Erythromycin Stearate

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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C₃₇H₆₇NO₁₃ · C₁₈H₃₆O₂           1018.40

Erythromycin octadecanoate (salt);

Erythromycin stearate (salt) CAS RN: 643-22-1; UNII: LXW024X05M.

1 DEFINITION

Erythromycin Stearate is the stearic acid salt of Erythromycin, with an excess of Stearic Acid. The sum of the percentages of erythromycin A, erythromycin B, and erythromycin C is NLT 55.0%, calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. _{(USP 1-Dec-2019)} SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197M

_{(CN 1-MAY-2020)}

Add the following:

B. The retention times of the erythromycin A, erythromycin B, and erythromycin C peaks in the Sample solution correspond to those of Standard solution 2, as obtained in the Assay _{(USP 1-Dec-2019)}

3 ASSAY

Change to read:

PROCEDURE

Use solutions containing erythromycin promptly, or within 1 day if stored in a refrigerator. (USP 1-Dec-2019)

Diluted phosphoric acid: Dilute 10 mL of phosphoric acid with water to 100 ml..

Solution A: 20 mg/mL of dibasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 8.0.

Solution B: 35 mg/mL of dibasic potassium phosphate in water. Adjust with potassium hydroxide TS or Diluted phosphoric acid, as appropriate, to a pH of 9.0.

Solution C: 20 mL of Solution A. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Acetonitrile, tertiary butyl alcohol, Solution B, and water (6:35:10:149)

Standard solution 1: 40 mg of USP Erythromycin RS in a conical flask. Add 5.0 mL of methanol, and swirl to dissolve. Add 5.0 mL of Solution A.

Standard solution 2: 6 mg each of USP Erythromycin RS, USP Erythromycin B RS. USP Erythromycin C. RS, and USP Erythromycin Related Compound N. RS in a 50-mL conical flask. Add 15.0 mL of methanol and swirl to dissolve. Add 15.0 mL of Solution A.

_{(USP 1-Dec-2019)}

Sample solution: 165 mg of Erythromycin Stearate in a 100-mL conical flask. Add 15.0 mL of methanol and swirl to dissolve. Add 15.0 mL of Solution A and mix. Allow the resulting suspension to settle, and pass a portion of the supernatant through a filter of 0.2-µm or finer pore size. Use the clear filtrate.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm x 25-cm; packing L21 (1000A)

Column temperature: 70^o

Flow rate: 2 mL/min

Injection volume: 100 µL

Run time: NLT 5 times the retention time of erythromycin A

System suitability

Samples: Standard solution 1 and Standard solution 2

The elution order of the components is erythromycin related compound N, erythromycin C, erythromycin A, and erythromycin B.

Suitability requirements

Resolution: NLT 0.8 between erythromycin related compound N and erythromycin C; NLT 5.5 between erythromycin related compound N and erythromycin A, Standard solution 2

Relative standard deviation: NMT 2.0%, Standard solution 1

Analysis

Samples: Standard solution 1, Standard solution 2, _{(USP 1-Dec-2019)} and Sample solution _{(USP 1-Dec-2019)}

Calculate the percentage of erythromycin A in the portion of Erythromycin Stearate taken:

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

r_u = peak response of erythromycin A from the Sample solution

r_s = peak response of erythromycin A from Standard solution 1

C_s = concentration of USP Erythromycin RS in Standard solution 1 (mg/mL)

C_u = concentration of Erythromycin Stearate in the Sample solution (mg/mL)

P = percentage of erythromycin A in USP Erythromycin RS

Calculate the percentage of erythromycin B and erythromycin C in the portion of Erythromycin Stearate taken:

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

r_u = peak response of the relevant analyte from the Sample solution

r_s = peak response of the relevant analyte from Standard solution 2

C_s = concentration of the corresponding Reference Standard in Standard solution 2 (mg/mL)

C_u = concentration of Erythromycin Stearate in the Sample solution (mg/mL)

P = potency of erythromycin B or erythromycin C in the corresponding Reference Standard (mg/mg) _{(USP 1-Dec-2019)}

Acceptance criteria: The sum of the percentages of erythromycin A, erythromycin B, and erythromycin C is NLT 55.0% on the anhydrous basis. The percentage of erythromycin B is NMT 12.0%, and the percentage of erythromycin C is NMT 5.0%.

4 IMPURITIES

RESIDUE ON IGNITION (281)

Sample: The charred residue is moistened with 2 mL of nitric acid and 5 drops of sulfuric acid.

Acceptance criteria: NMT 1.0%

Change to read:

ORGANIC IMPURITIES

Diluted phosphoric acid, Solution A, Solution B, Solution C, Mobile phase, Standard solution 2, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Peak identification solution: 5 mg of USP Erythromycin RS in 1 mL of methanol. Add 5 mL of Solution C, mix, and allow to stand for about 30 min. _{(USP 1-Dec-2019)}

Analysis

Samples: Standard solution 2, Sample solution, and Peak identification solution

Identify the erythromycin A enol ether peak using the Peak identification solution _{(USP 1-Dec-2019)}

Calculate the percentage of the largest single impurity (the largest peak other than erythromycin A, erythromycin B, erythromycin C, erythromycin A enol ether, erythromycin N-ethylsuccinate, and pseudoerythromycin A enol ether) in the portion of Erythromycin Stearate taken.

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

r_u = peak response of the largest single impurity (the largest peak other than erythromycin A, erythromycin B, erythromycin C, erythromycin A enol ether, erythromycin N-ethylsuccinate, and pseudoerythromycin A enol ether) from the Sample solution

r_s = peak response of erythromycin A from Standard solution 2

C_s = concentration of USP Erythromycin RS in Standard solution 2 (mg/mL)

C_u = concentration of Erythromycin Stearate in the Sample solution (mg/mL)

P = percentage of erythromycin A in USP Erythromycin RS

Calculate the percentage of erythromycin A enol ether in the portion of Erythromycin Stearate taken:

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

r_u = peak response of erythromycin A enol ether from the Sample solution

r_s = peak response of erythromycin A from Standard solution 2

C_s = concentration of USP Erythromycin RS in Standard solution 2 (mg/mL)

C_u = concentration of Erythromycin Stearate in the Sample solution (mg/mL)

P = percentage of erythromycin A in USP Erythromycin RS

F = relative response factor (see Table 1)

Calculate the percentage of pseudoerythromycin A enol ether in the portion of Erythromycin Stearate taken:

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

r_u = peak response of pseudoerythromycin A enol ether from the Sample solution

r_s = peak response of erythromycin A from Standard solution 2

C_s = concentration of USP Erythromycin RS in Standard solution 2 (mg/mL)

C_u = concentration of Erythromycin Stearate in the Sample solution (mg/mL)

P = percentage of erythromycin A in USP Erythromycin RS

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1.

Table 1

^a (2R,3S,6R,7S,8S,9R,10R)-3-[(2R,3R)-2,3-Dihydroxypentan-2-yl]-9-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2Hpyran-2-yl]oxy}-7-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2,6,8,10,12-pentamethyl-4,13- dioxabicyclo[8.2.1]tridec-1(12)-en-5-one.

^b (2R,3R,4S,5R,8R,9S,10S,11R)-11-{[(2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-5-ethyl-3,4-dihydroxy9-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2,4,8,10,12,14-hexamethyl-6,15- dioxabicyclo[10.2.1]pentadec-1(14)-en-7-one._{(USP 1-Dec-2019)}

^c The largest peak other than erythromycin A, erythromycin B, erythromycin C, erythromycin A enol ether, erythromycin N-ethylsuccinate, and pseudoerythromycin A enol ether.

5 SPECIFIC TESTS

WATER DETERMINATION (921), Method I

Sample solution: Use 20 ml of methanol containing 10% of imidazole in place of methanol in the titration vessel.

Acceptance criteria: NMT 4.0%

CRYSTALLINITY (695): Meets the requirements

ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

Change to read:

USP REFERENCE STANDARDS (11)

USP Erythromycin RS

USP Erythromycin B RS

12-Deoxyerythromycin;(3R,4S,5S,6R,7R,9R,11R,12S,13R,14R)-6-{[(2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12-dihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13 hexamethyloxacyclotetradecane-2,10- dione.

C₃₇H₆₇NO₁₂            717.94 _{(USP 1-Dec-2019)}

USP Erythromycin C RS

3″-O-Demethylerythromycin;(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-{[(2R,4R,5S,6S)-4,5-Dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13 hexamethyloxacyclotetradecane2,10-dione.

C₃₆H₆₅NO₁₃            719.91 _{(USP 1-Dec-2019)}

USP Erythromycin Related Compound N RS

N-Demethylerythromycin A; (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-Ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-6-{[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13 hexamethyloxacyclotetradecane-2,10-dione. _{(USP 1-Dec-2019)}

C₃₆H₆₅NO₁₃             719.91

USP Erythromycin Stearate RS