Salmeterol Xinafoate
C25H37NO4·C11H8O3 603.75
1,3-Benzenedimethanol, 4-hydroxy-
1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-, (±)-, 1-hydroxy-2-naphthalenecarboxylate (salt);
(±)-4-Hydroxy-1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-m-xylene-,¢-diol 1-hydroxy-2-naphthoate (salt)
[94749-08-3].
(sal mee' ter ol zye naf' oh ate).
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C25H37NO4·C11H8O3 603.75
1,3-Benzenedimethanol, 4-hydroxy-
1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-, (±)-, 1-hydroxy-2-naphthalenecarboxylate (salt);
(±)-4-Hydroxy-
1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-m-xylene-,¢-diol 1-hydroxy-2-naphthoate (salt)
[94749-08-3].DEFINITION
Salmeterol Xinafoate contains NLT 98.0% and NMT 102.0% of C25H37NO4·C11H8O3, calculated on the water- and solvent-free basis.
IDENTIFICATION
• B.
The retention time of the major peak from the Sample solution corresponds to that from the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Solution A:
0.1 M sodium dodecyl sulfate
Solution B:
0.1 M ammonium acetate
Mobile phase:
Acetonitrile, Solution A, and Solution B (13:6:6). Adjust with glacial acetic acid to a pH of 3.8.
System suitability solution:
0.25 mg/mL of USP Salmeterol Xinafoate RS and 0.017 mg/mL of USP Salmeterol Related Compound B RS in Mobile phase, prepared by diluting System suitability solution 1 in the test for Organic Impurities
Standard solution:
0.25 mg/mL of USP Salmeterol Xinafoate RS in Mobile phase
Sample solution:
0.25 mg/mL of Salmeterol Xinafoate in Mobile phase
Chromatographic system
Mode:
LC
Detector:
UV 278 nm
Column:
4.6-mm × 15-cm; packing L1
Flow rate:
2 mL/min
Injection size:
20 µL
System suitability
Sample:
System suitability solution
Suitability requirements
Resolution:
NLT 1.0 between salmeterol and salmeterol related compound B
Relative standard deviation:
NMT 2.0% for salmeterol
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C25H37NO4·C11H8O3 in the portion of Salmeterol Xinafoate 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 Salmeterol Xinafoate RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Salmeterol Xinafoate in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the water- and solvent-free basis
IMPURITIES
Inorganic Impurities
• Residue on Ignition 
281
:
NMT 0.1%
281:
NMT 0.1%
Organic Impurities
• Procedure
[Note—Use freshly prepared test solutions, and protect from light. ]
Solution A, Solution B, and Chromatographic system:
Proceed as directed in the Assay.
Diluent:
Acetonitrile and water (1:1)
Solution C:
Acetonitrile, Solution A, and Solution B (13:6:6). Adjust with glacial acetic acid to a pH of 3.8.
Solution D:
Acetonitrile
Mobile phase:
See the gradient table below.
| Time (min) |
Solution C (%) |
Solution D (%) |
|---|---|---|
| 0 | 100 | 0 |
| 16.0 | 100 | 0 |
| 36.0 | 30 | 70 |
| 45.0 | 30 | 70 |
| 45.1a | 100 | 0 |
|
a
Prior to the next injection, run the sytem at the initial condition until equilibration is achieved.
|
||
System suitability solution 1:
5.0 mg/mL of USP Salmeterol Xinafoate RS and 0.34 mg/mL of USP Salmeterol Related Compound B RS in Diluent
System suitability solution 2:
1.0 mg/mL of USP Salmeterol Related Compound A RS in Diluent
Sample solution:
5.0 mg/mL of Salmeterol Xinafoate in Diluent
System suitability
Samples:
System suitability solution 1 and System suitability solution 2
Suitability requirements
Resolution:
NLT 1.0 between salmeterol and salmeterol related compound B, System suitability solution 1
Tailing factor:
NMT 2.5 for salmeterol, System suitability solution 1
Relative standard deviation:
NMT 2.0% for the salmeterol related compound A peak, System suitability solution 2
Analysis
[Note—Disregard the peak due to hydroxynaphthoic acid and any peaks from blank injections. ]
Sample:
Sample solution
Calculate the percentage of any individual impurity in the portion of Salmeterol Xinafoate taken:
Result = (rU/rT) × 100
| rU | = | = peak response of each impurity from the Sample solution |
| rT | = | = sum of peak responses from the Sample solution |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 0.9% area. [Note—Calculate the total impurities from the sum of all impurity peaks greater than or equal to 0.05%. ]
Impurity Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Hydroxynaphthoic acida | 0.2 | — |
| Salmeterol related compound Ab | 0.3 | 0.2 |
| Salmeterol-phenylethoxyc | 0.5 | 0.1 |
| Salmeterol-phenylpropoxyd | 0.7 | 0.1 |
| Salmeterol-O-alkyle | 0.8 | 0.3 |
| Salmeterol related compound Bf | 0.9 | 0.1 |
| Salmeterol xinafoate | 1.0 | — |
| Salmeterol-deoxyg | 1.6 | 0.2 |
| Salmeterol-N-alkylh | 2.7 | 0.2 |
| Any unspecified impurity | — | 0.10 |
| Total unspecified impurities | — | 0.2 |
|
a
1-Hydroxy-naphthalene-2-carboxylic acid.
b
4-[1-Hydroxy-2-(4-phenylbutylamino)ethyl]-2-(hydroxymethyl)phenol.
c
4-[1-Hydroxy-2-(6-phenethoxyhexylamino)ethyl]-2-(hydroxymethyl)phenol.
d
4-{1-Hydroxy-2-[6-(3-phenylpropoxy)hexylamino]ethyl}-2-(hydroxymethyl)phenol.
e
4-{1-Hydroxy-2-[4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}-2-(hydroxymethyl)phenoxy]ethyl}-2-(hydroxymethyl)phenol.
f
4-{1-Hydroxy-2-[6-(4-phenylbutan-2-yloxy)hexylamino]ethyl}-2-(hydroxymethyl)phenol.
g
4-{1-Hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}-2-methylphenol.
h
4-{1-Hydroxy-2-[(2-hydroxy-5-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}benzyl)[6-(4-phenylbutoxy)hexyl]amino]ethyl}-2-(hydroxymethyl)phenol.
|
||
SPECIFIC TESTS
• Optical Rotation, Specific Rotation 781S:
0.5
to +0.5 (t = 20), calculated on the anhydrous and solvent-free basis
781S:
0.5 to +0.5 (t = 20), calculated on the anhydrous and solvent-free basis
Sample solution:
10 mg/mL in methanol
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and store at a temperature not exceeding 30.
.
• Labeling:
Salmeterol Xinafoate in the form of microcrystals is so labeled.
• USP Reference Standards 11
11
USP Salmeterol Xinafoate RS 
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USP Salmeterol Related Compound A RS
(4-[1-Hydroxy-2-(4-phenylbutylamino)ethyl]-2-(hydroxymethyl)phenol).
C19H25NO3 315.41
(4-[1-Hydroxy-2-(4-phenylbutylamino)ethyl]-2-(hydroxymethyl)phenol).
C19H25NO3 315.41
USP Salmeterol Related Compound B RS
(4-{1-Hydroxy-2-[6-(4-phenylbutan-2-yloxy)hexylamino]ethyl}-2-(hydroxymethyl)phenol).
C25H37NO4 415.57
(4-{1-Hydroxy-2-[6-(4-phenylbutan-2-yloxy)hexylamino]ethyl}-2-(hydroxymethyl)phenol).
C25H37NO4 415.57
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 4603
Pharmacopeial Forum: Volume No. 35(2) Page 307