Mirtazapine
(mir taz' a peen).
Pyrazino[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
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.
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%.
Residue on ignition 281:
not more than 0.1%.
Heavy metals, Method II 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%.
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
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. [noteDisregard 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).
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%.
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.
USP35NF30 Page 3932
Pharmacopeial Forum: Volume No. 34(4) Page 964
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