Loxapine Capsules

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

Loxapine Capsules contain an amount of loxapine succinate (C₁₈H₁₈ClN₃O · C₄H₆O₄) equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of loxapine (C₁₈H₁₈ClN₃O).

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.

Add the following:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.▲ (USP 1-Aug-2022)

3 ASSAY

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Procedure

Mobile phase: Dissolve 4 g of tetramethylammonium chloride in 800 mL of water, and add 200 mL of acetonitrile and 1 mL of phosphoric acid.

Standard solution: 0.136 mg/mL of USP Loxapine Succinate RS prepared as follows. Dissolve a suitable quantity of USP Loxapine Succinate RS in 0.01 N hydrochloric acid in a suitable volumetric flask, and dilute with Mobile phase to volume.

Sample solution: Nominally 0.1 mg/mL of loxapine prepared as follows. Weigh the contents of Capsules (NLT 20). Transfer a portion of the contents, nominally equivalent to NLT 50 mg of loxapine, to a suitable volumetric flask. Add 10% of the flask volume of 0.1 N hydrochloric acid. Shake, and sonicate for 5 min. Dilute with Mobile phase to volume, and filter. Discard the first 8 mL of the filtrate.

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 220–400 nm. (USP 1-Aug-2022)

Column: 4.6-mm × 15-cm; 5-μm packing L10

Flow rate: 1.6 mL/min

Injection volume: 20 μL

Run time: NLT 4 times the retention time of loxapine (USP 1-Aug-2022)

System suitability

Sample: Standard solution

Suitability requirements

(USP 1-Aug-2022)

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0% (USP 1-Aug-2022)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of loxapine (C₁₈H₁₈ClN₃O) in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of loxapine (USP 1-Aug-2022) from the Sample solution

r_S = peak response of loxapine (USP 1-Aug-2022) from the Standard solution

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

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

M_r1 = molecular weight of loxapine, 327.81

M_r2 = molecular weight of loxapine succinate, 445.90

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

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Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 1: 100 rpm

Time: 45 min

Standard solution: USP Loxapine Succinate RS at a known concentration in Medium

Sample solution: Dilute with water as needed.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.) (USP 1-Aug-2022)

Mode: UV

Analytical wavelength: 254 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of loxapine (C₁₈H₁₈ClN₃O) dissolved:

Result = (A_U/A_S) × C_S × (M_r1/M_r2) × V × D × (1/L) × 100

A_U = absorbance of loxapine from the Sample solution

A_S = absorbance of loxapine from the Standard solution

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

M_r1 = molecular weight of loxapine, 327.81

M_r2 = molecular weight of loxapine succinate, 445.90

V = volume of Medium, 900 mL

D = dilution factor of the Sample solution

L = label claim (mg/Capsule) (USP 1-Aug-2022)

Tolerances: NLT 75% (Q) of the labeled amount of loxapine (C₁₈H₁₈ClN₃O) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

Add the following:

5 IMPURITIES

Organic Impurities

Buffer: 3.9 g/L of ammonium acetate in water. Adjust with 20% acetic acid or 6 N ammonium hydroxide to a pH of 7.3.

Solution A: Buffer

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and Buffer (70:30)

System suitability solution: 0.3 mg/mL of USP Loxapine Succinate RS and 0.45 μg/mL of USP Loxapine Related Compound A RS in Diluent

Standard solution: 0.3 μg/mL each of USP Loxapine Succinate RS and USP Loxapine N-Oxide RS in Diluent

Sample solution: Nominally 0.22 mg/mL of loxapine prepared as follows. Weigh and mix the contents of Capsules (NLT 10). Transfer a portion of the contents, nominally equivalent to 22mg of loxapine, to a 100-mL volumetric flask. Add 70% of the flask volume of Diluent.

Shake, and sonicate for 5 min. Dilute with Diluent to volume, and filter.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 10-cm; 2.7-μm packing L1

Column temperature: 35°

Flow rate: 1.4 mL/min

Injection volume: 10 μL

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for the relative retention times. The relative retention times for amoxapine and loxapine related compound A are 0.46 and 1.03, respectively.]

Suitability requirements

Resolution: NLT 2.0 between loxapine and loxapine related compound A, System suitability solution

Relative standard deviation: NMT 5.0% for loxapine and loxapine N-oxide, Standard solution

Signal-to-noise ratio: NLT 10 for loxapine N-oxide, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of loxapine N-oxide in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of loxapine N-oxide from the Sample solution

r_S = peak response of loxapine N-oxide from the Standard solution

C_S = concentration of USP Loxapine N-Oxide RS in the Standard solution (mg/mL)

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

Calculate the percentage of any other individual degradation product in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 1/F × 100

r_U = peak response of any other individual degradation product from the Sample solution

r_S = peak response of loxapine from the Standard solution

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

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

M_r1 = molecular weight of loxapine, 327.81

M_r2 = molecular weight of loxapine succinate, 445.90

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.1%.

Table 2

a 2-Chlorodibenzo[b,f]-1,4-oxazepin-11-one. (USP 1-Aug-2022)

6 ADDITIONAL REQUIREMENTS

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Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. (USP 1-Aug-2022)

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USP Reference Standards 〈11〉

USP Loxapine Succinate RS

USP Loxapine N-Oxide RS

4-(2-Chlorodibenzo[b,f][1,4]oxazepin-11-yl)-1-methylpiperazine 1-oxide.

C₁₈H₁₈ClN₃O₂ 343.81

USP Loxapine Related Compound A RS

3-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine.

C₁₈H₁₈ClN₃O 327.81▲ (USP 1-Aug-2022)