Budesonide Nasal Spray

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

Budesonide Nasal Spray is an aqueous buffered suspension of Budesonide, supplied in a form suitable for nasal administration and contains suitable preservatives. It contains NLT 90.0% and NMT 110.0% of the labeled amount of budesonide (C₂₅H₃₄O₆).

2 IDENTIFICATION

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

B. The UV spectrum of the budesonide peak of the Sample solution exhibits a maximum and minimum at the same wavelengths as those of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Mobile phase: Acetonitrile and water (70:30)

[Note—Use low-actinic glassware for preparation of the Standard solution and Sample solution.]

Standard solution: 0.05 mg/mL of USP Budesonide RS in acetonitrile

Sample solution: Nominally 0.05 mg/mL of budesonide in acetonitrile prepared as follows. Prepare a composite by mixing NLT 5 containers of Nasal Spray in a suitable container. Weigh a quantity of the composite solution into a suitable volumetric flask. Dilute with acetonitrile to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 245 nm. For Identification B, use a diode array detector in the range of 200–400 nm.

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

Flow rate: 1 mL/min

Injection volume: 50 µL

Run time: NLT 2 times the retention time of budesonide

System suitability

Sample: Standard solution

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of budesonide (C₂₅H₃₄O₆) in the portion of Nasal Spray taken:

Result = (rU/rS) × (CS/CU) × 100

r_U = peak response of budesonide from the Sample solution

r_S = peak response of budesonide from the Standard solution

C_S = concentration of USP Budesonide RS in the Standard solution (mg/mL)

C_U = nominal concentration of budesonide in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 OTHER COMPONENTS

Content of Potassium Sorbate

Perform this test if potassium sorbate is a component in the Nasal Spray.

Buffer: 1.4 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to pH 3.0.

Mobile phase: Acetonitrile and Buffer (40:60)

Standard solution: 0.04 mg/mL of USP Potassium Sorbate RS in water

Sample solution: Nominally 0.04 mg/mL of potassium sorbate in water prepared as follows. Prepare a composite by mixing NLT 5 containers of Nasal Spray in a suitable container. Transfer 1.0 mL of the well-mixed composite solution to a 25-mL volumetric flask containing 10 mL of water. Add 5 drops of 0.5 N hydrochloric acid. Dilute with water to volume. Centrifuge for about 10 min at about 3600 rpm, and use the clear solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 nm

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

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 4 times the retention time of potassium sorbate

System suitability

Sample: Standard solution

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 potassium sorbate (C₆H₇KO₂) in the portion of Nasal Spray taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U= peak response of potassium sorbate from the Sample solution

r_S= peak response of potassium sorbate from the Standard solution

C_S= concentration of USP Potassium Sorbate RS in the Standard solution (mg/mL)

C_U= nominal concentration of potassium sorbate in the Sample solution (mg/mL)

Acceptance criteria: 50.0%–110.0%

Content of Edetate Disodium

Perform this test if edetate disodium is a component in the Nasal Spray.

Buffer: 17 g/L of tetrabutylammonium hydrogen sulfate in water. Adjust with 2 M ammonium acetate to a pH of 4.4.

Solution A: Methanol, Buffer, and water (12:20:68)

Solution B: Methanol, Buffer, and water (70:7:23)

Mobile phase: See Table 1.

Diluent: Dissolve 250 mg of cupric sulfate in 400 mL of water. Add 100 mL of Buffer. Mix well and filter.

Standard stock solution: 0.25 mg/mL of USP Edetate Disodium RS in water

Standard solution: 0.05 mg/mL of USP Edetate Disodium RS in Diluent from Standard stock solution

Sample solution: Nominally 0.05 mg/mL of edetate disodium in Diluent prepared as follows. Prepare a composite by mixing NLT 5 containers of Nasal Spray in a suitable container. Transfer 5.0 mL of the composite solution to a 10-mL volumetric flask. Add 0.5 mL of 0.5 N hydrochloric acid. Dilute with Diluent to volume. Centrifuge for about 10 min at about 3600 rpm, and use the supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Flow rate: 1 mL/min

Injection volume: 25 µL

System suitability

Sample: Standard solution

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 edetate disodium (C₁₀H₁₄N₂O₈·2H₂O·2Na) in the portion of Nasal Spray taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U= peak response of edetate disodium from the Sample solution

r_S= peak response of edetate disodium from the Standard solution

C_S= concentration of USP Edetate Disodium RS in the Standard solution (mg/mL)

C_U= nominal concentration of edetate disodium in the Sample solution (mg/mL)

Acceptance criteria: 75.0%–110.0%

5 PERFORMANCE TESTS

Delivered-Dose Uniformity (within container)

Mobile phase, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Standard solution: 3 µg/mL of USP Budesonide RS in acetonitrile

Sample solution: Nominally 3 µg/mL of budesonide in acetonitrile prepared as follows. Prime the metered spray by discharging a predetermined number of actuations to waste. Discharge the next selected actuation into a separate 10-mL volumetric flask for beginning and end-of-unit sample. [Note—Hold the 10-mL volumetric flask in an inverted position, and immediately turn upright after capturing the contents of the selected actuation.] Dilute with acetonitrile to volume. Repeat this procedure with 9 additional units.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of budesonide (C₂₅H₃₄O₆) in each dose of Nasal Spray taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U= peak response of budesonide from the Sample solution

r_S= peak response of budesonide from the Standard solution

C_S= concentration of USP Budesonide RS in the Standard solution (µg/mL)

C_U= nominal concentration of budesonide in the Sample solution (µg/mL)

Acceptance criteria

Tier 1

The mean results of 10 dosage units at each beginning-of-unit sample and at end-of-unit sample are within 85.0%–115.0% of the labeled amount of budesonide (C₂₅H₃₄O₆).

NMT 2 individual results outside of 80%–120% of the labeled amount of budesonide (C₂₅H₃₄O₆).

None of the individual results outside of 75%–125% of the labeled amount of budesonide (C₂₅H₃₄O₆).

If the criteria in Tier 1 cannot be met, proceed to Tier 2.

Tier 2

Test an additional 20 units at each actuation. All the 60 results (including the results from Tier 1) meet the following Acceptance criteria:

The mean results of 30 units at each beginning-of-unit sample and at end-of-unit sample are within 85.0%–115.0% of the labeled amount of budesonide (C₂₅H₃₄O₆).

NMT 6 of the 60 individual results outside of 80%–120% of the labeled amount of budesonide (C₂₅H₃₄O₆).

None of the 60 individual results outside of 75%–125% of the labeled amount of budesonide (C₂₅H₃₄O₆).

Minimum Fill 〈755〉: Meets the requirements

6 IMPURITIES

Organic Impurities

Buffer: 2.7 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.0.

Solution A: Acetonitrile and Buffer (27:73)

Solution B: Acetonitrile

Mobile phase: See Table 2.

Diluent: Acetonitrile and water (20:80)

Calcium chloride solution: 29 g/L of calcium chloride in water

[Note—Use low-actinic glassware for preparation of the Standard solution and Sample solution.]

Standard stock solution: 40 µg/mL of USP Budesonide RS in acetonitrile

Standard solution: 0.4 µg/mL of USP Budesonide RS in Diluent from Standard stock solution

Sensitivity solution: 0.1 µg/mL of USP Budesonide RS in Diluent from Standard solution

Sample solution: Nominally 100 µg/mL of budesonide prepared as follows. Prepare a composite by mixing NLT 5 containers of Nasal Spray in a suitable container. Transfer 4.0 mL of the well-stirred composite solution to a 10-mL volumetric flask. Add 0.5 mL of Calcium chloride solution. Mix and dilute with acetonitrile to volume. Transfer the solution into a centrifuge tube and centrifuge for about 10 min at about 3600 rpm. Pass the supernatant through a suitable syringe filter of 0.45-µm pore size into a test tube. Transfer 4.0 mL of the filtrate into a 10-mL volumetric flask and dilute with water to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 35°

Flow rate: 1.3 mL/min

Injection volume: 100 µL

System suitability

Samples: Standard solution and Sensitivity solution

[Note—See Table 3 for the relative retention times. Budesonide, the active ingredient, elutes as two peaks for epimer A and epimer B under the chromatographic conditions.]

Resolution: NLT 1.5 between epimer B and epimer A, Standard solution

Tailing factor: NMT 2.0 for epimer B and epimer A of budesonide, Standard solution

Relative standard deviation: NMT 5.0% for the sum of epimer B and epimer A, Standard solution

Signal-to-noise ratio: NLT 10 for epimer B and epimer A, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of budesonide glyoxal (epimers), budesonide acid, and any unspecified impurity in the portion of Nasal Spray taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U= peak response of budesonide glyoxal (epimers), budesonide acid, or any unspecified impurity from the Sample solution

r_S= sum of peak responses of budesonide epimer A and budesonide epimer B from the Standard solution

C_S= concentration of USP Budesonide RS in the Standard solution (µg/mL)

C_U= nominal concentration of budesonide in the Sample solution (µg/mL)

Acceptance criteria: See Table 3.

a 11β,16α,17,21-Tetrahydroxypregna-1,4-diene-3,20-dione.

b Process impurities, do not include in calculation of total impurities.

c 16α,17-[Ethylidenebis(oxy)]-11β,21-dihydroxypregna-1,4-diene-3,20-dione.

d 16α,17-[Butylidenebis(oxy)]-11β-hydroxy-17-(hydroxymethyl)-d-homoandrosta-1,4-diene-3,17a-dione; also known as d-homobudesonide.

e 16α,17-[1-Methylethylidenebis(oxy)]-11β, 21-dihydroxypregna-1,4-diene-3,20-dione.

f 16α,17-[Butylidenebis(oxy)]-11β-hydroxy-3,20-dioxopregna-1,4-dien-21-al; also known as 21-dehydrobudesonide.

g Includes both epimers.

h Also known as 14,15-dehydrobudesonide or budesonide 14-ene.

i 16α,17-[Butylidenebis(oxy)]-11β-hydroxy-3,20-dioxopregna-1,4-dien-21-oic acid.

j When budesonide related compound E and budesonide pyruvic acid analog coelute, the result is reported as degradation product budesonide pyruvic acid analog.

k Also known as 11-ketobudesonide.

l Also known as 1,2-dihydrobudesonide.

m 16α,17-[Butylidenebis(oxy)]-11β-hydroxypregna-1,4-diene-3,20-dione-21-yl acetate.

7 SPECIFIC TESTS

pH 〈791〉: 4.0–4.8

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉:

The total aerobic microbial viable count does not exceed 10² cfu/mL, and the total combined yeasts and molds count does not exceed 10¹ cfu/mL.

It meets the requirements of the tests for the absence of Escherichia coli, Salmonella species, Pseudomonas aeruginosa, and Staphylococcus aureus.

8 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Store at controlled room temperature in an upright position, protected from light.

USP Reference Standards 〈11〉

USP Budesonide RS

USP Edetate Disodium RS

USP Potassium Sorbate RS▲ (USP 1-Dec-2020)