Azithromycin Tablets

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Azithromycin Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of azithromycin (C₃₈H₇₂N₂O₁₂)

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A

Standard solution: 25 mg/mL of USP Azithromycin RS in acetonitrile. Pass the solution through a suitable filter, and remove the solvent by natural evaporation.

Sample solution: Equivalent to 25 mg/mL of azithromycin from Tablets in acetonitrile. Pass the solution through a suitable filter, and remove the solvent by natural evaporation.

Acceptance criteria: Meet the requirements

3 ASSAY

PROCEDURE

Buffer: Dissolve 4.6 g of monobasic potassium phosphate anhydrous in 900 mL of water. Adjust with 1 N sodium hydroxide to a pH of 7.5, and dilute with water to 1 L..

Mobile phase: Acetonitrile and Buffer (65:35)

Standard solution: 1 mg/mL of USP Azithromycin RS in Mobile phase. Sonicate and shake as needed to dissolve.

Sample solution: Nominally 1 mg/mL of azithromycin in Mobile phase from NLT 20 Tablets, finely powdered. Sonicate and shake as needed to dissolve.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 25-cm; 5-µm packing 11

Column temperature: 50°

Flow rate: 2 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of azithromycin (C₃₈H₇₂N₂O₁₂) in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × P × F × 100

r_u = peak response of azithromycin from the Sample solution

r_s = peak response of azithromycin from the Standard solution

C_s = concentration of USP Azithromycin RS in the Standard solution (mg/mL)

C_u = nominal concentration of azithromycin in the Sample solution (mg/mL)

P = potency of USP Azithromycin RS (µg/mg)

F = conversion factor, 0.001 mg/µg

Acceptance criteria: 90.0%–110.0%

PERFORMANCE TESTS

DISSOLUTION (711)

Medium: pH 6.0 phosphate buffer, 900 mL

Apparatus 2: 75 rpm.

Time: 30 min

Solution A: 4.4 mg/mL of dibasic potassium phosphate and 0.5 mg/mL of sodium 1-octanesulfonate; adjusted with phosphoric acid to a pH of 8.20±0.05

Mobile phase: Acetonitrile, methanol, and Solution A (9:3:8)

Diluent: 17.5 mg/mL of dibasic potassium phosphate. Adjust with phosphoric acid to a pH of 8.00 ±0.05. Prepare a mixture of this solution and acetonitrile (80:20).

Standard stock solution: Dissolve USP Azithromycin RS in Medium to obtain a solution with a known concentration of about (L/1000) mg/mL, where L is the label claim in mg/Tablet.

Standard solution: Dilute the Standard stock solution with Diluent to obtain a solution with a known concentration of about (L/2000) mg/mL, where L. is the label claim in mg/Tablet.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute a portion of the filtrate with Diluent to obtain a solution with a theoretical concentration of about (L/2000) mg/ml., where L is the label claim in mg/Tablet, assuming complete dissolution.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 15-cm; 5-µm packing 11

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of azithromycin (C₃₈H₇₂N₂O₁₂) dissolved:

Result = (r_u /r_s ) × (C_s /L) × V × D × 100

r_u = peak response of azithromycin from the Sample solution

r_s = peak response of azithromycin from the Standard solution

C_s = concentration of USP Azithromycin RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution, if necessary

Tolerances: NLT 80% (Q) of the labeled amount of azithromycin (C3HN₂O₁₂) is dissolved.

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

4 IMPURITIES

ORGANIC IMPURITIES

Protect all solutions containing azithromycin from light. Refrigerate the Standard solution and the Sample solution after preparation and during analysis, using a refrigerated autosampler set at 4". The solutions must be analyzed within 24 h of preparation.

Solution A: Water and ammonium hydroxide (2000:1.2). The pH of this solution is about 10.5.

Solution B: Acetonitrile, methanol, and ammonium hydroxide (1800:200:1.2)

Mobile phase: See Table 1.

Table 1

Buffer: 1.7 g/L of monobasic ammonium phosphate in water. Adjust with ammonium hydroxide to a pH of 10 ± 0.05.

Diluent A: Methanol, acetonitrile, and Buffer (350:300:350). [NOTE-Diluent A is stable for 24 h after mixing the organic and buffer phases.]

Diluent B: Methanol and Buffer (1:1)

System suitability stock solution: 0.1 mg/mL each of USP Desosaminylazithromycin RS, USP Azithromycin Related Compound F RS, and USP N-Demethylazithromycin RS in acetonitrile

System suitability solution: 0.028 mg/mL each of USP Desosaminylazithromycin RS, USP Azithromycin Related Compound F. RS, and USP N-Demethylazithromycin RS from the System suitability stock solution in Diluent A

Peak identification solution: 0.004 mg/mL each of USP Desosaminylazithromycin RS, USP Azithromycin Related Compound F.RS, and USP N-Demethylazithromycin RS from the System suitability solution in Diluent A

Standard stock solution: 0.4 mg/mL of USP Azithromycin RS in acetonitrile. Sonicate and shake as needed to dissolve.

Standard solution: 0.02 mg/mL of azithromycin from the Standard stock solution in Diluent A

Sensitivity solution: 0.004 mg/mL of azithromycin from the Standard solution in Diluent A

Sample stock solution: Nominally 14.3 mg/mL of azithromycin prepared as follows. Transfer nominally 1430 mg of azithromycin, from finely powdered Tablets (NLT 20), to a 100-ml volumetric flask. Add 75 mL of acetonitrile, and sonicate for NLT 15 min. Shake by mechanical means for NLT 15 min. Allow the solution to equilibrate to room temperature, dilute with acetonitrile to volume, and mix.

Sample solution: Nominally 4 mg/mL of azithromycin prepared as follows. Centrifuge an aliquot of the Sample stock solution for NLT 15 min. Transfer 7.0 mL of the supernatant to a 25-mL volumetric flask, and dilute with Diluent B to volume.

Blank: Diluent A

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing 11

Temperatures

Autosampler: 4°

Column: 50°

Flow rate: 1.2 mL/min

Injection volume: 100 µL

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

Suitability requirements

Resolution: NLT 1.0 between desosaminylazithromycin and azithromycin related compound F, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution, Sample solution, and Blank

Calculate the percentage of each impurity in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × P × F₁ × (1/F₂ ) × 100

r_u = peak response of each impurity from the Sample solution

r_s = peak response of azithromycin from the Standard solution

C_s = concentration of USP Azithromycin RS in the Standard solution (mg/mL)

C_u = nominal concentration of azithromycin in the Sample solution (mg/mL)

P = potency of USP Azithromycin RS (µg/mg)

F₁ = conversion factor, 0.001 mg/µg

F₂ = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.1%. Disregard any peaks in the Sample solution that correspond to peaks in the Blank.

Table 2

^a (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-0-methyl-a--ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylazinoyl)-ẞ-b-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-3-0-methyl-a-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3-formamido-3,4,6-trideoxy-ẞ-o-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

^c The system may resolve two rotamers. The limit is for the sum of the two rotamers.

^d (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-0-methyl-a-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-B-o-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

^e 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-α-l-ribohexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3-(N-methyl)formamido-3,4,6-trideoxy-β-d-xylohexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

^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-β-dxylo-hexopyranosyl]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-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-methylamino-β-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-3,3-dimethyl-α-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-β-d-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

ⁱ Process impurities that are controlled in the drug substance are not to be reported. They are listed here for information only. The unspecied impurities and total impurities limits do not include these impurities.

^j 9-Deoxo-9a-aza-9a-homoerythromycin A.

^k (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-l-ribo-hexopyranosyl)oxy]-2-propyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-d-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one dihydrate.

^l (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3-[N-(4-methylphenylsulfonyl)-N-methylamino]-3,4,6-trideoxy-β-d-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

^m (2R,3R,4S,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-4,10-dihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-d-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

5 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers. Store at controlled room temperature.

Change to read:

USP REFERENCE STANDARDS (11)

USP Azithromycin RS

USP Azithromycin Related Compound FRS

3-(N-Demethyl)-3'-N-formylazithromycin; (2R,3S,4R,5R,8R,10R,11R,125,135,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-0-methyl-a-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-B-o-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

C₃₈H₇₀N₂O₁₃         762.98 _{(CN 1-Aug-2024)}

USP N-Demethylazithromycin RS

(2R,3S,4R,5R,8R,10R,11R,125,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-0-methyl-a-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-ẞ-D-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

C₃₇H₇₀N₂O₁₂         734.97 _{(CN 1-Aug-2024)}

USP Desosaminy azithromycin RS

(2R,3S,4R,5R,8R,10R,11R,125,135,14R)-2-Ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-dimethylamino-β-D-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

C₃₀H₅₈N₂O₉              590.80 _{(CN 1-Aug-2024)}