Formoterol Fumarate
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840.91(±)-2¢-Hydroxy-5¢-[(R*)-1-hydroxy-2-[[(R*)-p-methoxy-
-methylphenethyl]amino]ethyl]formanilide fumarate (2:1) (salt), dihydrate
[43229-80-7].» Formoterol Fumarate contains not less than 98.5 percent and not more than 101.5 percent of (C19H24N2O4)2 · C4H4O4, calculated on the anhydrous basis.
Packaging and storage—
Preserve in well-closed, light-resistant containers.
Labeling—
The labeling states with which Content of related compound I the test article complies if a test other than Content of related compound I, Test 1 is used.
USP Reference standards 
11
—
11—
USP Formoterol Fumarate RS 
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USP Formoterol Fumarate System Suitability Mixture RS
It is a mixture of USP Formoterol Fumarate RS and formoterol related compounds A, B, C, D, E, F, G, and H.
Formoterol related compound A: 1-(3-Amino-4-hydroxyphenyl)-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol.
Formoterol related compound B: N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[2-(4-methoxyphenyl)ethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound C: N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]acetamide.
Formoterol related compound D: N-[2-Hydroxy-5-[1-hydroxy-2-[methyl[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound E: N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-3-methylphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound F: N-[2-Hydroxy-5-[1-[[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]amino]-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound G: (2RS)-1-(4-Methoxyphenyl)propan-2-amine.
Formoterol related compound H: N-[5-[(1RS)-2-[Benzyl[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]formamide (monobenzyl analogue).
It is a mixture of USP Formoterol Fumarate RS
and formoterol related compounds A, B, C, D, E, F, G, and H.
Formoterol related compound A: 1-(3-Amino-4-hydroxyphenyl)-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol.
Formoterol related compound B: N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[2-(4-methoxyphenyl)ethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound C: N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]acetamide.
Formoterol related compound D: N-[2-Hydroxy-5-[1-hydroxy-2-[methyl[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound E: N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-3-methylphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound F: N-[2-Hydroxy-5-[1-[[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]amino]-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
Formoterol related compound G: (2RS)-1-(4-Methoxyphenyl)propan-2-amine.
Formoterol related compound H: N-[5-[(1RS)-2-[Benzyl[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]formamide (monobenzyl analogue).
USP Formoterol Resolution Mixture RS
This standard is a mixture of formoterol and formoterol fumarate impurity I.
Impurity I: N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1SR)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide fumarate salt (2:1)(diastereoisomer).
This standard is a mixture of formoterol and formoterol fumarate impurity I.
Impurity I: N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1SR)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide fumarate salt (2:1)(diastereoisomer).
Optical rotation, Angular Rotation 781A:
between –0.10
and +0.10.
781A:
between –0.10 and +0.10.
Test solution:
10 mg per mL, in methanol.
pH 791:
between 5.5 and 6.5, in a solution in water containing 1 mg per mL.
791:
between 5.5 and 6.5, in a solution in water containing 1 mg per mL.
Water, Method I 921:
between 4.0% and 5.0%.
921:
between 4.0% and 5.0%.
Residue on ignition 281:
not more than 0.1%, determined on 1 g.
281:
not more than 0.1%, determined on 1 g.
Heavy metals, Method II 231:
not more than 0.002%.
231:
not more than 0.002%.
Related compounds—
Solution A—
Dissolve 3.73 g of sodium dihydrogen phosphate monohydrate and 0.35 g of phosphoric acid in water, dilute with water to 1000 mL, and mix. The pH of this solution is 3.1 ± 0.1.
Solution B—
Use acetonitrile.
Mobile phase—
Use variable mixtures of Solution A and Solution B as directed for Chromatographic system. Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Solution C—
Transfer 6.10 g of sodium dihydrogen phosphate monohydrate and 1.03 g of disodium hydrogen phosphate dihydrate to a 1000-mL volumetric flask, add 500 mL of water, and dissolve. Dilute with water to volume, and mix. The pH is 6.0 ± 0.1.
Diluent—
Prepare a filtered and degassed mixture of Solution C and acetonitrile (84:16, v/v).
System suitability solution—
Transfer about 5 mg of USP Formoterol Fumarate System Suitability Mixture RS (containing formoterol fumarate, and formoterol related compounds A, B, C, D, E, F, G, and H), accurately weighed, to a 25-mL volumetric flask, add 10 mL of Diluent, and sonicate to dissolve. Dilute with Diluent to volume, and mix.
Test solution—
Transfer about 20.0 mg of Formoterol Fumarate, accurately weighed, to a 100-mL volumetric flask, add 50 mL of Diluent, and sonicate to dissolve. Dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm × 15-cm column that contains packing L7. The flow rate is about 1.0 mL per minute. The chromatograph is programmed as follows.
Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between formoterol related compound G and formoterol related compound A is not less than 1.5; the peak-to-valley ratio (HP / HV) of formoterol related compound C and formoterol is not less than 2.5, where HP is the height above the baseline of the peak due to formoterol related compound C, and HV is the height above the baseline of the lowest point of the curve separating this peak from the peak due to formoterol; and the relative retention times and limits are as provided in Table 1.
621)—
The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm × 15-cm column that contains packing L7. The flow rate is about 1.0 mL per minute. The chromatograph is programmed as follows.
| Time (minutes) |
Solution A
(%) |
Solution B
(%) |
 Elution |
|---|---|---|---|
| 0 | 84 | 16 | equilibration |
| 0–10 | 84 | 16 | isocratic |
| 10–37 | 84®30 | 16®70 | linear gradient |
| 37–40 | 30®84 | 70®16 | linear gradient |
| 40–55 | 84 | 16 | isocratic |
Table 1
| Related Compound |
Relative Retention Time |
Relative Response Factor (F) |
Limit (%) |
|---|---|---|---|
| Ga | 0.4 | 2.64 | 0.1 |
| Ab | 0.5 | 1.75 | 0.3 |
| Bc | 0.7 | 1.00 | 0.2 |
| Cd | 1.2 | 1.10 | 0.2 |
| De | 1.3 | 1.12 | 0.2 |
| Ef | 1.8 | 0.67 | 0.1 |
| Fg | 2.0 | 1.00 | 0.2 |
| Hh | 2.2 | 1.24 | 0.1 |
| Any other individual impurity | 0.1 | ||
| Total unspecified impurities | 0.2 | ||
| Total impurities | 0.5 | ||
|
a
(2RS)-1-(4-Methoxyphenyl)propan-2-amine.
b
1-(3-Amino-4-hydroxyphenyl)-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol.
c
N-[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[2-(4-methoxyphenyl)ethyl]amino]ethyl]phenyl]formamide.
d
N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]acetamide.
e
N-[2-Hydroxy-5-[1-hydroxy-2-[methyl[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
f
N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-3-methylphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
g
N-[2-Hydroxy-5-[1-[[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]amino]-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide.
h
N-[5-[(1RS)-2-[Benzyl[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]formamide (monobenzyl analogue).
|
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Procedure—
Separately inject equal volumes (about 20 µL) of the System suitability solution and the Test solution into the chromatograph, record the chromatograms, and measure all of the peak responses. Disregard any peak representing less than 0.05%. Calculate the percentage of each formoterol related compound in the portion of Formoterol Fumarate taken by the formula:
100F(ri / rs)
in which F is the relative response factor for each formoterol related compound according to Table 1; ri is the peak response for each formoterol related compound; and rs is the sum of the responses for all the peaks.
Content of related compound I (diastereoisomer)—
test 1—
Standard solution—
Dissolve 10 mg of USP Formoterol Fumarate Resolution Mixture RS in 1 mL of dimethylformamide. Add 100 µL of N-(trimethylsilyl)imidazole, and mix.
Test solution—
Dissolve 10 mg of Formoterol Fumarate in 1 mL of dimethylformamide. Add 100 µL of N-(trimethylsilyl)imidazole, and mix.
Chromatographic system (see Chromatography 621)—
The gas chromatograph is equipped with a flame-ionization detector, a 0.32-mm × 30-m fused-silica capillary column coated with a 0.25-µm film of stationary phase G27, and a split injection system. The carrier gas is helium, flowing at a rate of about 2 mL per minute and a split ratio of about 75:1. The injection port and the detector temperatures are maintained at about 280 and 300, respectively. The column temperature is programmed as follows. Initially the column temperature is equilibrated at 220 for 5 minutes, then the temperature is increased at a rate of 1 per minute to 250, and maintained at 250 for 20 minutes. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the resolution, R, between formoterol related compound I and formoterol is not less than 1.2.
621)—
The gas chromatograph is equipped with a flame-ionization detector, a 0.32-mm × 30-m fused-silica capillary column coated with a 0.25-µm film of stationary phase G27, and a split injection system. The carrier gas is helium, flowing at a rate of about 2 mL per minute and a split ratio of about 75:1. The injection port and the detector temperatures are maintained at about 280 and 300, respectively. The column temperature is programmed as follows. Initially the column temperature is equilibrated at 220 for 5 minutes, then the temperature is increased at a rate of 1 per minute to 250, and maintained at 250 for 20 minutes. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the resolution, R, between formoterol related compound I and formoterol is not less than 1.2.
Procedure—
Separately inject equal volumes (about 2 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses for formoterol related compound I and formoterol. Disregard all other peaks. Calculate the percentage of formoterol related compound I in the portion of Formoterol Fumarate taken by the formula:
100(ri / rs)
in which ri is the peak response for formoterol related compound I, and rs is the sum of the responses of both formoterol and formoterol related compound I peaks: not more than 0.3% of formoterol related compound I is found.
test 2—
Potassium phosphate solution—
Dissolve 5.3 g of tribasic potassium phosphate, trihydrate, in 1000 mL of water, and mix. Adjust the pH with potassium hydroxide or phosphoric acid to 12.0 ± 0.1.
Mobile phase—
Prepare a filtered degassed mixture of Potassium phosphate solution and acetonitrile (88:12).
Standard solution—
Dissolve 5 mg of USP Formoterol Fumarate Resolution Mixture RS in water, dilute with water to 50 mL, and mix.
Test solution—
Dissolve 5 mg of Formoterol Fumarate in water, dilute with water to 50 mL, and mix.
Diluted test solution—
Dilute 1 mL of the Test solution with water to 20 mL. Dilute 1 mL of this solution with water to 25 mL.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 225-nm detector and a 4.6-mm × 15-cm column that contains packing L67 (see Chromatographic Reagents under Reagents, Indicators, and Solutions). The flow rate is about 0.5 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for the Procedure: the peak-to-valley ratio (HP / HV) of formoterol related compound I and formoterol is not less than 2.5, where HP is the height above the baseline of the peak due to formoterol related compound I, and HV is the height above the baseline of the lowest point of the curve separating this peak from the peak due to formoterol.
621)—
The liquid chromatograph is equipped with a 225-nm detector and a 4.6-mm × 15-cm column that contains packing L67 (see Chromatographic Reagents under Reagents, Indicators, and Solutions). The flow rate is about 0.5 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for the Procedure: the peak-to-valley ratio (HP / HV) of formoterol related compound I and formoterol is not less than 2.5, where HP is the height above the baseline of the peak due to formoterol related compound I, and HV is the height above the baseline of the lowest point of the curve separating this peak from the peak due to formoterol.
Procedure—
Separately inject equal volumes (20 µL) of the Test solution and the Diluted test solution into the chromatograph, record the chromatograms, and measure the peak responses for formoterol and formoterol related compound I. The area due to formoterol related compound I is not more than 1.5 times the area of the principal peak in the chromatogram obtained with the Diluted test solution: not more than 0.3% of formoterol related compound I is found.
Assay—
Transfer about 350 mg of Formoterol Fumarate, accurately weighed, to a titration vessel, dissolve in 50 mL of anhydrous acetic acid, and titrate with 0.1 M perchloric acid VS, determining the endpoint potentiometrically. Perform a blank determination, and make any necessary correction. Each mL of 0.1 M perchloric acid is equivalent to 40.24 mg of (C19H24N2O4)2 · C4H4O4.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 3278
Pharmacopeial Forum: Volume No. 33(3) Page 402