Theophylline Extended-Release Capsules

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 Extended-Release Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of anhydrous 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

3.1 Procedure

Solution A: 10 mM ammonium acetate prepared as follows. Transfer 0.77 g of ammonium acetate to a 1-L volumetric flask, and dissolve in 80% of the flask volume of 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

Diluent: Dilute 138 mL of ammonium hydroxide solution with water to 1 L.

Standard solution: 0.2 mg/mL of USP Theophylline RS

Sample stock solution: Nominally 4 mg/mL of theophylline prepared as follows. Transfer the contents of a suitable number of Capsules to a 500-mL volumetric flask. Add 150 mL of Diluent and heat on a hot plate to just boiling with occasional stirring. Remove from the hot plate and sonicate for 5 min while still hot. Cool to ambient temperature and dilute with water to volume.

Sample solution: Nominally 0.2 mg/mL of theophylline from Sample stock solution. Centrifuge and use the supernatant.

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm. For Identification 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

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Tailing factor: NMT 2

Relative standard deviation: NMT 1.0%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) in the portion of Capsules 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: 90.0%–110.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

[Note—The following tests, which were assigned numbers chronologically, are placed in groups corresponding to product dosing intervals. Thus, individual tests do not necessarily appear in numerical order.]

For products labeled for dosing every 12 h

Test 1: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1. Proceed as directed for Dissolution

〈711〉, Procedure, Apparatus 1 and 2, Delayed-Release Dosage Forms, Method B Procedure except to use Acceptance Table 2.

Medium: pH 1.2 simulated gastric fluid (without pepsin) for thefirst hour; pH 6.0 phosphate buffer (see Reagents, Indicators, and Solutions —Buffer Solutions); 900 mL

Apparatus 2: 50 rpm

Times: 1, 2, 4, 6, and 8 h

Standard solution: A known concentration of USP Theophylline RS in Medium

Sample solution: Filtered portions of the solution under test. Dilute with Medium, if necessary, to a concentration that is similar to that of the Standard solution.

Instrumental conditions

Mode: UV

Analytical wavelength: Maximum absorbance at about 271 nm

Analysis

Samples: Standard solution and Sample solution

Determine the percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at each time point using the UV absorption.

Tolerances: See Table 2.

Table 2

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Solution A: 6.8 g/L of monobasic potassium phosphate. Adjust with either 1 N hydrochloric acid or 1 N sodium hydroxide to a pH of 4.5 ± 0.05.

Medium: Solution A; 900 mL

Apparatus 2: 75 rpm

Times: 1, 2, 4, and 8 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 3.

Table 3

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3. Proceed as directed for Dissolution

〈711〉, Procedure, Apparatus 1 and 2, Delayed-Release Dosage Forms, Method B Procedure except to use Acceptance Table 2.

Medium: pH 1.2 simulated gastric fluid (without pepsin) for 1 h; pH 7.5 simulated intestinal fluid (without enzyme); 900 mL

Apparatus 2: 50 rpm

Times: 1, 2, 3, 4, and 7 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 4.

Table 4

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4. Proceed as directed for Dissolution

〈711〉, Procedure, Apparatus 1 and 2, Delayed-Release Dosage Forms, Method A Procedure except to use Acceptance Table 2.

Medium: pH 3.0 phosphate buffer prepared by adjusting 0.05 M potassium phosphate buffer with phosphoric acid to a pH of 3.0 ± 0.05, for the first 3.5 h, followed by the addition of 5.3 M sodium hydroxide to adjust to a pH of 7.4 ± 0.05; 900 mL

Apparatus 2: 50 rpm

Times: 1, 2, 3.5, and 5 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 5.

Table 5

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium, Apparatus 2, and Analysis: Proceed as directed in Test 4.

Times: 1, 3.5, 5, 7, and 10 h

Tolerances: See Table 6.

Table 6

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 7: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.

Solution A: Dissolve 40.8 g of monobasic potassium phosphate in 6 L of water, add 667 mg of octoxynol 9, and adjust with dilute hydrochloric acid or sodium hydroxide to a pH of 4.5.

Medium: Solution A; 900 mL

Apparatus 2: 50 rpm

Times: 1, 2, 4, and 8 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 7.

Table 7

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 8: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8.

Medium: pH 7.5 simulated intestinal

uid (without enzyme); 900 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, 6, and 8 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 8.

Table 8

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 9: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9.

Medium 1: 0.1 N hydrochloric acid; 900 mL

Medium 2: Simulated intestinal fluid (without enzyme); 900 mL

Apparatus 1: 50 rpm

Times: 1, 2, 3, 4, and 6 h

Determine the percentage of the labeled amount of theophylline dissolved at the times specified, using Medium 1 for the first h and Medium 2 for the next 5 h.

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 9.

Table 9

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Test 10: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10. Proceed as directed for Test 3.

Times: 1, 2, 4, and 8 h

Tolerances: See Table 10.

Table 10

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

For products labeled for dosing every 24 h

Test 6: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.

Medium: 0.05 M pH 6.6 phosphate buffer (see Reagents, Indicators, and Solutions—Buffer Solutions); 1000 mL

Apparatus 1: 100 rpm

Times: 1, 2, 4, 5, and 8 h

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 11.

Table 11

The percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) dissolved at the times given conforms to Dissolution 〈711〉,

Acceptance Table 2.

Change to read:

Uniformity of Dosage Units 〈905〉: Meet the requirements (CN 1-Aug-2023)

Procedure for content uniformity

Standard solution: 12 μg/mL of USP Theophylline RS

Sample solution: Nominally 12 μg/mL of theophylline, prepared as follows. Using a mortar and pestle, triturate the contents of 1 Capsule with 20 mL of water. With the aid of water, transfer the mixture to a 100-mL volumetric flask. Add 25 mL of 6 N ammonium hydroxide, shake or sonicate for 45 min, and cool to room temperature. Dilute with water to volume. Filter a portion of the mixture, discarding the first 20 mL of the filtrate. Dilute a portion of the filtrate with water to obtain the solution.

4.1 Instrumental conditions

Mode: UV

Analytical wavelength: Maximum absorbance at about 270 nm

Cell: 1 cm

Blank: Water

4.2 Analysis

Samples: Standard solution, Sample solution, and Blank

Concomitantly determine the absorbance of the Sample solution and Standard solution.

Calculate the percentage of the labeled amount of theophylline (C₇H₈N₄O₂ ) in each Capsule taken:

Result = (A_U /A ) × (C /C_U ) × 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)

5 IMPURITIES

5.1 Organic Impurities

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

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

System suitability solution: 1 μg/mL each of USP Theophylline RS and USP Theophylline Related Compound D RS from the Standard stock solution

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

Sample solution: Nominally 1.0 mg/mL of theophylline from the Sample stock solution. Centrifuge and use the supernatant.

5.2 System suitability

Sample: System suitability solution

[Note—See Table 12 for relative retention times.]

5.3 Suitability requirements

Relative standard deviation: NMT 5.0% for the theophylline and theophylline related compound D RS peaks

5.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of theophylline related compound D in the portion of Capsules 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 Capsules 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 12. Disregard peaks less than 0.1%.

Table 12

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

Labeling: The labeling indicates whether the product is intended for dosing every 12 or 24 h, and states with which in vitro Dissolution Test the product complies.

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