Diphenhydramine Citrate

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 · C₆H₈O₇               447.48

Ethanamine, 2-(diphenylmethoxy)-N,N-dimethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1);

2-(Diphenylmethoxy)-N,N-dimethylethylamine citrate (1:1) CAS RN: 88637-37-0; UNII: 40D433S209.

1 DEFINITION

Diphenhydramine Citrate contains NLT 98.0% and NMT 102.0% of diphenhydramine citrate (C₁₇H₂₁NO · C₆H₈O₇), 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, Citrate (191).

3 ASSAY

3.1 PROCEDURE

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

Mobile phase: See Table 1.

Table 1 
 

Diluent: Acetonitrile and Buffer (35:65)

System suitability solution: 0.15 mg/mL of USP Diphenhydramine Citrate RS and 0.1 mg/mL of USP Diphenhydramine Related Compound A RS in Diluent

Standard solution: 0.12 mg/mL of USP Diphenhydramine Citrate RS in Diluent

Sample solution: 0.12 mg/mL of Diphenhydramine Citrate in Diluent

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 citrate (C₁₇H₂₁NO · C₆H₈O₇) in the portion of Diphenhydramine Citrate taken:

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

r_U = peak response for diphenhydramine from the Sample solution

r_S = peak response for diphenhydramine from the Standard solution

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

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

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

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

Sample: 8 g

Analysis: To the Sample add 5 mL of sulfuric acid, and char. After the substance is thoroughly charred, add 4 mL of nitric acid and a few drops of sulfuric acid, heat gently until fumes are no longer evolved, and ignite at 800 ± 25° until the carbon is consumed. Place in a muffle furnace at 550 ± 50° for about 1 h. Continue the ignition until constant weight is attained.

Acceptance criteria: NMT 0.1% remains.

4.2 ORGANIC IMPURITIES

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

Mobile phase: Acetonitrile and Buffer (35:65)

System suitability solution: 0.15 mg/mL each of USP Diphenhydramine Related Compound A RS, benzhydrol, and USP Diphenhydramine Citrate RS in Mobile phase

Standard solution: 0.005 mg/mL of USP Diphenhydramine Citrate RS in Mobile phase

Sensitivity solution: 0.5 µg/mL of USP Diphenhydramine Citrate RS in Mobile phase from the Standard solution

Sample solution: 1.1 mg/mL of Diphenhydramine Citrate 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.

4.2.2 System suitability

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

Samples: System suitability solution and Sensitivity solution

4.2.3 Suitability requirements

Resolution: NLT 2.0 between diphenhydramine related compound A and diphenhydramine

Signal-to-noise ratio: NLT 10, Sensitivity solution

4.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Diphenhydramine Citrate 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 Citrate RS in the Standard solution (mg/mL) 

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

F = relative response factor (see Table 2)

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

Table 2 

^a Salt counter ion is included in the table for identification purposes only.

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

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

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

^e Diphenylmethanol.

^f Diphenylmethanone.

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Sample: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers.

USP REFERENCE STANDARDS (11)

USP Diphenhydramine Citrate BS

USP Diphenhydramine Related Compound A RS

2-(Diphenylmethoxy)-N-methylethanamine hydrochloride.

C₁₆H₁₉NO · HCI                277.79