Aminophylline Oral 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

Aminophylline Oral Solution is an aqueous solution of Aminophylline, prepared with the aid of Ethylenediamine. It contains an amount of aminophylline (C₁₆H₂₄N₁₀O₄) equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of anhydrous theophylline (C₇H₈N₄O₂). 

Aminophylline Oral Solution may contain an excess of ethylenediamine, but no other substance may be added for the purpose of pH adjustment.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

Analysis: Transfer a volume of Oral Solution equivalent to 500 mg of aminophylline to a suitable container and add, with constant stirring, 1 mL of 3 N hydrochloric acid or enough to completely precipitate the theophylline. Filter (retain the filtrate), wash the precipitate with small portions of cold water until free from chloride, and dry at 105° for 1 h.

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

B.

Analysis: To the filtrate obtained in Identification A 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, add 5 mL of 3 N hydrochloric acid to acidify, chill, collect the precipitated disulfonamide of ethylenediamine, wash with water, recrystallize from water, and dry at 105° for 1 h.

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

3 ASSAY

Procedure

Solution A: 10 mM ammonium acetate prepared as follows. Transfer an appropriate amount of ammonium acetate to a volumetric ask and dissolve in water (about 80% of the ask 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 2 µg/mL of USP Theophylline Related Compound F RS in water prepared as follows. Transfer 1 mg of USP Theophylline RS to a 25-mL volumetric ask and add 15 mL of water. Sonicate to dissolve, add 2 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 in water prepared as follows. Transfer an appropriate amount of anhydrous theophylline from a volume of Oral Solution to a suitable volumetric ask. Dissolve and dilute with water to volume.

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm

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

Column temperature: 40°

Flow rate: 0.4 mL/min

Injection volume: 1 µL

3.2 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 Oral Solution taken: 

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

r_U = peak response from the Sample solution

r_S = peak response 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: 90.0%–110.0%

4 OTHER COMPONENTS

Content of Ethylenediamine

Sample: A volume of Oral Solution equivalent to 500 mg of aminophylline

Diluent: Water

Titrimetric system

Mode: Direct titration

Titrant: 0.1 N hydrochloric acid VS

Endpoint detection: Visual

Analysis: If necessary, dilute the Sample with Diluent to 30 mL, add methyl orange TS, and titrate. Each mL of 0.1 N hydrochloric acid is equivalent to 3.005 mg of ethylenediamine (C₂H₈N₂).

Acceptance criteria: 176–283 mg of ethylenediamine (C₂H₈N₂) per gram of theophylline (C₇H₈N₄O₂) found in the Assay

5 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 in water prepared as follows. Transfer an appropriate amount of anhydrous aminophylline from a volume of Oral Solution to a suitable volumetric ask. Dissolve and dilute with water to volume.

5.1 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 present in the Standard solution

5.2 Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U /r_S ) × (C_S /C_U ) × 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 anhydrous theophylline in the Sample solution (mg/mL)

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

Result = (r_U /r_S ) × (C_S /C_U ) × 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 anhydrous theophylline in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. Disregard peaks less than 0.086%.

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.

6 SPECIFIC TESTS

pH 〈791〉: 8.5–9.7

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

Labeling: Label the Oral Solution 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 · HCl · 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