Anastrozole
(an as' troe zole).
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293.371,3-Benzenediacetonitrile,
,,¢,¢-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-.
,,¢,¢-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-m-benzenediacetonitrile
[120511-73-1].» Anastrozole contains not less than 98.0 percent and not more than 102.0 percent of C17H19N5, calculated on the anhydrous and solvent-free basis.
Packaging and storage—
Preserve in well-closed containers. Store at room temperature.
USP Reference standards 
11
—
11—
USP Anastrozole RS
USP Anastrozole Related Compound A RS 
2,2¢-(5-methyl-1,3-phenylene)bis(2-methylpropanenitrile).
C15H18N2 226.32
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2,2¢-(5-methyl-1,3-phenylene)bis(2-methylpropanenitrile).
C15H18N2 226.32
Identification—
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.
Water, Method Ic 921:
not more than 0.3%.
921:
not more than 0.3%.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
not more than 0.001%.
231:
not more than 0.001%.
Related compounds—
Solution A and Solution B—
Prepare as directed in the Assay.
Peak identification solution—
Transfer accurately weighed quantities of USP Anastrozole RS and USP Anastrozole Related Compound A RS to a suitable volumetric flask, add a quantity of acetonitrile equivalent to about 40% of the volume of the flask to dissolve, and dilute with Solution A to volume to obtain a solution having known concentrations of about 0.5 mg of each per mL. Transfer 1 mL of this solution to a 50-mL volumetric flask, and dilute with Solution A to volume.
Standard solution—
Dissolve an accurately weighed quantity of USP Anastrozole RS in acetonitrile, and dilute quantitatively, and stepwise if necessary, with Solution A to obtain a solution having a known concentration of about 0.02 mg per mL.
Test solution—
Transfer about 50 mg of Anastrozole to a 25-mL volumetric flask, and add about 10 mL of acetonitrile. Dissolve in and dilute with Solution A to volume.
Blank solution—
Transfer 10 mL of acetonitrile to a 25-mL volumetric flask, and dilute with Solution A to volume.
Chromatographic system
(see Chromatography 621)—Prepare as directed in the Assay. Chromatograph the Peak identification solution, and record the peak responses as directed for Procedure: the relative retention times for anastrozole and anastrozole related compound A are listed in Table 1. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the tailing factor of the anastrozole peak is between 0.9 and 1.4; and the relative standard deviation for replicate injections of the anastrozole peak is not more than 5%.
621)—Prepare as directed in the Assay. Chromatograph the Peak identification solution, and record the peak responses as directed for Procedure: the relative retention times for anastrozole and anastrozole related compound A are listed in Table 1. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the tailing factor of the anastrozole peak is between 0.9 and 1.4; and the relative standard deviation for replicate injections of the anastrozole peak is not more than 5%.
Procedure—
Separately inject equal volumes (about 10 µL) of the Blank solution, the Standard solution, and the Test solution into the chromatograph, record the chromatograms, and measure the peak areas. Adjust the peak areas for any interference from the Blank solution. Calculate the percentage of each anastrozole related compound in the portion of Anastrozole taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of anastrozole in the Standard solution; CU is the concentration, in mg per mL, of the Test solution; and rU and rS are the peak areas of anastrozole related compound obtained from the Test solution and the Standard solution, respectively. The limits are given in Table 1. [note—Any impurity of less than 0.05% is disregarded. ]
Table 1
| Name | Relative Retention Time | Limit (%) |
|---|---|---|
| Anastrozole related compound B1 | 0.6 | 0.2 |
| Anastrozole | 1.0 | — |
| Anastrozole related compound C2 | 2.0 | 0.2 |
| Anastrozole related compound A3 | 4.0 | — |
| Anastrozole related compound D4 | 4.3 | 0.1 |
| Anastrozole related compound E5 | 5.4 | 0.1 |
| Individual unspecified impurity | — | 0.1 |
| Total unspecified impurities | — | 0.2 |
| Total impurities | — | 0.5 |
|
1
2-(3-(1-Cyanoethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl)-2-methylpropionitrile [C16H17N5, 279.34].
2
2,3-Bis(3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl)-2-methylpropionitrile [C30H31N9, 517.63].
3
The relative retention time of anastrozole related compound A has been included for system suitability purposes only and is not intended for quantification.
4
2,2¢-(5-(Bromomethyl)-1,3-phenylene)bis(2-methylpropionitrile) [C15H17BrN2, 305.21].
5
2,2¢ -(5-(Dibromomethyl)-1,3-phenylene)bis(2-methylpropionitrile) [C15H16Br2N2, 384.11].
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Assay—
Solution A—
Prepare a mixture of water, methanol, acetonitrile, and trifluoroacetic acid (600:300:100:0.5). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Solution B—
Prepare a mixture of methanol, water, acetonitrile, and trifluoroacetic acid (450:400:150:0.5). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard preparation—
Transfer a suitable quantity of USP Anastrozole RS to a suitable volumetric flask, and add a quantity of acetonitrile equivalent to about 40% of the volume of the flask. Dissolve in and dilute with Solution A to volume to obtain a solution having a known concentration of about 0.5 mg per mL.
Assay preparation—
Transfer about 25 mg of Anastrozole to a 50-mL volumetric flask, and add about 20 mL of acetonitrile. Dissolve in and dilute with Solution A to volume.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 215-nm detector and a 3.2-mm × 10-cm column that contains 5-µm packing L42. The flow rate is about 0.75 mL per minute. The chromatograph is programmed as follows.
[note—These gradient elution times are established on an HPLC system with a dwell time of approximately 0 minutes. The gradient elution times in the table can be adjusted by subtracting the dwell time to achieve the separation described. ] Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor of the anastrozole peak is between 0.9 and 1.4; and the relative standard deviation for replicate injections of the anastrozole peak is not more than 1.5%.
621)—
The liquid chromatograph is equipped with a 215-nm detector and a 3.2-mm × 10-cm column that contains 5-µm packing L42. The flow rate is about 0.75 mL per minute. The chromatograph is programmed as follows.
| Time (minutes) |
Solution A
(%) |
Solution B
(%) |
 Elution |
|---|---|---|---|
| 0–10 | 100 | 0 | isocratic |
| 10–40 | 100®0 | 0®100 | linear gradient |
| 40–41 | 0®100 | 100®0 | linear gradient |
| 41–56 | 100 | 0 | equilibration |
Procedure—
Inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the peak areas. Calculate the percentage of C17H19N5 in the portion of Anastrozole taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of anastrozole in the Standard preparation; CU is the concentration of anastrozole in the Assay preparation; and rU and rS are the peak areas obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Feiwen Mao, M.S.
Senior Scientific Liaison 1-301-816-8320 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2217
Pharmacopeial Forum: Volume No. 34(2) Page 244