Theophylline Extended-Release Capsules
» Theophylline Extended-Release Capsules contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of anhydrous theophylline (C7H8N4O2).
Packaging and storage— Preserve in well-closed containers.
Labeling— The labeling indicates whether the product is intended for dosing every 12 or 24 hours, and states with which in vitro Dissolution Test the product complies.
USP Reference standards 11
USP Theophylline RS Click to View Structure
Identification—
A: Transfer a quantity of Capsule contents, equivalent to about 100 mg of anhydrous theophylline, to a suitable conical flask. Add 150 mL of methanol, and sonicate until the insoluble material is dispersed into fine particles. Shake by mechanical means for 15 minutes, and filter into a 250-mL volumetric flask. Dilute with water to volume, and mix. Pipet 5 mL of this solution into a 200-mL volumetric flask, dilute with 0.1 N hydrochloric acid to volume, and mix: the UV absorption spectrum of the solution so obtained exhibits maxima and minima at the same wavelengths as that of a similar solution of USP Theophylline RS, concomitantly measured.
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
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 hours
test 1— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1. Proceed as directed for Method B under Apparatus 1 and 2, Delayed-Release Dosage Forms, except to use Acceptance Table 2.
Medium: pH 1.2 simulated gastric fluid (without pepsin) for the first hour; pH 6.0 phosphate buffer (see Buffer Solutions in the section Reagents, Indicators, and Solutions); 900 mL.
Apparatus 2: 50 rpm.
Procedure— Determine the amount of C7H8N4O2 dissolved from UV absorbances at the wavelength of maximum absorbance at about 271 nm on filtered portions of the solution under test, diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Theophylline RS in the same Medium.
Times and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 3% and 15%
2 between 20% and 40%
4 between 50% and 75%
6 between 65% and 100%
8 not less than 80%
test 2— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
pH 4.5 Phosphate buffer— Dissolve 6.8 g of monobasic potassium phosphate in 750 mL of water, mix, and dilute with water to 1000 mL. Adjust with either 1 N hydrochloric acid or 1 N sodium hydroxide to a pH of 4.5 ± 0.05.
Medium: pH 4.5 Phosphate buffer; 900 mL.
Apparatus 2: 75 rpm.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentages of the labeled amount of C7H8N4O2 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 10% and 30%
2 between 30% and 55%
4 between 55% and 80%
8 not less than 80%
test 3— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3. Proceed as directed for Method B under Apparatus 1 and 2, Delayed-Release Dosage Forms, except to use Acceptance Table 2.
Medium: pH 1.2 simulated gastric fluid (without pepsin) for 1 hour; pH 7.5 simulated intestinal fluid (without enzyme); 900 mL.
Apparatus 2: 50 rpm.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 1% and 17%
2 between 30% and 60%
3 between 50% and 90%
4 not less than 65%
7 not less than 85%
test 4— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4. Proceed as directed for Method A under Apparatus 1 and 2, Delayed-Release Dosage Forms, 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 3½ hours, 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.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 13% and 38%
2 between 25% and 50%
3.5 between 37% and 65%
5 between 85% and 115%
test 5— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.
Medium, Apparatus, and Procedure— Proceed as directed under Test 4.
Times and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 10% and 30%
3.5 between 30% and 60%
5 between 50% and 80%
7 not less than 65%
10 not less than 80%
test 7— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.
Phosphate buffer— Dissolve 40.8 g of monobasic potassium phosphate in 6 L of water, add 667 mg of octoxynol 9, mix, and adjust with dilute hydrochloric acid or sodium hydroxide to a pH of 4.5.
Medium: Phosphate buffer; 900 mL.
Apparatus 2: 50 rpm.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentages of the labeled amount of C7H8N4O2 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 10% and 40%
2 between 35% and 70%
4 between 60% and 90%
8 not less than 85%
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 fluid (without enzyme); 900 mL.
Apparatus 1: 100 rpm.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentages of labeled amount of C7H8N4O2 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 3% and 30%
2 between 15% and 50%
4 between 45% and 80%
6 not less than 70%
8 not less than 85%
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.
Determine the amount of theophylline dissolved at the times specified, using Medium 1 for the first hour and Medium 2 for the next five hours.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 5% and 15%
2 between 25% and 45%
3 between 50% and 65%
4 not less than 70%
6 not less than 85%
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 and Tolerances— The percentage of the labeled amount of C7H8N4O2 dissolved at the times given conforms to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 6% and 27%
2 between 25% and 50%
4 between 65% and 85%
8 not less than 80%
for products labeled for dosing every 24 hours
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 Buffer Solutions in the section Reagents, Indicators, and Solutions); 1000 mL.
Apparatus 1: 100 rpm.
Procedure— Proceed as directed under Test 1.
Times and Tolerances— The percentages of the labeled amount of C7H8N4O2 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 5% and 15%
2 between 12% and 30%
4 between 25% and 50%
5 between 30% and 60%
8 between 55% and 75%
Uniformity of dosage units 905: meet the requirements.
Procedure for content uniformity— 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 about 45 minutes, and cool to room temperature. Dilute with water to volume, and mix. Filter a portion of the mixture, discarding the first 20 mL of the filtrate. Dilute a portion of the filtrate quantitatively, and stepwise if necessary, with water to obtain a solution containing about 12 µg of theophylline per mL. Concomitantly determine the absorbances of this solution and a Standard solution of USP Theophylline RS, similarly prepared, having a known concentration of about 12 µg per mL, in 1-cm cells, at the wavelength of maximum absorbance at about 270 nm, with a suitable spectrophotometer, using water as the blank. Calculate the quantity, in mg, of C7H8N4O2 in the Capsule taken by the formula:
(TC / D)(AU / AS)
in which T is the labeled quantity, in mg, of theophylline in the Capsule; C is the concentration, in µg per mL, of USP Theophylline RS in the Standard solution; D is the concentration, in µg per mL, of theophylline in the solution from the Capsule, based on the labeled quantity per Capsule and the extent of dilution; and AU and AS are the absorbances of the solution from the Capsule and the Standard solution, respectively.
Assay—
Buffer solution , Mobile phase, Internal standard solution, and Standard preparation—Prepare as directed in the Assay under Theophylline.
Assay preparation— Quantitatively transfer the contents of 10 Capsules to a 500-mL volumetric flask, and add 100 mL of water and 50 mL of 6 N ammonium hydroxide. Heat on a hot plate, with occasional stirring, just to boiling. Remove from the hot plate, and sonicate for about 1 minute while still hot. Cool to room temperature, dilute with water to volume, mix, and centrifuge. Transfer an accurately measured aliquot portion of this concentrate, equivalent to about 10 mg of theophylline, to a 100-mL volumetric flask. Add 20.0 mL of Internal standard solution, dilute with Mobile phase to volume, and mix.
Chromatographic system— Proceed as directed in the Assay under Theophylline, except for flow rate, which may be 1.0 to 2.0 mL per minute.
Procedure— Proceed as directed for Procedure in the Assay under Theophylline. Calculate the quantity, in mg, of C7H8N4O2 per Capsule taken by the formula:
5000(C / V)(RU / RS)
in which C is the concentration, in mg per mL, of USP Theophylline RS in the Standard preparation; V is the volume, in mL, of concentrate taken for the Assay preparation; and RU and RS are the response ratios of the theophylline peak to the internal standard peak obtained from the Assay preparation and the Standard preparation, respectively.
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