Accessed from 10.6.1.
1 by spen3tkzy on Thu Jul 06 00:34:52 EDT 2017
2920 Azithromycin / Official Monographs
.
Azithromycin
C38H72N2O12 748.98
C38H72N2O12 H2O 767.00
C38H72N2O12 2H2O 785.02
1-Oxa-6-azacyclopentadecan-15-one, 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-(dimethylamino)--D-xylo-hexopyranosyl]
oxy]-, [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,
14R*)];
(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-(dimethylamino)--D-xylo-hexopyranosyl]oxy]-
1-oxa-6-azacyclopentadecan-15-one;
9-Deoxo-9a-aza-9a-methyl-9a-homoerythromycin A
Anhydrous [83905-01-5].
Monohydrate [121470-24-4].
Dihydrate [117772-70-0].
DEFINITION
Azithromycin is anhydrous or contains one or two molecules
USP Monographs
of water of hydration. It contains the equivalent of NLT
945 g and NMT 1030 g of azithromycin (C38H72N2O12)
per mg, calculated on the anhydrous basis.
IDENTIFICATION
A. INFRARED ABSORPTION 197K: If a difference appears
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-
orate the solutions to dryness on a water bath, and dry
at 80 for 30 min under vacuum. Perform the test on the
residues.
B. The retention time of the azithromycin peak of the
Sample solution corresponds to that of the Standard solu-
tion, as obtained in the Assay.
ASSAY
PROCEDURE
Solution A: 10 M Potassium hydroxide
Solution B: 6.7 g/L of dibasic potassium phosphate ad-
justed with Solution A to a pH of 11.0
Solution C: 6.7 g/L of dibasic potassium phosphate ad-
justed with phosphoric acid to a pH of 8.0
Mobile phase: Acetonitrile and Solution B (60:40)
Diluent: Acetonitrile and Solution C (60:40)
System suitability solution: 0.5 mg/mL each of USP
Azithromycin RS and USP Azaerythromycin A RS pre-
pared as follows. Dissolve USP Azithromycin RS and USP
Azaerythromycin A RS first in acetonitrile, using 5% of
the final volume, and then dilute with Diluent to
volume.
Standard solution: 0.53 mg/mL of USP Azithromycin
RS prepared as follows. Dissolve USP Azithromycin RS
first in acetonitrile, using 2% of the final volume, and
then dilute with Diluent to volume.
Sample solution: 0.53 mg/mL of Azithromycin pre-
pared as follows. Dissolve Azithromycin first in acetoni-
Official from May 1, 2017
Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
USP 40
trile, using 2% of the final volume, and then dilute with
Diluent to volume.
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
Resolution: NLT 3.0 between azaerythromycin A and
azithromycin, System suitability solution
Tailing factor: 0.81.5 for azithromycin, Standard
solution
Relative standard deviation: NMT 1.10% for
azithromycin, Standard solution
Analysis
Samples: Standard solution and Sample solution
Calculate the quantity, in g, of azithromycin
(C38H72N2O12) in each mg of Azithromycin taken:
Result = (rU/rS) (CS/CU) P
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Azithromycin RS in the
Standard solution
CU = concentration of Azithromycin in the Sample
solution
P = potency of USP Azithromycin RS (g/mg of
azithromycin)
Acceptance criteria: 9451030 g/mg on the anhy-
drous basis
IMPURITIES
RESIDUE ON IGNITION 281: NMT 0.3%, the charred resi-
due being moistened with 2 mL of nitric acid and
5 drops of sulfuric acid
Delete the following:
HEAVY METALS, Method II 231: NMT 25 ppm (Official 1-
.
Jan-2018)
ORGANIC IMPURITIES, PROCEDURE 1
Use Organic Impurities, Procedure 1 when the impurity
profile includes erythromycin A oxime and erythromycin
A iminoether.
Use water that has a resistivity of NLT 18 Mohm-cm.
Solution A: 20 mM Dibasic potassium phosphate
Mobile phase: Acetonitrile and Solution A (250:750).
Adjust with 5 M potassium hydroxide to a pH of 10.55
0.05.
Standard stock solution: 45 g/mL of USP Desosamin-
ylazithromycin RS, 105 g/mL of USP N-Demethy-
lazithromycin RS, 150 g/mL of USP Azaerythromycin A
RS, and 160 g/mL of USP Azithromycin RS in acetoni-
trile. Sonicate as necessary to dissolve.
Standard solution: 0.9 g/mL of USP Desosaminylazi-
thromycin RS, 2.1 g/mL of USP N-Demethylazithro-
mycin RS, 3.0 g/mL of USP Azaerythromycin A RS, and
3.2 g/mL of USP Azithromycin RS from the Standard
stock solution in Mobile phase
Sample solution: 0.33 mg/mL of Azithromycin pre-
pared as follows. Transfer a suitable amount of Azithro-
mycin to a suitable volumetric flask. Add acetonitrile,
using 5% of the final volume, and sonicate as necessary
to dissolve. Dilute with Mobile phase to volume.
Accessed from 10.6.1.1 by spen3tkzy on Thu Jul 06 00:34:52 EDT 2017

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
.

Samples: Standard solution and Sample solution
Record the Sample solution chromatograms for NLT 3.3
times the retention time of the azithromycin peak.
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-hexopyra-
nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
e 9-Deoxo-9a-aza-9a-homoerythromycin A; 6-Demethylazithromycin.
.

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.
.

SPECIFIC TESTS
OPTICAL ROTATION, Specific Rotation 781S: 45 to 49,
at 20
Sample solution: 20 mg/mL in dehydrated alcohol
CRYSTALLINITY 695: Meets the requirements except,
where it is labeled as amorphous, most of the particles
do not exhibit birefringence and extinction positions
PH 791: 9.011.0
Sample stock solution: 4 mg/mL in methanol
Sample solution: 2 mg/mL obtained by mixing equal
volumes of Sample stock solution and water
WATER DETERMINATION, Method I 921
Where it is labeled as anhydrous: NMT 2.0%
Where it is labeled as the dihydrate: 4.0%5.0%
Where it is labeled as the monohydrate: 1.8%4.0%,
except that it may be 4.0%6.5% when the require-
ments of the Loss on Drying test are met
LOSS ON DRYING: Where it is labeled as Azithromycin
monohydrate and has a water content of 4.0%6.5%
(see Thermal Analysis 891)
[NOTEThe quantity taken for this procedure may be ad-
justed, if necessary, for instrument sensitivity.]
Analysis: Determine the percentage of volatile sub-
stances by thermogravimetric analysis in an appropri-
ately calibrated instrument, using about 10 mg of
Azithromycin. Heat the specimen at the rate of 10/min
between ambient temperature and 150 in an atmos-
phere of nitrogen at a constant flow rate of about
35 mL/min. From the thermogram plot the derivatives
of the loss on drying (percent loss/min), and identify
the inflection points of the two weight loss steps at
about 70 and 130.
Acceptance criteria: It loses NMT 4.5% of its weight
between ambient temperature and the inflection point
at about 70, and 1.8%2.6% between the inflection
USP Monographs
point at about 70 and the inflection point at about
130.
ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in tight containers.
LABELING: Label it to indicate whether it is anhydrous, or
the monohydrate, or the dihydrate. The amorphous form
is so labeled. Where the quantity of azithromycin is indi-
cated in the labeling of any preparation containing
Azithromycin, this shall be understood to be in terms of
anhydrous azithromycin (C38H72N2O12). The labeling
states with which Organic Impurities procedure the article
complies, if other than Procedure 1.
USP REFERENCE STANDARDS 11
USP Azaerythromycin A RS
9-Deoxo-9a-aza-9a-homoerythromycin A;
6-Demethylazithromycin.
C37H70N2O12 734.96
USP Azithromycin RS
USP Azithromycin Related Compound F RS
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-hexopyra-
nosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
C38H70N2O13 762.97
USP N-Demethylazithromycin RS
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dide-
oxy-3-C-methyl-3-O-methyl--L-ribo-hexopyra-
nosyl)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-aza-
cyclopentadecan-15-one.
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 Desosaminylazithromycin RS
(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-hex-
opyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
C30H58N2O9 590.79
.
Azithromycin Capsules
DEFINITION
Azithromycin Capsules contain the equivalent of NLT 90.0%
and NMT 110.0% of the labeled amount of azithromycin
(C38H72N2O12).
IDENTIFICATION
A. The retention time of the azithromycin peak of the
Sample solution corresponds to that of the Standard solu-
tion, as obtained in the Assay.
ASSAY
PROCEDURE
[NOTEUse water that has a resistivity of NLT 18 Mohm-
cm.]
Mobile phase: Dissolve 5.8 g of monobasic potassium
phosphate in 2130 mL of water, and add 870 mL of
acetonitrile. Adjust with about 6 mL of 10 N potassium
hydroxide to a pH of 11.0 0.1, and pass through a
suitable filter.
Standard stock solution: 0.165 mg/mL of USP Azithro-
mycin RS in acetonitrile. Swirl, and sonicate as
necessary.
Standard solution: 3.3 g/mL of USP Azithromycin RS
from the Standard stock solution in Mobile phase
System suitability stock solution: 0.16 mg/mL of USP
Azaerythromycin A RS in acetonitrile and Mobile phase
USP Monographs
(1:9). Dissolve first in acetonitrile, using 10% of the fi-
nal volume. Swirl, and sonicate to dissolve. Dilute with
Mobile phase to volume.
System suitability solution: 3.2 g/mL of azaerythro-
mycin A from the System suitability stock solution and
3.3 g/mL of azithromycin from the Standard stock solu-
tion in Mobile phase
Sample stock solution: Remove, as completely as pos-
sible, the contents of NLT 20 Capsules. Prepare a
1-mg/mL solution of anhydrous azithromycin in aceto-
nitrile. Dissolve a portion of the mixed Capsule contents
first in 70% of the final volume of acetonitrile, and
shake by mechanical means for 30 min. Dilute with ac-
etonitrile to volume. Place 40 mL of the resulting sus-
pension in a centrifuge tube, and centrifuge. Use the
supernatant to prepare the Sample solution.
Sample solution: 3.2 g/mL of azithromycin from the
Sample stock solution in Mobile phase
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
Detector: Amperometric electrochemical detector
Electrode: Dual glassy carbon electrodes
Mode: Oxidative screen mode
Electrode 1: +0.70 0.05 V
Electrode 2: +0.82 0.05 V
Background current: 85 15 nanoampheres
Columns
Guard: 4.6-mm 5-cm; 5-m packing L29
Analytical: 4.6-mm 15-cm; 5-m packing L29 or
3-m packing L49 without the guard column
Flow rate: 1.5 mL/min
Injection size: 50 L
System suitability
Samples: Standard solution and System suitability
solution
Official from May 1, 2017
Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
USP 40
[NOTEThe relative retention times for azaerythromycin
A and azithromycin with the L29 column are 0.7 and
1.0, respectively; the relative retention times for azae-
rythromycin A and azithromycin with the L49 column
are 0.8 and 1.0, respectively.]
Suitability requirements
Resolution: NLT 2.5 between azaerythromycin A and
azithromycin, System suitability solution
Column efficiency: NLT 1000 theoretical plates,
Standard solution
Tailing factor: 0.91.5, Standard solution
Relative standard deviation: NMT 2.0%, Standard
solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of
azithromycin (C38H72N2O12) in the portion of Capsules
taken:
Result = (rU/rS) (CS/CU) P F 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Azithromycin RS in the
Standard solution (g/mL)
CU = nominal concentration of azithromycin in the
Sample solution (g/mL)
P = potency of azithromycin in USP Azithromycin
RS (g/mg)
F = conversion factor, 0.001 mg/g
Acceptance criteria: 90.0%110.0%
PERFORMANCE TESTS
DISSOLUTION 711
[NOTEUse water that has a resistivity of NLT 18 Mohm-
cm.]
Medium: pH 6.0 sodium phosphate buffer (Prepare 6 L
of 0.1 M dibasic sodium phosphate. Adjust with about
40 mL of hydrochloric acid to a pH of 6.0 0.05, and
add 600 mg of trypsin); 900 mL
Apparatus 2: 100 rpm
Time: 45 min
Mobile phase, Chromatographic system, and System
suitability: Proceed as directed in the Assay.
Standard stock solution: 0.3 mg/mL of USP Azithro-
mycin RS in Medium. Sonicate briefly to dissolve.
Standard solution: 3.84 g/mL of azithromycin from
the Standard stock solution in Mobile phase
Sample solution: Pass a portion of the solution under
test through a suitable filter of 0.5-m or finer pore
size. Transfer 2.0 mL of the filtrate to a 25-mL volumet-
ric flask, and dilute with Mobile phase to volume. Trans-
fer 4.0 mL of this solution to a second 25-mL volumet-
ric flask, and dilute with Mobile phase to volume.
Analysis
Samples: Standard solution and Sample solution
Determine the amount of azithromycin (C38H72N2O12)
dissolved using the procedure in the Assay, making
any necessary modifications.
Calculate the percentage of azithromycin
(C38H72N2O12) dissolved:
Result = (rU/rS) (CS/L) D V 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Azithromycin RS in the
Standard solution (mg/mL)
L = label claim (mg/Capsule)
D = dilution factor of the Sample solution
V = volume of Medium, 900 mL
Tolerances: NLT 75% (Q) of the labeled amount of
azithromycin (C38H72N2O12) is dissolved.
UNIFORMITY OF DOSAGE UNITS 905: Meet the
requirements