Norgestimate

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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C₂₃H₃₁NO₃         369.51 _{(IRA 1-Aug-2024)}

18,19-Dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-; (+)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester) CAS RN: 35189-28-7; UNII: C291HFX4DY.

1 DEFINITION

Norgestimate is a mixture of (E)- and (Z)-isomers having a ratio of (E)- to (Z)-isomer between 1.27 and 1.78, and it contains NLT 98.0% and NMT 102.0% of norgestimate (C₂₃H₃₁NO₃), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or (IRA 1-Aug-2024) 197K _{(IRA 1-Aug-2024)}

Change to read:

B. The retention times of the major peaks for the (E)- and (Z)-isomers of the Sample solution correspond to those_{(IRA 1-Aug-2024)} of the Standard solution, as obtained in the Assay.

3 ASSAY

Change to read:

Procedure

Diluent: Methanol and water (80:20)

Mobile phase: Tetrahydrofuran, acetonitrile, and water (22:18:60)

Standard solution: 0.5 mg/mL of USP Norgestimate RS in Diluent _{(IRA 1-Aug-2024)}

Sample solution: 0.5 mg/mL of Norgestimate in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 244 nm

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

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 25 µL

Run time: NLT 1.5 times the retention time of (E)-norgestimate _{(IRA 1-Aug-2024)}

System suitability

Sample: Standard solution _{(IRA 1-Aug-2024)}

[Note—See Table 1 for the relative retention times for (Z)-norgestimate and (E)-norgestimate._{(IRA 1-Aug-2024)} ]

Suitability requirements

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

Tailing factor: NMT 1.5 for (E)-norgestimate and (Z)-norgestimate

Relative standard deviation: NMT 0.73% (IRA 1-Aug-2024) for the sum of the peak responses of (IRA 1-Aug-2024) (E)-norgestimate and (Z)-norgestimate _{(IRA 1-Aug-2024)}

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of norgestimate (C₂₃H₃₁NO₃) in the portion of Norgestimate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = sum of the peak responses _{(IRA 1-Aug-2024)} of (Z)-norgestimate and (E)-norgestimate from the Sample solution

r_s = sum of the peak responses _{(IRA 1-Aug-2024)} of (Z)-norgestimate and (E)-norgestimate from the Standard solution

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

C_u = concentration of Norgestimate in the Sample solution (mg/mL)

Calculate the percentages of the (Z)- and (E)-isomers, U and U , respectively, in the portion of Norgestimate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × P × 100

r_u = peak response of (Z)-norgestimate and (E)-norgestimate _{(IRA 1-Aug-2024)} from the Sample solution

r_s = peak response of the corresponding _{(IRA 1-Aug-2024)} norgestimate isomer from the Standard solution

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

C_u = concentration of Norgestimate in the Sample solution (mg/mL)

P = fraction of (E)- or (Z)-norgestimate in USP Norgestimate RS

Calculate the ratio of U to U :

Result = (U_e /U_z )

U_e = percentage of (E)-norgestimate in the Sample solution (%)

U_z = percentage of (Z)-norgestimate in the Sample solution (%) _{(IRA 1-Aug-2024)}

Acceptance criteria

Content: 98.0%–102.0% on the dried basis

Ratio of (E)- to (Z)-isomer: 1.27–1.78

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.3%

Change to read:

4.1 ORGANIC IMPURITIES, PROCEDURE 1

Diluent, Mobile phase, _{(IRA 1-Aug-2024)} and Sample solution: Prepare as directed in the Assay.

System suitability solution: 0.5 mg/mL each of USP Norgestimate RS, USP Norgestimate Related Compound A RS, and USP Norelgestromin RSA _{(IRA 1-Aug-2024)} in Diluent

Sensitivity solution: 0.4 µg/mL of USP Norgestimate RS in Diluent

Standard solution: 0.0008 mg/mL of USP Norgestimate RS in Diluent _{(IRA 1-Aug-2024)}

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 244 nm

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

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 25 µL

Run time: NLT 1.5 times the retention time of (E)-norgestimate _{(IRA 1-Aug-2024)}

System suitability

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

[Note—The relative retention times in Table 1 are provided as information that could aid in peak assignment.]

Table 1 _{(IRA 1-Aug-2024)}

Suitability requirements

Resolution: NLT 1.5 between (Z)-norelgestromin and (E)-norelgestromin; _{(IRA 1-Aug-2024)} NLT 1.5 between (E)-norelgestromin _{(IRA 1- Aug-2024)} and norgestimate related compound A, System suitability solution

Tailing factor: NMT 1.5 for (E)-norgestimate and (Z)-norgestimate, System suitability solution

Relative standard deviation: ANMT 5.0% for (E)-norgestimate, Standard solution (IRA 1-Aug-2024)

Signal-to-noise ratio: NLT 10 _{(IRA 1-Aug-2024)} for (E) _{(IRA 1-Aug-2024)} -norgestimate, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any _{(IRA 1-Aug-2024)} impurity in the portion of Norgestimate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × P × 100

r_u = peak response _{(IRA 1-Aug-2024)} of each impurity from the Sample solution

r_s = peak response _{(IRA 1-Aug-2024)} of (E)-norgestimate from the Standard solution

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

C_u = concentration of Norgestimate in the Sample solution (mg/mL)

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

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

Acceptance criteria: See Table 2. The reporting threshold is 0.05%. _{(IRA 1-Aug-2024)}

Table 2

^a The combined limits for (Z)- and (E)- norelgestromin. _{(IRA 1-Aug-2024)}

Change to read:

4.2 ORGANIC IMPURITIES, PROCEDURE 2

Mobile phase: Cyclohexane and absolute alcohol (50:1)

Sensitivity solution: 0.5 µg/mL of USP Norgestimate RS in Mobile phase _{(IRA 1-Aug-2024)}

Standard solution: 1.0 mg/mL of USP Norgestimate RS in Mobile phase

Sample solution: 1.0 mg/mL of Norgestimate in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 25-cm; 5-um packing 120

Flow rate: 1 mL/min

Injection volume: 25 µL

Run time: NLT 1.6 times the retention time of (E)-norgestimate _{(IRA 1-Aug-2024)}

System suitability

Samples: Sensitivity solution and Standard solution

[NOTE-The relative retention times in Table 3 are provided as information that could aid in peak assignment. _{(IRA 1-Aug-2024)}

Table 3 _{(IRA 1-Aug-2024)}

^a (Z)-13-Ethyl-17β-acetoxy-18,19-dinor-17α-pregn-5(10)-en-20-yn-3-one oxime.

^b (E)-13-Ethyl-17β-acetoxy-18,19-dinor-17α-pregn-5(10)-en-20-yn-3-one oxime.

^c Mixture of (E) and (Z)-13-Ethyl-17β-acetoxy-18,19-dinor-17α-pregn-5-en-20-yn-3-one oxime.

Suitability requirements

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

Tailing factor: NMT 1.5 for (Z)-norgestimate and (E)-norgestimate, _{(IRA 1-Aug-2024)} Standard solution

Relative standard deviation: NMT 2.0% for the peak area ratio of (Z)-norgestimate to (E)-norgestimate, Standard solution

Signal-to-noise ratio: NLT 3.0 for (E)-norgestimate, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any _{(IRA 1-Aug-2024)} impurity in the portion of Norgestimate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × P × 100

r_u = peak response _{(IRA 1-Aug-2024)} of each impurity from the Sample solution

r_s = peak response _{(IRA 1-Aug-2024)} of (E)-norgestimate from the Standard solution

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

C_u = concentration of Norgestimate in the Sample solution (mg/mL)

F = relative response factor for each impurity (see Table 4)

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

Acceptance criteria: See Table 4.

Table 4

^a Sum of the impurities found in Organic Impurities, Procedure 1 and Organic Impurities, Procedure 2.

Change to read:

LIMIT OF DIISOPROPYL ETHER _{(IRA 1-Aug-2024)}

Internal standard solution: 0.02 µL/mL _{(IRA 1-Aug-2024)} of isobutyl alcohol in dimethylformamide

Sensitivity solution: 0.0005 µL/mL of diisopropyl ether in Internal standard solution _{(IRA 1-Aug-2024)}

Standard solution: 0.05 µL/mL of diisopropyl ether _{(IRA 1-Aug-2024)} in Internal standard solution (IRA 1-Aug-2024)

Sample solution: 20 mg/mL of Norgestimate in Internal standard solution _{(IRA 1-Aug-2024)} Shake _{(IRA 1-Aug-2024)} to dissolve.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.53 - mm x 30 - m 1-µm coating of _{(IRA 1-Aug-2024)} phase 616

Temperatures

Injection port: 180°

Detector: 250°

Column: See Table 5.

Table 5
 

Carrier gas: Helium

Flow rate: 6 mL/min

Injection mode: Split

Split ow: 16 mL/min

Injection volume: 1 µL

System suitability

Samples: Internal standard solution, Sensitivity solution. (IRA 1-Aug-2024) and Standard solution

[NOTE-The relative retention times for diisopropyl ether and the isobutyl alcohol internal standard are 1.0 and 2.4, respectively. _{(IRA 1-Aug-2024)}

Suitability requirements

Blank interference: _{(IRA 1-Aug-2024)} There are no interfering peaks due to dimethylformamide, Internal standard solution. _{(IRA 1-Aug-2024)}

Relative standard deviation: NMT 3.0%, determined from the peak response ratio of diisopropyl ether _{(IRA 1-Aug-2024)} to the internal standard, Standard solution

Signal-to-noise ratio: NLT 2.0 for diisopropyl ether, Sensitivity solution _{(IRA 1-Aug-2024)}

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diisopropyl ether _{(IRA 1-Aug-2024)} in the portion of Norgestimate taken:

Result = (R_u /R_s ) × (C_s /C_u ) × F × D × 100 _{(IRA 1-Aug-2024)}

R_u = peak response ratio of diisopropyl ether _{(IRA 1-Aug-2024)} to the internal standard from the Sample solution

R_s = peak response ratio of diisopropyl ether _{(IRA 1-Aug-2024)} to the internal standard from the Standard solution

C_s = concentration of diisopropyl ether _{(IRA 1-Aug-2024)} in the Standard solution (µL _{(IRA 1-Aug-2024)} /mL)

C_u = concentration of Norgestimate in the Sample solution (mg/mL)

F = conversion factor, 0.001 mL/µL _{(IRA 1-Aug-2024)}

D = density of diisopropyl ether _{(IRA 1-Aug-2024)} (mg/mL) _{(IRA 1-Aug-2024)}

Acceptance criteria: _{(IRA 1-Aug-2024)} NMT 0.05%

5 SPECIFIC TESTS

Change to read:

OPTICAL ROTATION (781S), Procedures. Specific Rotation

Sample solution: 10 mg/mL in methylene chloride _{(IRA 1-Aug-2024)}

Acceptance criteria: +42.0° to +50.0°, determined at 20° _{(IRA 1-Aug-2024)}

LOSS ON DRYING (731)

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers.

Change to read:

USP REFERENCE STANDARDS (11)

USP Norelgestromin RSA _{(IRA 1-Aug-2024)}

USP Norgestimate RS

USP Norgestimate Related Compound A.RS

13-Ethyl-18,19-dinor-17a-pregn-4-en-20-yn-3-oxo-17ẞ-yl acetate;

Also known as _{(IRA 1-Aug-2024)} Levonorgestrel acetate.

C₂₃H₃₀O₃     354.49 _{(IRA 1-Aug-2024)}