Norgestimate and Ethinyl Estradiol Tablets
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).
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.
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-µm 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
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 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 = (RUE/RSE) × (CSE/CUE) × 100
| RUE | = | = ratio of the peak responses of ethinyl estradiol to dibutyl phthalate from the Sample solution |
| RSE | = | = ratio of the peak responses of ethinyl estradiol to dibutyl phthalate from the Standard solution |
| CSE | = | = concentration of USP Ethinyl Estradiol RS in the Standard solution (mg/mL) |
| CUE | = | = 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 = (CSN/CUN) × [PA(RUA/RSA) + PS(RUS/RSS)] × 100
| CSN | = | = concentration of USP Norgestimate RS in the Standard solution (mg/mL) |
| CUN | = | = nominal concentration of norgestimate in the Sample solution (mg/mL) |
| PA | = | = fraction of (E)-norgestimate in USP Norgestimate RS |
| RUA | = | = ratio of the peak responses of (E)-norgestimate to dibutyl phthalate from the Sample solution |
| RSA | = | = ratio of the peak responses of (E)-norgestimate to dibutyl phthalate from the Standard solution |
| PS | = | = fraction of (Z)-norgestimate in the USP Norgestimate RS |
| RUS | = | = ratio of the peak responses of (Z)-norgestimate to dibutyl phthalate from the Sample solution |
| RSS | = | = 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:
CZ/CE = [(CSN × PS) × (RUS/RSS)]/[CSE(RUE/RSE)]
The terms are as defined above.
Acceptance criteria:
90.0%–110.0% each of ethinyl estradiol and norgestimate
PERFORMANCE TESTS
• Disintegration 
701
:
15 min
701:
15 min
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
• Organic Impurities
Mobile phase, Standard solution, and Sample solution:
Prepare as directed in the Assay.
Chromatographic system
Mode:
LC
Detector:
254 nm
Column:
4.6-mm × 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 = (rU/rZ) × (CZ/CE) × F × 100
| rU | = | = peak response for each impurity |
| rZ | = | = peak response for (Z)-norgestimate |
| CZ/CE | = | = ratio of (Z)-norgestimate to ethinyl estradiol, as defined 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%.
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers.
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Mary S. Waddell
Scientific Liaison 1-301-816-8124 |
(SM42010) Monographs - Small Molecules 4 |
| 701 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4084
Pharmacopeial Forum: Volume No. 37(1)