Norgestimate
(nor jes' ti mate).
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369.5018,19-Dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, oxime, (17
)-(+)-.
(+)-13-Ethyl-17-hydroxy-18,19-dinor-17
-pregn-4-en-20-yn-3-one oxime acetate (ester)
[35189-28-7].» 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 not less than 98.0 percent and not more than 102.0 percent of C23H31NO3, calculated on the dried basis.
Packaging and storage—
Preserve in well-closed containers.
USP Reference standards 
11
—
11—
USP Norgestimate RS 
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USP Norgestimate Related Compound A RS
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USP Deacetylnorgestimate RS
Mixture of syn-17-deacetylnorgestimate and anti-17-deacetylnorgestimate.
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Mixture of syn-17-deacetylnorgestimate and anti-17-deacetylnorgestimate.
Identification—
A:
Infrared Absorption 197K—
197K—
Test specimen—
Use a dispersion in potassium bromide prepared by mixing the specimen with potassium bromide in a 1 to 100 ratio.
B:
The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Loss on drying 731—
Dry it at 105
for 3 hours: it loses not more than 0.5% of its weight.
731—
Dry it at 105 for 3 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281:
not more than 0.3%.
281:
not more than 0.3%.
Heavy metals, Method II 231:
0.002%.
231:
0.002%.
Limit of residual solvents—
Internal standard solution—
Prepare a solution of isobutyl alcohol in dimethylformamide containing 2 µL of isobutyl alcohol per 100 mL of solution.
Standard solution—
Prepare a solution in Internal standard solution containing 5 µL each of acetone, alcohol, chloroform, diisopropyl ether, and methanol per 100 mL of solution.
System suitability solution—
Dilute a portion of the Standard solution with Internal standard solution to obtain a solution containing 0.05 µL each of acetone, alcohol, chloroform, diisopropyl ether, and methanol per 100 mL of solution.
Test solution—
Transfer about 40 mg of Norgestimate and 2 mL of Internal standard solution to a 5-mL volumetric flask or a suitable vial, and shake well to dissolve.
Chromatographic system (see Chromatography 621)—
The gas chromatograph is equipped with a flame-ionization detector, a 0.53-mm × 30-m fused-silica capillary column bonded with a 1-µm layer of phase G16, and a split injection system. The detector temperature is maintained at about 250, and the injection port temperature is maintained at about 180. The chromatograph is programmed as follows. The column temperature is maintained at about 65 for 2.5 minutes, then the temperature is increased at a rate of 35 per minute to 100, maintained at 100 for 2 minutes, then increased at a rate of 30 per minute to 160, and maintained at 160 for 2.5 minutes. The carrier gas is helium, flowing at a rate of about 6 mL per minute, and the split flow rate is about 16 mL per minute. Chromatograph the Internal standard solution, the Standard solution, and the System suitability solution, and record the peak responses as directed for Procedure: there are no interfering peaks due to dimethylformamide; the retention time of isobutyl alcohol in the chromatogram of the Internal standard solution is between 4 and 5 minutes; the signal-to-noise ratio for alcohol obtained from the System suitability solution is not less than 2.0; and the relative standard deviation for replicate injections of the Standard solution, determined from the peak response ratios of each solvent to the internal standard, is not more than 3.0%.
621)—
The gas chromatograph is equipped with a flame-ionization detector, a 0.53-mm × 30-m fused-silica capillary column bonded with a 1-µm layer of phase G16, and a split injection system. The detector temperature is maintained at about 250, and the injection port temperature is maintained at about 180. The chromatograph is programmed as follows. The column temperature is maintained at about 65 for 2.5 minutes, then the temperature is increased at a rate of 35 per minute to 100, maintained at 100 for 2 minutes, then increased at a rate of 30 per minute to 160, and maintained at 160 for 2.5 minutes. The carrier gas is helium, flowing at a rate of about 6 mL per minute, and the split flow rate is about 16 mL per minute. Chromatograph the Internal standard solution, the Standard solution, and the System suitability solution, and record the peak responses as directed for Procedure: there are no interfering peaks due to dimethylformamide; the retention time of isobutyl alcohol in the chromatogram of the Internal standard solution is between 4 and 5 minutes; the signal-to-noise ratio for alcohol obtained from the System suitability solution is not less than 2.0; and the relative standard deviation for replicate injections of the Standard solution, determined from the peak response ratios of each solvent to the internal standard, is not more than 3.0%.
Procedure—
Separately inject equal volumes (about 1 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of each solvent in the portion of Norgestimate taken by the formula:
200(CD/W)(RU / RS)
in which C is the concentration, in mL per mL, of each solvent in the Standard solution; D is the density, in mg per mL, of each solvent; W is the weight, in mg, of Norgestimate taken to prepare the Test solution; and RU and RS are the peak response ratios of the appropriate analyte to the internal standard obtained from the Test solution and the Standard solution, respectively. Option 1: not more than 0.5% each of acetone and alcohol is found, not more than 0.05% of diisopropyl ether is found, not more than 0.006% of chloroform is found, and not more than 0.3% of methanol is found; or Option 2: meets the requirements.
Chromatographic purity—
test 1—
Diluent, Mobile phase, and Sensitivity solution—
Proceed as directed in the Assay.
Standard solution—
Use the Standard preparation, prepared as directed in the Assay.
Test solution—
Use the Assay preparation.
Resolution solution—
Dissolve accurately weighed quantities of USP Norgestimate RS, USP Norgestimate Related Compound A RS and USP Deacetylnorgestimate RS in Diluent to obtain a solution containing about 0.5 mg of each per mL.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 244-nm detector and a 4.6-mm × 10-cm column that contains 3-µm packing L1. The flow rate is about 1.2 mL per minute. The column temperature is maintained at about 40. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.50 for (Z)-17-deacetylnorgestimate, about 0.56 for (E)-17-deacetylnorgestimate, about 0.72 for norgestimate related compound A, 0.86 for (Z)-norgestimate, and 1.0 for (E)-norgestimate; and the resolution, R, between (Z)-17-deacetylnorgestimate and (E)-17-deacetylnorgestimate is not less than 1.5, and that between (E)-17-deacetylnorgestimate and norgestimate related compound A is not less than 1.5; the tailing factor for (E)-norgestimate and for (Z)-norgestimate is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area ratio of (E)-norgestimate to (Z)-norgestimate, is not more than 2.0%. Chromatograph the Sensitivity solution, and record the peak areas as directed for Procedure: the signal-to-noise ratio for (Z)-norgestimate is not less than 3.0.
621)—
The liquid chromatograph is equipped with a 244-nm detector and a 4.6-mm × 10-cm column that contains 3-µm packing L1. The flow rate is about 1.2 mL per minute. The column temperature is maintained at about 40. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.50 for (Z)-17-deacetylnorgestimate, about 0.56 for (E)-17-deacetylnorgestimate, about 0.72 for norgestimate related compound A, 0.86 for (Z)-norgestimate, and 1.0 for (E)-norgestimate; and the resolution, R, between (Z)-17-deacetylnorgestimate and (E)-17-deacetylnorgestimate is not less than 1.5, and that between (E)-17-deacetylnorgestimate and norgestimate related compound A is not less than 1.5; the tailing factor for (E)-norgestimate and for (Z)-norgestimate is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area ratio of (E)-norgestimate to (Z)-norgestimate, is not more than 2.0%. Chromatograph the Sensitivity solution, and record the peak areas as directed for Procedure: the signal-to-noise ratio for (Z)-norgestimate is not less than 3.0.
Procedure—
Separately inject equal volumes (about 25 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak areas. Calculate the percentage of each impurity in the portion of Norgestimate taken by the formula:
5000(CP/W)(ri /FrS)
in which C is the concentration, in mg per mL, of USP Norgestimate RS in the Standard solution; P is the fraction of (E)-norgestimate in USP Norgestimate RS; W is the weight, in mg, of Norgestimate taken to prepare the Test solution; ri is the peak area for each impurity obtained from the Test solution; F is the relative response factor for each impurity; and rS is the peak area of (E)-norgestimate, eluting at about 13.5 minutes, obtained from the Standard solution. The impurities meet the requirements specified in the table below.
| Impurities | Relative Response Time |
Relative Response Factor |
Limit (not more than) |
|---|---|---|---|
| (Z)-17-Deacetylnorgestimate* | 0.50 | 0.83 | 0.3% |
| (E)-Deacetylnorgestimate* | 0.56 | 1.13 | 0.3% |
| Norgestimate related compound A (levonorgestrel acetate) | 0.72 | 0.85 | 0.3% |
| Any other impurity | — | 1.0 | 0.1% |
|
*
Provided as a mixture called USP Deacetylnorgestimate RS; their combined limits are not more than 0.3%.
|
|||
test 2—
Mobile phase—
Prepare a filtered and degassed mixture of cyclohexane and absolute alcohol (50:1). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard solution—
Dissolve an accurately weighed quantity of USP Norgestimate RS in Mobile phase, and dilute quantitatively, and stepwise if necessary, with Mobile phase to obtain a solution having a known concentration of about 1.0 mg per mL.
System suitability solution—
Dilute a portion of the Standard solution quantitatively, and stepwise if necessary, with Mobile phase to obtain a solution having a known concentration of about 0.5 µg per mL.
Test solution—
Transfer about 10 mg of Norgestimate, accurately weighed, to a 10-mL volumetric flask, dissolve in and dilute with Mobile phase to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 210-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L20. The flow rate is about 1 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the signal-to-noise ratio for (E)-norgestimate is not less than 3.0. Chromatograph the Standard solution, and record the peak areas as directed for Procedure: the retention time is about 18.6 minutes for (E)-norgestimate; the relative retention times are about 1.0 for (E)-norgestimate and 1.1 for (Z)-norgestimate; the resolution, R, between (Z)-norgestimate and (E)-norgestimate is not less than 1.5; the tailing factor is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area of (Z)-norgestimate to (E)-norgestimate, is not more than 2.0%.
621)—
The liquid chromatograph is equipped with a 210-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L20. The flow rate is about 1 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the signal-to-noise ratio for (E)-norgestimate is not less than 3.0. Chromatograph the Standard solution, and record the peak areas as directed for Procedure: the retention time is about 18.6 minutes for (E)-norgestimate; the relative retention times are about 1.0 for (E)-norgestimate and 1.1 for (Z)-norgestimate; the resolution, R, between (Z)-norgestimate and (E)-norgestimate is not less than 1.5; the tailing factor is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area of (Z)-norgestimate to (E)-norgestimate, is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 25 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak areas. Calculate the percentage of each impurity in the portion of Norgestimate taken by the formula:
1000(CP/W)(ri / FrS)
in which C is the concentration, in mg per mL, of USP Norgestimate RS in the Standard solution; P is the fraction of (E)-norgestimate in USP Norgestimate RS; W is the weight, in mg, of Norgestimate taken to prepare the Test solution; ri is the peak area for each impurity obtained from the Test solution; F is the relative response factor and is equal to 1.4 for any peak having a relative retention time of 0.74, 1.5 for any peak having a relative retention time of 0.78, and 1.2 for any peak having a relative retention time of 0.91; and rS is the peak area of (E)-norgestimate obtained from the Standard solution. Not more than 0.2% of the impurity having a relative retention time of 0.74 is found; and not more than 0.1% each of the impurities having relative retention times of 0.78 and 0.91 is found. Not more than 1.0% of total impurities is found, the results for Test 1 and Test 2 being added.
Assay—
Diluent—
Prepare a mixture of methanol and water (4:1).
Mobile phase—
Prepare a filtered and degassed mixture of water, tetrahydrofuran, and acetonitrile (30:11:9). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard preparation—
Dissolve an accurately weighed quantity of USP Norgestimate RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.5 mg per mL.
Sensitivity solution—
Dilute a portion of Standard preparation, quantitatively and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.05 µg per mL.
Assay preparation—
Transfer about 25 mg of Norgestimate, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 244-nm detector and a 4.6-mm × 10-cm column that contains 3-µm packing L1. The flow rate is about 1.2 mL per minute. The column temperature is maintained at about 40. Chromatograph the Sensitivity solution,and record the peak areas as directed for Procedure: the signal-to-noise ratio for (Z)-norgestimate is not less than 3.0. Chromatograph the Standard preparation, and record the peak areas as directed for Procedure: the relative retention times are about 0.86 for (Z)-norgestimate and 1.0 for (E)-norgestimate; the resolution, R, between (Z)-norgestimate and (E)-norgestimate is not less than 1.5; the tailing factor for (E)-norgestimate and for (Z)-norgestimate is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area ratio of (E)-norgestimate to (Z)-norgestimate, is not more than 2.0%.
621)—
The liquid chromatograph is equipped with a 244-nm detector and a 4.6-mm × 10-cm column that contains 3-µm packing L1. The flow rate is about 1.2 mL per minute. The column temperature is maintained at about 40. Chromatograph the Sensitivity solution,and record the peak areas as directed for Procedure: the signal-to-noise ratio for (Z)-norgestimate is not less than 3.0. Chromatograph the Standard preparation, and record the peak areas as directed for Procedure: the relative retention times are about 0.86 for (Z)-norgestimate and 1.0 for (E)-norgestimate; the resolution, R, between (Z)-norgestimate and (E)-norgestimate is not less than 1.5; the tailing factor for (E)-norgestimate and for (Z)-norgestimate is not more than 1.5; and the relative standard deviation for replicate injections, determined from the peak area ratio of (E)-norgestimate to (Z)-norgestimate, is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 25 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantity, in mg, of C23H31NO3 in the portion of Norgestimate taken by the formula:
50C(rU / rS)
in which C is the concentration, in mg per mL, of USP Norgestimate RS in the Standard preparation; and rU and rS are the sums of the peak areas of (Z)-norgestimate and (E)-norgestimate obtained from the Assay preparation and the Standard preparation, respectively. Calculate the percentages of the (Z)- and (E)-isomers, UZ and UE, respectively, in the portion of Norgestimate taken by the formula:
5000(CP/W)(rU / rS)
in which C is the concentration, in mg per mL, of USP Norgestimate RS in the Standard preparation; P is the fraction of (E)- or (Z)-norgestimate in USP Norgestimate RS; W is the weight, in mg, of Norgestimate taken to prepare the Assay preparation; and rU and rS are the peak responses of the appropriate norgestimate isomer obtained from the Assay preparation and the Standard preparation, respectively. Calculate the ratio of (E)-norgestimate to (Z)-norgestimate, that is, the ratio of UE to UZ.
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 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4083
Pharmacopeial Forum: Volume No. 32(4) Page 1094