Salmeterol Xinafoate
(sal mee' ter ol zye naf' oh ate).
Click to View Image

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%
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
•  Water Determination, Method I 921: NMT 0.25%
Sample:  0.5 g
•  Optical Rotation, Specific Rotation 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
USP Salmeterol Xinafoate RS Click to View Structure
USP Salmeterol Related Compound A RS
(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
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