Albuterol Extended-Release Tablets

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 

Albuterol Extended-Release Tablets contain albuterol sulfate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of albuterol (C₁₃H₂₁NO₃). 

2 IDENTIFICATION 

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

B. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U_{(CN 1-May-2020)} 

Standard solution: 80 µg/mL of albuterol from USP Albuterol Sulfate RS in methanol 

Sample solution: 80 µg/mL of albuterol in methanol, prepared as follows. Transfer a suitable number of Tablets to a volumetric ask, and dilute with methanol to volume. Stir for 30 min, and centrifuge. 

Wavelength range: 210–350 nm 

Cell path: 0.2 cm 

Acceptance criteria: The Sample solution exhibits maxima and minima only at the same wavelengths as the Standard solution. 

3 ASSAY 

Procedure 

Buffer: 0.65 g/L of sodium 1-octane sulfonate and 21.7 g/L of ammonium acetate in water 

Mobile phase: Glacial acetic acid, 2-propanol, methanol, and Buffer (4:3:1:92) 

Diluent: 10 mL/L of triethylamine in water 

Standard stock solution: 0.2 mg/mL of USP Albuterol Sulfate RS in Diluent 

Standard solution: 0.02 mg/mL of USP Albuterol Sulfate RS in Diluent, from the Standard stock solution. Transfer an aliquot of the Standard stock solution to a suitable volumetric ask, and add 4% of the ask volume of methanol. Allow to cool to room temperature, and dilute with Diluent to volume. 

Sample solution: Nominally 0.016 mg/mL of albuterol, prepared as follows. Transfer Tablets (NLT 10) to a suitable volumetric ask, add 10% of the ask volume of methanol, and sonicate for 30 min with regular swirling. Add 60% of the ask volume of Diluent, and sonicate for 30 min with swirling. Stir for 60 min, allow the solution to cool to room temperature, and dilute with Diluent to volume. Centrifuge a portion of 

this solution at 2500 rpm for 15 min. Transfer 10 mL of the supernatant into a 50-mL volumetric ask, add 1 mL of methanol, cool to room temperature, and dilute with Diluent to volume. Pass the solution though a 1-µm glass ber or equivalent lter, and discard the rst 3 mL of the ltrate. 

3.1 Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 276 nm 

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

Column temperature: 30° 

Flow rate: 1 mL/min 

Injection volume: 40 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Column eciency: NLT 2000 theoretical plates 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 2.0% 

3.2 Analysis 

Samples: Standard solution and Sample solution 

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

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

r_U = peak response from the Sample solution  

r_S = peak response from the Standard solution 

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

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

M = moles of albuterol per mole of albuterol sulfate, 2 

M_r1 = molecular weight of albuterol, 239.31  

M_r2 = molecular weight of albuterol sulfate, 576.70 

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Dissolution 〈711〉 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 50 rpm, with helix sinker 

Time: 1, 2, 4, and 9 h 

Buffer, Mobile phase, Chromatographic system, and System suitability: Proceed as directed in the Assay, except to use an Injection volume of 50 µL. 

Standard stock solution: 0.2 mg/mL of albuterol, using USP Albuterol Sulfate RS, in Medium 

Standard solution: Dilute the Standard stock solution with Medium to obtain a nal concentration of (L/1000) mg/mL of albuterol, where L is the label claim in mg/Tablet of albuterol. 

Sample solution: Pass a portion of the solution under test through a suitable lter. 
Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C ) of albuterol (C₁₃H₂₁NO₃) in the sample withdrawn from the vessel at each time point (i):

Resulti = (r_U /r_S ) × CS 

r_U = peak response from the Sample solution  

r_S = peak response from the Standard solution 

C_S = concentration of albuterol in the Standard solution (mg/mL)  

Calculate the percentage of the labeled amount of albuterol (C₁₃H₂₁NO₃) released at each time point (i): 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S )] + [C₁ × V_S ]} × (1/L) × 100 

Result₃ = {[C₃ × (V − (2 × V_S ))] + [(C₂ + C₁ ) × V_S ]} × (1/L) × 100 

Result₄ = {[C₄ × (V − (3 × V_S ))] + [(C₃ + C₂ + C₁ ) × V_S ]} × (1/L) × 100 

C_i = concentration of albuterol in the portion of sample withdrawn at time point i (mg/mL) 

V = volume of the Medium (900 mL) 

L = label claim (mg/Tablet) 

V_S = volume of the Sample solution withdrawn from the Medium (mL)  

Tolerances: See Table 1. 

Table 1 

The cumulative percentages of the labeled amount of albuterol (C₁₃H₂₁NO₃), released at the times specied, conform to Acceptance Table in Dissolution 〈711〉. 

Uniformity of Dosage Units 〈905〉: Meet the requirements 

4.1 IMPURITIES 

Organic Impurities, Procedure 1 

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with hydrochloric acid to a pH of 3.0. 

Mobile phase: Methanol and Buffer (5:95) 

System suitability solution: 2 µg/mL each of USP Albuterol Sulfate RS and USP Albuterol Related Compound B RS in Mobile phase Standard solution: 2.4 µg/mL of USP Albuterol Sulfate RS, 0.80 µg/mL of USP Levalbuterol Related Compound C RS, and 0.25 µg/mL of USP Levalbuterol Related Compound D RS (equivalent to 0.20 µg/mL free base) in Mobile phase 

Sensitivity solution: 0.06 µg/mL of USP Albuterol Sulfate RS in Mobile phase 

Sample solution: Transfer an amount of powder from NLT 20 Tablets to a suitable volumetric ask to obtain a solution with a nal nominal concentration of 0.2 mg/mL of albuterol. Add 70% of the ask volume of Mobile phase, and sonicate for 10 min. Stir for 30 min, and dilute with Mobile phase to volume. Pass the solution though a 1-µm glass ber or equivalent lter, and discard the rst 3 mL of the ltrate. Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 225 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L11 

Column temperature: 30° 

Flow rate: 1.5 mL/min 

Injection volume: 80 µL 

Run time: 5 times the retention time of albuterol 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—Identify the impurities using the relative retention times shown in Table 2.] 

Suitability requirements: 

Tailing factor: NMT 2.0 for each compound, Standard solution 

Resolution: NLT 2 between albuterol and albuterol related compound B, System suitability solution Relative standard deviation: NMT 10.0% for each compound, Standard solution 

Analysis 

Samples: Standard solution, Sensitivity solution, and Sample solution 

[Note—Identify the impurities using the relative retention times shown in Table 2.] 

Calculate the percentage of levalbuterol related compound C in the portion of Tablets taken: 

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

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

r_S = peak response of levalbuterol related compound C from the Standard solution 

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

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

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

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

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

r_S = peak response of the levalbuterol related compound D from the Standard solution 

C_S = concentration of USP Levalbuterol Related Compound D RS (as the free base) in the Standard solution (mg/mL) S 

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

Calculate the percentage of any other impurity in the portion of Tablets taken: 

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

r_U = peak response of the impurity 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 (mg/mL) 

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

M = moles of albuterol per mole of albuterol sulfate, 2 

M_r1 = molecular weight of albuterol, 239.31 

M_r2 = molecular weight of albuterol sulfate, 576.70 

Acceptance criteria: See Table 2. Disregard peaks eluting after levalbuterol related compound C or with areas less than that of the Sensitivity solution. 

Table 2 

^a 2-(tert-Butylamino)-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone. 

^b Process impurity included in the table for identication only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product. 

^c 2-(tert-Butylamino)-1-[3-chloro-4-hydroxy-5-(hydroxymethyl)phenyl]ethanone. 

^d 4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-chloro-6-(hydroxymethyl)phenol. 

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

^f 5-[2-{(1,1-Dimethylethyl)amino}-1-hydroxyethyl]-2-hydroxy-benzaldehyde. 

^g α-[{(1,1-Dimethylethyl)amino}methyl]-4-hydroxy-3-(methoxymethyl)-benzenemethanol. 

^h Disregard peaks eluting after levalbuterol related compound C. 

Organic Impurities, Procedure 2 

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with hydrochloric acid to a pH of 3.0. 

Mobile phase: Methanol and Buffer (30:70) 

Diluent: Methanol and Buffer (5:95) 

Peak identication solution: 2.4 µg/mL of USP Albuterol Sulfate RS, 1.0 µg/mL of USP Levalbuterol Related Compound C RS, and 1.2 µg/mL of USP Levalbuterol Related Compound D RS in Diluent 

Standard solution: 2.4 µg/mL of USP Albuterol Sulfate RS and 1.0 µg/mL of USP Albuterol Related Compound E RS in Diluent Sensitivity solution: 0.06 µg/mL of USP Albuterol Sulfate RS in Diluent from Standard solution 

Sample solution: Transfer an amount of powder from NLT 20 Tablets to a suitable volumetric ask to obtain a solution with a nal concentration of 0.2 mg/mL of albuterol. Add 70% of the ask volume of Diluent, and sonicate for 10 min. Stir for 30 min, and dilute with Diluent to volume. Pass the solution though a glass ber or equivalent lter of 1-µm pore size, and discard the rst 3 mL of the ltrate. 

4.2 Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 225 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L11 

Flow rate: 0.7 mL/min 

Injection volume: 80 µL 

Run time: 5 times the retention time of albuterol 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 for each compound 

Relative standard deviation: NMT 10.0% for each compound 

4.3 Analysis 

Samples: Standard solution, Peak identication solution, Sensitivity solution, and Sample solution 

Calculate the percentage of albuterol related compound E in the portion of Tablets taken: 

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

r_U = peak response of albuterol related compound E from the Sample solution  

r_S = peak response of albuterol related compound E from the Standard solution 

C_S = concentration of USP Albuterol Related Compound E RS in the Standard solution (mg/mL) 

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

Calculate the percentage of any other impurity in the portion of Tablets taken: 

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

r_U = peak response of the impurity 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 (mg/mL) 

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

M = moles of albuterol per mole of albuterol sulfate, 2 

M_r1 = molecular weight of albuterol, 239.31 

M_r2 = molecular weight of albuterol sulfate, 576.70  

Acceptance criteria: See Table 3. Disregard the levalbuterol related compound C peak and any peak eluting before it. Disregard peaks with areas less than that of the Sensitivity solution. 

Table 3 

^a 2,2'-Oxybis(methylene)bis{4-[2-(tert-butylamino)-1-hydroxyethyl]phenol}.

^b From the sum of the impurities in Procedure 1 and Procedure 2. 

5 ADDITIONAL REQUIREMENTS 

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

USP Reference Standards 〈11〉 

USP Albuterol Sulfate RS 

USP Albuterol Related Compound B RS 

2-(tert-Butylamino)-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone. 

C₁₃H₁₉NO₃ 237.29 

USP Albuterol Related Compound E RS 

2,2′-Oxybis(methylene)bis{4-[2-(tert-butylamino)-1-hydroxyethyl]phenol}. 

C₂₆H₄₀N₂O₅ 460.61 

USP Levalbuterol Related Compound C RS 

α-[{(1,1-Dimethylethyl)amino}methyl]-4-hydroxy-3-(methoxymethyl)-benzenemethanol. 

C₁₄H₂₃N0₃ 253.34 

USP Levalbuterol Related Compound D RS 

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

(C₁₃H₁₉NO₃)  · H₂SO₄ 572.67