Trazodone Hydrochloride

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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C₁₉H₂₂CIN₅O · HCI             408.32

1,2,4-Triazolo[4,3-a]pyridin-3(2H)-one, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-, monohydrochloride;

2-[3-[4-(m-Chlorophenyl)-1-piperazinyl]propyl]-s-triazolo[4,3-a]-pyridin-3(2H)-one monohydrochloride CAS RN^®: 25332-39-2; UNII: 6E8Z08LRNM.

1 DEFINITION

Trazodone Hydrochloride contains NLT 98.0% and NMT 102.0% of trazodone hydrochloride (C₁₉H₂₂CIN₅O · HCI), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K (CN 1-MAY-2020)

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

Solution A: 0.01% (v/v) of triethylamine in water

Solution B: 0.01% (v/v) of triethylamine in acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (80:20)

System suitability solution: 1 µg/mL each of USP Trazodone Related Compound C RS and USP Trazodone Related Compound D.RS, and 0.1 mg/mL of USP Trazodone Hydrochloride RS in Diluent

Standard solution: 1 mg/mL of USP Trazodone Hydrochloride RS in Diluent

Sample solution: 1 mg/mL of Trazodone Hydrochloride in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 7.5-cm; 3.5-µm packing L1

Flow rate: 2 mL/min

Injection volume: 10 µL

[NOTE-A mixture of acetonitrile, 2-propanol, acetone, and formic acid (400:300:300:2) is recommended for injector wash to minimize the sample carry-over.]

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between trazodone related compound C and trazodone; NLT 2.8 between trazodone and trazodone related compound D, System suitability solution

Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of trazodone hydrochloride (C₁₉H₂₂CIN₅O · HCI) in the portion of Trazodone Hydrochloride taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of trazodone from the Sample solution

r_S = peak response of trazodone from the Standard solution

C_S = concentration of USP Trazodone Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Trazodone Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.2%

4.2 ORGANIC IMPURITIES

Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 1 µg/mL each of USP Trazodone Related Compound C RS and USP Trazodone Related Compound D RS in the Standard solution

Standard solution: 1 µg/mL of USP Trazodone Hydrochloride RS in Diluent

Sample solution: 1 mg/mL of Trazodone Hydrochloride in Diluent

System suitability

Sample: System suitability solution

[NOTE-Refer to Table 2 for the relative retention times.]

Suitability requirements

Relative standard deviation: NMT 5.0% for the trazodone peak

Resolution: NLT 1.5 between trazodone related compound C and trazodone; NLT 2.8 between trazodone and trazodone related compound D

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Trazodone Hydrochloride taken:

                         Result = (r_U/r_S) × (C_S/C_U) x (1/F) x 100

r_U = peak response of each individual impurity from the Sample solution

r_S = peak response of trazodone from the Standard solution

C_S = concentration of USP Trazodone Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Trazodone Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

Table 2

^a [1,2,4] Triazolo[4,3-a]pyridin-3(2H)-one.

^b 4-(3-Chlorophenyl)-1-[3-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)propyl]piperazine 1-oxide.

^c 2-[3-(4-Phenylpiperazin-1-yl)propyl]-[1,2,4]triazolo [4,3-a]pyridin-3(2H)-one.

^d 2-(3-[4-(3-Chloro-4-ethylphenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

^e 1-(3-Chlorophenyl)-4-(3-isobutoxypropyl)piperazine.

^f 1,3-Bis(4-(3-chlorophenyl)piperazin-1-yl)propane.

4.3 LIMIT OF TRAZODONE RELATED COMPOUND F AND CYCLOPHOSPHAMIDE RELATED COMPOUND A

[NOTE-Perform this test only if trazodone related compound F and Cyclophosphamide related compound A are known process impurities.]

Solution A: 5 mM ammonium bicarbonate solution

Solution B: Acetonitrile

Diluent: Acetonitrile, water, and formic acid (100:900:1)

Standard solution: 0.025 µg/mL each of USP Trazodone Related Compound F RS and USP Cyclophosphamide Related Compound A RS, in Diluent

Sample solution: 0.01 g/mL of Trazodone Hydrochloride in Diluent

Mobile phase: See Table 3.

Table 3

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: MS/MS (tandem mass spectrometer)

MS conditions

Ionization: Triple quadrupole ionization in positive ion mode

Acquisition mode: Multiple reaction monitoring (MRM) of the following mass transitions:

Cyclophosphamide related compound A 142 → 63

Trazodone related compound F 273 → 120

Column: 4.6-mm x 7.5-cm; 3.5-µm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Flow rate to ion source: 0.5 mL/min

Injection volume: Adjust to between 5 and 50 µL, depending on the mass spectrometer. [NOTE-A mixture of 2-propanol, water, and formic acid (800:200:1) is recommended for the injector wash to minimize the sample carry-over.]

System suitability

Sample: Standard solution

[NOTE-The relative retention times of cyclophosphamide related compound A and trazodone related compound F are 0.4 and 1.0, respectively.]

Suitability requirements

Signal-to-noise ratio: NLT 100 for the trazodone related compound F peak and NLT 50 for the cyclophosphamide related compound A peak

Relative standard deviation: NMT 15.0% each for trazodone related compound F and cyclophosphamide related compound A

Analysis

Samples: Standard solution and Sample solution

[NOTE-Under the chromatographic conditions, the elution order is cyclophosphamide related compound A, trazodone, and trazodone related compound F. Use of an appropriate switching valve program in order to completely divert the trazodone peak to waste between the elution times of the two impurities is recommended.]

Calculate, in µg/g, the amount of trazodone related compound F and cyclophosphamide related compound A in the portion of Trazodone Hydrochloride taken:

                         Result = (r_U/r_S) × (C_S/C_U)

r_U = peak response of trazodone related compound F or cyclophosphamide related compound A from the Sample solution

r_S = peak response of trazodone related compound For cyclophosphamide related compound A from the Standard solution

C_S = concentration of USP Trazodone Related Compound F. RS or USP Cyclophosphamide Related Compound A RS in the Standard solution (µg/mL)

C_U = concentration of Trazodone Hydrochloride in the Sample solution (g/mL)

Acceptance criteria: NMT 2.5 µg/g each of trazodone related compound F and cyclophosphamide related compound A

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry at a pressure of 50 mm of mercury at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers.

USP REFERENCE STANDARDS (11)

USP Cyclophosphamide Related Compound A RS

Bis(2-chloroethyl)amine hydrochloride.

C₄H₁₀CI₃N          178.48

USP Trazodone Hydrochloride RS

USP Trazodone Related Compound C RS

2-(3-[4-(4-Chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride.

C₁₉H₂₂CIN₅O · HCI          408.32

USP Trazodone Related Compound D. RS

2-(3-[4-(3-Bromophenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride.

C₁₉H₂₂BrN₅O · HCI             452.78

USP Trazodone Related Compound F. RS

1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride.

C₁₃H₁₈CI₂N₂ · HCI              309.66