Norethindrone Acetate 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

Norethindrone Acetate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃).

2 IDENTIFICATION

Delete the following:

2.1 A. Infrared Absorption 〈197K〉

Analysis: Mix an amount of powdered Tablets equivalent to 50 mg of norethindrone with 15 mL of solvent hexane. Stir the solution occasionally for 15 min. Centrifuge the mixture, then decant and discard the solvent hexane. Extract the residue with two 10-mL portions of solvent hexane, centrifuging and decanting as before, and discard the solvent hexane. Add 25 mL of chloroform to the residue, mix by shaking for 1–2 min, and filter. Evaporate the filtrate to about 3 mL, add a few mL of solvent hexane to induce crystallization, and evaporate to dryness.

Acceptance criteria: The IR absorption spectrum of a potassium bromide dispersion prepared from the residue so obtained exhibits maxima only at the same wavelengths as that of a similar preparation of USP Norethindrone Acetate RS. 

Add the following:

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY

Change to read:

3.1 Procedure

Solution A: Water

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Methanol and water (60:40)

System suitability stock solution: 0.1 mg/mL each of USP Norethindrone Acetate RS, USP Norethindrone RS, and USP Norethindrone Related Compound B RS prepared as follows. Transfer the Reference Standards to a suitable volumetric flask. Add 50% of the final flask volume of acetonitrile to dissolve, and dilute with Diluent to volume.

System suitability solution: 0.05 mg/mL each of USP Norethindrone Acetate RS, USP Norethindrone RS, and USP Norethindrone Related Compound B RS in Diluent from System suitability stock solution.

Standard solution: 0.1 mg/mL of USP Norethindrone Acetate RS in Diluent.

Sample solution: Nominally 0.1 mg/mL of norethindrone acetate in Diluent prepared as follows. Transfer a quantity of finely powdered Tablets (NLT 20) equivalent to 20 mg of norethindrone acetate to a 20-mL volumetric flask. Add 15 mL of Diluent and sonicate for 30 min. Dilute with Diluent to volume. Centrifuge to obtain a clear supernatant. Transfer 5.0 mL of the supernatant to a 50-mL volumetric flask, and dilute with Diluent to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 200–400 nm.
• Column: 4.6-mm × 25-cm; 5-µm packing L7
• Column temperature: 40°
• Flow rate: 1.2 mL/min
• Injection volume: 50 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-See Table 2 for relative retention times.]
• Suitability requirements
• Resolution: NLT 2.0 between norethindrone related compound B and norethindrone, System suitability solution
• Tailing factor: NMT 1.5, Standard solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃) in the portion of Tablets 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 Norethindrone Acetate RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of norethindrone acetate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

4.1.1 Test 1

Medium: Dilute hydrochloric acid (1 in 100) containing 0.02% of sodium lauryl sulfate; 900 mL

Apparatus 1: 100 rpm

Time: 60 min

Standard solution: A known concentration of USP Norethindrone Acetate RS in Medium. [Note-The Standard solution may be prepared by dissolving the Reference Standard in a volume of methanol, not exceeding 0.5% of the final volume of the solution, and diluting quantitatively with Medium.]

Sample solution: Filter portions of the solution under test. Dilute with Medium if necessary.

Instrumental conditions

• Mode: UV
• Analytical wavelength: Maximum absorbance at about 248 nm, measured from a baseline drawn from 350 to 310 nm and extending beyond the maximum peak.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃) dissolved:

Result = (Aᵤ/Aₛ) × (Cₛ/L) × D × V × 100

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

L = label claim (mg/Tablet)

D = dilution factor of the Sample solution

V = volume of Medium, 900 mL

Tolerances: NLT 70% (Q) of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃) is dissolved.

4.1.2 Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.2 g/L of sodium lauryl sulfate and 10 mL/L of hydrochloric acid in water; 900 mL

Apparatus 1: 100 rpm

Time: 30 min

Mobile phase: Acetonitrile and water (60:40)

Standard stock solution: 0.275 mg/mL of USP Norethindrone Acetate RS prepared as follows. Transfer an appropriate amount of USP Norethindrone Acetate RS to a suitable volumetric flask and dissolve in 50% of the flask volume of methanol. Sonicate to dissolve as needed. Dilute with Medium to volume.

Standard solution: 0.0011 mg/mL of USP Norethindrone Acetate RS from the Standard stock solution prepared as follows. Dilute 2 mL of the Standard stock solution with Medium to 100 mL. Further dilute 5 mL of the resultant solution with Mobile phase to 25 mL. Pass a portion through a suitable filter paper.

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute 5 mL of the filtrate with Mobile phase to 25 mL.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 254 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Flow rate: 1 mL/min
• Injection volume: 100 µL
• Run time: 1.5 times the retention time of norethindrone acetate

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃) dissolved:

Result = (rᵤ/rₛ) × Cₛ × V × (1/L) × D × 100

rᵤ = peak response of norethindrone acetate from the Sample solution

rₛ = peak response of norethindrone acetate from the Standard solution

Cₛ = concentration of USP Norethindrone Acetate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

D = dilution factor of the Sample solution, 5

Tolerances: NLT 80% (Q) of the labeled amount of norethindrone acetate (C₂₂H₂₈O₃) is dissolved.

Change to read:

4.2 Uniformity of Dosage Units 〈905〉, Content Uniformity

Meet the requirements

5 IMPURITIES

Add the following:

5.1 Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, and System suitability solution: Prepare as directed in the Assay.

Standard solution: 0.005 mg/mL of USP Norethindrone Acetate RS in Diluent

Sample solution: Nominally 1.0 mg/mL of norethindrone acetate in Diluent prepared as follows. Transfer a quantity of finely powdered Tablets (NLT 20) equivalent to 20 mg of norethindrone acetate to a 20-mL volumetric flask. Add 15 mL of Diluent and sonicate for 30 min. Dilute with Diluent to volume. Centrifuge to obtain a clear supernatant. Use the supernatant.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm for norethindrone acetate 5(10)-ene isomer; UV 254 nm for all other impurities
• Column: 4.6-mm × 25-cm; 5-µm packing L7
• Column temperature: 40°
• Flow rate: 1.2 mL/min
• Injection volume: 50 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-See Table 2 for relative retention times.]
• Suitability requirements
• Resolution: NLT 2.0 between norethindrone and norethindrone related compound B, System suitability solution
• Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of norethindrone acetate 5(10)-ene isomer (detected at UV 210 nm) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak response of norethindrone acetate 5(10)-ene isomer from the Sample solution

rₛ = peak response of norethindrone acetate from the Standard solution

Cₛ = concentration of USP Norethindrone Acetate RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of norethindrone acetate in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Calculate the percentage of each specified or unspecified degradation product (detected at UV 254 nm) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

rᵤ = peak response of each specified or unspecified degradation product from the Sample solution

rₛ = peak response of norethindrone acetate from the Standard solution

Cₛ = concentration of USP Norethindrone Acetate RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of norethindrone acetate in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. The reporting threshold is 0.1%.

Table 2

ᵃ 6β-Hydroxy-3-oxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate.

ᵇ Process impurity included in the table for identification only. Process impurities are controlled in the drug substance and are not to be reported or included in the total impurities of the drug product.

ᶜ 3,6-Dioxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate.

ᵈ 6β-Acetyl-3-oxo-19-nor-17α-pregn-4-en-20-yn-17-yl acetate.

ᵉ 3,20-Dioxo-19-nor-17α-pregn-4-en-17-yl acetate.

ᶠ 3-Ethoxy-19-nor-17βα-pregn-3,5-dien-20-yn-17-yl acetate.

ᵍ 3-Isopropoxy-19-nor-17βα-pregn-3,5-dien-20-yn-17-yl acetate.

ʰ 3-Oxo-19-nor-17α-pregn-5-en-20-yn-17-yl acetate.

ᶦ 3-Oxo-19-nor-17α-pregn-5(10)-en-20-yn-17-yl acetate.

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

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

Change to read:

USP Reference Standards 〈11〉

USP Norethindrone RS

USP Norethindrone Acetate RS

USP Norethindrone Related Compound B RS

Estr-4-ene-3,17-dione.

C₁₈H₂₄O₂ 272.39