Lorazepam 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

Lorazepam Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of lorazepam.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M

Sample: Stir a portion of finely powdered Tablets, equivalent to 15 mg of lorazepam, with 40 mL of acetone for 5 min. Pass through very retentive filter paper pre-washed with acetone. Evaporate the filtrate to dryness on a steam bath with the aid of a current of air. Dissolve the residue in 1 mL of acetone, and add 20 mL of 2,2,4-trimethylpentane. Heat the solution on a hot plate to a gentle boil, and evaporate to a volume of about 10 mL. Remove the solution from the hot plate, and evaporate to dryness with the aid of a current of air. Dry the residue under vacuum at 60° for 1 h.

Acceptance criteria: Meet the requirements

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

3 ASSAY

Procedure

Diluent: Methanol and water (85:15)

Mobile phase: Acetonitrile, glacial acetic acid, and water (40: 0.4: 60)

Standard solution: 0.1 mg/mL of USP Lorazepam RS in Diluent

Sample solution: Nominally 0.1 mg/mL of lorazepam prepared as follows. Transfer 20 Tablets to a 100-mL volumetric flask, add 50 mL of

Diluent, sonicate for 10 min, and shake by mechanical means for 20 min. Dilute with Diluent to volume, mix, and centrifuge a portion of the solution at 2000 rpm for 10 min. Dilute a portion of the clear supernatant with Diluent.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Flow rate: 1 mL/min

Injection volume: 20 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 percentage of the labeled amount of lorazepam (C₁₅H₁₀Cl₂N₂O₂) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Dissolution 〈711〉

Medium: Water; 500 mL

Apparatus 1: 100 rpm

Times: 30 and 60 min

Mobile phase and Chromatographic system: Prepare as directed in the Assay, except use an Injection volume of 50 μL.

Standard solution: USP Lorazepam RS at a known concentration in Medium. Initially, use a volume of alcohol not exceeding 10% of the final volume of the Standard solution to dissolve the Reference Standard.

Sample solution: Sample per Dissolution 〈711〉.

Analysis

Samples: Standard solution and Sample solution

Tolerances: NLT 60% (Q) of the labeled amount of lorazepam (C₁₅H₁₀Cl₂N₂O₂) is dissolved in 30 min. NLT 80% (Q) of the labeled amount of lorazepam (C₁₅H₁₀Cl₂N₂O₂) is dissolved in 60 min.

Change to read:

Uniformity of Dosage Units 〈905〉: Meet the requirements (CN 1-Aug-2023)

Procedure for content uniformity

Diluent, Mobile phase, Standard solution, and Chromatographic system: Proceed as directed in the Assay.

Sample solution: Nominally, 0.1 mg/mL of lorazepam prepared as follows. Place 1 Tablet in a volumetric flask of appropriate size, based on the labeled quantity, in mg, of lorazepam in the Tablet. Add a volume of Diluent equal to about 50% of the volume of the flask, sonicate for 10 min, and shake by mechanical means for 20 min. Dilute with Diluent to volume, mix, and centrifuge a portion of the solution for 10 min at 2000 rpm.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of lorazepam (C₁₅H₁₀Cl₂N₂O₂) in the portion of the Tablet taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

(CN 1-Aug-2023)

5 IMPURITIES

Organic Impurities

Buffer: 67.7 g/L of sodium acetate trihydrate in water. Adjust with glacial acetic acid to a pH of 5.0 ± 0.05.

Mobile phase: Acetonitrile, glacial acetic acid, and water (50: 1.2: 50)

Diluent: Methanol and Buffer (75:25)

Standard solution: 1.6 μg/mL of USP Lorazepam RS in Diluent

Peak identification solution: 0.16 mg/mL of USP Lorazepam RS, 1.6 μg/mL each of USP Lorazepam Related Compound A RS, USP

Lorazepam Related Compound B RS, USP Lorazepam Related Compound C RS, USP Lorazepam Related Compound D RS, and USP

Lorazepam Related Compound E RS in Diluent

Sample solution: Nominally 0.16 mg/mL of lorazepam prepared as follows. Transfer a weighed amount of lorazepam, equivalent to 21.3 mg from powdered Tablets, to a 25-mL volumetric flask. Add 20 mL of Diluent, and stir for 15 min. Do not dilute to volume. Centrifuge at 2000rpm for 15 min. Pass the supernatant through a polyethersulfone membrane of 0.45-μm pore size. Dilute a portion of the

ltrate with Diluent.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC. Use an instrument equipped with a sample compartment chiller maintained at 4°.

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Column temperature: 5°

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: At least 50 min

System suitability

Samples: Standard solution and Peak identification solution

[Note—See Table 1 for the approximate relative retention times.]

Suitability requirements

Resolution: NLT 1.2 between lorazepam related compound A and lorazepam related compound E, Peak identification solution

Tailing factor: NMT 2.0, Standard 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) × (C_S/C_U) × (1/F) × 100

r_U = peak response for each impurity from the Sample solution

r_S = peak response for lorazepam from the Standard solution

C_S = concentration of lorazepam in the Standard solution (mg/mL)

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

F = relative response factor for any given impurity (see Table 1)

Acceptance criteria: See Table 1.

Table 1

^a 6-Chloro-4-(o-chlorophenyl)-2-quinazolinecarboxylic acid.

^b 7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepin-2-one.

^c Lorazepam related compound A is included only for peak identification purposes. It is not quantified and should not be included in the total impurities calculation.

^d 6-Chloro-4-(o-chlorophenyl)-2-quinazoline methanol.

^e 6-Chloro-4-(o-chlorophenyl)-2-quinazolinecarboxaldehyde.

^f 2-Amino-2′,5-dichlorobenzophenone.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

USP Reference Standards 〈11〉

USP Lorazepam RS

USP Lorazepam Related Compound A RS

7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepin-2-one.

C₁₇H₁₂Cl₂N₂O₃ 363.20

USP Lorazepam Related Compound B RS

2-Amino-2′,5-dichlorobenzophenone.

C₁₃H₉Cl₂NO 266.12

USP Lorazepam Related Compound C RS

6-Chloro-4-(o-chlorophenyl)-2-quinazolinecarboxaldehyde.

C₁₅H₈Cl₂N₂O 303.14

USP Lorazepam Related Compound D RS

6-Chloro-4-(o-chlorophenyl)-2-quinazolinecarboxylic acid.

C₁₅H₈Cl₂N₂O₂ 319.14

USP Lorazepam Related Compound E RS

6-Chloro-4-(o-chlorophenyl)-2-quinazoline methanol.

C₁₅H₁₀Cl₂N₂O 305.16