Theophylline 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

Theophylline Oral Solution contains NLT 95.0% and NMT 105.0% of the labeled amount of theophylline (C₇H₈N₄O₂ ).

2 IDENTIFICATION

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

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

3 ASSAY

Procedure

Solution A: 10 mM ammonium acetate prepared as follows. Transfer 771 mg/L of ammonium acetate to a suitable flask, and dissolve in water. Adjust with glacial acetic acid to a pH of 5.4 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

Standard solution: 0.2 mg/mL of USP Theophylline RS in water

Sample solution: Nominally 0.2 mg/mL of theophylline from Oral Solution in water. Centrifuge and use the supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm. For Identi

cation test A, use a photodiode array detector in the range of 210–400 nm.

Column: 2.1-mm × 10-cm; 1.7-μm packing L7

Column temperature: 40 ± 2°

Flow rate: 0.4 mL/min

Injection volume: 1 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2

Relative standard deviation: NMT 1.0%

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 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: 95.0%–105.0%

4 IMPURITIES

Organic Impurities

Solution A, Solution B, Mobile phase, and Chromatographic system: Proceed as directed in the Assay.

Impurity stock solution: 0.1 mg/mL each of USP Theophylline RS and USP Theophylline Related Compound D RS in water

System suitability solution: 10 μg/mL each of USP Theophylline RS and USP Theophylline Related Compound D RS from Impurity stock

solution, and 10 μg/mL of USP Saccharin Sodium RS in water

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

Sample solution: Nominally 1.0 mg/mL of theophylline from a portion of Oral Solution in water. Centrifuge and use the supernatant.

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between theophyllidine and saccharin, System suitability solution

Relative standard deviation: NMT 3.0% for theophylline and theophylline related compound D peaks, Standard solution

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 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 theophylline in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. Disregard peaks less than 0.1%.

Table 2

^a Included as a potential excipient. Do not include in the calculation of total impurities.

5 SPECIFIC TESTS

Microbial Enumeration Tests 〈61〉andTests for Specified Microorganisms 〈62〉: Meets the requirements of the tests for absence of Salmonella species and Escherichia coli. The total aerobic microbial count does not exceed 1 × 10² cfu/mL, and the total combined molds and yeasts count does not exceed 5 × 10¹ cfu/mL.

pH 〈791〉: 3.0–4.7

Alcohol Determination 〈611〉, Method II(if present)

Analysis: Use acetone as the internal standard.

Acceptance criteria: 90.0%–115.0% of the labeled amount of alcohol (C₂H₅OH)

6 ADDITIONAL REQUIREMENTS

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

Labeling: Label it to indicate the alcohol content (if present).

USP Reference Standards 〈11〉

USP Alcohol Determination—Acetonitrile RS

USP Alcohol Determination±Alcohol RS

USP Saccharin Sodium RS

USP Theophylline RS

USP Theophylline Related Compound D RS

Theophyllidine;

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

C₇H₈N₄O₂ · HCl · H₂O