Mirtazapine

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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C₁₇H₁₉N₃                          265.35

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          CAS RN: 85650-52-8; UNII: A051Q2099Q.

1 DEFINITION

Mirtazapine contains NLT 98.0% and NMT 102.0% of mirtazapine (C₁₇H₁₉N₃), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Standard solution: 0.3 mg/mL of USP Mirtazapine RS in Diluent OFFICIAL

Diluent: Acetonitrile and water (1:1)

Buffer : Dissolve 18 g of tetramethylammonium hydroxide pentahydrate in 950 mL of water. Adjust with phosphoric acid to a pH of 7.4. Dilute with water to 1 L.

12.5:7.5:65) Mobile phase: Acetonitrile, methanol, tetrahydrofuran, and Buffer (15:12.5:7.5:65)

Sample solution: 0.3 mg/mL of Mirtazapine in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 290 nm

Column: 4.6-mm x 25-cm; packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 7000 theoretical plates

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of mirtazapine (C₁₇H₁₉N₃) in the portion of Mirtazapine taken:

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

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

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

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

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

RESIDUE ON IGNITION (281); NMT 0.1%

ORGANIC IMPURITIES

Diluent, Buffer, and Mobile phase: Prepare as directed in the Assay.

System suitability solution: 1.5 mg/mL of USP Mirtazapine Resolution Mixture RS in Diluent

Standard solution: 0.0015 mg/mL of USP Mirtazapine RS in Diluent

Sample solution: 1.5 mg/mL of Mirtazapine in Diluent

Chromatographic system

(See Chromatography (621) System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 25-cm; packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: Twice the retention time of mirtazapine

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times are listed in Table 1.1

Suitability requirements

Resolution: NLT 1.5 between acyclomirtazapine methyl derivative (impurity E) and 10-ketomirtazapine (impurity F), System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 10.0%, Standard solution.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Mirtazapine taken:

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

r_u = peak response of any impurity from the Sample solution

r_s = peak response of mirtazapine from the Standard solution

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

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

F = relative response factor (see Table 1)

[Note—Disregard any peak with a result of 0.05% or less, as calculated using the formula given above.]

Acceptance criteria: See Table 1.

Table 1

[Note—Disregard any peak representing less than 0.05% of the main peak and any peak that is due to the Diluent.]

^a 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine 2-oxide (Impurity A).

^b (2-(4-Methyl-2-phenylpiperazin-1-yl)pyridin-3-yl)methanol (Impurity B).

^c (2-Methyl-3,4,10,14b-tetrahydrobenzo[c]pyrazino[1,2-a]pyrido[3,2-f]azepin-1(2H)-one (Impurity C).

^d 1,2,3,4,10,14b-Hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine (Impurity D).

^e 4-Methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine (Impurity E).

^f 2-Methyl-1,2,3,4-tetrahydrobenzo[c]pyrazino[1,2-a]pyrido[3,2-f]azepin-10(14bH)-one (Impurity F).

5 SPECIFIC TESTS

 Water Determination, Method I 〈921〉: NMT 3.5%

Optical Rotation, Specific Rotation 〈781S〉

Sample solution: 10 mg/mL, in denatured alcohol

Acceptance criteria: +2° to −2°

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

Labeling: Label it to indicate whether it is anhydrous or hemihydrate.

Change to read:

USP Reference Standards 〈11〉

USP Mirtazapine RS

USP Mirtazapine Resolution Mixture RS

Mirtazapine.

Impurity A: 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine 2-oxide.

Impurity B: (2-(4-Methyl-2-phenylpiperazin-1-yl)pyridin-3-yl)methanol.

Impurity C: (2-Methyl-3,4,10,14b-tetrahydrobenzo[c]pyrazino[1,2-a]pyrido[3,2-f]azepin-1(2H)-one.

Impurity D: [Note—This impurity may be available either as the free base form or as the hydrochloride salt form.] (ERR 1-Apr-2021) 1,2,3,4,10,14b-Hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine or 1,2,3,4,10,14b-Hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine hydrochloride. (ERR 1-Apr-2021)

Impurity E: 4-Methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine.

Impurity F: 2-Methyl-1,2,3,4-tetrahydrobenzo[c]pyrazino[1,2-a]pyrido[3,2-f]azepin-10(14bH)-one.