Azithromycin for Oral Suspension

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 for Oral Suspension is a dry mixture of Azithromycin and one or more buffers, sweeteners, diluents, anticaking agents, and flavors. It contains NLT 90.0% and NMT 110.0% of the labeled amount of azithromycin (C₃₈H₇₂N₂O₁₂).

2 IDENTIFICATION

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

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

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

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

Analysis: Examine the spectra of the Standard and the Sample in the range between 3800 and 650 cm^-1.

Acceptance criteria: The Sample exhibits bands at about 900, 995, 1165, 1376, 1456, 1725, and 2936 cm^-1 similar to the spectrum from the Standard similarly obtained.

3 ASSAY

PROCEDURE

[NOTE-Solutions containing azithromycin are stable up to 12 h at 10°.]

Solution A: Dissolve 8.7 g of dipotassium hydrogen phosphate anhydrous in 1000 mL of water and adjust with potassium hydroxide or dilute phosphoric acid to a pH of 8.2.

Solution B: Acetonitrile

Mobile phase: Solution A and Solution B (30:70)

Diluent: Acetonitrile, methanol, and water (40:40:20)

Standard solution: 0.6 mg/ml of USP Azithromycin RS in Diluent. Sonicate in cool water to dissolve as needed.

Sample solution: Nominally 0.6 mg/mL of azithromycin in Diluent prepared as follows. Transfer an accurately measured portion of the constituted suspension to a suitable volumetric flask. Add Diluent equal to 50% of the volume of the flask, and sonicate for 20 min with shaking in cool water. Dilute with Diluent to volume. Pass a portion of this solution through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 2 mL/min

Injection volume: 50 µL

Run time: NLT 2 times the retention time of azithromycin

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 Azithromycin for Oral Suspension 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%

4 PERFORMANCE TESTS

DELIVERABLE VOLUME (698): Meets the requirements

UNIFORMITY OF DOSAGE UNITS (905)

For single-unit containers: Meets the requirements

Change to read:

DISSOLUTION (711)

4.1 Test 1 (RB 1-May-2024)

[NOTE-Solutions containing azithromycin are stable up to 12 h at 10°.]

Medium: Sodium phosphate buffer, pH 6.0 (14.2 g/L of sodium phosphate, dibasic, anhydrous in water, adjusted with dilute hydrochloric acid to pH 6.0); 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Solution A: Dissolve 8.7 g of dipotassium hydrogen phosphate anhydrous in 1000 mL of water and adjust with potassium hydroxide or dilute phosphoric acid to a pH of 8.2.

Solution B: Acetonitrile

Mobile phase: Solution A and Solution B (35:65)

Standard stock solution: 0.55 mg/mL of USP Azithromycin RS prepared as follows. Transfer an accurately weighed amount of USP Azithromycin RS to a suitable volumetric flask. Add acetonitrile to fill 5% of the volume of the flask and sonicate in cool water for 5 min to dissolve completely. Dilute with Medium to volume.

Standard solution

For Azithromycin for Oral Suspension labeled to contain 100 mg/5 mL: 0.11 mg/mL of USP Azithromycin RS in Medium from Standard stock solution

For Azithromycin for Oral Suspension labeled to contain 200 mg/5 mL: 0.22 mg/mL of USP Azithromycin RS in Medium from Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Temperatures

Autosampler: 10°

Column: 50°

Flow rate: 2 mL/min

Injection volume: 100 µL

Run time: NLT 2 times the retention time of azithromycin

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 (Q) of the labeled amount of azithromycin (C₃₈H₇₂N₂O₁₂) dissolved:

Result = (r_u /r_s ) × (C_s /L) × D × (d/W) × V × 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 of Azithromycin for Oral Suspension (mg/5 mL)

D = dilution factor, necessary only if the Sample solution requires dilution (mL/mL)

d = density of the Sample solution (g/mL)

W = weight of Azithromycin for Oral Suspension taken (g)

V = volume of Medium, 900 mL

38 Tolerances: NLT 75% (Q) of the labeled amount of azithromycin (CH2N2012) is dissolved.

4.2 Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

NOTE-Solutions containing azithromycin may be stable for 72 h at 10°.)

Medium: Sodium phosphate buffer, pH 6.0 (14.2 g/L of sodium phosphate, dibasic, anhydrous in water, adjusted with dilute hydrochloric acid to a pH of 6.0); 900 mL

Apparatus 2: 25 rpm

Time: 45 min

Buffer: Dissolve 8.7 g of dipotassium hydrogen phosphate anhydrous in 1000 mL of water. Adjust with potassium hydroxide or dilute phosphoric acid to a pH of 8.2.

Mobile phase: Acetonitrile and Buffer (65:35)

Standard stock solution: 0.55 mg/mL of USP Azithromycin RS prepared as follows. Transfer a quantity of USP Azithromycin RS to an appropriate volumetric flask and dissolve in 5% of the flask volume of acetonitrile. Sonicate in cool water for about 5 min. Dilute with Medium to volume.

Standard solution

For Azithromycin for Oral Suspension constituted to 100 mg/5 mL: 0.11 mg/mL of USP Azithromycin RS from Standard stock solution in Medium

For Azithromycin for Oral Suspension constituted to 200 mg/5 mL: 0.22 mg/mL of USP Azithromycin RS from Standard stock solution in

Medium

Sample solution: Proceed constitution as directed in the Labeling. Determine the density, d (g/mL), of the constituted suspension using appropriate means. Using a suitable syringe, collect approximately 5 mL of suspension, and record the weight. With the paddles lowered, gently add the collected suspension into each vessel containing the Medium. Start rotating the paddles. Reweigh the syringe, and determine the weight, W (g), of suspension delivered into each vessel. At the end of 45 min, withdraw a suitable volume of the solution under test. Pass through a suitable filter, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

OFFIC

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

Temperatures

Autosampler: 10°

Column: 50°

Flow rate: 2 mL/min

Injection volume: 100 µL

Run time: NLT 2 times the retention time of azithromycin

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 × V × (d/W) × (1/L) × 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)

V = volume of Medium, 900 mL

d = density of the constituted suspension (g/mL)

W = weight of the constituted suspension taken (g)

L = label claim of constituted suspension (100 mg/5 mL, or 200 mg/5 mL)

Tolerances: NLT 80% (Q) of the labeled amount of azithromycin (C H N O ) is dissolved. _{(RB 1-May-2024)}

5 IMPURITIES

5.1 Organic Impurities

Solution A: Dissolve 1.8 g of disodium hydrogen phosphate dihydrate in 1000 mL of water and adjust with dilute phosphoric acid to a pH of 8.9.

Solution B: Acetonitrile and methanol (75:25)

Mobile phase: See Table 1.

Table 1

Buffer: Dissolve 1.73 g of ammonium dihydrogen phosphate in 1000 mL of water and adjust with ammonia solution to a pH of 10.0 ± 0.05.

Diluent: Buffer, methanol, and acetonitrile (35:35:30)

System suitability solution: 0.015 mg/mL of USP Azithromycin Related Compound. F.RS and 0.025 mg/mL of USP Desosaminylazithromycin RS in Diluent

Standard solution: 0.04 mg/mL of USP Azithromycin RS in Diluent. Sonicate in cool water to dissolve as needed.

Sample solution: Nominally 4.0 mg/mL solution of azithromycin in Diluent prepared as follows. Transfer a portion of the constituted suspension, equivalent to about 400.0 mg of azithromycin, to a 100-ml volumetric flask. Add 70 mL of Diluent and sonicate in cool water for about 15 min. Dilute with Diluent to volume. Pass a portion of this solution through a suitable filter of 0.45-um pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Temperatures

Autosampler: 10°

Column: 60°

Flow rate: 0.9 mL/min

Injection volume: 100 µL

Run time: NLT 2 times the retention time of azithromycin

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between desosaminylazithromycin and azithromycin related compound F, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Azithromycin for Oral Suspension 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. Disregard any peaks at relative retention times before 0.29 and after 1.31.

Table 2

^a (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-(dimethylazinoyl)-β-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-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3-formamido-3,4,6-trideoxy-β-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-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3-amino-3,4,6-trideoxy-β-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-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.

^e (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-βd-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

^f (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.

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

^h 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.

ⁱ (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.

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

^k Specied unidentied impurity.

^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-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.

^m (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.

ⁿ (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-dihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-o-xylo-hexopyranosyl)oxy]-1-oxa-6-azacyclopentadecan-15-one.

6 SPECIFIC TESTS

pH 〈791〉

For a solid packaged in single-unit containers

Sample: The suspension constituted as directed in the labeling

Acceptance criteria: 9.0–11.0

For a solid packaged in multiple-unit containers

Sample: The suspension constituted as directed in the labeling

Acceptance criteria: 8.5–11.0

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

Add the following:

Labeling: The labeling states the Dissolution test used only if Test 1 is not used. _{(RB 1-May-2024)}

USP Reference Standards 〈11〉

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

C₃₈H₇₀N₂O₁₃                        762.98

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-β-dxylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

C₃₀H₅₈N₂O₉                         590.80