Atomoxetine Hydrochloride
C17H21NO·HCl 291.82
Benzenepropanamine, N-methyl-
-(2-methylphenoxy)-, hydrochloride (
);
()-N-Methyl-3-phenyl-3-(o-tolyloxy)propylamine hydrochloride
[82248-59-7].
231
:
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C17H21NO·HCl 291.82
Benzenepropanamine, N-methyl-
-(2-methylphenoxy)-, hydrochloride ();
(
)-N-Methyl-3-phenyl-3-(o-tolyloxy)propylamine hydrochloride
[82248-59-7].DEFINITION
Atomoxetine Hydrochloride contains NLT 98.0% and NMT 102.0% of atomoxetine hydrochloride (C17H21NO·HCl), calculated on the dried basis.
IDENTIFICATION
• 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, Chloride 191:
Meets the requirements of the silver nitrate precipitate test
191:
Meets the requirements of the silver nitrate precipitate test
ASSAY
• Procedure
Buffer:
2.9 g/L of phosphoric acid in water. Adjust with 5 M potassium hydroxide solution 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-Propanol and Buffer (27:73). [Note—The ratio of n-propanol 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
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:
1.3 times the retention time of atomoxetine
System suitability
Samples:
System suitability solution and Standard solution
[Note—See Table 1 in Organic Impurities, Procedure 1 for 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% for atomoxetine, 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 = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Atomoxetine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Atomoxetine Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the dried basis
IMPURITIES
• Residue on Ignition 281:
NMT 0.1%
281:
NMT 0.1%
Delete the following:
231:
[Note—It is required to perform Organic Impurities, Procedure 1 and Organic Impurities, Procedure 2.
(Official 1-Dec-2015)
• Organic Impurities, Procedure 1
Buffer and Mobile phase:
Prepare as directed in the Assay.
System suitability solution:
0.10 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:
0.0025 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 to use a run time of 2.6 times the retention time of atomoxetine.
System suitability
[Note—See Table 1 for relative retention times. ]
Samples:
System suitability solution and Standard solution
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% from three injections, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Atomoxetine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of atomoxetine from the Standard solution |
| CS | = | = concentration of USP Atomoxetine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Atomoxetine Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
See Table 1.
Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
||
|---|---|---|---|---|
| Mandelic acida | 0.20 | — | ||
| Atomoxetine related compound Aa | 0.27 | — | ||
| Desmethyl atomoxetineb | 0.73 | 0.3 | ||
| Atomoxetine | 1.0 | — | ||
| Any individual unspecified impurity | — | 0.10 | ||
| Total impurities | — | 0.5 | ||
|
a
For system suitability purposes only.
b
(R)-N-Methyl-3-phenoxy-3-phenylpropan-1-amine.
|
||||
• Organic Impurities, Procedure 2
Mobile phase:
Isopropyl alcohol, diethylamine, trifluoroacetic acid, and n-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 final volume. Dilute with n-hexane to volume.
Sample solution:
3.5 mg/mL of Atomoxetine Hydrochloride prepared by first dissolving it in absolute alcohol, using 25% of final volume. Dilute with n-hexane to volume.
Chromatographic system
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:
1.3 times the retention time of atomoxetine
System suitability
Sample:
System suitability solution
[Note—See Table 2 for relative retention times. ]
Suitability requirements
Resolution:
NLT 1.75 between atomoxetine S-isomer and atomoxetine related compound B
Tailing factor:
NMT 1.8 for atomoxetine
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 = (rU/rT) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rT | = | = sum of all the peak responses of atomoxetine related compound B, atomoxetine related compound C, atomoxetine S-isomer, and atomoxetine from the Sample solution |
SPECIFIC TESTS
• Loss on Drying 731
731
Analysis:
Dry a sample under vacuum at 105 for 2 h.
for 2 h.
Acceptance criteria:
NMT 0.5%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers. Store at room temperature.
• USP Reference Standards 11
11
USP Atomoxetine Hydrochloride RS 
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USP Atomoxetine Related Compound A RS
3-(Methylamino)-1-phenylpropan-1-ol.
C10H15NO 165.23
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3-(Methylamino)-1-phenylpropan-1-ol.
C10H15NO 165.23
USP Atomoxetine Related Compound B RS
N-Methyl-3-phenyl-3-(m-tolyloxy)propan-1-amine hydrochloride.
C17H21NO·HCl 291.82
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N-Methyl-3-phenyl-3-(m-tolyloxy)propan-1-amine hydrochloride.
C17H21NO·HCl 291.82
USP Atomoxetine S-Isomer RS
(S)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine hydrochloride.
C17H21NO·HCl 291.82
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(S)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine hydrochloride.
C17H21NO·HCl 291.82
USP Mandelic Acid RS
-Hydroxyphenylacetic acid.
C8H8O3 152.15
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-Hydroxyphenylacetic acid.
C8H8O3 152.15
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Heather R. Joyce, Ph.D.
Associate Scientific Liaison (301) 998-6792 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP38–NF33 Page 2313
Pharmacopeial Forum: Volume No. 41(2)