 0.8 and 1.8 for both drospirenone and ethinyl estradiol

Relative standard deviation: NMT 2.0% for both drospirenone and ethinyl estradiol

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of drospirenone (C₂₄H₃₀O₃) in the portion of Tablets taken:

Result = (r_U/(r_S) × (C_S /C_U) x 100

r_U = peak response of drospirenone from the Sample solution

r_S = peak response of drospirenone from the Standard solution

C_S = concentration of USP Drospirenone RS in the Standard solution (mg/mL)

C_U = nominal concentration of drospirenone in the Sample solution (mg/mL)

Calculate the percentage of the labeled amount of ethinyl estradiol (C,H,O) in the portion of Tablets taken:

Result = (r_U/(r_S) × (C_S /C_U) x 100

r_U = peak responce of ethinyl estradiol from the Sample solution

r_S = peak response of ethinyl estradiol from the Standard solution

C_S = concentration of USP Ethinyl Estradiol in the Standard solution (mg/ml)

C_U = nominal concentration of ethinyl estradiol in the Sampir solution (mg/ml)

Acceptance criteria: 90.0%-110,0% of ethinyl estradiol 90.0%-110.0% of drospirenone

4 PERFORMANCE TESTS

Test 1: For drug products labided to contain 3 mg of drospirenone and 0.03 mg af ethinyl estradiol, or 3 mg of drosperenone and 0.02 mg of

ethinyl estradiol

Medium: Water, 900 ml

Apparatus 2:50 rpm

Time: 30 mm

Standard solution:(L/900) mg/ml of USP Drospirenone RS and USP Ethinyl Estradiol RS in Medium, where is the Tablet label claim of each compound A volume of calltuned not exceeding 23 of the final total solame of solution may be used to and in diving these compounds

Sample solution: Pass a portion of the solution under test through a suitable cellulkise filter of 1.45 um pore size, discarding the first 10 mil

Mobile phase: Acetonitrile and water (40:50)

Chromatographic system

(See Chromatography 1621) Sustem Sullaby)

Mode: LC

Detector: UV 270 nm (for drospirenone), in series with a fluorescence detector (for ethinyl estradiol with excitation at 210 mm and detection at 315 nm, or with exortation at 281 nem and detection at 305 mm

Column: 4.6 mm x 6cm 3 μm packing 11

Column temperature: 22°

Flese rate: 1 mL/min

Injection volume: 100 μL

System sultability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 2000 for both drospirenone and ethinyl estradiol

Talling factor: Between 0 and 1.5 for both drospirenone and ethinyl estradiol

Relative standard deviation: NMT 31% for both drospirenone and ethinyl estradioli

Samples: Standard solution and Sample solution

Nom-In Medium, drospirenone is partially convertest into 17-epitrospirenone, which has a relative retention time of approximately 1.2 relative to drospirenone. The amount of hospirenone skissolved is calculated from the sum of drospirenone and 17-epidrospirenone Calculate the porcentage of the labeled amounts of drospirenone (C₂₄H₃₀O₃) and ethinyl estradisi (C₂₄H₃₀O₂) dissolved:

Result = (r_U/(r_S) × (C_S /L) x V x 100

r_U = peak responce from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of the Standard solution (mg/ml)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 85% (Q) of the labeled amount of drospininone and NLT 75% (0) of the labeled amount of ethenyl estradiol is disaved Test 2: For drug products labeled to contain 3 mg of drospirenone and 0.02 mg of ethinyl estradiol if the product complies with this test, the

labeling indicates that it meets USP Dissolution Test 2

Medium: Water, 900 mL.

Apparatus 2: 50 rpm

Time: 30 min

Standard solution: (L/900) mg/mL of USP Dessicanane RS and USE Ettens Eltatul BS in Medfurn, where is the Tablet label claim of each compound

Sample solution: Centrifuge a portion of the solution under test at 3500 rpm for 15 min, and use the supematant

Mobile phase: Acetonmile methanol, and waiter (40:5:55)

Chromatographic system

Mode: LC

Detector: UV 260 nm (for drospirenone), in series with a

uorescence detector (for ethinyl estradiol), with excitation at 280 nm and

detection at 310 nm

Column: 4.6-mm × 10-cm; 3-μm packing L1

Temperatures

Column: 30°

Autosampler: 5°

Flow rate: 1 mL/min

Injection volume: 200 μL

System suitability

Sample: Standand solution

Suitability requirements

Talling factor: NMT 2 for both drospirenone and ethinyl estradiol

Relative standard deviation NMT 2% for both drospirenone and ethinyl estradiol

Samples: Somiedon and Sample solution

Calculate the percentage of the labeled amounts of drospirenone (C₂₄H₃₀O₃) and ethinyl estradisi (C₂₄H₃₀O₂) dissolved:

Result = (r_U/(r_S) × (C_S /L) x V x 100

r_U = peak responce from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of the Standard solution (mg/ml)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of drospirenone and NLT 85% (0) of the labeled amount of ethinyl estradiol is dissolved

Test 2: For drug producta labeled to contain 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, or 3 mg of drospirenone and 0.02 mg of ethinyl estradiol. if the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3

Medium: Water: 900 m

Apparatus 2: 80 rpm

Timex 30 mm

Mobile phase: Astuntil and water (50:50)

Standard stock solution A: 2.8 µg/mL of the Estradiol RS in acetonitis. Sonicate as needed

Standard stock solution B: 168 µg/ml, of USP Dropeitonane RS in acidonibile Sonicate as needed

Standard solution: (1/900) mg/ml of Drostenone RS and USP this Estadio RS in Medium from Standard stock solution A and Standani stock solution, where in the Tablet label claim of each compound.

Chromatographic system

Sample solution: Pasa a portion of the solution under test through a suitable glass fiter of 1 um pore size, discarding the first 5 mi

Mode: LC

Detector: UV 265 mm (for drospirenons), in series with a fluorescence detector (for ethinyl estradiol with excitation at 285 nm and

detection at 310

Column: 4.6-mm × 15-cm; 5-μm packing L11

Temperatures

Column: 30

Autosampler: 10°

Flow rate: 1 mL/min

Injection volume: 50

System sulñability

Sample: Standard solution

Sultability requirements

Tailing factor: NMT 2.0 for both spirenone and ethinyl estradiol

Relative standard deviation NMT 2.0% for both drospirenone and ethinyl estradiol

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of drospirenone (C₂₄H₃₀O₃) and ethinyl estradisi (C₂₄H₃₀O₂) dissolved

Result = (r_U/(r_S) × C_S x V × (1/L) ×100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (2) of the labeled amount of drospirenone and NLT 75% (2) of the labeled amount of ethinyl estradiol is dissolved

Dace thats 19055: Meet the requirements

5 IMPURITIES

Change to read:

Organic Impurities

Solution A: Acetonitrile, methanol, and water (26:19:55)

Solution B: Acetonitrile, methanol, and water (76:19:5)

Mobile phase: See Table

System suitability stock solution: (L × 18/100) μg/mL of USP Drospirenone RS in Solution A, where L is the label claim (μg/Tablet) of drospirenone

System sultability solution: Transfer 1.0 ml of the System sulfablity stock solution into a 10-m volumeric fisak, add 10 ml of DN hydrochloric acid and heat for 30 min in a 40 water bath, immediately add 1 ml of 0.1 Nadium hydroxide (NaOH) and allow to reach room temperature. Dilute with Solution A to volume to obtain a solution containing drospirenone and 17-epidrospirenone Non-Sodum hydroxide (Na) must be added immediately after heating for the reaction to proceed property. The cruspirenone to 17-epidrusgrenone ratio munt be between 21 and 7:1]

Standard solution: (L₁ × 15/1000) μg/mL of USP Drospirenone RS, (L × 30/1000) μg/mL of USP Ethinyl Estradiol RS, and (L × 30/1000)μg/mL of USP Ethinyl Estradiol Related Compound B RS in Solution A, where L and L are the label claim (μg/Tablet) of drospirenone and ethinyl estradiol, respectively

Sensitivity solution: (L₁ × 15/10,000) μg/mL of USP Drospirenone RS, (L × 30/10,000) μg/mL of USP Ethinyl Estradiol RS, and (L × 30/10,000) μg/mL of USP Ethinyl Estradiol Related Compound B RS in Solution A, where L and L are the label claim (μg/Tablet) of drospirenone and ethinyl estradiol, respectively, prepared from the Standard solution

Sample solution: Transfer 15 Tablets to a 10-mL glass-stoppered test tube, and add 5.0 mL of Solution A. Shake vigorously, sonicate for NLT 5 min, and place in an ice bath for NLT 10 min. Centrifuge the sample at least until an almost clear supernatant is obtained. Filter the supernatant, and use the ltrate.

Chromatographic system

Mode: LC

Detector 1: UV 222 mm

Detector 2: Moorescence, excitation wavelength at 215 ren, emosion wavelength at 315 mm. Monitor the signal at 344 mm for etland extradil related compound B (typically between 37 and 42 min), Non-Detector 1 and Detector 2 are connected in aurken thue the response at 344 nm ta quantify ethinyl estradiol related compound B

Column: 3.0-mm × 30-cm; 3-μm packing L1 followed, in series, by a 4.6-mm × 10-cm; chromolith packing L1

Column temperature: 40°

Flow rate: See Table 1

Injection volume: 20 μL

System sultability

Samples: System suitability solution, Standard solution, and Sensitivity solution

Sultability requirements

Tailing factor: Between 0.8 and 1.5 for both drospirenone and ethinyl estradiol, Standard solution

Resolution: NLT 2.0 between drospirenone and 17-epidrospirenone, System suitability solution

Relative standard deviation: NMT 5.0% for both drospirenone and ethinyl estradiol, Standard solution

Signal-to-noise ratio: NLT 10 for drospirenone and ethinyl estradiol related compound B and NLT 7.0 for ethinyl estradiol, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

dentify the ethinyl estradiol degradation products using the neiative retention times given in Table 2.

Calculate the percentage of each ethinyl estradiol degradation product and unspecified degradation products in the portion of Tablets taken:

Result = (r_U/(r_S) × (C_S /C_U) × (1/F) x 100

r_U = peak response of each ethinyl estradiol degradation product from the Sample solu

r_S = peak response of ethinyl estradiol from the Standard solution

C_S = concentration of thir Estradiol in the Standard solution (ug/ml)

C_U = nominal concentration of ethinyl estradiol in the Sample solution (ug/ml)

F = relative response factor for each degradation product (see Table 2)

Samples: Standard solution and Sample solution

Calculate the percentage of ethinyl estradiol related compound in the portion of Tablets taken:

Result = (r_U/(r_S) × (C_S /C_U) x 100

r_U = peak response of ethinyl estradiol related compound & from the Sample solution

r_S = peak response of ethinyl estradiol related compound from the Stand

C_S = concentration of USP Ethyl Estradiol Related Compound & in the Standard solution (μg/mL)

C_S = nominal concentration of ethinyl estradiol in the Sample solution (μg/mL)

Samples: Standin solus and Samgile solution

Identify the droopitenore degradation prockicts using the relative retention fines given in Table 3

Calculate the percentage of each drospirenone degradation product in the portion of Tablets taken

Result = (r_U/(r_S) × (C_S /C_U) × (1/F) x 100

r_U = peak response of drospirenone degradation product from the Sample solu

r_S = peak response of drospirenone from the Standard solution

C_S = concentration of USP drospirenone RS in the Standard solution (ug/ml)

C_U = nominal concentration of drospirenone in the Sample solution (ug/ml)

F = relative response factor for each degradation product (see Table 3)

Acceptance criteria Non-Report only degradation products greater than 0.7%

Individual degradation products: See Table for anylestradiol and Jabil 3 for crospirenon.

Total degradation products: NMT 3.5%

^a Limits for drug products labeled to contain 3 mg of drospirenone and 0.03 mg of ethinyl estradiol.

^b Limits for drug products labeled to contain 3 mg of drospirenone and 0.02 mg of ethinyl estradiol.

^c 19-Nor-6α,17α-pregna-1,3,5(10)-trien-20-yne-3,6,17-triol.

^d 19-Nor-6β,17α-pregna-1,3,5(10)-trien-20-yne-3,6,17-triol.

^e 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol-6-one.

^f Δ9,11-Ethinyl estradiol. 19-Nor-17α-pregna-1,3,5(10),9(11)-tetraen-20-yne-3,17-diol.

^g Fl = Fluorescence.

^h Determine unknown impurities using both modes of detection. Report the values from the detection mode that yield higher impurity levels.

^a Limits for drug products labeled to contain 3 mg of drospirenone and 0.03 mg of ethinyl estradiol.

^b Limits for drug products labeled to contain 3 mg of drospirenone and 0.02 mg of ethinyl estradiol.

^c 17-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17β-pregn-4-ene-21-carboxylic acid, γ-lactone.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.