Atomoxetine Hydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

Atomoxetine Hydrochloride

Change to read:

C₁₇H₂₁NO · HCl 291.82

Benzenepropanamine, N-methyl-γ-(2-methylphenoxy)-, hydrochloride, (-);

(-)-N-Methyl-3-phenyl-3-(o-tolyloxy)propylamine hydrochloride;

(R)-N-Methyl-3-phenyl-3-(2-tolyloxy)propylamine hydrochloride

CAS RN®: 82248-59-7; UNII: 57WVB6I2W0.

1 DEFINITION

Atomoxetine Hydrochloride contains NLT 98.0% and NMT 102.0% of atomoxetine hydrochloride (C₁₇H₂₁NO · HCl), calculated on the dried 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 atomoxetine R-isomer from the System suitability solution, as obtained in the test for Organic Impurities, Procedure 2.

C. Identification Tests—General 〈191〉, Chemical Identification Tests, Chloride: Meets the requirements

3 ASSAY

Procedure

Solution A: 280 g/L of potassium hydroxide in water

Buffer: 2.9 g/L of phosphoric acid in water. Adjust with Solution A to a pH of 2.5. To 1 L of this solution add 5.9 g of octanesulfonic acid sodium salt monohydrate.

Mobile phase: n-Propyl alcohol and Buffer (27:73). [Note—The ratio of n-propyl alcohol in Buffer can be varied between 26:74 and 29:71 to meet system suitability requirements.]

System suitability solution: 0.1 mg/mL of USP Mandelic Acid RS, 0.15 mg/mL of USP Atomoxetine Related Compound A RS, and 0.25 mg/mL of USP Atomoxetine Hydrochloride RS in Mobile phase

Standard solution: 0.25 mg/mL of USP Atomoxetine Hydrochloride RS in Mobile phase. Sonication may be used to aid in dissolution.

Sample solution: 0.25 mg/mL of Atomoxetine Hydrochloride in Mobile phase. Sonication may be used to aid in dissolution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L7

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of atomoxetine

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 5.0 between mandelic acid and atomoxetine related compound A, System suitability solution

Tailing factor: NMT 1.5 for atomoxetine, System suitability solution

Relative standard deviation: NMT 0.73%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of atomoxetine hydrochloride (C₁₇H₂₁NO · HCl) in the portion of Atomoxetine Hydrochloride taken:

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

r_U = peak response of atomoxetine from the Sample solution

r_S= peak response of atomoxetine from the Standard solution

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

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

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

Atomoxetine-Hydrochloride-ttt

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities, Procedure 1

[Note—It is required to perform Organic Impurities, Procedure 1 and Organic Impurities, Procedure 2.]

Buffer, Mobile phase, and System suitability solution: Prepare as directed in the Assay.

Sensitivity solution: 0.0013 mg/mL of USP Atomoxetine Hydrochloride RS in Mobile phase

Standard solution: 0.0025 mg/mL of USP Atomoxetine Hydrochloride RS in Mobile phase

Sample solution: 2.5 mg/mL of Atomoxetine Hydrochloride in Mobile phase

Chromatographic system: Proceed as directed in the Assay, except for Run time.

Run time: NLT 2.6 times the retention time of atomoxetine

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

[Note—See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 5.0 between mandelic acid and atomoxetine related compound A, System suitability solution

Tailing factor: NMT 1.5 for atomoxetine, System suitability solution

Relative standard deviation: NMT 5%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Atomoxetine Hydrochloride taken:

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

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

r_S= peak response of atomoxetine from the Standard solution

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

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

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

ᵃ (R)-N-Methyl-3-phenoxy-3-phenylpropan-1-amine.

Organic Impurities, Procedure 2

Mobile phase: Isopropyl alcohol, diethylamine, trifluoroacetic acid, and chromatographic solvent hexane (150: 1.5: 2.0: 846.5)

System suitability solution: 3.5 mg/mL of USP Atomoxetine Hydrochloride RS, 17.5 µg/mL of USP Atomoxetine S-Isomer RS, and 3.5 µg/mL of USP Atomoxetine Related Compound B RS, prepared by first dissolving the Reference Standards in absolute alcohol, using 25% of the final volume. Dilute with chromatographic solvent hexane to volume.

Sensitivity solution: 0.0018 mg/mL of USP Atomoxetine Hydrochloride RS prepared by first dissolving it in absolute alcohol, using 25% of the final volume. Dilute with chromatographic solvent hexane to volume.

Sample solution: 3.5 mg/mL of Atomoxetine Hydrochloride prepared by first dissolving it in absolute alcohol, using 25% of the final volume. Dilute with chromatographic solvent hexane to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 273 nm

Column: 4.6-mm × 25-cm; 5-µm packing L40

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.3 times the retention time of atomoxetine

System suitability

Samples: System suitability solution and Sensitivity solution

[Note—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.75 between atomoxetine S-isomer and atomoxetine related compound B, System suitability solution

Tailing factor: NMT 1.8 for atomoxetine, System suitability solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of atomoxetine related compound B, atomoxetine related compound C, and atomoxetine S-isomer in the portion of Atomoxetine Hydrochloride taken:

Result = (r_U / r_S)× 100

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

r_S= sum of all the peak responses of atomoxetine related compound B, atomoxetine related compound C, atomoxetine S-isomer, and atomoxetine from the Sample solution

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

ᵃ (R)-N-Methyl-3-phenyl-3-(4-tolyloxy)propan-1-amine; also known as (R)-N-Methyl-3-phenyl-3-(p-tolyloxy)propan-1-amine.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 105° for 2 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at room temperature.

Change to read:

USP Reference Standards 〈11〉

USP Atomoxetine Hydrochloride RS

USP Atomoxetine Related Compound A RS

3-(Methylamino)-1-phenylpropan-1-ol.

C₈H₁₁NO₂ 165.23

USP Atomoxetine Related Compound B RS

(R)-N-Methyl-3-phenyl-3-(3-tolyloxy)propan-1-amine hydrochloride.

C₁₇H₂₁NO · HCl 291.82

USP Atomoxetine S-Isomer RS

(S)-N-Methyl-3-phenyl-3-(2-tolyloxy)propan-1-amine hydrochloride; also known as (S)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine hydrochloride.

C₁₇H₂₁NO · HCl 291.82

USP Mandelic Acid RS

2-Hydroxy-2-phenylacetic acid.

C₈H₈O₃ 152.15