Theophylline Extended-Release Capsules »Theophylline Extended-Release Capsules contain not less than 90.0percent and not more than 110.0percent 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 12or 24hours,and states with which in vitro Drug Release Testthe product complies. USP Reference standards á11ñ USP Theophylline RS. Identification— A: Transfer a quantity of Capsule contents,equivalent to about 100mg of anhydrous theophylline,to a suitable conical flask.Add 150mLof methanol,and sonicate until the insoluble material is dispersed into fine particles.Shake by mechanical means for 15minutes,and filter into a 250-mLvolumetric flask.Dilute with water to volume,and mix.Pipet 5mLof this solution into a 200-mLvolumetric flask,dilute with 0.1Nhydrochloric acid to volume,and mix:the UVabsorption 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 preparationcorresponds to that of the Standard preparationas obtained in the Assay. Drug release á724ñ [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 EVERY12HOURSTest 1: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 1.Proceed as directed for Method Bunder Delayed-release ArticlesGeneral Drug Release Standard,except to use Acceptance Table 1under Extended-Release Articles—General Drug Release Standard. Medium: pH1.2simulated gastric fluid (without pepsin)for the first hour;pH6.0phosphate buffer (see Buffer Solutionsin the section Reagents,Indicators,and Solutions);900mL. Apparatus 2: 50rpm. Procedure— Determine the amount of C7H8N4O2dissolved from UVabsorbances at the wavelength of maximum absorbance at about 271nm of filtered portions of the solution under test,diluted with Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Theophylline RSin the same medium. Timesand tolerances: 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 USPDrug Release Test 2. Medium: 4.5phosphate buffer,prepared by dissolving 6.8g of monobasic potassium phosphate in 750mLof water,mix,and dilute with water to 1000mL.Adjust the pHto 4.5±0.05using either 1Nhydrochloric acid or 1Nsodium hydroxide;900mL. Apparatus 2: 75rpm. Procedure— Proceed as directed under Test 1. Timesand tolerances— The percentages of the labeled amount of C7H8N4O2dissolved at the times specified conform to Acceptance Table 1. 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 USPDrug Release Test 3.Proceed as directed for Method Bunder Delayed-Release ArticlesGeneral Drug Release Standard,except to use Acceptance Table 1under Extended-Release Articles—General Drug Release Standard. Medium: pH1.2simulated gastric fluid (without pepsin)for 1hour;pH7.5simulated intestinal fluid (without enzyme);900mL. Apparatus 2: 50rpm. Procedure— Proceed as directed under Test 1. Timesand tolerances: 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 USPDrug Release Test 4.Proceed as directed for Method Aunder Delayed-Release ArticlesGeneral Drug Release Standard,except to use Acceptance Table 1under Extended-Release Articles—General Drug Release Standard. Medium: pH3.0phosphate buffer,0.05Mpotassium phosphate buffer adjusted with phosphoric acid to a pHof 3.0±0.05,for the first 3½hours,followed by the addition of 5.3Msodium hydroxide to adjust to a pHof 7.4±0.05;900mL. Apparatus 2: 50rpm. Procedure— Proceed as directed under Test 1. Timesand tolerances: 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 USPDrug Release Test 5. Medium ,Apparatus,and Procedure—Proceed as directed under Test 4. Timesand tolerances: 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 USPDrug Release Test 7. Phosphate buffer— Dissolve 40.8g of monobasic potassium phosphate in 6liters of water,add 667mg of octoxynol 9,mix,and adjust with dilute hydrochloric acid or sodium hydroxide to a pHof 4.5. Medium:Phosphate buffer; 900mL. Apparatus 2: 50rpm. Procedure— Proceed as directed under Test 1. Timesand tolerances— The percentages of the labeled amount of C7H8N4O2dissolved at the times specified conform to Acceptance Table 1. 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 USPDrug Release Test 8. Medium: pH7.5simulated intestinal fluid (without enzyme);900mL. Apparatus 1: 100rpm. Procedure: Proceed as directed under Test 1. Timesand tolerances— The percentages of labeled amount of C7H8N4O2dissolved at the times specified conform to Acceptance Table 1. 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 USPDrug Release Test 9. Medium 1: 0.1Nhydrochloric acid;900mL. Medium 2: simulated intestinal fluid (without enzyme);900mL. Apparatus 1: 50rpm. Determine the amount of theophylline dissolved at the times specified,using Medium 1for the first hour and Medium 2for the next five hours. Procedure— Proceed as directed under Test 1. Timesand tolerances: 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 Drug Release Test 10.Proceed as directed for Test 3. Timesand Tolerances: 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 EVERY24HOURS Test 6: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 6. Medium: 0.05MpH6.6phosphate buffer (see Buffer Solutionsin the section Reagents,Indicators,and Solutions);1000mL. Apparatus 1: 100rpm. Procedure— Proceed as directed under Test 1. Timesand tolerances— The percentages of the labeled amount of C7H8N4O2dissolved at the times specified conform to Acceptance Table 1. 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 á905ñ: meet the requirements. Procedure for content uniformity— Using a mortar and pestle,triturate the contents of 1Capsule with 20mLof water.With the aid of water,transfer the mixture to a 100-mLvolumetric flask.Add 25mLof 6Nammonium hydroxide,shake or sonicate for about 45minutes,and cool to room temperature.Dilute with water to volume,and mix.Filter a portion of the mixture,discarding the first 20mLof the filtrate.Dilute a portion of the filtrate quantitatively,and stepwise if necessary,with water to obtain a solution containing about 12µg 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 12µg per mL,in 1-cm cells,at the wavelength of maximum absorbance at about 270nm,with a suitable spectrophotometer,using water as the blank.Calculate the quantity,in mg,of C7H8N4O2in the Capsule taken by the formula: (TC/D)(AU/AS), in which Tis the labeled quantity,in mg,of theophylline in the Capsule,Cis the concentration,in µg per mL,of USP Theophylline RSin the Standard solution,Dis 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 AUand ASare 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 Assayunder Theophylline. Assay preparation— Quantitatively transfer the contents of 10Capsules to a 500-mLvolumetric flask,and add 100mLof water and 50mLof 6Nammonium hydroxide.Heat on a hot plate,with occasional stirring,just to boiling.Remove from the hot plate,and sonicate for about 1minute 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 10mg of theophylline,to a 100-mLvolumetric flask.Add 20.0mLof Internal standard solution,dilute with Mobile phaseto volume,and mix. Chromatographic system— Proceed as directed in the Assayunder Theophylline,except for flow rate,which may be 1.0to 2.0mLper minute. Procedure— Proceed as directed for Procedurein the Assayunder Theophylline.Calculate the quantity,in mg,of C7H8N4O2per Capsule taken by the formula: 5000(C/V)(RU/RS), in which Cis the concentration,in mg per mL,of USP Theophylline RSin the Standard preparation,Vis the volume,in mL,of concentrate taken for the Assay preparation,and RUand RSare the response ratios of theophylline peak to the internal standard peak obtained from the Assay preparationand the Standard preparation,respectively. Auxiliary Information— Staff Liaison:Karen A Russo,Ph.D.,Scientist Expert Committee:(PA1)Pharmaceutical Analysis 1 USP28–NF23Page 1897 Phone Number:1-301-816-8379