Mirtazapine
(mir taz' a peen).
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265.35Pyrazino[2,1-a]pyrido[2,3-c][2]benzazepine,1,2,3,4,10,14b-hexahydro-2-methyl-.
1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]-benzazepine
[85650-52-8].» Mirtazapine contains not less than 98.0 percent and not more than 102.0 percent of C17H19N3, calculated on the anhydrous basis.
Packaging and storage—
Preserve in tight containers, and store at controlled room temperature.
Labeling—
Label it to indicate whether it is anhydrous or hemihydrate.
USP Reference standards 
11
—
11—
USP Mirtazapine RS 
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USP Mirtazapine Resolution Mixture RS
This resolution mixture contains approximately 0.1% w/w each of the following:
Impurity A: 14bRS-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c]benzazepine 2-oxide.
Impurity B: [2-[(2RS)-4-methyl-2-phenylpiperazin-1-yl]pyridin-3-yl]methanol.
Impurity C: (14bRS)-2-methyl-3,4,10,14b-tetrahydropyrazinol[2,1-a]pyridol[2,3-c][2]benzazepin-1(2H)-one.
Impurity F: (14bRS)-2-methyl-1,3,4,14b-tetrahydropyrazino[2,1-a]pyrido[2,3-c]benzazepin-10(2H)-one.
Impurity E: 0.2% w/w of (2RS)-4-methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine.
Impurity D: 0.5% w/w of (14bRS)-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine.
This resolution mixture contains approximately 0.1% w/w each of the following:
Impurity A: 14bRS-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c]benzazepine 2-oxide.
Impurity B: [2-[(2RS)-4-methyl-2-phenylpiperazin-1-yl]pyridin-3-yl]methanol.
Impurity C: (14bRS)-2-methyl-3,4,10,14b-tetrahydropyrazinol[2,1-a]pyridol[2,3-c][2]benzazepin-1(2H)-one.
Impurity F: (14bRS)-2-methyl-1,3,4,14b-tetrahydropyrazino[2,1-a]pyrido[2,3-c]benzazepin-10(2H)-one.
Impurity E: 0.2% w/w of (2RS)-4-methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine.
Impurity D: 0.5% w/w of (14bRS)-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine.
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 I 921:
not more than 3.5%.
921:
not more than 3.5%.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
0.001%.
231:
0.001%.
Related compounds—
Diluent, Buffer solution, and Mobile phase—
Proceed as directed in the Assay.
System suitability solution—
Dissolve a suitable quantity of USP Mirtazapine Resolution Mixture RS in Diluent to obtain a solution with a final concentration of about 1.5 mg per mL.
Standard solution—
Dilute quantitatively a suitable volume of the Standard preparation, as prepared in the Assay, with Diluent to obtain a solution having a known concentration of about 0.0015 mg per mL (1.5 µg per mL).
Test solution—
Proceed as directed for the Assay stock preparation, as prepared in the Assay.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 240-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 40
. Chromatograph the System suitability solution. Identify the impurity peaks using the relative retention time (RRT) values given in Table 1. The resolution between peaks due to impurity E and F is not less than 1.5. Chromatograph the Standard solution, and record the peak response as directed for Procedure: the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 10.0%.
621)—
The liquid chromatograph is equipped with a 240-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 40. Chromatograph the System suitability solution. Identify the impurity peaks using the relative retention time (RRT) values given in Table 1. The resolution between peaks due to impurity E and F is not less than 1.5. Chromatograph the Standard solution, and record the peak response as directed for Procedure: the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 10.0%.
Procedure—
Separately inject equal volumes (about 10 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms for about twice the retention time of mirtazapine, and measure the responses for the major peaks. Identify the impurity peaks using the relative retention time values given in Table 1.
Table 1
| Impurity Name | Approximate RRT |
F | Limit (%) |
|---|---|---|---|
| A1 | 0.2 | 0.8 | 0.1 |
| B2 | 0.3 | 0.8 | 0.1 |
| C3 | 0.35 | 1.0 | 0.1 |
| D4 | 0.4 | 1.0 | 0.1 |
| Mirtazapine | 1.0 | — | — |
| E5 | 1.3 | 1.0 | 0.1 |
| F6 | 1.35 | 5 | 0.1 |
| Individual unspecified impurity | — | — | 0.10 |
| Total impurities | — | — | 0.5 |
|
1
(14bRS)-2-Methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine 2-oxide.
2
[2-[(2RS)-4-Methyl-2-phenylpiperazin-1-yl]pyridin-3-yl]methanol.
3
(14bRS)-2-Methyl-3,4,10,14b-tetrahydropyrazinol[2,1-a]pyrido[2,3-c][2]benzazepin-1(2H)-one.
4
(14bRS)-1,2,3,4,10,14b-Hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine.
5
(2RS)-4-Methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine.
6
(14bRS)-2-Methyl-1,3,4,14b-tetrahydropyrazino[2,1-a]pyrido[2,3-c]benzazepin-10(2H)-one.
|
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Calculate the percentage of each impurity in the portion of Mirtazapine taken by the formula:
100(CS / CU)(ri / rS)(1/ F) in which CS
is the concentration, in mg per mL, of USP Mirtazapine RS in the Standard solution; CU is the concentration, in mg per mL, of Mirtazapine in the Test solution; ri is the peak response of any impurity obtained from the Test solution; rS is the mirtazapine peak response obtained from the Standard solution; and F is the corresponding relative response factor for the impurity obtained from Table 1. [note—Disregard any peak with a result of 0.05% or less, as calculated using the formula given above. ]
Assay—
Diluent:
a mixture of acetonitrile and water (50:50).
Buffer solution—
Transfer about 36.0 g of tetramethylammonium hydroxide pentahydrate to a 2000-mL volumetric flask, and dissolve in about 1900 mL of water. While stirring, adjust with phosphoric acid to a pH of 7.4, dilute with water to volume, and mix.
Mobile phase—
Prepare a filtered and degassed mixture of Buffer solution, acetonitrile, methanol, and tetrahydrofuran (65:15:12.5:7.5). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard preparation—
Dissolve an accurately weighed quantity of USP Mirtazapine RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.3 mg per mL.
Assay stock preparation—
Dissolve a suitable quantity of Mirtazapine with Diluent to obtain a solution with a final known concentration of about 1.5 mg per mL.
Assay preparation—
Quantitatively dilute a suitable volume of the Assay stock preparation with Diluent to obtain a solution with a final concentration of about 0.3 mg per mL.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 290-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 40. Chromatograph the Standard preparation, and record the peak response as directed for Procedure: the column efficiency is not less than 7000 theoretical plates; the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 1.0%.
621)—
The liquid chromatograph is equipped with a 290-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 40. Chromatograph the Standard preparation, and record the peak response as directed for Procedure: the column efficiency is not less than 7000 theoretical plates; the tailing factor is not more than 2.0; and the relative standard deviation for replicate injections is not more than 1.0%.
Procedure—
Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of C17H19N3 in the portion of Mirtazapine taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of USP Mirtazapine RS in the Standard preparation; CU is the concentration, in mg per mL, of Mirtazapine in the Assay preparation; and rU and rS are the peak responses 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 | Hariram Ramanathan, M.S.
Associate Scientific Liaison 1-301-816-8313 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 3932
Pharmacopeial Forum: Volume No. 34(4) Page 964