Add the following:
Alprazolam Orally Disintegrating Tablets
DEFINITION
Alprazolam Orally Disintegrating Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of alprazolam (C17H13ClN4).
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
Buffer:  6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.
Diluent:  Acetonitrile and water (3:2)
Mobile phase:  Acetonitrile, methanol, and Buffer (7:2:11)
Standard solution:  10 µg/mL of USP Alprazolam RS in Diluent
Sample solution:  10 µg/mL of alprazolam in Diluent. Prepare using 10 Tablets, and pass through a suitable filter. [Note—Sonicate with intermittent shaking to help dissolve, if necessary. ]
Chromatographic system 
Mode:  LC
Detector:  UV 221 nm
Column:  4.6-mm × 15-cm; 5-µm packing L7
Column temperature:  30
Flow rate:  1.5 mL/min
Injection size:  30 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Tailing factor:  NMT 1.5
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of alprazolam (C17H13ClN4) 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 (µg/mL)
CU== nominal concentration of alprazolam in the Sample solution (µg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
•  Disintegration 701
Time:  NMT 60 s
•  Dissolution 711
Medium:  pH 6.0 phosphate buffer (80 g/L of monobasic potassium phosphate and 20 g/L of dibasic potassium phosphate in water. Adjust with phosphoric acid or diluted sodium hydroxide to a pH of 6.0 ± 0.1); 900 mL
Apparatus 2:  50 rpm
Time:  10 min
Mobile phase, Chromatographic system, and System suitability:  Proceed as directed in the Assay, except use an injection size of 100 µL.
Standard stock solution:  50 µg/mL of USP Aprazolam RS in methanol. [Note—Sonicate to help dissolve, if necessary. ]
Standard solution:  L/1000 µg/mL of USP Aprazolam RS in Medium from the Standard stock solution, where L is the Tablet label claim in µg
Sample solution:  Pass a portion of the solution under test through a nylon membrane filter of 0.45-µm pore size, discarding the first few mL.
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of alprazolam (C17H13ClN4) dissolved:
Result = (rU/rS) × CS × (V/L) × 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)
V== volume of Medium, 900 mL
L== label claim (mg/Tablet)
Tolerances:  NLT 80% (Q) of the label claim of C17H13ClN4 is dissolved.
•  Uniformity of Dosage Units 905: Meet the requirements
IMPURITIES
Organic Impurities 
•  Procedure
Buffer and Diluent:  Prepare as directed in the Assay.
Solution A:  Acetonitrile, methanol, and Buffer (5:4:11)
Solution B:  Acetonitrile, methanol, and Buffer (8:1:11)
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
12 100 0
15 0 100
60 0 100
65 100 0
70 100 0
Standard solution:  0.6 µg/mL of USP Alprazolam RS in Diluent
Sample solution:  200 µg/mL of alprazolam in Diluent. Prepare using 10 Tablets, and pass through a suitable filter.
Chromatographic system 
Mode:  LC
Detector:  UV 240 nm
Column:  4.6-mm × 15-cm; 5-µm packing L7
Column temperature:  30
Flow rate:  1.2 mL/min
Injection size:  25 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Theoretical plates:  NLT 2000
Tailing factor:  NMT 1.5
Relative standard deviation:  NMT 6.0%
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 each impurity from the Sample solution
rS== peak response of alprazolam from the Standard solution
CS== concentration of USP Alprazolam RS in the Standard solution (µg/mL)
CU== nominal concentration of alprazolam in the Sample solution (µg/mL)
F== relative response factor (see Impurity Table 1)
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 2.0%. [Note—Disregard any peaks less than 0.05%. ]
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Alprazolam related compound Aa,b 0.8
Alprazolam 1.0
2-Amino-5-chlorobenzophenone 2.9 1.9 0.5
Any other unknown impurity 1.0 0.5
a  2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine.
b  Disregard the peak due to alprazolam related compound A, because it is a process impurity in alprazolam.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.
•  USP Reference Standards 11
USP Alprazolam RS Click to View Structure
USP35
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Topic/Question Contact Expert Committee
Monograph Ravi Ravichandran, Ph.D.
Principal Scientific Liaison
1-301-816-8330
(SM42010) Monographs - Small Molecules 4
701 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
1-301-816-8106
(GCDF2010) General Chapters - Dosage Forms
711 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
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(GCDF2010) General Chapters - Dosage Forms
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1-301-816-8129
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USP35–NF30 Page 2106
Pharmacopeial Forum: Volume No. 36(4) Page 890