Ipratropium Bromide

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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C₂₀H₃₀BrNO₃ .H₂O 430.38 

C₂₀H₃₀BrNO₃ 412.37 

8-Azoniabicyclo[3.2.1]octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide, monohydrate(endo,syn)-, (±)-; (8r)-3α-Hydroxy-8-isopropyl-1αH,5αH-tropanium bromide (±)-tropate monohydrate; 

(1R,3r,5S,8r)-3-[(3-Hydroxy-2-phenylpropanoyl)oxy]-8-isopropyl-8-methyl-8-azabicyclo[3.2.1]octan-8-ium bromide monohydrate CAS RN®:  66985-17-9; UNII: J697UZ2A9J.. 

Anhydrous CAS RN®: 22254-24-6; UNII: VJV4X1P2Z1.. 

1 DEFINITION 

Ipratropium Bromide contains NLT 98.0% and NMT 102.0% of ipratropium bromide (C₂₀H₃₀BrNO₃), calculated on the anhydrous basis

2 IDENTIFICATION 

Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M 

Identification Tests—General 〈191〉, Chemical Identification Tests, Bromide 

Sample solution: 10 mg/mL of Ipratropium Bromide in water 

Acceptance criteria: Meets the requirements 

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

3 ASSAY 

Procedure 

Solution A: 89 g/L of dibasic sodium phosphate dihydrate in water 

Buffer: 14.3 g/L of monobasic sodium phosphate dihydrate and 2.0 g/L of tetrapropylammonium chloride in water. Adjust with Solution A to a pH of 5.5. 

Mobile phase: Methanol and Buffer (13:87). [Note—Do not use the Mobile phase after 36 h.] 

System suitability solution: 0.5 mg/mL of USP Ipratropium Bromide RS and 0.1 mg/mL of USP Ipratropium Bromide Related Compound C RS in Mobile phase 

Standard solution: 0.5 mg/mL of USP Ipratropium Bromide RS in Mobile phase 

Sample solution: 0.5 mg/mL of Ipratropium Bromide in Mobile phase 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 220 nm 

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

Column temperature: 30° 

Flow rate: 1.5 mL/min 

Injection volume: 5 µL 

Run time: NLT 6 times the retention time of ipratropium 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for ipratropium bromide related compound C and ipratropium are about 0.7 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 4 between ipratropium bromide related compound C and ipratropium, System suitability solution Tailing factor: NMT 2.5, Standard solution 

Relative standard deviation: NMT 0.73%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of ipratropium bromide (C₂₀H₃₀BrNO₃) in the portion of Ipratropium Bromide 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 = concentration of ipratropium bromide in the Sample solution (µg/mL) 

Acceptance criteria: 98.0%–102.0% on the anhydrous basis 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.1% 

Limit of Ipratropium Bromide Related Compound A 

Buffer: 3.9 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 4.0. 

Mobile phase: Acetonitrile and Buffer (90:10) 

Diluent: 0.01 N hydrochloric acid 

Standard stock solution: 10 µg/mL of USP Ipratropium Bromide Related Compound A RS in Diluent 

Standard solution: 0.1 µg/mL of USP Ipratropium Bromide Related Compound A RS from Standard stock solution in Diluent Sensitivity solution: 0.01 µg/mL of USP Ipratropium Bromide Related Compound A RS from Standard solution in Diluent Sample solution: 100 µg/mL of Ipratropium Bromide in Diluent 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: Mass spectrometer 

Ionization: Electrospray positive ion. [Note—Adjustments to the electrospray source parameters including the probe temperature, cone voltage, and capillary voltage may be necessary to meet Suitability requirements.] 

Acquisition mode: Selected ion monitoring (SIM) mode with m/z of 184.2 for the ipratropium related compound A cation Column: 3.0-mm × 5-cm; 5-µm packing L9 

Column temperature: 20° 

Flow rate: 0.6 mL/min 

Injection volume: 5 µL 

Run time: NLT 1.5 times the retention time of ipratropium bromide related compound A 

System suitability 

Samples: Standard solution and Sensitivity solution 

Suitability requirements 

Relative standard deviation: NMT 10.0%, Standard solution 

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

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of ipratropium bromide related compound A in the portion of Ipratropium Bromide taken: 

Result = (r_U/r_S) × (C_S/C_U) x 100 

r_U = peak response of ipratropium bromide related compound A from the Sample solution

r_S = peak response of ipratropium bromide related compound A from the Standard solution

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

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

Acceptance criteria: NMT 0.10% 

Organic Impurities 

Solution A, Buffer, Mobile phase, and Chromatographic system: Proceed as directed in the Assay. 

System suitability solution: 0.03 mg/mL of USP Ipratropium Bromide RS and 0.01 mg/mL of USP Ipratropium Bromide Related Compound B RS in Mobile phase 

Sensitivity solution: 0.005 mg/mL of USP Ipratropium Bromide RS in Mobile phase 

Standard solution: 0.03 mg/mL of USP Ipratropium Bromide RS in Mobile phase 

Sample solution: 10 mg/mL of Ipratropium Bromide in Mobile phase 

System suitability 

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

[Note—See Table 1 for the relative retention times.] 

Suitability requirements 

Resolution: NLT 4 between ipratropium and ipratropium bromide related compound B, System suitability solution 

Tailing factor: NMT 2.5, Standard solution 

Relative standard deviation: NMT 5%, Standard solution 

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

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each impurity in the portion of Ipratropium Bromide taken: 

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

r_U = peak response of each impurity 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 = concentration of ipratropium bromide in the Sample solution (µg/mL) 

F = relative response factor (see Table 1) 

Acceptance criteria: See Table 1. The reporting threshold is 0.05%. Disregard the bromide counterion peak eluting at a relative retention time of about 0.1. 

Table 1 

^a Also known as tropic acid. 

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

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

Add the following: 

5 SPECIFIC TESTS 

Water Determination 〈921〉, Method I: 3.9%−4.4%  

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight, light-resistant containers, and store at controlled room temperature. 

USP Reference Standards 〈11〉 

USP Ipratropium Bromide RS 

USP Ipratropium Bromide Related Compound A RS 

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

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

C₁₁H₂₂BrNO 264.20 

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. 

C₉H₁₀O₃ 166.17