Alprazolam Extended-Release Tablets

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

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

DOWNLOAD PDF HERE 

1 DEFINITION

Alprazolam Extended-Release 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

Mobile phase: Acetonitrile, water, and phosphoric acid (350:650:1)

Standard solution: 0.05 mg/mL of USP Alprazolam RS in methanol

Sample solution: Nominally 0.05 mg/mL of alprazolam prepared as follows. Transfer an appropriate number of Tablets to a suitable volumetric flask. Sonicate in 80% of the flask volume of methanol for 15 min, and shake mechanically for 30 min. Dilute with methanol to final volume, filter a portion of the solution, and discard the first 3 mL of filtrate.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

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

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Column efficiency: NLT 3000 theoretical plates

Relative standard deviation: NMT 2.0%

3.4 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 (mg/mL)

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

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

4.1.1 Test 1

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 or potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL

Apparatus 1: 100 rpm

Times: 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 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

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 10-cm; 5-µm packing L7

Flow rate: 1 mL/min

Injection volume: 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 the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved:

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution s

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

L = label claim (mg/Tablet)

V = volume of Medium, 500 mL

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) released at the times specified conform to Dissolution (711). Acceptance Table 2.

4.1.2 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 (8.0 g/L of monobasic potassium phosphate and 2.0 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 1: 100 rpm

Times: 1, 4, 8, and 16 h

Mobile phase: Acetonitrile, tetrahydrofuran, and Medium (35:5:60)

Standard stock solution: 0.05 mg/mL of USP Alprazolam RS in methanol

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

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1.3 mL/min

Injection volume: 80 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 concentration (C) of alprazolam (C₁₇H₁₃CIN₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of alprazolam from the Sample solution at each time point

r_S = peak response of alprazolam from the Standard solution

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

Calculate the percentage of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V - V_s)] + (C₁ x V_S)} x (1/L) x 100

Result₃ = ({C₃ x [V - (2 x V_S)]} + [(C₂ + C₁) x V_S]) x (1/L) x 100

Result₄ = ({C₄ x [V - (3 x V_S)]} + [(C₃ + C₂ + C₁) x V_S]) x (1/L) x 100

C_i = concentration of alprazolam in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) released at the times specified conform to Dissolution (711). Acceptance Table 2.

4.1.3 Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

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 or potassium hydroxide to a pH of 6.0 ± 0.1); 500 mL, deaerated

Apparatus 1: 100 rpm

Times: 1, 4, and 8 h for Tablets labeled to contain 0.5 mg or 1 mg; 1, 4, 8, and 16 h for Tablets labeled to contain 2 mg or 3 mg

Mobile phase: Acetonitrile and Medium (40:60)

Standard stock solution: 0.5 mg/mL of USP Alprazolam RS in methanol

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 of 1-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 10-cm; 3-µm or 5-um packing L7

Flow rate: 1 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of alprazolam (C₁₇H₁₃CIN₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of alprazolam from the Sample solution at each time point

r_S = peak response of alprazolam from the Standard solution

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

Calculate the percentage of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V - V_s)] + (C₁ x V_S)} x (1/L) x 100

Result₃ = ({C₃ x [V - (2 x V_S)]} + [(C₂ + C₁) x V_S]) x (1/L) x 100

Result₄ = ({C₄ x [V - (3 x V_S)]} + [(C₃ + C₂ + C₁) x V_S]) x (1/L) x 100

C = concentration of alprazolam in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) released at the times specified conform to Dissolution (711). Acceptance Table 2.

4.1.4 Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

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 or potassium hydroxide to a pH of 6.0); 500 mL

Apparatus 1 (20-mesh basket): 100 rpm

Times: 1, 4, 8, and 16 h

Mobile phase: Acetonitrile and Medium (32:68)

Standard stock solution: 0.4 mg/mL of USP Alprazolam RS in methanol

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. Pass through a suitable filter of 0.45-µm pore size, and use the filtrate.

Sample solution: At the end of specified time intervals, withdraw a known volume (V_S) of the solution from the dissolution vessel, and replace an equal volume of fresh Medium into the dissolution vessel. Pass the withdrawn sample through a suitable filter of 0.45-µm pore size, and use the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 100 µL

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 concentration (C_i) of alprazolam (C₁₇H₁₃CIN₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of alprazolam from the Sample solution at each time point

r_S = peak response of alprazolam from the Standard solution

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

Calculate the percentage of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = [(C₂ x V) + (C₁ x V_S)] x (1/L) x 100

Result₃ = {[C₃ x V] + [(C₂ + C₁)×V_S]} x (1/L) x 100

Result₄ = {[C₄ x V] + [(C₃ + C₂ + C₁) x V_S]} x (1/L) x 100

C_i = concentration of alprazolam in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) released at the times specified conform to Dissolution (711). Acceptance Table 2.

4.1.5 Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

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 of 6.0); 500 mL

Apparatus 1: 100 rpm

Times: 1, 4, 8, and 16 h

Mobile phase: Acetonitrile, water, and phosphoric acid (350:650:1)

Standard stock solution: 0.5 mg/mL of USP Alprazolam RS in methanol

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 of 0.45-µm pore size, and use the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 50 µL

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 concentration (C_i) of alprazolam (C₁₇H₁₃CIN₄) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) x C_S

r_U = peak response of alprazolam from the Sample solution at each time point

r_S = peak response of alprazolam from the Standard solution

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

Calculate the percentage of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) dissolved at each time point (i):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V - V_s)] + (C₁ x V_S)} x (1/L) x 100

Result₃ = ({C₃ x [V - (2 x V_S)]} + [(C₂ + C₁) x V_S]) x (1/L) x 100

Result₄ = ({C₄ x [V - (3 x V_S)]} + [(C₃ + C₂ + C₁) x V_S]) x (1/L) x 100

C_i = concentration of alprazolam in the Sample solution at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of alprazolam (C₁₇H₁₃CIN₄) released at the times specified conform to Dissolution (711). Acceptance Table 2.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

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)

Mobile phase: See Table 6.

Table 6

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 filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution [NOTE-The relative retention times are listed in Table 7.]

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

r_U = peak response of the impurity 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)

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

F = relative response factor (see Table 7)

Acceptance criteria: See Table 7.

Table 7

^a If possible from the manufacturing process.

^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.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, and store at room temperature.

LABELING: The labeling states the Dissolution test used only if Test 1 is not used.

USP REFERENCE STANDARDS (11).

USP Alprazolam RS

USP Alprazolam Related Compound A RS

2-(2-Acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine.

C₁₇H₁₅CIN₄O 326.78

USP Chlordiazepoxide Related Compound A RS

7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide.

C₁₅H₁₁CIN₂O₂ 286.71

USP Nordazepam RS