Ipratropium Bromide Inhalation Solution

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 

Ipratropium Bromide Inhalation Solution is an isotonic sterile solution of ipratropium bromide monohydrate (C₂₀H₃₀BrNO₃ .H₂O). It may contain isotonicity agents and pH-adjusting agents. It contains NLT 90.0% and NMT 110.0% of the labeled amount of ipratropium bromide (C₂₀H₃₀BrNO₃). 

2 IDENTIFICATION 

The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. Protect solutions containing ipratropium bromide from light. 

3 ASSAY 

Procedure 

Phosphate solution: Dissolve 8.9 g of dibasic sodium phosphate dihydrate in 100 mL of water. 

Buffer: Dissolve 14.3 g of monobasic sodium phosphate dihydrate and 2 g of tetrapropylammonium chloride in 1 L of water. Adjust with Phosphate solution to a pH of 5.5. 

Solution A: Buffer 

Solution B: Methanol 

Mobile phase: See Table 1. 

Table 1 

Diluent: Methanol and Buffer (13:87) 

System suitability solution: 0.1 mg/mL each of USP Ipratropium Bromide RS and USP Ipratropium Bromide Related Compound C RS in Diluent. Sonicate to dissolve. 

Standard solution: 0.1 mg/mL of USP Ipratropium Bromide RS in Diluent. Sonicate to dissolve. 

Sample solution: Nominally 0.1 mg/mL of ipratropium bromide from Inhalation Solution prepared as follows. Pool the contents from NLT 8 vials of Inhalation Solution. Transfer a suitable volume of the pooled Inhalation Solution to a suitable volumetric flask and dilute with Diluent to volume. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm. For Identification B, use a diode array detector in the range of 200–400 nm. 

Column: 3.9-mm × 15-cm; 4-µm packing L1 

Column temperature: 30° 

Flow rate: 2 mL/min 

Injection volume: 25 µL 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for ipratropium bromide related compound C and ipratropium are 0.65 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 2.5 between ipratropium bromide related compound C and ipratropium, System suitability solution Tailing factor: NMT 2.0, Standard solution 

Relative standard deviation: NMT 1.0%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of ipratropium bromide (C₂₀H₃₀BrNO₃) in the portion of Inhalation Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) x 100 

r_U = peak response of ipratropium from the Sample solution

r_S = peak response of ipratropium from the Standard solution 

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

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

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Uniformity of Dosage Units 〈905〉: Meets the requirements 

5 IMPURITIES

Change to read: Organic Impurities 

Buffer: 13.6 g/L of monobasic potassium phosphate in water. Adjust with 10% phosphoric acid to a pH of 4.0. Solution A: Acetonitrile and Buffer (5:95) 

Solution B: Acetonitrile and Buffer (30:70) 

Mobile phase: See Table 2. 

Table 2 

Diluent: Acetonitrile and water (5:95) 

System suitability solution: 10 µg/mL of USP Ipratropium Bromide RS and 1 µg/mL each of USP Ipratropium Bromide Related Compound B RS and USP Ipratropium Bromide Related Compound C RS in Diluent 

Sensitivity solution: 0.1 µg/mL of USP Ipratropium Bromide RS in Diluent 

Standard solution: 1 µg/mL of USP Ipratropium Bromide RS in Diluent 

Sample solution: Nominally 200 µg/mL of ipratropium bromide from the pooled contents of NLT 8 vials of Inhalation Solution Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

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

Column temperature: 30° 

Flow rate: 1.2 mL/min 

Injection volume: 100 µL 

System suitability 

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

[Note—See Table 3 for the relative retention times.] 

Suitability requirements 

Resolution: NLT 4.0 between ipratropium bromide related compound B and ipratropium, System suitability solution Tailing factor: NMT 2.0, Standard solution 

Relative standard deviation: NMT 5.0%, Standard solution 

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

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of any specified and unspecified degradation products in the portion of Inhalation Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100 

r_U = ppeak response of the degradation product from the Sample solution  

r_S = peak response of ipratropium from the Standard solution 

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

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

F = relative response factor for the corresponding degradation product (see Table 3) 

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

Table 3 

^a Process impurity is controlled in the drug substance and it is not included in the total degradation products. 

^b(1R,3r,5S)-8-Isopropyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate. 

^c 2-Phenylacrylic acid. 

^d(1R,3r,5S,8r)-8-Isopropyl-8-methyl-3-[(2-phenylacryloyl)oxy]-8-azabicyclo[3.2.1]octan-8-ium. 

6 SPECIFIC TESTS 

Sterility Tests 〈71〉: Meets the requirements 

pH 〈791〉: 3.0–4.0 

Particulate Matter in Injections 〈788〉, Method 1 Light Obscuration Particle Count Test 

Sample: Pool the contents of NLT 10 units. 

Acceptance criteria: See Table 4. 

Table 4 

7 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Store between 15° and 30°. Protect from light. 

USP Reference Standards 〈11〉 

USP Ipratropium Bromide RS 

USP Ipratropium Bromide Related Compound B RS 

(1R,3r,5S,8s)-3-[(3-Hydroxy-2-phenylpropanoyl)oxy]-8-isopropyl-8-methyl-8-azabicyclo[3.2.1]octan-8-ium bromide; 

Also known as (1R,3r,5S,8s)-3-[[(2RS)-3-Hydroxy-2-phenylpropanoyl]oxy]-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane, bromide. 

C₂₀H₃₀BrNO₃    412.37 

USP Ipratropium Bromide Related Compound C RS 

3-Hydroxy-2-phenylpropionic acid; 

Also known as (2RS)-3-Hydroxy-2-phenylpropanoic acid.