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2920 Azithromycin / Official Monographs USP 40

trile, using 2% of the final volume, and then dilute with


Diluent to volume.
.

Azithromycin Chromatographic system


(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 210 nm
Column: 4.6-mm 25-cm; 5-m packing L67
Column temperature: 40
Flow rate: 1 mL/min
Injection volume: 10 L
System suitability
Samples: System suitability solution and Standard
solution
[NOTEThe relative retention times for azaerythromycin
A and azithromycin are 0.7 and 1.0, respectively.]
Suitability requirements
C38H72N2O12 748.98 Resolution: NLT 3.0 between azaerythromycin A and
C38H72N2O12 H2O 767.00 azithromycin, System suitability solution
Tailing factor: 0.81.5 for azithromycin, Standard
C38H72N2O12 2H2O 785.02 solution
1-Oxa-6-azacyclopentadecan-15-one, 13-[(2,6-dideoxy-3-C- Relative standard deviation: NMT 1.10% for
methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl- azithromycin, Standard solution
3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4, Analysis
6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl] Samples: Standard solution and Sample solution
oxy]-, [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*, Calculate the quantity, in g, of azithromycin
14R*)]; (C38H72N2O12) in each mg of Azithromycin taken:
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-
methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl- Result = (rU/rS) (CS/CU) P
3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,
6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]oxy]- rU = peak response from the Sample solution
1-oxa-6-azacyclopentadecan-15-one; rS = peak response from the Standard solution
9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A CS = concentration of USP Azithromycin RS in the
Anhydrous [83905-01-5]. Standard solution
Monohydrate [121470-24-4]. CU = concentration of Azithromycin in the Sample
Dihydrate [117772-70-0]. solution
P = potency of USP Azithromycin RS (g/mg of
DEFINITION azithromycin)
Azithromycin is anhydrous or contains one or two molecules Acceptance criteria: 9451030 g/mg on the anhy-
USP Monographs

of water of hydration. It contains the equivalent of NLT drous basis


945 g and NMT 1030 g of azithromycin (C38H72N2O12)
per mg, calculated on the anhydrous basis. IMPURITIES
RESIDUE ON IGNITION 281: NMT 0.3%, the charred resi-
IDENTIFICATION due being moistened with 2 mL of nitric acid and
A. INFRARED ABSORPTION 197K: If a difference appears 5 drops of sulfuric acid
in the IR spectra of the analyte and the Standard, dis-
solve equal portions of the test specimen and the USP
Reference Standard in equal volumes of methanol. Evap- Delete the following:
orate the solutions to dryness on a water bath, and dry
at 80 for 30 min under vacuum. Perform the test on the HEAVY METALS, Method II 231: NMT 25 ppm (Official 1-
.

residues. Jan-2018)
B. The retention time of the azithromycin peak of the ORGANIC IMPURITIES, PROCEDURE 1
Sample solution corresponds to that of the Standard solu- Use Organic Impurities, Procedure 1 when the impurity
tion, as obtained in the Assay. profile includes erythromycin A oxime and erythromycin
A iminoether.
ASSAY Use water that has a resistivity of NLT 18 Mohm-cm.
PROCEDURE Solution A: 20 mM Dibasic potassium phosphate
Solution A: 10 M Potassium hydroxide Mobile phase: Acetonitrile and Solution A (250:750).
Solution B: 6.7 g/L of dibasic potassium phosphate ad- Adjust with 5 M potassium hydroxide to a pH of 10.55
justed with Solution A to a pH of 11.0 0.05.
Solution C: 6.7 g/L of dibasic potassium phosphate ad- Standard stock solution: 45 g/mL of USP Desosamin-
justed with phosphoric acid to a pH of 8.0 ylazithromycin RS, 105 g/mL of USP N-Demethy-
Mobile phase: Acetonitrile and Solution B (60:40) lazithromycin RS, 150 g/mL of USP Azaerythromycin A
Diluent: Acetonitrile and Solution C (60:40) RS, and 160 g/mL of USP Azithromycin RS in acetoni-
System suitability solution: 0.5 mg/mL each of USP trile. Sonicate as necessary to dissolve.
Azithromycin RS and USP Azaerythromycin A RS pre- Standard solution: 0.9 g/mL of USP Desosaminylazi-
pared as follows. Dissolve USP Azithromycin RS and USP thromycin RS, 2.1 g/mL of USP N-Demethylazithro-
Azaerythromycin A RS first in acetonitrile, using 5% of mycin RS, 3.0 g/mL of USP Azaerythromycin A RS, and
the final volume, and then dilute with Diluent to 3.2 g/mL of USP Azithromycin RS from the Standard
volume. stock solution in Mobile phase
Standard solution: 0.53 mg/mL of USP Azithromycin Sample solution: 0.33 mg/mL of Azithromycin pre-
RS prepared as follows. Dissolve USP Azithromycin RS pared as follows. Transfer a suitable amount of Azithro-
first in acetonitrile, using 2% of the final volume, and mycin to a suitable volumetric flask. Add acetonitrile,
then dilute with Diluent to volume. using 5% of the final volume, and sonicate as necessary
Sample solution: 0.53 mg/mL of Azithromycin pre- to dissolve. Dilute with Mobile phase to volume.
pared as follows. Dissolve Azithromycin first in acetoni-

Official from May 1, 2017


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USP 40 Official Monographs / Azithromycin 2921

Chromatographic system Table 1


(See Chromatography 621, System Suitability.) Relative Acceptance
Mode: LC Retention Criteria,
Detector: Amperometric electrochemical Name Time NMT (%)
Detector type: Dual glassy carbon electrodes
Detector mode: Oxidative screen mode Erythromycin A iminoethera . 0.19 0.5
Detector settings Desosaminylazithromycinb . 0.29 0.3
Electrode 1: +0.70V Erythromycin A oximec . 0.37 0.5
Electrode 2: +0.82V N-Demethylazithromycind 0.49 0.7
Column: 4.6-mm 15-cm; 3-m packing L49
.

Azaerythromycin Ae 0.80 1.0


Temperatures
.

Azithromycin 1.0
Detector preheater: 28
Autosampler: 5 3-Deoxyazithromycin
Flow rate: 1 mL/min (azithromycin B)f . 2.33 1.0
Injection volume: 50 L Total impurities 3.0
System suitability a (3R,4R,5S,6R,9R,10S,11S,12R,13S,15R,Z)-12-[[3,4,6-Trideoxy-3-(dimethyl-
amino)--D-xylo-hexopyranosyl]oxy]-6-ethyl-4,5-dihydroxy-10-[(2,6-dide-
.

Sample: Standard solution oxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-3,5,9,11,13,15-


Suitability requirements hexamethyl-7,16-dioxa-2-azabicyclo[11.2.1]hexadec-1-en-8-one.
Resolution: NLT 3.0 between azithromycin and azae- b (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-Ethyl-3,4,10,13-tetrahydroxy-3,
rythromycin A 5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-dimethylamino--D-xylo-
.

Tailing factor: NMT 2.0 for azithromycin; NMT 2.5 hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.


for N-demethylazithromycin c (3R,4S,5S,6R,7R,9R,11S,12R,13S,14R,E)-6-[[3,4,6-Trideoxy-3-(dimethyl-
amino)--D-xylo-hexopyranosyl]oxy]-14-ethyl-7,12,13-trihydroxy-4-[(2,6-
.

Relative standard deviation: NMT 10.0% for dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-10-(hydroxy-


azithromycin, azaerythromycin A, N-demethylazithro- imino)-3,5,7,9,11,13-hexamethyloxacyclotetradecan-2-one.
mycin, and desosaminylazithromycin d (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-

Analysis
.

methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,
Samples: Standard solution and Sample solution 12,14-heptamethyl-11-[[3,4,6-trideoxy-3-methylamino--D-xylo-hexopyra-
nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
Record the Sample solution chromatograms for NLT 3.3 e 9-Deoxo-9a-aza-9a-homoerythromycin A; 6-Demethylazithromycin.
times the retention time of the azithromycin peak. .

f (2R,3R,4S,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-
Calculate the percentages of desosaminylazithromycin, .

methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-4,10-dihydroxy-3,5,6,8,10,12,
N-demethylazithromycin, and azaerythromycin A in 14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyra-
the portion of Azithromycin taken: nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

Result = (rU/rS) (CS/CU) F 100 ORGANIC IMPURITIES, PROCEDURE 2


Use Organic Impurities, Procedure 1 when the impurity
rU = peak area of the relevant analyte from the profile includes erythromycin A oxime and erythromycin
Sample solution A iminoether.
rS = peak area of the relevant analyte from the Solution A: 1.8 mg/mL of anhydrous dibasic sodium

USP Monographs
Standard solution phosphate in water. Adjust with 1 N sodium hydroxide
CS = concentration of the appropriate USP or 10% phosphoric acid to a pH of 8.9.
Reference Standard in the Standard solution Solution B: Acetonitrile and methanol (3:1)
(g/mL) Solution C: 1.73 mg/mL of monobasic ammonium
CU = concentration of the Sample solution (mg/mL) phosphate. Adjust with ammonia TS to a pH of 10.0
F = conversion factor, 0.001 mg/g 0.05.
Calculate the percentages of other related substances in Solution D: Methanol, acetonitrile, and Solution C
the portion of Azithromycin taken: (7:6:7)
Mobile phase: See Table 2.
Result = (rU/rS) (CS/CU) F 100
Table 2
rU = peak area of each additional impurity from the
Sample solution Time Solution A Solution B
rS = peak area of the azithromycin peak from the (min) (%) (%)
Standard solution 0 50 50
CS = concentration of USP Azithromycin RS in the 25 45 55
Standard solution (g/mL) 30 40 60
CU = concentration of the Sample solution (mg/mL) 80 25 75
F = conversion factor, 0.001 mg/g
81 50 50
Acceptance criteria: See Table 1.
93 50 50

System suitability solution: 0.0165 mg/mL of USP


Azithromycin Related Compound F RS and 0.027 mg/
mL of USP Desosaminylazithromycin RS in Solution D
Standard solution: 86 g/mL of USP Azithromycin RS
in Solution D
Sample solution: 8.6 mg/mL of Azithromycin in Solu-
tion D
Chromatographic system
(See Chromatography 621, System Suitability.)

Official from May 1, 2017


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2922 Azithromycin / Official Monographs USP 40

Mode: LC Analysis
Detector: UV 210 nm Samples: Standard solution and Sample solution
Column: 4.6-mm 25-cm; 5-m packing L1 Calculate the percentage of each related compound in
Column temperature: 60 the portion of Azithromycin taken:
Flow rate: 1 mL/min
Injection volume: 50 L Result = (rU/rS) (CS/CU) P F1 (100/F2)
System suitability
Samples: System suitability solution and Standard rU = peak response of each impurity from the
solution Sample solution
Suitability requirements rS = peak response of azithromycin from the
Tailing factor: 0.81.5, Standard solution Standard solution
Peak-to-valley ratio: NLT 1.4, System suitability solu- CS = concentration of USP Azithromycin RS in the
tion. Calculate the peak-to-valley ratio as follows: Standard solution (mg/mL)
CU = concentration of Azithromycin in the Sample
Result = HP/HV solution (mg/mL)
P = potency of USP Azithromycin RS (g/mg of
HP = height above the baseline of the azithromycin)
desosaminylazithromycin peak F1 = conversion factor, 0.001 mg/g
HV = height above the baseline of the lowest point F2 = relative response factor (see Table 3)
of the curve separating the Acceptance criteria: See Table 3. Disregard peaks elut-
desosaminylazithromycin and azithromycin ing before azithromycin N-oxide and after 3-deoxy-
related compound F peaks azithromycin (azithromycin B). Disregard peaks with a
response less than 0.1 times the response of the
azithromycin peak in the Standard solution (0.1%).

Table 3
Relative Relative Acceptance
Retention Response Criteria,
Name Time Factor NMT (%)
AzithromycinN-oxidea . 0.29 0.43 0.5
3-(N,N-Didemethyl)-3-N-formylazithromycinb . 0.37 1.7 0.5
3-(N,N-Didemethyl) azithromycin (aminoazithro-
mycin)c . 0.43 1.0 0.5
Azithromycin related compound Fd,e . . . 0.51 3.8 0.5
Desosaminylazithromycinf . 0.54 1.0 0.3
3-N-{[4-(Acetylamino)phenyl]sulfonyl}-3,3-
USP Monographs

didemethylazithromycing . 0.55 12 0.15


N-Demethylazithromycinh . 0.61 1.0 0.7
Azithromycin C (3-O-demethylazithromycin)i . 0.73 1.0 0.5
3-De(dimethylamino)-3-oxoazithromycinj . 0.76 1.5 0.5
3-N-{[4-(Acetylamino)phenyl]sulfonyl}-3-demethy-
lazithromycink . 0.79 10 0.5
Azaerythromycin Al . 0.83 1.0 0.5
Azithromycin impurity Pm . 0.92 1.0 0.2
Azithromycin 1.0
a (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylazinoyl)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

b (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-formamido-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

c (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-amino-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

d 3-N-Demethyl-3-N-formylazithromycin; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-
3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3-(N-methyl)formamido-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

e The system may resolve two rotamers of azithromycin related compound F. The sum of the two rotamers is reported.
.

f (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-Ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-dimethylamino--D-xylo-hexopyra-
.

nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
g (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-acetamidophenylsulfonyl)amino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

h (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-methylamino--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

i (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[
[3,4,6-trideoxy-3-dimethylamino--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

j (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3,3-dimethyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-
[[3,4,6-trideoxy-3-oxo--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

k (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-acetamidophenylsulfonyl)-N-methylamino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

l 9-Deoxo-9a-aza-9a-homoerythromycin A; 6-Demethylazithromycin.
.

m Specified unidentified impurity.


.

n (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-propyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

o (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-methylphenylsulfonyl)-N-methylamino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

p (2R,3R,4S,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-4,10-dihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

Official from May 1, 2017


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USP 40 Official Monographs / Azithromycin 2923

Table 3 (Continued)
Relative Relative Acceptance
Retention Response Criteria,
Name Time Factor NMT (%)
2-Desethyl-2-propylazithromycinn . 1.23 1.0 0.5
3-N-Demethyl-3-N-[(4-methylphenyl)sulfony-
l]azithromycino . 1.26 5 0.5
3-Deoxyazithromycin (azithromycin B)p . 1.31 1.0 1.0
Any individual, unidentified impurity 1.0 0.2
Total impurities 3.0
a (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylazinoyl)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

b (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-formamido-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

c (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-amino-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

d 3-N-Demethyl-3-N-formylazithromycin; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-
3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3-(N-methyl)formamido-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

e The system may resolve two rotamers of azithromycin related compound F. The sum of the two rotamers is reported.
.

f (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-Ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-dimethylamino--D-xylo-hexopyra-
.

nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
g (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-acetamidophenylsulfonyl)amino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

h (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-methylamino--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

i (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[
[3,4,6-trideoxy-3-dimethylamino--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

j (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3,3-dimethyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-
[[3,4,6-trideoxy-3-oxo--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

k (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-acetamidophenylsulfonyl)-N-methylamino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

l 9-Deoxo-9a-aza-9a-homoerythromycin A; 6-Demethylazithromycin.
.

m Specified unidentified impurity.


.

n (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-propyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

o (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3-[N-(4-methylphenylsulfonyl)-N-methylamino]-3,4,6-trideoxy--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

p (2R,3R,4S,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-4,10-dihydroxy-3,5,6,8,10,12,14-
heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
.

USP Monographs
SPECIFIC TESTS point at about 70 and the inflection point at about
OPTICAL ROTATION, Specific Rotation 781S: 45 to 49, 130.
at 20
Sample solution: 20 mg/mL in dehydrated alcohol ADDITIONAL REQUIREMENTS
CRYSTALLINITY 695: Meets the requirements except, PACKAGING AND STORAGE: Preserve in tight containers.
where it is labeled as amorphous, most of the particles LABELING: Label it to indicate whether it is anhydrous, or
do not exhibit birefringence and extinction positions the monohydrate, or the dihydrate. The amorphous form
PH 791: 9.011.0 is so labeled. Where the quantity of azithromycin is indi-
Sample stock solution: 4 mg/mL in methanol cated in the labeling of any preparation containing
Sample solution: 2 mg/mL obtained by mixing equal Azithromycin, this shall be understood to be in terms of
volumes of Sample stock solution and water anhydrous azithromycin (C38H72N2O12). The labeling
WATER DETERMINATION, Method I 921 states with which Organic Impurities procedure the article
Where it is labeled as anhydrous: NMT 2.0% complies, if other than Procedure 1.
Where it is labeled as the dihydrate: 4.0%5.0% USP REFERENCE STANDARDS 11
Where it is labeled as the monohydrate: 1.8%4.0%, USP Azaerythromycin A RS
except that it may be 4.0%6.5% when the require- 9-Deoxo-9a-aza-9a-homoerythromycin A;
ments of the Loss on Drying test are met 6-Demethylazithromycin.
LOSS ON DRYING: Where it is labeled as Azithromycin C37H70N2O12 734.96
monohydrate and has a water content of 4.0%6.5% USP Azithromycin RS
(see Thermal Analysis 891) USP Azithromycin Related Compound F RS
[NOTEThe quantity taken for this procedure may be ad- 3-N-Demethyl-3-N-formylazithromycin; (2R,3S,4R,5R,
justed, if necessary, for instrument sensitivity.] 8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-
Analysis: Determine the percentage of volatile sub- 3-O-methyl--L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,
stances by thermogravimetric analysis in an appropri- 10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3-(N-
ately calibrated instrument, using about 10 mg of methyl)formamido-3,4,6-trideoxy--D-xylo-hexopyra-
Azithromycin. Heat the specimen at the rate of 10/min nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
between ambient temperature and 150 in an atmos- C38H70N2O13 762.97
phere of nitrogen at a constant flow rate of about USP N-Demethylazithromycin RS
35 mL/min. From the thermogram plot the derivatives (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dide-
of the loss on drying (percent loss/min), and identify oxy-3-C-methyl-3-O-methyl--L-ribo-hexopyra-
the inflection points of the two weight loss steps at nosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,
about 70 and 130. 14-heptamethyl-11-[[3,4,6-trideoxy-3-methylamino--
Acceptance criteria: It loses NMT 4.5% of its weight D-xylo-hexopyranosyl]oxy]-1-oxa-6-aza-
between ambient temperature and the inflection point cyclopentadecan-15-one.
at about 70, and 1.8%2.6% between the inflection C37H70N2O12 734.96

Official from May 1, 2017


Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 10.6.1.1 by spen3tkzy on Thu Jul 06 00:34:52 EDT 2017

2924 Azithromycin / Official Monographs USP 40

USP Desosaminylazithromycin RS [NOTEThe relative retention times for azaerythromycin


(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-Ethyl-3,4, A and azithromycin with the L29 column are 0.7 and
10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl- 1.0, respectively; the relative retention times for azae-
11-[[3,4,6-trideoxy-3-dimethylamino--D-xylo-hex- rythromycin A and azithromycin with the L49 column
opyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. are 0.8 and 1.0, respectively.]
C30H58N2O9 590.79 Suitability requirements
Resolution: NLT 2.5 between azaerythromycin A and
azithromycin, System suitability solution
Column efficiency: NLT 1000 theoretical plates,
.

Standard solution
Azithromycin Capsules Tailing factor: 0.91.5, Standard solution
Relative standard deviation: NMT 2.0%, Standard
DEFINITION solution
Azithromycin Capsules contain the equivalent of NLT 90.0% Analysis
and NMT 110.0% of the labeled amount of azithromycin Samples: Standard solution and Sample solution
(C38H72N2O12). Calculate the percentage of the labeled amount of
azithromycin (C38H72N2O12) in the portion of Capsules
IDENTIFICATION taken:
A. The retention time of the azithromycin peak of the
Sample solution corresponds to that of the Standard solu- Result = (rU/rS) (CS/CU) P F 100
tion, as obtained in the Assay.
rU = peak response from the Sample solution
ASSAY rS = peak response from the Standard solution
PROCEDURE CS = concentration of USP Azithromycin RS in the
[NOTEUse water that has a resistivity of NLT 18 Mohm- Standard solution (g/mL)
cm.] CU = nominal concentration of azithromycin in the
Mobile phase: Dissolve 5.8 g of monobasic potassium Sample solution (g/mL)
phosphate in 2130 mL of water, and add 870 mL of P = potency of azithromycin in USP Azithromycin
acetonitrile. Adjust with about 6 mL of 10 N potassium RS (g/mg)
hydroxide to a pH of 11.0 0.1, and pass through a F = conversion factor, 0.001 mg/g
suitable filter. Acceptance criteria: 90.0%110.0%
Standard stock solution: 0.165 mg/mL of USP Azithro-
mycin RS in acetonitrile. Swirl, and sonicate as PERFORMANCE TESTS
necessary. DISSOLUTION 711
Standard solution: 3.3 g/mL of USP Azithromycin RS [NOTEUse water that has a resistivity of NLT 18 Mohm-
from the Standard stock solution in Mobile phase cm.]
System suitability stock solution: 0.16 mg/mL of USP Medium: pH 6.0 sodium phosphate buffer (Prepare 6 L
Azaerythromycin A RS in acetonitrile and Mobile phase of 0.1 M dibasic sodium phosphate. Adjust with about
USP Monographs

(1:9). Dissolve first in acetonitrile, using 10% of the fi- 40 mL of hydrochloric acid to a pH of 6.0 0.05, and
nal volume. Swirl, and sonicate to dissolve. Dilute with add 600 mg of trypsin); 900 mL
Mobile phase to volume. Apparatus 2: 100 rpm
System suitability solution: 3.2 g/mL of azaerythro- Time: 45 min
mycin A from the System suitability stock solution and Mobile phase, Chromatographic system, and System
3.3 g/mL of azithromycin from the Standard stock solu- suitability: Proceed as directed in the Assay.
tion in Mobile phase Standard stock solution: 0.3 mg/mL of USP Azithro-
Sample stock solution: Remove, as completely as pos- mycin RS in Medium. Sonicate briefly to dissolve.
sible, the contents of NLT 20 Capsules. Prepare a Standard solution: 3.84 g/mL of azithromycin from
1-mg/mL solution of anhydrous azithromycin in aceto- the Standard stock solution in Mobile phase
nitrile. Dissolve a portion of the mixed Capsule contents Sample solution: Pass a portion of the solution under
first in 70% of the final volume of acetonitrile, and test through a suitable filter of 0.5-m or finer pore
shake by mechanical means for 30 min. Dilute with ac- size. Transfer 2.0 mL of the filtrate to a 25-mL volumet-
etonitrile to volume. Place 40 mL of the resulting sus- ric flask, and dilute with Mobile phase to volume. Trans-
pension in a centrifuge tube, and centrifuge. Use the fer 4.0 mL of this solution to a second 25-mL volumet-
supernatant to prepare the Sample solution. ric flask, and dilute with Mobile phase to volume.
Sample solution: 3.2 g/mL of azithromycin from the Analysis
Sample stock solution in Mobile phase Samples: Standard solution and Sample solution
Chromatographic system Determine the amount of azithromycin (C38H72N2O12)
(See Chromatography 621, System Suitability.) dissolved using the procedure in the Assay, making
Mode: LC any necessary modifications.
Detector: Amperometric electrochemical detector Calculate the percentage of azithromycin
Electrode: Dual glassy carbon electrodes (C38H72N2O12) dissolved:
Mode: Oxidative screen mode
Electrode 1: +0.70 0.05 V Result = (rU/rS) (CS/L) D V 100
Electrode 2: +0.82 0.05 V rU = peak response from the Sample solution
Background current: 85 15 nanoampheres rS = peak response from the Standard solution
Columns CS = concentration of USP Azithromycin RS in the
Guard: 4.6-mm 5-cm; 5-m packing L29 Standard solution (mg/mL)
Analytical: 4.6-mm 15-cm; 5-m packing L29 or L = label claim (mg/Capsule)
3-m packing L49 without the guard column D = dilution factor of the Sample solution
Flow rate: 1.5 mL/min V = volume of Medium, 900 mL
Injection size: 50 L Tolerances: NLT 75% (Q) of the labeled amount of
System suitability azithromycin (C38H72N2O12) is dissolved.
Samples: Standard solution and System suitability UNIFORMITY OF DOSAGE UNITS 905: Meet the
solution requirements

Official from May 1, 2017


Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.