Alprazolam Extended-Release Tablets

Printed on: Sat Jun 26 2021, 06:23:30 AM Official Status: Currently Official on 26-Jun-2021 DocId: 1_GUID-30C4B537-E2F1-457D-8C6C-EA85A6AADDC0_2_en-US
(EST)
Printed by: Nguyen Nhan Official Date: Official as of 01-May-2017 Document Type: USP @2021 USPC
1
Standard stock solution: 0.5 mg/mL of USP

Alprazolam Extended-Release Tablets Alprazolam RS in acetonitrile
DEFINITION Standard solution: (L/500) mg/mL of USP Alprazolam RS
Alprazolam Extended-Release Tablets contain NLT 90.0% and in Medium from the Standard stock solution, where L is the
NMT 110.0% of the labeled amount of alprazolam label claim in mg/Tablet
(C17H13CIN4). Sample solution: Pass a portion of the solution under test
through a suitable filter.
IDENTIFICATION Chromatographic system
• A. The retention time of the major peak of the Sample (See Chromatography á621ñ, System Suitability.)
solution corresponds to that of the Standard solution, as Mode: LC
obtained in the Assay. Detector: UV 254 nm
• B. The UV spectrum of the major peak of the Sample Column: 4.6-mm × 10-cm; 5-µm packing L7
solution corresponds to that of the Standard solution, as Flow rate: 1 mL/min
obtained in the Assay. Injection volume: 100 µL
System suitability
ASSAY Sample: Standard solution
• PROCEDURE Suitability requirements
Mobile phase: Acetonitrile, water, and phosphoric acid Tailing factor: NMT 2.0
(350:650:1) Column efficiency: NLT 3000 theoretical plates
Standard solution: 0.05 mg/mL of USP Alprazolam RS in Relative standard deviation: NMT 2.0%
methanol Analysis
Sample solution: Nominally 0.05 mg/mL of alprazolam Samples: Standard solution and Sample solution
prepared as follows. Transfer an appropriate number of
al
Calculate the percentage of the labeled amount of
Tablets to a suitable volumetric flask. Sonicate in 80% of the alprazolam (C17H13CIN4) dissolved:
flask volume of methanol for 15 min, and shake
mechanically for 30 min. Dilute with methanol to final Result = (rU/rS) × (CS/L) × V × 100
volume, filter a portion of the solution, and discard the first
3 mL of filtrate. rU = peak response from the Sample solution
Chromatographic system
(See Chromatography á621ñ, System Suitability.)
Mode: LC
ci rS
CS
= peak response from the Standard solution
= concentration of USP Alprazolam RS in the
Standard solution (mg/mL)
Detector: UV 254 nm. For Identification B, use a diode array L = label claim (mg/Tablet)
detector in the range of 200–400 nm. V = volume of Medium, 500 mL
ffi
Column: 4.6-mm × 15-cm; 5-µm packing L7
Column temperature: 30° Tolerances: See Table 1.
Flow rate: 1 mL/min
Injection volume: 10 µL Table 1
System suitability
Amount Dissolved
Sample: Standard solution
O
Suitability requirements Time 2-mg Tablet 3-mg Tablet

Tailing factor: NMT 2.0 (h) 0.5-mg Tablet (%) (%) (%)
Column efficiency: NLT 3000 theoretical plates 1 NMT 25 NMT 20 NMT 20
Relative standard deviation: NMT 2.0%
Analysis 4 40–60 30–55 30–55
Samples: Standard solution and Sample solution 8 70–90 65–90 65–90
Calculate the percentage of the labeled amount of
alprazolam (C17H13ClN4) in the portion of Tablets taken: 12 NLT 85 NLT 85 NLT 85
Result = (rU/rS) × (CS/CU) × 100 The percentages of the labeled amount of alprazolam
(C17H13CIN4) released at the times specified conform to
rU = peak response from the Sample solution Dissolution á711ñ, Acceptance Table 2.
rS = peak response from the Standard solution Test 2: If the product complies with this test, the labeling
CS = concentration of USP Alprazolam RS in the indicates that it meets USP Dissolution Test 2.
Standard solution (mg/mL) Medium: pH 6.0 phosphate buffer (8.0 g/L of monobasic
CU = nominal concentration of alprazolam in the potassium phosphate and 2.0 g/L of dibasic potassium
Sample solution (mg/mL) phosphate in water. Adjust with phosphoric acid or
potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL
Acceptance criteria: 90.0%–110.0% Apparatus 1: 100 rpm
PERFORMANCE TESTS Times: 1, 4, 8, and 16 h
• DISSOLUTION á711ñ Mobile phase: Acetonitrile, tetrahydrofuran, and Medium
Test 1 (35:5:60)
Medium: pH 6.0 phosphate buffer (8.0 g/L of monobasic Standard stock solution: 0.05 mg/mL of USP
potassium phosphate and 2.0 g/L of dibasic potassium Alprazolam RS in methanol
phosphate in water. Adjust with phosphoric acid or Standard solution: (L/500) mg/mL of USP Alprazolam RS
potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL in Medium from the Standard stock solution, where L is the
Apparatus 1: 100 rpm label claim in mg/Tablet
Times: 1, 4, 8, and 12 h Sample solution: Pass a portion of the solution under test
Mobile phase: Acetonitrile, tetrahydrofuran, and Medium through a suitable filter.
(7:1:12)
https://online.uspnf.com/uspnf/document/1_GUID-30C4B537-E2F1-457D-8C6C-EA85A6AADDC0_2_en-US 1/5
(EST)
2
Chromatographic system potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL,

(See Chromatography á621ñ, System Suitability.) deaerated
Mode: LC Apparatus 1: 100 rpm
Detector: UV 254 nm Times: 1, 4, and 8 h for Tablets labeled to contain 0.5 mg
Column: 4.6-mm × 7.5-cm; 5-µm packing L7 or 1 mg; 1, 4, 8, and 16 h for Tablets labeled to contain
Flow rate: 1.3 mL/min 2 mg or 3 mg
Injection volume: 80 µL Mobile phase: Acetonitrile and Medium (40:60)
System suitability Standard stock solution: 0.5 mg/mL of USP
Sample: Standard solution Alprazolam RS in methanol
Suitability requirements Standard solution: (L/500) mg/mL of USP Alprazolam RS
Tailing factor: NMT 1.5 in Medium from the Standard stock solution, where L is the
Relative standard deviation: NMT 2.0% label claim in mg/Tablet
Analysis Sample solution: Pass a portion of the solution under test
Samples: Standard solution and Sample solution through a suitable filter of 1-µm pore size.
Calculate the concentration (Ci) of alprazolam Chromatographic system
(C17H13CIN4) in the sample withdrawn from the vessel at (See Chromatography á621ñ, System Suitability.)
each time point (i): Mode: LC
Detector: UV 254 nm
Resulti = (rU/rS) × CS Column: 4.6-mm × 10-cm; 3-µm or 5-µm packing L7
Flow rate: 1 mL/min
rU = peak response of alprazolam from the Sample Injection volume: 100 µL
solution at each time point System suitability
al
rS = peak response of alprazolam from the Standard Sample: Standard solution
solution Suitability requirements
CS = concentration of USP Alprazolam RS in the Relative standard deviation: NMT 5.0%
Standard solution (mg/mL) Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of Calculate the concentration (Ci) of alprazolam
alprazolam (C17H13CIN4) dissolved at each time point (i):
Result1 = C1 × V × (1/L) × 100

ci (C17H13CIN4) in the sample withdrawn from the vessel at
each time point (i):
Resulti = (rU/rS) × CS
Result2 = {[C2 × (V − VS)] + (C1 × VS)} × (1/L) × 100
ffi
rU = peak response of alprazolam from the Sample
Result3 = ({C3 × [V − (2 × VS)]} + [(C2 + C1) × VS]) × (1/L) × solution at each time point
100 rS = peak response of alprazolam from the Standard
solution
Result4 = ({C4 × [V − (3 × VS)]} + [(C3 + C2 + C1) × VS]) × (1/ CS = concentration of USP Alprazolam RS in the
L) × 100 Standard solution (mg/mL)
O
Ci = concentration of alprazolam in the Sample Calculate the percentage of the labeled amount of
solution at the specified time point (mg/mL) alprazolam (C17H13CIN4) dissolved at each time point (i):
V = volume of Medium, 500 mL
L = label claim (mg/Tablet) Result1 = C1 × V × (1/L) × 100
VS = volume of the Sample solution withdrawn at each
time point (mL) Result2 = {[C2 × (V − VS)] + (C1 × VS)} × (1/L) × 100
Tolerances: See Table 2. Result3 = ({C3 × [V − (2 × VS)]} + [(C2 + C1) × VS]) × (1/L) ×
100
Table 2
Amount Dissolved Result4 = ({C4 × [V − (3 × VS)]} + [(C3 + C2 + C1) × VS]) × (1/
Time L) × 100
Point Time 0.5-mg 1-mg 2-mg 3-mg
(i) (h) Tablet (%) Tablet (%) Tablet (%) Tablet (%)
Ci = concentration of alprazolam in the Sample
1 1 NMT 25 NMT 25 NMT 20 NMT 20 solution at the specified time point (mg/mL)
2 4 45–60 40–55 30–50 25–45
L = label claim (mg/Tablet)
3 8 70–90 65–85 55–75 50–70 VS = volume of the Sample solution withdrawn at each
4 16 NLT 85 NLT 85 NLT 85 NLT 80 time point (mL)
Tolerances: See Table 3.

The percentages of the labeled amount of alprazolam
(C17H13CIN4) released at the times specified conform to Table 3
Dissolution á711ñ, Acceptance Table 2. Amount Dissolved
Test 3: If the product complies with this test, the labeling Time
indicates that it meets USP Dissolution Test 3. Point Time 0.5-mg 1-mg 2-mg 3-mg
Medium: pH 6.0 phosphate buffer (8.0 g/L of monobasic (i) (h) Tablet (%) Tablet (%) Tablet (%) Tablet (%)
potassium phosphate and 2.0 g/L of dibasic potassium 1 1 15–35 10–30 10–30 5–25
phosphate in water. Adjust with phosphoric acid or
2 4 50–75 45–65 30–55 25–50
(EST)
3
Table 3 (continued) Result4 = {[C4 × V] + [(C3 + C2 + C1) × VS]} × (1/L) × 100

Amount Dissolved
Time Ci = concentration of alprazolam in the Sample
Point Time 0.5-mg 1-mg 2-mg 3-mg solution at the specified time point (mg/mL)
(i) (h) Tablet (%) Tablet (%) Tablet (%) Tablet (%)
3 8 NLT 75 NLT 70 60–80 50–75 L = label claim (mg/Tablet)
VS = volume of the Sample solution withdrawn at each
4 16 — — NLT 85 NLT 80
time point and replaced with Medium (mL)
The percentages of the labeled amount of alprazolam Tolerances: See Table 4.
(C17H13CIN4) released at the times specified conform to
Dissolution á711ñ, Acceptance Table 2. Table 4
Test 4: If the product complies with this test, the labeling Amount Dissolved
indicates that it meets USP Dissolution Test 4. Time
Medium: pH 6.0 phosphate buffer (8.0 g/L of monobasic Point Time 0.5-mg Tab- 1-mg Tablet 2-mg Tablet 3-mg Tablet
(i) (h) let (%) (%) (%) (%)
potassium phosphate and 2.0 g/L of dibasic potassium
phosphate in water. Adjust with phosphoric acid or 1 1 NMT 40 NMT 35 NMT 35 NMT 35
potassium hydroxide to a pH of 6.0); 500 mL
2 4 50–75 45–65 35–55 30–55
Apparatus 1 (20-mesh basket): 100 rpm
Times: 1, 4, 8, and 16 h 3 8 NLT 75 70–90 55–75 50–70
Mobile phase: Acetonitrile and Medium (32:68) 4 16 NLT 85 NLT 85 NLT 85 NLT 75
Standard stock solution: 0.4 mg/mL of USP
Alprazolam RS in methanol
al
Standard solution: (L/500) mg/mL of USP Alprazolam RS The percentages of the labeled amount of alprazolam
in Medium from the Standard stock solution, where L is the (C17H13CIN4) released at the times specified conform to
label claim in mg/Tablet. Pass through a suitable filter of Dissolution á711ñ, Acceptance Table 2.
0.45-µm pore size, and use the filtrate. Test 5: If the product complies with this test, the labeling
Sample solution: At the end of specified time intervals, indicates that it meets USP Dissolution Test 5.
withdraw a known volume (VS) of the solution from the
dissolution vessel, and replace an equal volume of fresh
Medium into the dissolution vessel. Pass the withdrawn
ci Medium: pH 6.0 phosphate buffer (8.0 g/L of monobasic
potassium phosphate and 2.0 g/L of dibasic potassium
phosphate in water. Adjust with phosphoric acid to a pH
sample through a suitable filter of 0.45-µm pore size, and of 6.0); 500 mL
use the filtrate. Apparatus 1: 100 rpm
ffi
Chromatographic system Times: 1, 4, 8, and 16 h
(See Chromatography á621ñ, System Suitability.) Mobile phase: Acetonitrile, water, and phosphoric acid
Mode: LC (350:650:1)
Detector: UV 254 nm Standard stock solution: 0.5 mg/mL of USP
Column: 4.6-mm × 15-cm; 5-µm packing L1 Alprazolam RS in methanol
Flow rate: 1.5 mL/min Standard solution: (L/500) mg/mL of USP Alprazolam RS
O
Injection volume: 100 µL in Medium from the Standard stock solution, where L is the
System suitability label claim in mg/Tablet
Sample: Standard solution Sample solution: Pass a portion of the solution under test
Suitability requirements through a suitable filter of 0.45-µm pore size, and use the
Tailing factor: NMT 2.0 filtrate.
Relative standard deviation: NMT 2.0% Chromatographic system
Analysis (See Chromatography á621ñ, System Suitability.)
Samples: Standard solution and Sample solution Mode: LC
Calculate the concentration (Ci) of alprazolam Detector: UV 254 nm
(C17H13CIN4) in the sample withdrawn from the vessel at Column: 4.6-mm × 15-cm; 5-µm packing L7
each time point (i): Column temperature: 30°
Flow rate: 1 mL/min
Resulti = (rU/rS) × CS Injection volume: 50 µL
System suitability
rU = peak response of alprazolam from the Sample Sample: Standard solution
solution at each time point Suitability requirements
rS = peak response of alprazolam from the Standard Tailing factor: NMT 2.0
solution Relative standard deviation: NMT 2.0%
CS = concentration of USP Alprazolam RS in the Analysis
Standard solution (mg/mL) Samples: Standard solution and Sample solution
Calculate the concentration (Ci) of alprazolam
Calculate the percentage of the labeled amount of (C17H13CIN4) in the sample withdrawn from the vessel at
alprazolam (C17H13CIN4) dissolved at each time point (i): each time point (i):
Result1 = C1 × V × (1/L) × 100 Resulti = (rU/rS) × CS
Result2 = [(C2 × V) + (C1 × VS)] × (1/L) × 100 rU = peak response of alprazolam from the Sample
solution at each time point
Result3 = {[C3 × V] + [(C2 + C1) × VS]} × (1/L) × 100 rS = peak response of alprazolam from the Standard
solution
(EST)
4
CS = concentration of USP Alprazolam RS in the Standard solution: 0.4 µg/mL of USP Alprazolam RS in
Standard solution (mg/mL) methanol
Sample solution: From NLT 20 Tablets ground to a fine
Calculate the percentage of the labeled amount of powder, transfer an amount of powder to a suitable flask to
alprazolam (C17H13CIN4) dissolved at each time point (i): obtain a nominal concentration of 0.2 mg/mL of
alprazolam in methanol. [NOTE—Sonicate for 15 min to
Result1 = C1 × V × (1/L) × 100 dissolve the contents.] Filter a portion, and discard the first
1 mL of filtrate.
Result2 = {[C2 × (V − VS)] + (C1 × VS)} × (1/L) × 100 Chromatographic system
(See Chromatography á621ñ, System Suitability.)
Result3 = ({C3 × [V − (2 × VS)]} + [(C2 + C1) × VS]) × (1/L) × Mode: LC
100 Detector: UV 230 nm
Column: 4.6-mm × 25-cm; 5-µm packing L7
Result4 = ({C4 × [V − (3 × VS)]} + [(C3 + C2 + C1) × VS]) × (1/ Flow rate: 1.5 mL/min
L) × 100 Injection volume: 10 µL
System suitability
Ci = concentration of alprazolam in the Sample Samples: System suitability solution and Standard solution
solution at the specified time point (mg/mL) [NOTE—The relative retention times are listed in Table
V = volume of Medium, 500 mL 7.]
L = label claim (mg/Tablet) Suitability requirements
VS = volume of the Sample solution withdrawn at each Resolution: NLT 1.5 between nordazepam and
time point (mL) alprazolam; NLT 1.5 between chlordiazepoxide related
al
compound A and alprazolam related compound A,
Tolerances: See Table 5. System suitability solution
Tailing factor: NMT 2.0 for the alprazolam peak, System
Table 5 suitability solution
Time Point Time Relative standard deviation: NMT 5%, Standard
(i) (h) Amount Dissolved (%) solution
1
2
1
4
NMT 25
40–65
ci Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of
3 8 65–95 Tablets taken:
ffi
4 16 NLT 85 Result = (rU/rS) × (CS/CU) × (1/F) × 100
The percentages of the labeled amount of alprazolam rU = peak response of the impurity from the Sample
(C17H13CIN4) released at the times specified conform to solution
Dissolution á711ñ, Acceptance Table 2. rS = peak response from the Standard solution
• UNIFORMITY OF DOSAGE UNITS á905ñ: Meet the CS = concentration of USP Alprazolam RS in the
O
requirements Standard solution (mg/mL)

CU = nominal concentration of alprazolam in the
IMPURITIES Sample solution (mg/mL)
• ORGANIC IMPURITIES F = relative response factor (see Table 7)
Buffer: 5.4 g/L of monobasic potassium phosphate
(KH2PO4) in water. Adjust with phosphoric acid to a pH of Acceptance criteria: See Table 7.
3.4.
Solution A: Acetonitrile, methanol, and Buffer (27:10:63) Table 7
Solution B: Acetonitrile, methanol, and Buffer (7:3:10) Relative Relative Acceptance
Mobile phase: See Table 6. Retention Response Criteria,
Name Time Factor NMT (%)
Table 6 Chlordiazepoxide
Time Solution A Solution B related compound Aa 0.36 1.0 0.2
(min) (%) (%)
Alprazolam related com-
0 95 5 pound A 0.45 0.7 0.5
a, b
22 95 5 Nordazepam 0.8 1.0 0.2
25 15 85 Alprazolam 1.0 — —
60 15 85 2-Amino-5-chloro-benzo-
phenone 1.8 0.9 0.5
60.1 95 5
c
Amino-derivative 2.2 1.2 0.5
70 95 5
Any other individual degra-
dation —
System suitability solution: 1 µg/mL each of USP product 1.0 0.2
Chlordiazepoxide Related Compound A RS, USP Total impurities — — 2.0
Alprazolam Related Compound A RS, and USP
Nordazepam RS; and 0.4 µg/mL of USP Alprazolam RS in a If possible from the manufacturing process.
methanol b 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one.
c 7-Chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinolin-4-amine.
(EST)
5
ADDITIONAL REQUIREMENTS USP Chlordiazepoxide Related Compound A RS

• PACKAGING AND STORAGE: Preserve in tight, light-resistant 7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-
containers, and store at room temperature. one 4-oxide.
• LABELING: The labeling states the Dissolution test used only C15H11ClN2O2 286.71
if Test 1 is not used. USP Nordazepam RS
• USP REFERENCE STANDARDS á11ñ
USP Alprazolam RS
USP Alprazolam Related Compound A RS
2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-
benzodiazepine.
C17H15ClN4O 326.78
al
ci
ffi
O

Alprazolam Extended-Release Tablets

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Alprazolam Extended-Release Tablets

Uploaded by

Copyright:

Available Formats

Printed on: Sat Jun 26 2021, 06:23:30 AM Official Status: Currently Official on 26-Jun-2021 DocId: 1_GUID-30C4B537-E2F1-457D-8C6C-EA85A6AADDC0_2_en-US

Standard stock solution: 0.5 mg/mL of USP

Suitability requirements Time 2-mg Tablet 3-mg Tablet

Chromatographic system potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL,

Result1 = C1 × V × (1/L) × 100

Tolerances: See Table 3.

Table 3 (continued) Result4 = {[C4 × V] + [(C3 + C2 + C1) × VS]} × (1/L) × 100

Result1 = C1 × V × (1/L) × 100 Resulti = (rU/rS) × CS

requirements Standard solution (mg/mL)

ADDITIONAL REQUIREMENTS USP Chlordiazepoxide Related Compound A RS

You might also like