Alprazolam Orally Disintegrating Tablets

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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1 DEFINITION

Alprazolam Orally Disintegrating Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of alprazolam (C₁₇H₁₃CIN₄).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 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 (60:40)

Mobile phase: Acetonitrile, methanol, and Buffer (35:10:55)

Standard solution: 10 µg/mL of USP Alprazolam RS in Diluent

Sample solution: Nominally 10 µg/mL of alprazolam from Tablets prepared as follows. Transfer 10 Tablets to a suitable volumetric flask. Add Diluent to volume and pass through a suitable filter. [NOTE-Sonicate with intermittent shaking to help dissolve, if necessary.]

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 221 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 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 the labeled amount of alprazolam (C₁₇H₁₃CIN₄) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Alprazolam RS in the Standard solution (µg/mL)

C_U = nominal concentration of alprazolam in the Sample solution (µg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISINTEGRATION (701)

Test 1

Time: NMT 60 s

Test 2: If the product complies with this test, the labeling indicates that it meets USP Disintegration Test 2.

Time: NMT 30 s

4.2 DISSOLUTION (711)

4.2.1 Test 1

Medium: pH 6.0 phosphate buffer (8 g/L of monobasic potassium phosphate and 2 g/L of dibasic potassium phosphate in water. Adjust with phosphoric acid or diluted potassium 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 volume of 100 µL.

Standard stock solution: 0.05 mg/mL of USP Alprazolam RS in methanol. [NOTE-Sonicate to help dissolve, if necessary.]

Standard solution: (L/1000) mg/mL of USP Alprazolam RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

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 the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved:

Result = (r_U/r_S) x C_S x V x (1/L) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = 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 labeled amount of alprazolam (C₁₇H₁₃CIN₄) is dissolved.

4.2.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: pH 6.0 phosphate buffer (8 g/L of monobasic potassium phosphate and 2 g/L of dibasic potassium phosphate in water. Adjust with phosphoric acid or potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL

Apparatus 2: 50 rpm

Time: 10 min

Buffer: 1.36 g/L of monobasic potassium phosphate. Adjust with dilute sodium hydroxide to a pH of 6.0.

Mobile phase: Acetonitrile and Buffer (35:65)

Standard stock solution: 0.05 mg/mL of USP Alprazolam RS in methanol. [NOTE-Sonicate to help dissolve, if necessary.]

Standard solution: (L/500) mg/mL of USP Alprazolam RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a 5-mL aliquot of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 3 mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm x 7.5-cm; 5-µm packing L7

Flow rate: 1.5 mL/min

Injection volume: 40 µL

Run time: 3 times the retention time of alprazolam

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved:

Result = (r_U/r_S) x C_S x V x (1/L) x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Alprazolam RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 70% (Q) of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) is dissolved.

4.3 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Diluent: Prepare as directed in the Assay.

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.0.

Solution A: Acetonitrile, methanol, and Buffer (25:20:55)

Solution B: Acetonitrile, methanol, and Buffer (40:5:55)

Mobile phase: See Table 1.

Table 1

Standard solution: 0.6 µg/mL of USP Alprazolam RS in Diluent

Sample solution: Nominally 200 µg/mL of alprazolam in Diluent. Prepare using 10 Tablets, and pass through a suitable filter.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 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 = (r_U/r_S) x (C_S/C_U) x (1/F) x 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of alprazolam from the Standard solution

C_S = concentration of USP Alprazolam RS in the Standard solution (µg/mL)

C_U = nominal concentration of alprazolam in the Sample solution (µg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. Disregard any peaks less than 0.05%.

Table 2

^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.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, and store at controlled room temperature.

LABELING: When more than one Disintegration test is given, the labeling states the Disintegration test used only if Test 1 is not used. When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP REFERENCE STANDARDS (11)

USP Alprazolam RS