Cromolyn Sodium

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

Cromolyn Sodium contains NLT 98.0% and NMT 101.0% of cromolyn sodium (C₂₃H₂₄Na₂O₁₁), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

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

197A or 197K

Analysis: Dry at 105° to constant weight.

Acceptance criteria: Meets the requirements (USP 1-Dec-2023)

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

2.3 C. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Sodium: Meets the requirements

3 ASSAY

3.1 PROCEDURE

Buffer: 2.1 g/L of sodium acetate in water. Adjust with glacial acetic acid to a pH of 5.5.

Mobile phase: Methanol and Buffer (20:80)

Standard solution: 0.1 mg/mL of USP Cromolyn Sodium RS in water

Sample solution: 0.1 mg/mL of Cromolyn Sodium in water

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Column temperature: 35°

Flow rate: 1.7 mL/min

Injection volume: 20 µL

Run time: NLT 2 times the retention time of cromolyn

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of cromolyn sodium (C₂₃H₂₄Na₂O₁₁) in the portion of Cromolyn Sodium taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of cromolyn from the Sample solution

r_s = peak response of cromolyn from the Standard solution S

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

C_u = concentration of Cromolyn Sodium in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-101.0% on the anhydrous basis

4 IMPURITIES

Change to read:

4.1 ORGANIC IMPURITIES

[NOTE-The Sample solution and Standard solutions are stable for 6 h at 4°.]

Diluent A: Acetonitrile and water (20:80)

Diluent B: Methanol and water (30:70)

Buffer: 2.1 g/L of sodium acetate in water. Adjust with glacial acetic acid to a pH of 5.5.

Solution A: Methanol and Buffer (20:80)

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Standard stock solution: 0.15 mg/mL of USP Cromolyn Related Compound A RS and 0.06 mg/mL of USP Cromolyn Related Compound B RS in acetonitrile

Standard solution A: 0.0075 mg/mL of USP Cromolyn Related Compound A RS and 0.003 mg/mL of USP Cromolyn Related Compound B RS from the Standard stock solution in Diluent A

Standard solution B: 0.0015 mg/mL of USP Cromolyn Sodium RS in Diluent B

Sensitivity solution: 0.75 µg/mL of USP Cromolyn Sodium RS from Standard solution B in Diluent B

Sample solution: 1.5 mg/mL of Cromolyn Sodium in Diluent B

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Temperatures

Autosampler: 4°

Column: 35°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Samples: Standard solution A, Standard solution B, and Sensitivity solution

[NOTE- The relative retention times in Table 2 are provided as information that could aid in peak assignment.]

Table 2

a 5-(3-[(2-Carboxy-4-oxo-4H-chromen-5-yl)oxy]-2-hydroxypropoxy)-8-(3-[(2-carboxy-4-oxo-4H-chromen-5-yl)oxy]-2-hydroxypropyl)-4-oxo-4H-chromene-2-carboxylic acid.

b 1-(2,6-Dihydroxyphenyl)ethan-1-one; also known as 2,6-dihydroxyacetophenone.

Suitability requirements

Resolution: NLT 2.5 between cromolyn related compound A and cromolyn related compound B, Standard solution A

Relative standard deviation: NMT 5.0%, Standard solution B

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

Analysis

Samples: Standard solution A, Standard solution B, and Sample solution

Calculate the percentage of cromolyn related compound A and cromolyn related compound BA (USP 1-Dec-2023) in the portion of Cromolyn Sodium taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of cromolyn related compound A or cromolyn related compound B from the Sample solution

r_s = peak response of cromolyn related compound A or cromolyn related compound B from Standard solution A

C_s = concentration of the corresponding cromolyn related compound in Standard solution A (mg/mL)

C_u = concentration of Cromolyn Sodium in the Sample solution (mg/mL)

Calculate the percentage of cromolyn tricarboxylic acid analog. (USP 1-Dec-2023) 2-acetylresorcinol, and any (USP 1-Dec-2023) unspecified impurity in the portion of Cromolyn Sodium taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of cromolyn tricarboxylic acid analog, 2-acetylresorcinol, or any (USP 1-Dec-2023) unspecified impurity from the Sample solution

r_s = peak response of cromolyn from Standard solution B

C_s = concentration of USP Cromolyn Sodium RS in Standard solution B (mg/mL)

C_u = concentration of Cromolyn Sodium in the Sample solution (mg/mL)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3

4.2 LIMIT OF OXALATE

Standard solution: To 0.35 mg of oxalic acid in 20 mL of water, add 5.0 mL of iron salicylate TS and dilute with water to 50 mL.

Sample solution: To 100 mg of Cromolyn Sodium in 20 mL of water, add 5.0 mL of iron salicylate TS and dilute with water to 50 mL.

Instrumental conditions

Mode: Vis

Analytical wavelength: 480 nm

Blank: Water

Analysis

Samples: Standard solution and Sample solution

Determine the absorbance of the Standard solution and the Sample solution at 480 nm.

Acceptance criteria: The absorbance of the Sample solution is no less than that of the Standard solution (NMT 0.35% of oxalate).

5 SPECIFIC TESTS

5.1 WATER DETERMINATION (921), Method I: NMT 10.0%

5.2 STERILITY TESTS (71): Where the label states that it is sterile, it meets the requirements.

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE:

Preserve in tight containers.

6.2 LABELING:

Where it is intended for use in preparing sterile dosage forms, the label states that it is sterile or must be subjected to further processing during the preparation of sterile dosage forms.

6.3 USP REFERENCE STANDARDS (11)

USP Cromolyn Sodium RS

USP Cromolyn Related Compound A RS

1,3-Bis(2-acetyl-3-hydroxyphenoxy)propan-2-ol.

C₁₉H₂₀O₇       360.36

USP Cromolyn Related Compound B RS

Diethyl 5,5'-[(2-hydroxypropane-1,3-diyl)bis(oxy)]bis(4-oxo-4H-chromene-2-carboxylate).

C₂₇H₂₄O₁₁         524.48