Ipratropium Bromide and Albuterol Sulfate 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)

DOWNLOAD PDF HERE

1 DEFINITION 

Ipratropium Bromide and Albuterol Sulfate Inhalation Solution is an isotonic sterile solution of ipratropium bromide and albuterol sulfate. It may contain chelating agents, isotonicity agents, and pH adjusting agents. It contains NLT 90.0% and NMT 110.0% of the labeled amount of ipratropium bromide (C₂₀H₃₀BrNO₃) and albuterol (C₁₃H₂₁NO₃) as albuterol sulfate. 

2 IDENTIFICATION 

The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay. B. The UV spectra of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Change to read: 

Procedure 

Buffer: 2.7 g/L of monobasic potassium phosphate in water 

Solution A: Acetonitrile and Buffer (5:95). [Note—The pH of the solution is about 4.7.] 

Solution B: Acetonitrile and Buffer (40:60). [Note—The pH of the solution is about 5.4.] 

Mobile phase: See Table 1. 

Table 1 

System suitability solution: 0.1 mg/mL of USP Ipratropium Bromide RS, 0.5 mg/mL of USP Albuterol Sulfate RS, and 0.05 mg/mL each of USP Ipratropium Bromide Related Compound B RS and USP Ipratropium Bromide Related Compound C RS in water Standard solution: 0.04 mg/mL of USP Ipratropium Bromide RS and 0.25 mg/mL of USP Albuterol Sulfate RS in water Sample solution: Nominally 0.04 mg/mL of ipratropium bromide and 0.25 mg/mL of albuterol sulfate from the pooled contents of NLT 20 vials of Inhalation Solution prepared as follows. Transfer a suitable volume of the pooled composite Inhalation Solution to a suitable volumetric ask. Dilute with water to obtain the nal nominal concentration. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm. For Identification B, use a diode array detector in the range of 200–300 nm. 

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

Column temperature: 15° 

Flow rate: 1 mL/min 

Injection volume: 20 µL 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for the components relative to ipratropium are shown in Table 2.] 

Table 2 

Suitability requirements 

Resolution: NLT 2.0 between ipratropium and ipratropium related compound B, System suitability solution 

Tailing factor: NMT 2.0 for albuterol and ipratropium,  Standard solution 

Relative standard deviation: NMT 1.0% for albuterol and ipratropium,  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) 

Calculate the percentage of the labeled amount of albuterol (C₁₃H₂₁NO₃) in the portion of Inhalation Solution taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × (M_r1/M_r2) × 100 

r_U = peak response of levalbuterol related compound D from the Sample solution

r_S = peak response of albuterol from the Standard solution 

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

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

F = relative response factor of the corresponding degradation product (see Table 4) 

M_r1 = molecular weight of of albuterol,  239.31

M_r2 = molecular weight of albuterol sulfate, 576.70

N = number of moles of albuterol per mole of albuterol sulfate, 2 

Acceptance criteria 

Ipratropium bromide: 90.0%–110.0% 

Albuterol: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Uniformity of Dosage Units 〈905〉: Meets the requirements 

5 IMPURITIES 

Change to read: 

Organic Impurities 

Solution A: Dissolve 2.7 g of monobasic potassium phosphate in 1 L of water. Adjust with phosphoric acid to a pH of 3.9. Solution B: Acetonitrile 

Mobile phase: See Table 3. 

Table 3 

System suitability solution: 0.18 mg/mL of USP Ipratropium Bromide RS, 1 mg/mL of USP Albuterol Sulfate RS, and 0.005 mg/mL each of USP Levalbuterol Related Compound D RS, USP Ipratropium Bromide Related Compound B RS, and USP Ipratropium Bromide Related Compound C RS in water 

Standard solution: 0.9 µg/mL of USP Ipratropium Bromide RS and 5 µg/mL of USP Albuterol Sulfate RS in water 

Sample solution: Nominally 170 µg/mL of ipratropium bromide and 833 µg/mL of albuterol prepared by pooling the contents of 10 vials of Inhalation Solution into a suitable vessel. Shake well and inject as such. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L7 

Column temperature: 30° 

Flow rate: 1 mL/min 

Injection volume: 50 µL 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—See Table 4 for relative retention times.] 

Suitability requirements 

Resolution: NLT 1.5 between ipratropium related compound C and ipratropium; NLT 2.0 between ipratropium and ipratropium related compound B, System suitability solution 

Tailing factor: NMT 2.0 for albuterol and ipratropium,  Standard solution 

Relative standard deviation: NMT 5.0% for albuterol and ipratropium, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of levalbuterol related compound D in the portion of Inhalation Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × (M_r1/M_r2) × 100 

r_U = peak response of levalbuterol related compound D from the Sample solution

r_S = peak response of albuterol from the Standard solution 

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

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

F = relative response factor of the corresponding degradation product (see Table 4) 

M_r1 = molecular weight of of albuterol,  239.31

M_r2 = molecular weight of albuterol sulfate, 576.70

N = number of moles of albuterol per mole of albuterol sulfate, 2 

Calculate the percentage of atropic acid and ipratropium related compound C in the portion of Inhalation Solution taken: 

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

r_U = peak response of atropic acid or ipratropium related compound C  from the Sample solution U 

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 of the corresponding degradation product (see Table 4) 

Calculate the percentage of each unspecified degradation product in the portion of Inhalation Solution taken: 

Result = (r_U/r_T) × 100 

r_U = peak response of each unspecified degradation product from the Sample solution 

r_T = sum of all the peak responses from the Sample solution 

Acceptance criteria: See Table 4. The reporting threshold is 0.1%. 

Table 4 

^a Counter ion of ipratropium bromide; not to be included in total degradation products. 

^b 4-{2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl}-2-methylphenol. 

^c Process impurity; controlled in the drug substance. 

^d 2,2′-Oxybis(methylene)bis{4-[2-(tert-butylamino)-1-hydroxyethyl]phenol}; also known as 1,1′[Oxybis[methylene(4-hydroxy-1,3- phenylene)]]bis[2-[(1,1-dimethylethyl)amino]ethanol]. 

^e Also known as tropic acid. 

^f (1R,3r,5S,8r)-8-Isopropyl-8-methyl-3-[(2-phenylacryloyl)oxy]-8-azabicyclo[3.2.1]octan-8-ium; also known as (1R,3r,5S,8r)-8-Methyl-8-(1- methylethyl)-3-[(2-phenylpropenoyl)oxy]-8-azoniabicyclo[3.2.1]octane or apo-ipratropium.  

^g 1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-(tert-butylamino)ethanol; also known as α-{[(1,1-Dimethylethyl)amino]methyl}-4- (phenylmethoxy)-1,3-benzenedimethanol or (1RS)-2-[(1,1-Dimethylethyl)amino]-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]ethanol. h 2-Phenylacrylic acid. 

6 SPECIFIC TESTS 

Sterility Tests 〈71〉: Meets the requirements 

pH 〈791〉: 3.4–4.5 

Particulate Matter 

(See Particulate Matter in Injections 〈788〉, Method 1 Light Obscuration Particle Count Test.) 

Sample: Pool the contents of NLT 20 units. 

Acceptance criteria: See Table 5. 

Table 5 

Osmolality and Osmolarity 〈785〉: 278–349 mOsmol/kg 

7 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Protect from light. Store in pouch until the time of use. Store at controlled room temperature. Change to read: 

USP Reference Standards 〈11〉 

USP Albuterol Sulfate RS 

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. 

C₉H₁₀O₃    166.17 

USP Levalbuterol Related Compound D RS 

5-[2-{(1,1-Dimethylethyl)amino}-1-hydroxyethyl]-2-hydroxy-benzaldehyde sulfate (2:1);  

Also known as 5-[2-(tert-Butylamino)-1-hydroxyethyl]-2-hydroxybenzaldehyde sulfate (2:1) (salt).  

(C₁₃H₁₉NO₃)₂. H₂SO₄ 572.67