Levalbuterol Hydrochloride

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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C₁₃H₂₁NO₃ · HCl 275.77

Phenol, 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl), hydrochloride, (R)-;

(R)-α-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-α,α′-diol hydrochloride; (IRA 1-Nov-2022)

(R)-α1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-α,α′-diol hydrochloride CAS RN®: 50293-90-8; UNII: WDQ1526QJM. (IRA 1-Nov-2022)

1 DEFINITION

Levalbuterol Hydrochloride contains NLT 98.0% and NMT 102.0% of levalbuterol hydrochloride (C H NO · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

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B. The retention time of the major peak of the Identification sample solution (IRA 1-Nov-2022) corresponds to that of the levalbuterol peak of the System suitability solution, as obtained in the test for Limit of S-Albuterol.

3 ASSAY

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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: Solution A

Standard solution: 100 μg/mL of USP Levalbuterol Hydrochloride RS in Diluent

Sample solution: 100 μg/mL of Levalbuterol Hydrochloride 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: 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 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of levalbuterol hydrochloride (C₁₃H₂₁NO₃ · HCl) in the portion of Levalbuterol Hydrochloride taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

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

r_S = peak response of levalbuterol (IRA 1-Nov-2022) from the Standard solution

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

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

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

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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: Mobile phase

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: 0.8 mg/mL of Levalbuterol Hydrochloride in Diluent

Identification sample solution: (IRA 1-Nov-2022) 0.1 mg/mL of Levalbuterol Hydrochloride (IRA 1-Nov-2022) from the Sample solution in

Diluent (IRA 1-Nov-2022)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

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

Flow rate: 1 mL/min

Injection volume: 10 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 2.0 between levalbuterol and (S)-albuterol

Tailing factor: NMT 2.2 for levalbuterol and (S)-albuterol

Analysis

Sample: Sample solution

(IRA 1-Nov-2022)

Calculate the percentage of (S)-albuterol in the portion of Levalbuterol Hydrochloride 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 for levalbuterol and (S)-albuterol from the Sample solution

Acceptance criteria: NMT 0.2% of (S)-albuterol

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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: 0.03 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)

Name Relative Retention Time

Levalbuterol 1.0

Levalbuterol related compound A 1.2

Levalbuterol related compound Ha 1.3

Albuterol related compound A (IRA 1-Nov-2022) 1.5

Levalbuterol related compound C 1.6

Levalbuterol related compound D 1.7

Levalbuterol related compound Eb 2.1

Levalbuterol related compound Fc 3.5

^a 4-[2-(tert-Butylamino)-1-methoxyethyl]-2-(hydroxymethyl)phenol (IRA 1-Nov-2022) .

^b 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.

^c 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 levalbuterol, System suitability solution

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

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Levalbuterol Hydrochloride taken:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

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

F = relative response factor for each impurity (see Table 4)

Acceptance criteria: See Table 4. The reporting threshold is 0.03%.

Table 4

5 SPECIFIC TESTS

pH 〈791〉

Sample solution: 10 mg/mL of Levalbuterol Hydrochloride

Acceptance criteria: 4.5–5.5

Water Determination 〈921〉, Method I, Method Ic: NMT 0.3%

6 ADDITIONAL REQUIREMENTS

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

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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