Dimenhydrinate

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 · C₇H₇ClN₄O₂ 469.96

1H-Purine-2,6-dione, 8-chloro-3,7-dihydro-1,3-dimethyl-, compd. with 2-(diphenylmethoxy)-N,N-dimethylethanamine (1:1);

8-Chlorotheophylline, compound with 2-(diphenylmethoxy)-N,N-dimethylethylamine (1:1)   CAS RN®: 523-87-5; UNII: JB937PER5C

1 DEFINITION

Dimenhydrinate contains NLT 53.0% and NMT 55.5% of diphenhydramine (C₁₇H₂₁NO) and NLT 44.0% and NMT 47.0% of 8-chlorotheophylline (C₇H₇ClN₄O₂), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

Add the following:

B. The retention time of the diphenhydramine peak in the Sample solution corresponds to that of the Standard solution, as obtained in the Assay, Procedure 1: Diphenhydramine.

Add the following:

C. The retention time of the 8-chlorotheophylline peak in the Sample solution corresponds to that of the Standard solution, as obtained in the Assay, Procedure 2: 8-Chlorotheophylline.

3 ASSAY

Change to read:

3.1 Procedure 1: Diphenhydramine

Solution A: 10.0 g/L (equivalent to 13.8 mL/L) of triethylamine in water; adjusted with phosphoric acid to a pH of 2.5

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Return to original conditions, and re-equilibrate the system for NLT 10 min.

Diluent: Acetonitrile and water (18:82)

System suitability solution: 0.114 mg/mL of USP Diphenhydramine Hydrochloride RS and 0.1 mg/mL each of USP Diphenhydramine Related Compound A RS, USP Theophylline RS, and USP Dimenhydrinate Related Compound E RS in Diluent. Sonicate to dissolve, if necessary.

Standard solution: 0.05 mg/mL of USP Diphenhydramine Hydrochloride RS in Diluent

Sample solution: 0.1 mg/mL of Dimenhydrinate in Diluent

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 225 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Column temperature: 30°
• Flow rate: See Table 1.
• Injection volume: 10 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-See Table 2 for relative retention times.]
• Suitability requirements
• Resolution: NLT 1.5 between diphenhydramine related compound A and diphenhydramine, System suitability solution
• Tailing factor: NMT 2.0, Standard solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diphenhydramine (C₁₇H₂₁NO) in the portion of Dimenhydrinate taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (M_r1/M_r2) × 100

rᵤ = peak response of diphenhydramine from the Sample solution

rₛ = peak response of diphenhydramine from the Standard solution

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

Cᵤ = concentration of Dimenhydrinate in the Sample solution (mg/mL)

M_r1 = molecular weight of diphenhydramine, 255.36

M_r2 = molecular weight of diphenhydramine hydrochloride, 291.82

Acceptance criteria: 53.0%–55.5% on the dried basis

Change to read:

3.2 Procedure 2: 8-Chlorotheophylline

3.3 Solution A, Solution B, Mobile phase, Diluent, Sample solution, and Chromatographic system: Proceed as directed in the Assay, Procedure 1: Diphenhydramine.

Standard solution: 0.05 mg/mL of USP 8-Chlorotheophylline RS in Diluent

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 1.0%

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of 8-chlorotheophylline (C₇H₇ClN₄O₂) in the portion of Dimenhydrinate taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of 8-chlorotheophylline from the Sample solution

rₛ = peak response of 8-chlorotheophylline from the Standard solution

Cₛ = concentration of USP 8-Chlorotheophylline RS in the Standard solution (mg/mL)

Cᵤ = concentration of Dimenhydrinate in the Sample solution (mg/mL)

Acceptance criteria: 44.0%–47.0% on the dried basis

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.3%

Change to read:

4.2 Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, System suitability solution, and Chromatographic system: Proceed as directed in the Assay, Procedure 1: Diphenhydramine.

Standard solution: 2.28 µg/mL of USP Diphenhydramine Hydrochloride RS in Diluent

Sensitivity solution: 0.57 µg/mL of USP Diphenhydramine Hydrochloride RS in Diluent, from the Standard solution

Sample solution: 1.0 mg/mL of Dimenhydrinate in Diluent

System suitability

• Samples: System suitability solution, Standard solution, and Sensitivity solution
• Suitability requirements
• Resolution: NLT 1.5 between diphenhydramine related compound A and diphenhydramine, System suitability solution
• Relative standard deviation: NMT 5.0%, Standard solution
• Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Dimenhydrinate taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (M_r1/M_r2) × 100

rᵤ = peak response of each individual impurity from the Sample solution

rₛ = peak response of diphenhydramine from the Standard solution

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

Cᵤ = concentration of Dimenhydrinate in the Sample solution (mg/mL)

M_r1 = molecular weight of diphenhydramine, 255.36

M_r2 = molecular weight of diphenhydramine hydrochloride, 291.82

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

5 SPECIFIC TESTS

5.1 Loss on Drying 〈731〉

Analysis: Dry under vacuum over phosphorus pentoxide for 24 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in well-closed containers.

Change to read:

6.2 USP Reference Standards 〈11〉

USP 8-Chlorotheophylline RS

8-Chloro-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione.

C₇H₇ClN₄O₂    214.61

USP Dimenhydrinate RS

USP Dimenhydrinate Related Compound E RS

8-Chlorocaffeine;

8-Chloro-3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione.

C₈H₉ClN₄O₂    228.64

USP Diphenhydramine Hydrochloride RS

USP Diphenhydramine Related Compound A RS

2-(Diphenylmethoxy)-N-methylethanamine hydrochloride.

C₁₆H₁₉NO·HCl     277.79

USP Theophylline RS