Diphenhydramine 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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C₁₇H₂₁NO · HCI            291.82

Ethanamine, 2-(diphenylmethoxy)-N,N-dimethyl-, hydrochloride;

2-(Diphenylmethoxy)-N,N-dimethylethylamine hydrochloride CAS RN^®: 147-24-0; UNII: TC2D6JAD40.

1 DEFINITION

Diphenhydramine Hydrochloride contains NLT 98.0% and NMT 102.0% of diphenhydramine hydrochloride (C₁₇H₂₁NO · HCI), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K _{▲(CN 1-MAY-2020)}

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

C. IDENTIFICATION TESTS GENERAL, Chloride (191)

3 ASSAY

3.1 PROCEDURE

Buffer: 5.4 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH to 3.0.

Diluent: Acetonitrile and Buffer (35:65)

System suitability solution: 0.1 mg/mL each of USP Diphenhydramine Hydrochloride RS and USP Diphenhydramine Related Compound ARS in Diluent

Standard solution: 0.07 mg/mL of USP Diphenhydramine Hydrochloride RS in Diluent

Sample solution: 0.07 mg/ml. of Diphenhydramine Hydrochloride in Diluent

Mobile phase: See Table 1.

Table 1

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1.2 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

3.1.3 Suitability requirements

[NOTE-The relative retention times for diphenhydramine related compound A and diphenhydramine are 0.9 and 1.0, respectively.]

Resolution: NLT 1.5 between diphenhydramine related compound A and diphenhydramine, System suitability solution

Tailing factor: NMT 1.8, Standard solution

Relative standard deviation: NMT 0.85% for six replicate injections, Standard solution

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diphenhydramine hydrochloride (C₁₇H₂₁NO · HCI) in the portion of sample taken:

                Result = (r_U/r_S) x (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 Diphenhydramine Hydrochloride RS in the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281): NMT 0.1%

4.2 ORGANIC IMPURITIES

Buffer: 5.4 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (35:65)

System suitability solution: 0.1 mg/mL each of USP Diphenhydramine Related Compound A RS, benzhydrol, and USP Diphenhydramine Hydrochloride RS in Mobile phase

Standard solution: 0.0035 mg/mL of USP Diphenhydramine Hydrochloride RS in Mobile phase

Sample solution: 0.7 mg/mL of Diphenhydramine Hydrochloride in Mobile phase

4.2.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1.2 mL/min

Injection volume: 10 µL

Run time: 7 times the retention time of diphenhydramine

4.2.2 System suitability

[NOTE-See Table 2 for the relative retention times.]

Sample: System suitability solution

4.2.3 Suitability requirements

Resolution: NLT 2.0 between diphenhydramine related compound A and diphenhydramine

4.2.4 Analysis

Samples: Standard solution and Sample solution

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

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of diphenhydramine from the Standard solution

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

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. [NOTE-Disregard peaks that are less than 0.05% of the diphenhydramine peak.]

Table 2 

^a 2-(Diphenylmethoxy)-N-methylethanamine.

^b 2-[(RS)-(4-Methylphenyl)phenylmethoxy]-N,N-dimethylethanamine.

^c 2-[(RS)-(4-Bromophenyl)phenylmethoxy]-N,N-dimethylethanamine.

^d Diphenylmethanol.

^e Diphenylmethanone.

5 SPECIFIC TESTS

5.1 ACIDITY OR ALKALINITY

Sample solution: 50 mg/mL of Diphenhydramine Hydrochloride in carbon dioxide-free water.

Analysis: To 10 mL of the Sample solution, add 0.15 mL of methyl red TS 2 and 0.25 mL of 0.01 N hydrochloric acid. The solution is pink. 

Titrate with 0.01 N sodium hydroxide.

Acceptance criteria: NMT 0.5 mL of 0.01 N sodium hydroxide is required to change the color of the solution to yellow.

5.2 LOSS ON DRYING (731)

Sample: Dry a sample at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

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

USP REFERENCE STANDARDS (11)

USP Diphenhydramine Hydrochloride RS

USP Dighenhydramine Related Compound A RS

2-(Diphenylmethoxy)-N-methylethanamine hydrochloride.

C₁₆H₁₉NO · HCI              277.79