Should you have any questions, please contact Mary P. Koleck, Ph.D., Scientific Liaison ( or

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1 Alfuzosin Hydrochloride Extended Release Tablets Type of Posting Posting Date 27 May 2016 Official Date 01 Jun 2016 Expert Committee Chemical Medicines Monographs 5 Reason for Revision Compliance In accordance with the Rules and Procedures of the Council of Experts, the Chemical Medicines Monographs 5 Expert Committee has revised the Alfuzosin Hydrochloride Extended-Release Tablets monograph. The purpose for the revision is to add a dis test for a generic product approved by the FDA. The liquid chromatographic procedure in Dis Test 7 is based on analyses performed with an Inertsil C8-3 brand of L7 column. The typical retention time for alfuzosin is about 2.6 min. The Alfuzosin Hydrochloride Extended Release Tablets supersedes the current official monograph. The will be incorporated into USP 40 NF 35. Should you have any questions, please contact Mary P. Koleck, Ph.D., Scientific Liaison ( or mpk@usp.org).

2 Official June 1, 2016 Alfuzosin 1. Alfuzosin Hydrochloride ExtendedRelease Tablets DEFINITION Alfuzosin Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of alfuzosin hydrochloride (C19H27N5O4 HCl). IDENTIFICATION A. INFRARED ABSORPTION 197 : [NOTE Methods described in 197K or 197A may be used.] Sample: Grind 4 Tablets, and add 20 ml of water. [NOTE When analyzing multi-layer Tablets, isolate the layer containing alfuzosin hydrochloride using a suitable tool.] Add 20 ml of strong ammonia. Extract with 20 ml of methylene chloride, and separate the organic layer. Repeat the extraction successively with 20 ml, then with 10 ml of methylene chloride. Wash the combined organic layers with 20 ml of water. Dry the organic using a phase separation filter. Take 2.0 ml of the dried organic, and mix with 200 mg of finely ground potassium bromide. Evaporate the methylene chloride at 60, then at 105 for 30 min. Make a disk. Alternatively, evaporate methylene chloride from the dried organic at 60, then at 105 for 30 min. Perform the IR spectrum. Acceptance criteria: The maxima of the spectrum obtained from the Sample correspond in position and relative intensity to those obtained from USP Alfuzosin Hydrochloride RS, treated in the same manner as the Sample, beginning with add 20 ml of water. B. The retention time of the major peak of the Sample corresponds to that of the Standard, as obtained in the Assay. ASSAY PROCEDURE Solution A: 5.0 ml of perchloric acid in 900 ml of water. Adjust with 2 M sodium hydroxide to a ph of 3.5, and dilute with water to 1000 ml. Mobile phase: Acetonitrile, tetrahydrofuran, and Solution A (20:1:80) Diluent: 0.01 N hydrochloric acid Standard stock : 0.15 mg/ml of USP Alfuzosin Hydrochloride RS in methanol Standard : 0.03 mg/ml of USP Alfuzosin Hydrochloride RS in Diluent from the Standard stock Sample stock : Place a suitable number of Tablets into a suitable volumetric flask to obtain a having a concentration of 0.16 mg/ml of alfuzosin hydrochloride. Add 80% of the flask volume of methanol, and stir for at least 1 h using a magnetic stirrer. Add 10% of the flask volume of Diluent, mix, and allow it to cool to room temperature. Dilute the resulting suspension with methanol to volume, stir, and allow to settle for 30 min. Sample : 0.03 mg/ml of alfuzosin hydrochloride in Diluent from the Sample stock supernatant. Pass through a suitable filter. (See Chromatography 621, System Suitability.) Detector: UV 254 nm Column: 4.6-mm 15-cm; 5-µm packing L1 Flow rate: 1.5 ml/min Injection volume: 20 µl Sample: Standard Tailing factor: for alfuzosin Samples: Standard and Sample Calculate the percentage of the labeled amount of alfuzosin hydrochloride (C19H27N5O4 HCl) in the portion of Tablets taken: Result = (ru/rs) (CS/CU) 100 = peak response from the Sample = peak response from the Standard = concentration of USP Alfuzosin Hydrochloride RS in the Standard (mg/ml) CU = nominal concentration of the Sample (mg/ml) Acceptance criteria: 90.0% 110.0% ru rs CS PERFORMANCE TESTS Change to read: DISSOLUTION 711 Test 1 Medium: 0.01 N hydrochloric acid; 500 ml Apparatus 2: 100 rpm, with Tablet holder (see Figure 1) Figure mm (l) 20-mm (d) stainless steel cylinders are used as sample holders. The cylinders contain screw caps drilled with seven 4.5-mm holes. Seven 4.5-mm holes are drilled in the bottom, and 12 longitudinal series of five 5-mm holes are drilled on the cylinders, alternatively starting and ending with one 1.7-mm hole. Sample : Pass a portion of the under test through a suitable filter. Standard : (L/500) mg/ml of USP Alfuzosin Hydrochloride RS in Medium, where L is the Tablet label claim in mg 2016 The United States Pharmacopeial Convention All Rights Reserved.

3 2 Alfuzosin Official June 1, 2016 Detector: UV 330 nm Blank: Medium Detector: UV 244 nm Path length: 1 cm Column: 4.6-mm 15-cm; 5-µm packing L7 Tolerances: See Table 1. Column temperature: 30 Flow rate: 1.2 ml/min Table 1 Injection volume: 20 µl Time Dissolved Sample: Standard Level (h) (%) Each Tablet: Tailing factor: NMT Column efficiency: NLT 3000 theoretical plates Samples: Standard and Sample L1 20 NLT 85 Calculate the concentration (C i) of alfuzosin hydro- Average of 12 Tablets complies with chloride (C 19H 27N 5O 4 HCl) in the sample withdrawn L1 and each Tablet: r U = peak response from the Sample L2 20 NLT 77 r S = peak response from the Standard Average of 24 Tablets complies with C S = concentration of USP Alfuzosin Hydrochloride L1, NMT 2 Tablets outside L2, and RS in the Standard (mg/ml) all Tablets within: Calculate the percentage of the labeled amount of alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved at each time point (i): Result 1 = C 1 V (1/L) L3 20 NLT 68 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dis Test 2. Result 2 = [(C 2 V) + (C 1 V S)] (1/L) 100 Medium: 0.01 N hydrochloric acid; 900 ml Apparatus 2: 100 rpm Result 3 = {(C 3 V) + [(C 2 + C 1) V S]} (1/L) 100 Times: 1, 3, 12, and 24 h Buffer: Dilute 5.0 ml of perchloric acid in 900 ml of water, adjust with diluted sodium hydroxide (0.1 g/ Result 4 = {(C 4 V) + [(C 3 + C 2 + C 1) V S]} (1/L) ml) to a ph of 3.5 ± 0.5, and dilute with water to L. Mobile phase: Acetonitrile and Buffer (25:75) C i = concentration of alfuzosin hydrochloride in the Standard stock : 0.28 mg/ml of USP Altime point (mg/ml) fuzosin Hydrochloride RS, prepared as follows. In a 200-mL volumetric flask dissolve 55.5 mg of USP Al- V = volume of Medium, 900 ml fuzosin Hydrochloride RS in 5 ml of methanol, soni- cate to dissolve, and dilute with Medium to volume. V S = volume of the Sample withdrawn at Standard : mg/ml of USP Alfuzosin each time point and replaced with Medium (ml) Tolerances: See Table 2. Sample : Pass a portion of the under test through a suitable filter. Replace the portion of Table 2 withdrawn with an equal volume of Medium. (See Chromatography 621, System Suitability.) 1 1 NMT NLT 80 hydrochloride dissolved at the times specified conform to Dis 711, Acceptance Table 2. Test 3: If the product complies with this test, the labeling indicates that it meets USP Dis Test 3. Medium: 0.25% sodium dodecyl sulfate in 0.05 M sodium phosphate buffer, ph 6.8 (2.5 g/l of sodium dodecyl sulfate, 6.9 g/l of monobasic sodium phosphate monohydrate, and 0.83 g/l of sodium hydroxide in water previously degassed with helium. Adjust with either phosphoric acid or 1 N sodium hydroxide to a ph of 6.8 ± 0.05 ); 900 ml

4 Official June 1, 2016 Alfuzosin 3 Apparatus 1: 100 rpm A U = absorbance of the Sample Times: 1, 6, 12, and 24 h A S = absorbance of the Standard Standard stock : 1.1 mg/ml of USP Alfuzosin C S = concentration of USP Alfuzosin Hydrochloride Hydrochloride RS in methanol RS in the Standard (mg/ml) Standard : mg/ml of USP Alfuzosin Calculate the percentage of the labeled amount of alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved at each time point (i): Sample : Pass a portion of the under test through a suitable filter. Result 1 = C 1 V (1/L) 100 Instrumental conditions (See.Ultraviolet-Visible Spectroscopy 857.) (CN 1-May- 2016) Mode: UV-Vis Result 2 = {[C 2 (V V S)] + (C 1 V S)} (1/L) 100 Analytical wavelength: 331 nm, background correc- Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) (1/ tion at 490 nm L) 100 Blank: Medium Cell: 1.0 cm Result 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) Samples: Standard and Sample (1/L) 100 Calculate the percentage of the labeled amount of alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved at C i = concentration of alfuzosin hydrochloride in the each time point (i): Result i = (A U/A S) C S V (1/L) 100 V = volume of Medium, 900 ml A U = absorbance of the Sample V S = volume of the Sample withdrawn at A S = absorbance of the Standard each time point (ml) C S = concentration of USP Alfuzosin Hydrochloride Tolerances: See Table 4. RS in the Standard (mg/ml) V L = volume of Medium (ml) = label claim (mg/tablet) Table 4 Tolerances: See Table 3. Table NMT NMT NLT hydrochloride dissolved at the times specified con NLT 80 form to Dis 711, Acceptance Table 2. Test 5: If the product complies with this test, the label- ing indicates that it meets USP Dis Test 5. hydrochloride dissolved at the times specified con- Medium: 0.01 N hydrochloric acid; 900 ml form to Dis 711, Acceptance Table 2. Apparatus 2: 100 rpm Test 4: If the product complies with this test, the label- Times: 1, 3, 6, 12, and 20 h ing indicates that it meets USP Dis Test 4. Buffer: Add 1 ml of triethylamine in 1000 ml of Medium: 0.01 N hydrochloric acid; 900 ml water. Adjust with phosphoric acid to a ph of 2.5 ± Apparatus 2: 100 rpm Pass through a suitable filter of 0.45-µm pore size. Standard : 0.01 mg/ml of USP Alfuzosin Hy- Mobile phase: Methanol and Buffer (40:60) drochloride RS in Medium Standard stock : 0.55 mg/ml of USP Al- Sample : Centrifuge a portion of the fuzosin Hydrochloride RS. Prepare by transferring a under test. portion of USP Alfuzosin Hydrochloride RS to a suita- Instrumental conditions ble flask. Add methanol to 20% of the flask volume, (See.Ultraviolet-Visible Spectroscopy 857.) (CN 1-Mayand sonicate at room temperature to dissolve. Dilute 2016) with Medium to volume. Mode: UV Standard : mg/ml of USP Alfuzosin Analytical wavelength: 245 nm Blank: Medium. Pass through a suitable filter of 0.45-µm pore Path length: 0.2 cm size. Sample : Pass a portion of the under Samples: Standard and Sample test through a suitable filter of 0.45-µm pore size. Calculate the concentration (C i) of alfuzosin hydro- chloride (C 19H 27N 5O 4 HCl) in the sample withdrawn (See Chromatography 621, System Suitability.) Result i = (A U/A S) C S

5 4 Alfuzosin Official June 1, 2016 Medium: 0.01 N hydrochloric acid; 900 ml Detector: UV 245 nm Apparatus 2: 100 rpm. Adjust the paddle height to Column: 4.6-mm 15-cm; 5-µm packing L1 4.5 cm above the bottom of the vessel and use a 10# Flow rate: 1 ml/min mesh basket as sinker. Injection volume: 10 µl Buffer: 2.3 g/l of anhydrous dibasic sodium phos- Sample: Standard phate and 1.75 g/l of monobasic potassium phosphate Tailing factor: NMT 2.0 Mobile phase: Acetonitrile and Buffer (50:50) Column efficiency: NLT 2000 theoretical plates Standard stock : 0.45 mg/ml of USP Al- fuzosin Hydrochloride RS. Prepare by transferring a portion of USP Alfuzosin Hydrochloride RS to a suita- Samples: Standard and Sample ble flask. Add 20% of the flask volume of water. Soni- Calculate the concentration (C i) of alfuzosin hydro- cate to dissolve, and dilute with Medium to volume. chloride (C 19H 27N 5O 4 HCl) in the sample withdrawn Standard : mg/ml of USP Alfuzosin Sample : Pass a portion of the under test through a suitable filter. Replace with the same r U = peak response from the Sample volume of Medium. r S = peak response from the Standard C S = concentration of USP Alfuzosin Hydrochloride (See Chromatography 621, System Suitability.) RS in the Standard (mg/ml) Calculate the percentage of the labeled amount of Detector: UV 254 nm alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved Column: 4.6-mm 25-cm; 5-µm packing L1 at each time point (i): Column temperature: 30 Result 1 = C 1 V (1/L) 100 Flow rate: 1 ml/min Injection volume: 20 µl Result Sample: Standard 2 = {[C 2 (V V S)] + (C 1 V S)} (1/L) 100 Tailing factor: NMT 2.0 Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) (1/ Column efficiency: NLT 3500 theoretical plates L) 100 Samples: Standard and Sample Result 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) Calculate the concentration (C i) of alfuzosin hydro- (1/L) 100 chloride (C 19H 27N 5O 4 HCl) in the sample withdrawn Result 5 = ({C 5 [V (4 V S)]} + [(C 4 + C 3 + C 2 + C 1) V S]) (1/L) 100 r U = peak response from the Sample C i = concentration of alfuzosin hydrochloride in the r S = peak response from the Standard C S = concentration of USP Alfuzosin Hydrochloride RS in the Standard (mg/ml) V = volume of Medium, 900 ml Calculate the percentage of the labeled amount of alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved V S = volume of the Sample withdrawn at at each time point (i): each time point (ml) Tolerances: See Table 5. Result 1 = C 1 V (1/L) 100 Table 5 Result 2 = [(C 2 V) + (C 1 V S)] (1/L) 100 Result 3 = {(C 3 V) + [(C 2 + C 1) V S]} (1/L) NMT Result 4 = {(C 4 V) + [(C 3 + C 2 + C 1) V S]} (1/L) NLT 80 C i = concentration of alfuzosin hydrochloride in the hydrochloride dissolved at the times specified con- V = volume of Medium, 900 ml form to Dis 711, Acceptance Table 2. Test 6: If the product complies with this test, the labeleach time point and replaced with Medium V S = volume of the Sample withdrawn at ing indicates that it meets USP Dis Test 6. (ml) Tolerances: See Table 6.

6 Official June 1, 2016 Alfuzosin 5 Table 6 C i = concentration of alfuzosin hydrochloride in the V = volume of Medium, 900 ml 1 1 NMT 30 V S = volume of the Sample withdrawn at each time point (ml) Tolerances: See Table NLT 85 Table 7 hydrochloride dissolved at the times specified con- form to Dis 711, Acceptance Table 2..Test 7: If the product complies with this test, the labeling indicates that it meets USP Dis Test NMT 25 Medium: 0.01 N hydrochloric acid; 900 ml Apparatus 2: 100 rpm with sinker; see Dis , Figure 2a NLT 85 Solution A: 500 g/l of sodium hydroxide Solution B: 100 g/l of sodium hydroxide hydrochloride dissolved at the times specified con- Buffer: Add 5 ml of perchloric acid in 1000 ml of form to Dis 711, Acceptance Table 2. (RB 1-Junwater. Adjust with Solution A to a ph of 2.5, then 2016) adjust with Solution B to a ph of 3.50 ± Pass UNIFORMITY OF DOSAGE UNITS 905 : Meet the through a suitable filter of 0.45-µm pore size. requirements Mobile phase: Acetonitrile and Buffer (24:76) Standard : 0.01 mg/ml of USP Alfuzosin Hydrochloride RS in Medium IMPURITIES Sample : Centrifuge or pass a portion of the under test through a suitable filter. Change to read: (See Chromatography 621, System Suitability.) ORGANIC IMPURITIES Solution A, Mobile phase, Diluent, Sample, Detector: UV 245 nm and : Proceed as directed in Column: 4.6-mm 5-cm; 3-µm packing L7 the Assay. Flow rate: 1.5 ml/min stock : 0.4 mg/ml of USP Injection volume: 10 µl Alfuzosin System Suitability Mixture A RS in methanol Run time: NLT 1.5 times the retention time of : 0.03 mg/ml of USP Alalfuzosin fuzosin System Suitability Mixture A RS in Diluent from the stock Sample: Standard Standard stock : 0.15 mg/ml of USP Alfuzosin Hydrochloride RS in methanol Tailing factor: NMT 1.8 Standard : 0.03 mg/ml of USP Alfuzosin Hy- drochloride RS in Diluent from the Standard stock Samples: Standard and Sample Calculate the concentration (C i) of alfuzosin hydro Samples: and Standard chloride (C 19H 27N 5O 4 HCl) in the sample withdrawn Re: NLT 1.0 between alfuzosin and the furamide analog; NLT 1.0 between deacylated alfuzosin and the N-formyl analog, r U = peak response from the Sample r S = peak response from the Standard, Standard C S = concentration of USP Alfuzosin Hydrochloride RS in the Standard (mg/ml) Calculate the percentage of the labeled amount of Samples: Standard and Sample alfuzosin hydrochloride (C 19H 27N 5O 4 HCl) dissolved Calculate the percentage of each impurity in the porat each time point (i): tion of Tablets taken: Result 1 = C 1 V (1/L) 100 Result = (r U/r S) (C S/C U) 100 Result 2 = {[C 2 (V V S)] + (C 1 V S)} (1/L) 100 r U = peak response of each impurity from the Sample r S = peak response of alfuzosin from the Sample Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) (1/ C S = concentration of USP Alfuzosin Hydrochloride L) 100 RS in the Standard (mg/ml) C U = nominal concentration of alfuzosin Result hydrochloride in the Sample 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) (1/L) 100 (mg/ml)

7 6 Alfuzosin Official June 1, 2016 Acceptance criteria: See.Table 8. LABELING: When more than one Dis test is given, the labeling states the Dis test used only if Test 1 Table is not used. 8 (RB 1-Jun-2016) USP REFERENCE STANDARDS 11 Relative Acceptance USP Alfuzosin Hydrochloride RS Retention Criteria, USP Alfuzosin System Suitability Mixture A RS Name Time NMT (%) Furamide analog: N-{3-[(4-Amino-6,7-dimethoxy- Deacylated alfuzosin a quinazolin-2-yl)(methyl)amino]propyl}furan- N-Formyl analog carboxamide. Alfuzosin 1.0 C 19H 23N 5O Deacylated alfuzosin: N 2.-(3-Aminopropyl)-6,7- Furamide analog 1.18 dimethoxy-n 2.-methylquinazoline-2,4-diamine. c. d. Any individual unspecified C 14H 21N 5O impurity 0.20 N-Formyl analog: N-[3-[(4-Amino-6,7-dimethoxy- Total impurities 0.80 quinazolin-2-yl)(methyl)amino]propyl]formamide. a. N 2.-(3-Aminopropyl)-6,7-dimethoxy-N2.-methylquinazoline-2,4-diamine. C 15H 21N 5O b. N-[3-[(4-Amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]propyl]formamide. c. N-{3-[(4-Amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]propyl}furan-2-carboxamide. d. Furamide analog, a component of USP Alfuzosin System Suitability Mixture A RS, is not a specified impurity. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Protect from light and moisture. Store at controlled room temperature.