Levalbuterol 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

Levalbuterol Inhalation Solution is a sterile, aqueous solution of Levalbuterol Hydrochloride, prepared with Sodium Chloride. It contains NLT 90.0% and NMT 110.0% of the labeled amount of levalbuterol (C₁₃H₂₁NO₃).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the System suitability solution, as obtained in the test for Limit of S-Albuterol.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the major peak of the System suitability solution, as obtained in the test for Limit of S-Albuterol.

3 ASSAY

Procedure

Solution A: Dilute 1 mL of phosphoric acid with water to 1 L.

Solution B: Acetonitrile, methanol, and water (35:35:30). To each liter of the solution add 1 mL of phosphoric acid.

Mobile phase: See Table 1.

Table 1

Diluent: Dissolve 9.0 g of sodium chloride in 950 mL of water. Adjust with dilute sulfuric acid to a pH of 4.0, and dilute with water to 1000 mL.

Standard solution: 0.1 mg/mL of USP Levalbuterol Hydrochloride RS in Diluent

Sample solution: Nominally 0.1 mg/mL of levalbuterol hydrochloride (equivalent to 0.087 mg/mL of levalbuterol free base) in Diluent from an appropriately diluted volume of Inhalation Solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.3

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

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

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

r_U = peak response of levalbuterol from the Sample solution

r_S = peak response of levalbuterol from the Standard solution

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

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

M_r1 = molecular weight of levalbuterol (free base), 239.31

M_r2 = molecular weight of levalbuterol hydrochloride, 275.77

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Uniformity of Dosage Units 〈905〉: Meets the requirements

5 IMPURITIES

Change to read:

Limit of S-Albuterol

Mobile phase: Acetonitrile and methanol (50:50). To each liter of the solution add 3 mL of acetic acid and 1 mL of triethylamine.

Diluent: Prepare as directed in the Assay.

System suitability solution: 0.10 mg/mL of USP Levalbuterol Hydrochloride RS and 0.04 mg/mL of USP Albuterol RS in Diluent

Sample solution: Inhalation Solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm. For Identi

cation B use a diode array detector in the range of 200–400 nm.

Column: 4.6-mm × 25-cm; 5-μm packing L63

Flow rate: 1 mL/min

Injection volume: 40 μL

Run time: NLT 1.5 times the retention time of levalbuterol

System suitability

Sample: System suitability solution

[Note—The relative retention times for levalbuterol and (S)-albuterol are 1.0 and 1.16, respectively.]

Suitability requirements

Resolution: NLT 3.0 between levalbuterol and (S)-albuterol

Tailing factor: NMT 1.6 for levalbuterol and NMT 2.0 for (S)-albuterol

Analysis

Sample: Sample solution

Calculate the percentage of (S)-albuterol in the portion of Inhalation Solution taken:

Result = (r_U/r_T) × 100

r_U = peak response of (S)-albuterol from the Sample solution

r_T = sum of the peak responses of levalbuterol and (S)-albuterol from the Sample solution

Acceptance criteria: NMT 2.50% of (S)-albuterol

(IRA 1-Nov-2022)

Change to read:

Organic Impurities

Solution A, Solution B, Diluent, and Sample solution: Prepare as directed in the Assay.

Mobile phase: See Table 2.

Table 2

System suitability solution: 100 μg/mL of USP Levalbuterol Hydrochloride RS and 0.05 μg/mL each of USP Levalbuterol Related Compound A RS, USP Albuterol Related Compound A RS, (IRA 1-Nov-2022) USP Levalbuterol Related Compound C RS, and USP Levalbuterol Related Compound D RS in Diluent Sensitivity solution: 0.05 μg/mL of USP Levalbuterol Hydrochloride RS in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Column temperature: 45°

Flow rate: 1 mL/min

Injection volume: 50 μL

System suitability

Samples: System suitability solution and Sensitivity solution

[Note—The relative retention times in Table 3 are provided as information that could aid in peak assignment.]

Table 3 (IRA 1-Nov-2022)

^a 5-[2-(tert-Butylamino)-1-hydroxyethyl]-3-(hydroxymethyl)benzene-1,2-diol.

^b 4-[2-(tert-Butylamino)-1-methoxyethyl]-2-(hydroxymethyl)phenol.

^c 4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(ethoxymethyl)phenol; also known as (IRA 1-Nov-2022) α-{[(1,1-Dimethylethyl)amino]methyl}-3- (ethoxymethyl)-4-hydroxy-benzenemethanol.

^d 1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-(tert-butylamino)ethan-1-ol (IRA 1-Nov-2022) .

Suitability requirements

Resolution: NLT 4.9 between levalbuterol and levalbuterol related compound A; NLT 1.5 between albuterol related compound A (IRA 1-

Nov-2022) and levalbuterol related compound C, System suitability solution

Tailing factor: NMT 4.0 for the levalbuterol peak, System suitability solution

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

Analysis

Sample: Sample solution

Calculate the percentage of each degradation product (IRA 1-Nov-2022) in the portion of Inhalation Solution taken:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each degradation product (IRA 1-Nov-2022) from the Sample solution

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

F = relative response factor for each degradation product (IRA 1-Nov-2022) (see Table 4)

Acceptance criteria: See Table 4. The reporting threshold is 0.05%.

Table 4

6 SPECIFIC TESTS

Sterility Tests 〈71〉: Meets the requirements

pH 〈791〉: 3.3–4.5

Particulate Matter in Injections 〈788〉: See Table 5.

Table 5

Osmolality and Osmolarity 〈785〉, Osmolality: 280–320 mOsmol/kg

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in low-density polyethylene single-use ampuls, with a multilayer foil overwrap. Store at controlled room

temperature.

Labeling: The outer label indicates that the unit-dose container should be discarded if the solution is not colorless.

Change to read:

USP Reference Standards 〈11〉

USP Albuterol RS

USP Albuterol Related Compound A RS

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

(C₁₃H₂₁NO₂)₂ ∙ H₂SO₄ 544.70 (IRA 1-Nov-2022)

USP Levalbuterol Hydrochloride RS

USP Levalbuterol Related Compound A RS

4-[2-(tert-Butylamino)ethyl]-2-(hydroxymethyl)phenol; Also known as (IRA 1-Nov-2022) 4-(2-tert-Butylamino-ethyl)-2-hydroxymethyl-phenol.

C₁₃H₂₁NO₂ 223.32 (IRA 1-Nov-2022)

USP Levalbuterol Related Compound C RS

4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(methoxymethyl)phenol; Also known as (IRA 1-Nov-2022) α-{[(1,1-Dimethylethyl)amino]methyl}-4- hydroxy-3-(methoxymethyl)-benzenemethanol.

C₁₄H₂₃NO₃ 253.34

USP Levalbuterol Related Compound D RS

5-[2-(tert-Butylamino)-1-hydroxyethyl]-2-hydroxybenzaldehyde sulfate (2:1)

(IRA 1-Nov-2022) ;

Also known as 5-[2-{(1,1-Dimethylethyl)amino}-1-hydroxyethyl]-2-hydroxy-benzaldehyde sulfate(2:1).

(C₁₃H₁₉NO₃)₂ · H₂SO₄ 572.67