Aminophylline 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

Aminophylline Tablets contain an amount of aminophylline equivalent to NLT 93.0% and NMT 107.0% of the labeled amount of anhydrous theophylline (C₇H₈N₄O₂).

[NOTE-The ammoniacal odor present in the vapor space above the Tablets is often quite strong, especially when bottles having suitably tight closures are newly opened. This is due to ethylenediamine vapor pressure build-up, a natural condition in the case of aminophylline.]

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

Analysis: Macerate a quantity of Tablets, equivalent to 500 mg of aminophylline, with 25 mL of water, and filter. The filtrate is alkaline to litmus. To the filtrate add 1 mL of 3 N hydrochloric acid, stir, and if necessary, chill to precipitate the theophylline. Filter, and retain the filtrate, free from washings. Use the filtrate in Identification C. Wash the theophylline crystals so obtained with small quantities of ice-cold water, and dry at 105° for 1 h.

Acceptance criteria: The IR spectrum of theophylline so obtained corresponds to that of USP Theophylline RS.

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

C.

Sample: The filtrate obtained in Identification A

Analysis: To the Sample add 0.5 mL of benzenesulfonyl chloride and 5 mL of 1 N sodium hydroxide to render alkaline, shake by mechanical means for 10 min, and add 5 mL of 3 N hydrochloric acid to acidify. Chill, collect the precipitated disulfonamide of ethylenediamine, and wash with water. Recrystallize the washed precipitate from water, and dry at 105° for 1 h.

Acceptance criteria: The dried precipitate melts at 164°-171°.

3 ASSAY

3.1 PROCEDURE

Solution A: 10 mM ammonium acetate prepared as follows. Transfer 770.8 mg of ammonium acetate to a 1-L volumetric flask, and dissolve in water to 80% of the flask volume. Adjust with glacial acetic acid to a pH of 5.5 and dilute with water to volume. Pass through a suitable filter of 0.2-µm pore size.

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Impurity stock solution: 25 µg/mL of USP Theophylline Related Compound F RS in water

System suitability solution: 0.8 mg/mL of USP Theophylline RS and 1 µg/mL of USP Theophylline Related Compound F. RS in water prepared as follows. Transfer 21 mg of USP Theophylline RS to a 25-mL volumetric flask and add 15 mL of water. Sonicate to dissolve, add 1 mL of Impurity stock solution, and dilute with water to volume.

Standard solution: 0.17 mg/mL of USP Theophylline RS in water. Sonicate to dissolve as needed.

Sample solution: Nominally 0.17 mg/mL of anhydrous theophylline from NLT 20 finely powdered Tablets in water prepared as follows. Transfer 34 mg of anhydrous theophylline from a portion of the powder to a 200-mL volumetric flask. Add 20 mL of water and mix for 1 min. Add an additional 140 mL of water and sonicate for 30 min. Dilute with water to volume. Pass through a suitable filter of 0.22-µm pore size, discarding the first 2-3 mL.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 270 nm

Column: 2.1-mm x 10-cm; 1.7-µm packing L1

Column temperature: 40°

Flow rate: 0.4 mL/min

Injection volume: 1 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between theophylline and theophylline related compound F, System suitability solution

Relative standard deviation: NMT 1.0%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of theophylline (C₇H₈N₄O₂) in the portion of Tablets taken:

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

r_U = peak response of theophylline from the Sample solution

r_S = peak response of theophylline from the Standard solution

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

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

Acceptance criteria: 93.0%-107.0%

4 OTHER COMPONENTS

4.1 CONTENT OF ETHYLENEDIAMINE

Sample solution: Transfer a portion of the powdered Tablets, equivalent to 350 mg of aminophylline, prepared in the Assay, into a 100-mL conical flask. Add 20 mL of water, and digest at 50°, with frequent shaking, for 30 min. Cool, filter into a 250-mL conical flask, and wash with water until the last washing is neutral to litmus. Use the combined filtrate and washings.

Titrimetric system

Mode: Direct titration

Titrant: 0.1 N hydrochloric acid VS

Endpoint detection: Visual

Analysis: Add methyl orange e TS to the Sample solution, and titrate. Each mL of 0.1 N hydrochloric acid is equivalent to 3.005 mg of ethylenediamine (C₂H₈N₂).

Acceptance criteria: 140-190 mg of ethylenediamine (C₂H₈N₂) per gram of theophylline (C₇H₈N₄O₂) found in the Assay

Change to read:

5 PERFORMANCE TESTS

5.1 DISSOLUTION (711)

For uncoated or plain coated tablets

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Standard solution: USP Theophylline RS in Medium

Sample solution: Proceed as directed in the chapter for sample. Dilute with water to a concentration that is similar to that of the Standard solution.

Instrumental conditions

Mode: UV-Vis

Analytical wavelength: UV about 269 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of theophylline (C₇H₈N₄O₂) dissolved.

Tolerances: NLT 75% (Q) of the labeled amount of theophylline (C₇H₈N₄O₂) is dissolved.

5.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements (CN 1-Aug-2023)

Procedure for content uniformity

Standard solution: 10 µg/mL of USP Theophylline RS

Sample solution: Place 1 Tablet in a 250-mL volumetric flask, add 200 mL of water, and shake by mechanical means until disintegration is complete. Add water to volume. Filter a portion of the mixture, discarding the first 20 mL of the filtrate.

Instrumental conditions

Mode: UV

Analytical wavelength: About 269 nm

Cell: 1 cm

Blank: Water

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of anhydrous theophylline (C₇H₈N₄O₂) in the Tablet taken:

Result = (A_U/A_S) x (C_S/C_U) x 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

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

(CN 1-Aug-2023)

6 IMPURITIES

ORGANIC IMPURITIES

Solution A, Solution B, Mobile phase, Impurity stock solution, System suitability solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 2.0 µg/mL each of USP Theophylline RS and USP Theophylline Related Compound D RS in water

Sample solution: Nominally 1.0 mg/mL of anhydrous aminophylline from NLT 20 finely powdered Tablets in water prepared as follows. Transfer 10 mg of anhydrous aminophylline from a portion of the powder to a 10-mL volumetric flask. Add 5 mL of water and sonicate for 30 min. Dilute with water to volume. Pass through a suitable filter of 0.22-µm pore size, discarding the first 2-3 mL.

System suitability

Samples: System suitability solution and Standard solution [NOTE-See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between theophylline and theophylline related compound F, System suitability solution

Relative standard deviation: NMT 3.0% for each peak, Standard solution

Analysis

Samples: Standard solution and Sample solution

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

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

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

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

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

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

Calculate the percentage of any other individual unspecified degradation product in the portion of Tablets taken:

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

r_U = peak response of any other individual unspecified degradation product from the Sample solution

r_S = peak response of theophylline from the Standard solution

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

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

Acceptance criteria: See Table 2. Disregard peaks less than 0.05%.

Table 2

^a Process impurity included for identification only and not to be included in the calculation of total degradation products.

^b N-(6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) formamide.

^c 3-Methyl-1H-purine-2,6-dione.

^d 1,3-Dimethyl-7,9-dihydro-1H-purine-2,6,8(3H)-trione.

^e 3,7-Dihydro-3,7-dimethylpurine-2,6(1H)-dione.

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers. Store at controlled room temperature.

LABELING: Label the Tablets to state the content of anhydrous theophylline.

USP REFERENCE STANDARDS (11)

USP Theophylline RS

USP Theophylline Related Compound D RS

Theophyllidine;

N-Methyl-5-(methylamino)-1H-imidazole-4-carboxamide hydrochloride monohydrate.

C₆H₁₀N₄O·HCI·H₂O 208.65

USP Theophylline Related Compound F RS

7-(2-Hydroxyethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione.

C₉H₁₂N₄O₃ 224.22