Alprazolam Extended-Release Tablets
DEFINITION
Alprazolam Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of alprazolam (C17H13CIN4).
IDENTIFICATION
• The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Mobile phase:
Acetonitrile, water, and phosphoric acid (350:650:1)
Standard solution:
0.05 mg/mL of USP Alprazolam RS 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 alprazolam. Sonicate in 80% of the flask volume of methanol for 15 min, shake mechanically for 30 min, dilute with methanol to final volume, filter a portion, and discard the first 3 mL of filtrate.
Chromatographic system
Mode:
LC
Detector:
UV 254 nm
Column:
4.6-mm × 15-cm; 5-µm packing L7
Column temperature:
30
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 2.0 for alprazolam
Efficiency:
NLT 3000 theoretical plates for alprazolam
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C17H13ClN4, based on the label claim, in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Alprazolam RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of alprazolam in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 
711
711
Medium:
pH 6.0 phosphate buffer (dissolve 8.0 g of monobasic potassium phosphate and 2.0 g of dibasic potassium phosphate in 1 L of water; adjust with phosphoric acid or 5 N potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL
Apparatus 1:
100 rpm
Time:
1, 4, 8, and 12 h
Mobile phase:
Acetonitrile, tetrahydrofuran, and Medium (7:1:12)
Standard stock solution:
0.5 mg/mL of USP Alprazolam RS in acetonitrile
Standard solution:
(L/500) mg/mL of USP Alprazolam RS in Medium from the Standard stock solution, where L is the label claim in mg/Tablet
Sample solution:
Pass a portion of the solution under test through a suitable filter.
Chromatographic system
Mode:
LC
Detector:
UV 254 nm
Column:
4.6-mm × 10-cm; 5-µm packing L7
Flow rate:
1 mL/min
Injection size:
100 µL
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 2.0
Column efficiency:
NLT 3000 theoretical plates
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of alprazolam dissolved:
Result = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Alprazolam RS in the Standard solution (mg/mL) |
| L | = | = label claim (mg/Tablet) |
| V | = | = volume of Medium, 500 mL |
Tolerances:
The percentages of the labeled amount of C17H13CIN4 released at the times specified conform to Acceptance Table 2 in 711.
711.
| Time (h) |
Amount Dissolved | ||
|---|---|---|---|
| 0.5-mg Tablet | 2-mg Tablet | 3-mg Tablet | |
| 1 | NMT 25% | NMT 20% | NMT 20% |
| 4 | 40%–60% | 30%–55% | 30%–55% |
| 8 | 70%–90% | 65%–90% | 65%–90% |
| 12 | NLT 85% | NLT 85% | NLT 85% |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Buffer:
5.4 g/L of monobasic potassium phosphate (KH2PO4) in water. Adjust with phosphoric acid to a pH of 3.4.
Solution A:
Acetonitrile, methanol, and Buffer (27:10:63)
Solution B:
Acetonitrile, methanol, and Buffer (7:3:10)
System suitability solution:
1 µg/mL each of USP Chlordiazepoxide Related Compound A RS, USP Alprazolam Related Compound A RS, and USP Nordazepam RS; and 0.4 µg/mL of USP Alprazolam RS in methanol
Standard solution:
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 suitable 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 the filtrate.
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 95 | 5 |
| 22 | 95 | 5 |
| 25 | 15 | 85 |
| 60 | 15 | 85 |
| 60.1 | 95 | 5 |
| 70 | 95 | 5 |
Chromatographic system
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 25-cm; 5-µm packing L7
Flow rate:
1.5 mL/min
Injection size:
10 µL
System suitability
Samples:
System suitability solution and Standard solution
[Note—The relative retention times are in Impurity Table 1. ]
Suitability requirements
Resolution:
NLT 1.5 between nordazepam and alprazolam; NLT 1.5 between chlordiazepoxide related compound A and alprazolam related compound A, System suitability solution
Tailing factor:
NMT 2.0 for the alprazolam peak, System suitability solution
Relative standard deviation:
NMT 5%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of the impurity from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Alprazolam RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of alprazolam in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 1) |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 2.0%
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Chlordiazepoxide related compound Aa,e | 0.36 | 1.0 | — |
| USP Alprazolam Related Compound A RSb | 0.45 | 0.7 | 0.5 |
| Nordazepamc,e | 0.8 | 1.0 | — |
| Alprazolam | 1.0 | — | — |
| 2-Amino-5-chloro-benzophenone | 1.8 | 0.9 | 0.5 |
| Amino-derivatived | 2.2 | 1.2 | 0.5 |
| Any other individual degradation product | — | 1.0 | 0.2 |
|
a
 -Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide.
b
2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine.
c
7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (reported as unspecified impurity).
d
7-Chloro-1-methyl-5-phenyl[1,2,4]triazolo[4,3-a]quinolin-4-amine.
e
If present meets the requirement for any other individual degradation product.
|
|||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers, and store at room temperature.
• USP Reference Standards 11
11
USP Alprazolam RS 
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USP Alprazolam Related Compound A RS
2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine.
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2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine.
USP Chlordiazepoxide Related Compound A RS
7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide.
C15H11ClN2O2 286.72
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7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide.
C15H11ClN2O2 286.72
USP Nordazepam RS
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2105
Pharmacopeial Forum: Volume No. 36(3) Page 655