Norgestimate 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

Norgestimate and Ethinyl Estradiol Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of norgestimate (C₂₃H₃₁NO₃) and ethinyl estradiol (C₂₀H₂₄O₂).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Mobile phase: Tetrahydrofuran, methanol, and water (5:2:13)

Internal standard solution: 0.05 mg/mL of dibutyl phthalate in methanol

Standard solution: Dissolve appropriate quantities of USP Ethinyl Estradiol RS and USP Norgestimate RS in a volume of Internal standard solution equivalent to 80% of the final volume. Add a volume of water equivalent to 20% of the final volume, and mix to obtain a solution having a known concentration of about 7 µg/mL of ethinyl estradiol and a known concentration of norgestimate similar to that expected in the Sample solution. Pass through a suitable filter of 0.45-um pore size.

Sample solution: Add a number of Tablets, equivalent to 0.35 mg of ethinyl estradiol, to a suitable glass container. Add 10 mL of water, and mix with a vortex mixer until the Tablets are completely disintegrated. Add 40 mL of Internal standard solution, and mix with a vortex mixer for at least 23 min. Sonicate the sample for at least 5 min, pass an aliquot through a suitable filter of 0.45-µm pore size, and use the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm x 5-cm; 5-µm packing L1

Flow rate: 2.1 mL/min

Injection size: 25 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for ethinyl estradiol, (Z)-norgestimate, (E)-norgestimate, and dibutyl phthalate are about 0.5, 1.0, 1.2, and 1.5, respectively.]

Suitability requirements

Resolution: NLT 1.5 between (Z)-norgestimate and (E)-norgestimate

Relative standard deviation: NMT 2.0% for the peak response ratio of ethinyl estradiol, (Z)-norgestimate, and (E)-norgestimate to dibutyl phthalate

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ethinyl estradiol (C₂₀H₂₄O₂) in the portion of Tablets taken:

Result = (R_ue /R_se ) × (C_se /C_ue ) × 100

R_ue = ratio of the peak responses of ethinyl estradiol to dibutyl phthalate from the Sample solution

R_se = ratio of the peak responses of ethinyl estradiol to dibutyl phthalate from the Standard solution

C_ue = concentration of USP Ethinyl Estradiol RS in the Standard solution (mg/mL)

C_se = nominal concentration of ethinyl estradiol in the Sample solution (mg/mL)

Calculate the percentage of the labeled amount of norgestimate (C₂₃H₃₁NO₃) in the portion of Tablets taken:

Result = (C_sn /C_un ) × [P_a (R_ua /R_sa ) + P_s (R_us /R_ss )] × 100

C_sn = concentration of USP Norgestimate RS in the Standard solution (mg/mL)

C_un = nominal concentration of norgestimate in the Sample solution (mg/mL)

P_a = fraction of (E)-norgestimate in USP Norgestimate RS

R_ua = ratio of the peak responses of (E)-norgestimate to dibutyl phthalate from the Sample solution

R_sa = ratio of the peak responses of (E)-norgestimate to dibutyl phthalate from the Standard solution

P_s = fraction of (Z)-norgestimate in the USP Norgestimate RS

R_us = ratio of the peak responses of (Z)-norgestimate to dibutyl phthalate from the Sample solution

R_ss = ratio of the peak responses of (Z)-norgestimate to dibutyl phthalate from the Standard solution

Calculate the ratio of the content of (Z)-norgestimate to ethinyl estradiol in the portion of Tablets taken, for use in the test for Organic Impurities:

C_z /C_e = [(C_sn × P_s ) × (R_us /R_ss )]/[C_se (R_ue /R_se )]

The terms are as dened above.

Acceptance criteria: 90.0%–110.0% each of ethinyl estradiol and norgestimate

4 PERFORMANCE TESTS

DISINTEGRATION (701): 15 min

UNIFORMITY OF DOSAGE UNITS (905); Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Mobile phase, Standard solution, and Sample solution: Prepare as directed in the Assay.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: 254 nm

Column: 4.6-mm x 5-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection size: 50 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for ethinyl estradiol, (Z)-norgestimate, and (E)-norgestimate are about 0.5, 1.0, and 1.2, respectively.]

Suitability requirements

Resolution: NLT 1.5 between (Z)-norgestimate and (E)-norgestimate

Relative standard deviation: NMT 2.0% for the (Z)-norgestimate and (E)-norgestimate peaks

Analysis

Sample: Sample solution

Calculate the percentage of any impurity having a relative retention time of about 0.2 or 0.4, relative to the (Z)-norgestimate peak, and detected at 254 nm in the portion of Tablets taken:

Result = (r_u /r_z ) × (C_z /C_e ) × F × 100

r_u = peak response for each impurity

r_z = peak response for (Z)-norgestimate

C_z /C_e = ratio of (Z)-norgestimate to ethinyl estradiol, as dened in the Assay

F = relative response factor of these impurities, 1.54

Acceptance criteria: The sum of the impurities having relative retention times of about 0.2 and 0.4 is NMT 4.0%.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

USP Reference Standards 〈11〉

USP Ethinyl Estradiol RS

USP Norgestimate RS