Azelastine Hydrochloride

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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C₂₂H₂₄CIN₃O . HCI  418.36

1(2H)-Phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl), monohydrochloride;

4-(p-Chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)-phthalazinone monohydrochloride CAS RN^®: 79307-93-0.

UNII: OL591QR101

1 DEFINITION

Azelastine Hydrochloride contains NLT 99.0% and NMT 101.0% of azelastine hydrochloride (C₂₂H₂₄CIN₃O . HCI), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of the Identification solution, as obtained in the test for Organic Impurities.

C. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Chloride: Meets the requirements

3 ASSAY

Change to read:

3.1 PROCEDURE

Sample: 300 mg

Blank: 5 mL of anhydrous formic acid and 30 mL of acetic anhydride

Titrimetric system

(See Titrimetry (541).)

Mode: Direct titration

Titrant: 0.1 N perchloric acid in glacial acetic acid VS (USP 1-Dec-2021)

Endpoint detection: Potentiometric

Analysis: In order to avoid overheating in the reaction medium, mix thoroughly throughout and stop the titration immediately after the

endpoint has been reached.

Dissolve the Sample in 5 mL of anhydrous formic acid, and add 30 mL of acetic anhydride. Titrate with Titrant.

Calculate the percentage of azelastine hydrochloride (C₂₂H₂₄CIN₃O . HCI) in the portion of Azelastine Hydrochloride taken:

Result = {[(V_S -V_B) x N x F]/W} x 100

V_S = Titrant volume consumed by the Sample (mL)

V_B = Titrant volume consumed by the Blank (mL)

N = actual normality of the Titrant (mEq/mL)

F = equivalency factor, 418.4 (USP 1-Dec-2021) mg/mEq

W = weight of the Sample (mg)

Acceptance criteria: 99.0%-101.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.2%

Change to read:

4.2 ORGANIC IMPURITIES

Solution A: 127 mL/L of phosphoric acid in water (USP 1-Dec-2021)

Buffer: 2.9 g/L of octanesulfonic acid sodium salt and 0.9 g/L of monobasic potassium phosphate in water. Adjust with Solution A to a pH of 3.0. (USP 1-Dec-2021)

Mobile phase: Acetonitrile and Buffer (23:77) (USP 1-Dec-2021)

Diluent: Acetonitrile and water (45:55)

Identification solution: 2.5 mg/mL of USP Azelastine Hydrochloride RS in Diluent. [NOTE-This solution is used for Identification B.]

System suitability stock solution: 0.5 mg/mL each of benzoyl hydrazide, (USP 1-Dec-2021) USP Azelastine Related Compound B RS.

chlorophenylacetylbenzoic acid, (USP 1-Dec-2021) USP Azelastine Related Compound D RS, and USP Azelastine Related Compound E RS in

acetonitrile. [NOTE-The concentration of each related compound is in terms of the free form.] (USP 1-DEC-2021)

System suitability solution: 0.05 mg/mL (USP 1-Dec-2021) each of benzoyl hydrazide, (USP 1-Dec-2021) USP Azelastine Related Compound B RS, chlorophenylacetylbenzoic acid, (USP 1-Dec-2021) USP Azelastine Related Compound D RS, and USP Azelastine Related Compound E RS from the System suitability stock solution and 2.5 mg/mL of USP Azelastine Hydrochloride RS in Diluent. [NOTE-The concentration of

each related compound is in terms of the free form.) (USP 1-DEC-2021)

Standard stock solution: 0.05 mg/mL (USP 1-Dec-2021) of USP Azelastine Hydrochloride RS in acetonitrile

Standard solution: 0.0025 mg/mL (USP 1-Dec-2021) of USP Azelastine Hydrochloride RS in Diluent

Sensitivity solution: 0.0013 mg/mL of USP Azelastine Hydrochloride RS in Diluent from the Standard solution (USP 1-Dec-2021)

Sample solution: 2.5 mg/mL of Azelastine Hydrochloride in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 25-cm; 5-µm packing (USP 1-Dec-2021) L10

Column: 4.6-mm x 25-cm; 5-µm packing (USP 1-Dec-2021) L10

Column temperature: 30°

Flow rate: 2 mL/min

Injection volume: 10 µL

Run time: ANLT (USP 1-Dec-2021) 2.4 times the retention time of azelastine

System suitability

Samples: System suitability solution and Standard solution

[NOTE-See Table 1 for the relative retention times.) (USP 1-DEC-2021)

Suitability requirements

Resolution: NLT 1.5 between benzoyl hydrazide and azelastine related compound B; NLT 1.5 between chlorophenylacetylbenzoic acid and azelastine related compound D; (USP 1-Dec-2021) NLT 1.5 between azelastine related compound D and azelastine; NLT 1.5 between azelastine and azelastine related compound E, System suitability solution

Tailing factor: 0.9-2.0, Standard solution (USP 1-Dec-2021)

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-Dec-2021)

Analysis

Samples: (USP 1-Dec-2021) Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Azelastine Hydrochloride taken:

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

r_U = peak area of each impurity from the Sample solution

r_S = peak area of azelastine from the Standard solution

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

C_U = concentration of Azelastine Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05% (USP 1-Dec-2021)

Table 1

^a Benzohydrazide.

^b 2-[2-(4-Chlorophenyl)acetyl benzoic acid.

5 SPECIFIC TESTS

5.1 LOSS ON DRYING (731)

Analysis: Dry at 105° to constant weight.

Acceptance criteria: NMT 1.0%

Delete the following:

5.2 ACIDITY OR ALKALINITY

Sample solution: 10 mg/mL of Azelastine Hydrochloride in water

Analysis: Add 0.2 mL of bromothymol blue TS to 10 mL of the Sample solution.

Acceptance criteria: NMT 0.1 mL of 0.01 M hydrochloric acid or 0.01 M sodium hydroxide is required to produce a color change. (USP 1-Dec-2021)

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers. Protect from light and moisture. Store at controlled room temperature.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Azelastine Hydrochloride RS

USP Azelastine Related Compound B RS

N'-(1-Methylazepan-4-yl)benzohydrazide hydrochloride.

C₁₄H₂₁N₃O . HCI  283.80 (USP 1-Dec-2021)

USP Azelastine Related Compound D RS

4-(4-Chlorobenzyl)phthalazin-1(2H)-one.

C₁₅H₁₁CIN₂O  270.71

USP Azelastine Related Compound E RS

3-(4-Chlorobenzylidene)isobenzofuran-1(3H)-one.

C₁₅H₉OCIO₂  256.68