Revision Bulletin Official April 1, 2014 Alprazolam 1

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1 . Apparatus Official April 1, 2014 Alprazolam 1 1: 100 rpm Alprazolam Extended-Release Tablets s: 1, 4, 8, and 12 h Mobile phase: Acetonitrile, tetrahydrofuran, and Medium (7:1:12) DEFINITION Alprazolam Extended-Release Tablets contain NLT 90.0% lam RS in acetonitrile and NMT 110.0% of the labeled amount of alprazolam : (L/500) mg/ml of USP Alprazo- (C 17H 13CIN 4). lam IDENTIFICATION where L is the label claim in mg/tablet Sample solution: Pass a portion of the solution under A. The retention time of the major peak of the Sample solution corresponds to that of the, as test through a suitable filter. obtained in the Assay. ASSAY PROCEDURE Mobile phase: Acetonitrile, water, and phosphoric acid Column: 4.6-mm 10-cm; 5-µm packing L7 (350:650:1) : 0.05 mg/ml of USP Alprazolam RS Injection volume: 100 µl in methanol Sample solution: Transfer an appropriate number of Tablets into a suitable volumetric flask to obtain a nominal concentration of about 0.05 mg/ml of al- prazolam. Sonicate in 80% of the flask volume of Column efficiency: NLT 3000 theoretical plates methanol for 15 min, and shake mechanically for 30 min. Dilute with methanol to final volume, filter a por- tion of the solution, and discard the first 3 ml of filtrate. al- prazolam (C 17H 13CIN 4) dissolved: Result = (r U/r S) (C S/L) V 100 Column: 4.6-mm 15-cm; 5-µm packing L7 r U = peak response from the Sample solution Column temperature: 30 r S = peak response from the Injection volume: 10 µl Tolerances: See Table 1. for alprazolam Column efficiency: NLT 3000 theoretical plates for Table 1 alprazolam (h) 0.5-mg Tablet 2-mg Tablet 3-mg Tablet 1 NMT 25% NMT 20% NMT 20% Calculate the percentage of alprazolam (C 17H 13ClN 4), 4 40% 60% 30% 55% 30% 55% based on the label claim, in the portion of Tablets 8 70% 90% 65% 90% 65% 90% taken: 12 NLT 85% NLT 85% NLT 85% Result = (r U/r S) (C S/C U) 100 r U = peak response from the Sample solution to Acceptance Table 2 in Dissolution 711. r S = peak response from the Test 2: If the product complies with this test, the label- ing indicates that it meets USP Dissolution Test 2. C U = nominal concentration of alprazolam in the basic potassium phosphate and 2.0 g/l of dibasic po- Sample solution (mg/ml) Acceptance criteria: 90.0% 110.0% acid or potassium hydroxide to a ph of 6.0 ± 0.1); 500 ml PERFORMANCE TESTS s: 1, 4, 8, and 16 h Change to read: Mobile phase: Acetonitrile, tetrahydrofuran, and Medium (35:5:60) DISSOLUTION 711 Standard stock solution: 0.05 mg/ml of USP Al- Test 1 prazolam RS in methanol Medium: ph 6.0 phosphate buffer (8.0 g/l of monolam : (L/500) mg/ml of USP Alprazobasic potassium phosphate and 2.0 g/l of dibasic powhere L is the label claim in mg/tablet acid or potassium hydroxide to a ph of 6.0 ± 0.1); Sample solution: Pass a portion of the solution under 500 ml test through a suitable filter.

2 2 Alprazolam Official April 1, 2014 s: 1, 4, and 8 h for Tablets labeled to contain Column: 4.6-mm 7.5-cm; 5-µm packing L7 0.5 mg or 1 mg; 1, 4, 8, and 16 h for Tablets labeled Flow rate: 1.3 ml/min to contain 2 mg or 3 mg Injection volume: 80 µl Mobile phase: Acetonitrile and Medium (40:60) lam RS in methanol : (L/500) mg/ml of USP Alprazo- Tailing factor: NMT 1.5 lam where L is the label claim in mg/tablet Sample solution: Pass a portion of the solution under test through a suitable filter of 1-µm pore size. (C 17H 13CIN 4) in the sample withdrawn from the ves- Column: 4.6-mm 10-cm; 3-µm or 5-µm packing L7 r U = peak response of alprazolam from the Sample Injection volume: 100 µl r S = peak response of alprazolam from the Relative standard deviation: NMT 5.0% alprazolam (C 17H 13CIN 4) dissolved at each time point (C 17H 13CIN 4) in the sample withdrawn from the vessel at each time point Result2 = {[C 2 (V V S)] + (C 1 V S)} Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) (1/L) 100 Result 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) r U = peak response of alprazolam from the Sample r S = peak response of alprazolam from the alprazolam (C 17H 13CIN 4) dissolved at each time point V = volume of Medium, 500 ml V S = volume of the Sample solution withdrawn at each time point and replaced with Medium Result 2 = {[C 2 (V V S)] + (C 1 V S)} Tolerances: See Table 2. Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) (1/L) 100 Table 2 Result 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) Point 0.5-mg 1-mg 2-mg 3-mg NMT NMT % NMT 25% 20% NMT 20% % 60% 40% 55% 30% 50% 25% 45% % 90% 65% 85% 55% 75% 50% 70% V S = volume of the Sample solution withdrawn at 4 16 NLT 85% NLT 85% NLT 85% NLT 80% each time point and replaced with Medium (C Tolerances: See Table 3. 17H 13CIN 4) released at the times specified conform to Acceptance Table 2 in Dissolution 711. Test 3: If the product complies with this test, the labeling Table 3 indicates that it meets USP Dissolution Test 3. Point 0.5-mg 1-mg 2-mg 3-mg basic potassium phosphate and 2.0 g/l of dibasic po- acid or potassium hydroxide to a ph of 6.0 ± 0.1); % 35% 10% 30% 10% 30% 5% 25% 500 ml, deaerated % 75% 45% 65% 30% 55% 25% 50%

3 Official April 1, 2014 Alprazolam 3 Table 3 (Continued) alprazolam (C 17H 13CIN 4) dissolved at each time point Point 0.5-mg 1-mg 2-mg 3-mg 3 8 NLT 75% NLT 70% 60% 80% 50% 75% NLT % NLT 80% Result 2 = [(C 2 V) + (C 1 V S)] Result 3 = {[C 3 V] + [(C 2 + C 1) V S]} to Acceptance Table 2 in Dissolution 711..Test 4: If the product complies with this test, the Result 4 = {[C 4 V] + [(C 3 + C 2 + C 1) V S]} (1/L) labeling indicates that it meets USP Dissolution Test Medium: ph 6.0 phosphate buffer (8.0 g/l of monobasic potassium phosphate and 2.0 g/l of dibasic po- acid or potassium hydroxide to a ph of 6.0); 500 ml Apparatus 1 (20-mesh basket): 100 rpm s: 1, 4, 8, and 16 h V S = volume of the Sample solution withdrawn at Mobile phase: Acetonitrile and Medium (32:68) each time point and replaced with Medium Standard stock solution: 0.4 mg/ml of USP Alprazo- lam RS in methanol Tolerances: See Table 4. : (L/500) mg/ml of USP Alprazolam where L is the label claim in mg/tablet. Pass through Table 4 a suitable filter of 0.45-µm pore size, and use the Point Sample solutions: At the end of specified time inter- 0.5-mg 1-mg 2-mg 3-mg vals, withdraw a known volume (V S) of the solution NMT NMT NMT from the dissolution vessel, and replace an equal vol- 1 1 NMT 40% 35% 35% 35% ume of fresh Medium into the dissolution vessel. Pass the withdrawn sample through a suitable filter of % 75% 45% 65% 35% 55% 30% 55% 0.45-µm pore size, and use the filtrate. 3 8 NLT 75% 70% 90% 55% 75% 50% 70% 4 16 NLT 85% NLT 85% NLT 85% NLT 75% Column: 4.6-mm 15-cm; 5-µm packing L1 to Acceptance Table 2 in Dissolution 711. (RB 1-Aug- Flow rate: 1.5 ml/min 2013) Injection volume: 100 µl.test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5. basic potassium phosphate and 2.0 g/l of dibasic po- acid to a ph of 6.0); 500 ml s s: 1, 4, 8, and 16 h Mobile phase: Acetonitrile, water, and phosphoric (C 17H 13CIN 4) in the sample withdrawn from the ves- acid (350:650:1) lam RS in methanol : (L/500) mg/ml of USP Alprazolam r U = peak response of alprazolam from the Sample where L is the label claim in mg/tablet Sample solutions: Pass a portion of the solution r S = peak response of alprazolam from the under test through a suitable filter of 0.45-µm pore size, and use the filtrate.

4 4 Alprazolam Official April 1, 2014 Solution A: Acetonitrile, methanol, and Buffer (27:10:63) Column: 4.6-mm 15-cm; 5-µm packing L7 Solution B: Acetonitrile, methanol, and Buffer (7:3:10) Column temperature: 30 Mobile phase: See Table 6. Injection volume: 50 µl Table 6 Solution A Solution B (min) (%) (%) s (C 17H 13CIN 4) in the sample withdrawn from the ves solution: 1 µg/ml each of USP Chlordiazepoxide Related Compound A RS, USP Alprazolam Related Compound A RS, and USP r U = peak response of alprazolam from the Sample Nordazepam RS; and 0.4 µg/ml of USP Alprazolam RS r S = peak response of alprazolam from the in methanol : 0.4 µg/ml of USP Alprazolam RS in methanol Sample solution: From NLT 20 Tablets ground to a fine powder, transfer an amount of powder to a suitaalprazolam (C 17H 13CIN 4) dissolved at each time point ble flask to obtain a nominal concentration of 0.2 mg/ ml of alprazolam in methanol. [NOTE Sonicate for 15 min to dissolve the contents.] Filter a portion, and discard the first 1 ml of filtrate. Result 2 = {[C 2 (V V S)] + (C 1 V S)} Detector: UV 230 nm Column: 4.6-mm 25-cm; 5-µm packing L7 Result 3 = ({C 3 [V (2 V S)]} + [(C 2 + C 1) V S]) Flow rate: 1.5 ml/min (1/L) 100 Injection volume: 10 µl Result 4 = ({C 4 [V (3 V S)]} + [(C 3 + C 2 + C 1) V S]) Samples: solution and Standard solution [NOTE The relative retention times are listed in Table 6.] Resolution: NLT 1.5 between nordazepam and al- prazolam; NLT 1.5 between chlordiazepoxide related V S = volume of the Sample solution withdrawn at compound A and alprazolam related compound A, each time point solution Tolerances: See Table 5. for the alprazolam peak, solution Relative standard deviation: NMT 5%, Standard Table 5 solution Point (i) (h) 1 1 NMT 25% Calculate the percentage of each impurity in the por % 65% tion of Tablets taken: % 95% Result = (r U/r S) (C S/C U) (1/F) NLT 85% r U = peak response of the impurity from the Sample solution r S = peak response from the to Acceptance Table 2 in Dissolution 711. (RB 1-Apr-2014) UNIFORMITY OF DOSAGE UNITS 905 : Meet the requirements C U = nominal concentration of alprazolam in the Sample solution (mg/ml) IMPURITIES F = relative response factor (see Table 7) ORGANIC IMPURITIES Acceptance criteria: See Table 7. Buffer: 5.4 g/l of monobasic potassium phosphate (KH 2PO 4) in water. Adjust with phosphoric acid to a ph of 3.4.

5 Official April 1, 2014 Alprazolam 5.. Table 7 LABELING: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 Relative Relative Acceptance is not used. Retention Response Criteria, USP REFERENCE STANDARDS 11 Name Factor NMT (%) USP Alprazolam RS Chlordiazepoxide USP Alprazolam Related Compound A RS related compound 2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4- A benzodiazepine. a. Alprazolam related USP Chlordiazepoxide Related Compound A RS compound A Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin- Nordazepam, b a one 4-oxide. Alprazolam 1.0 C 15H 11ClN 2O Amino-5-chlorobenzophenone USP Nordazepam RS Amino-derivative c Any other individual degradation product Total impurities 2.0 a. If present meets the requirement for any other individual degradation product. b. 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (reported as unspecified impurity). c. 7-Chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinolin-4-amine. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, and store at room temperature.