Diphenhydramine Hydrochloride Oral Powder

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

Diphenhydramine Hydrochloride Oral Powder contains NLT 90.0% and NMT 110.0% of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO · HCI).

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.

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

3 ASSAY

Change to read:

3.1 PROCEDURE

(USP 1-Dec-2022)

Buffer: 5.52 g/L of monobasic potassium hexafluorophosphate in water ^▲_{▲(USP 1-Dec-2022)}

Solution A: ^▲Add 0.5 mL of phosphoric acid per 1 L of Buffer. _{▲(USP 1-Dec-2022)}

Solution B: ^▲For each liter, mix 700 mL of acetonitrile with 300 mL of Buffer. Add 0.5 mL of phosphoric acid per 1 L of this mixture. _{▲ (USP 1-Dec-2022)}

Mobile phase: See Table 1.

Table 1

Diluent: ^▲For each liter, mix 300 mL of acetonitrile, 700 mL of water, and 10 mL of acetic acid, glacial _{▲(USP 1-Dec-2022)}

System suitability solution: 0.0025 mg/mL each of USP Diphenhydramine Hydrochloride RS. USP Diphenhydramine Related Compound A.RS. and USP Benzhydrol RS in Diluent. ^▲Pass the solution through a polytetrafluoroethylene (PTFE) filter of 0.2-um pore size. _{▲(USP 1-Dec-2022)}

Standard solution: 0.25 mg/ml. of USP Diphenhydramine Hydrochloride RS in Diluent. ^▲Pass the solution through a PTFE filter of 0.2-um pore size _{▲(USP 1-Dec-2022)}

Sample solution: Nominally 0.25 mg/mL of diphenhydramine hydrochloride in Diluent prepared as follows. Remove the contents of NLT 5 pouches as completely as possible, and weigh. Transfer a portion of the composite powder, equivalent to 50 mg of diphenhydramine hydrochloride, to a 200-mL volumetric flask. Dilute with Diluent to volume. ^▲Pass the solution through a PTFE filter of 0.2-um pore size. _{▲(USP 1-Dec-2022)}

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm. For Identification B, use a diode array detector in the range of 210-400 nm.

Column: 2.1-mm x 5-cm; 1.7-µm packing 11

Column temperature: 40°

Flow rate: 0.9 mL/min

Injection volume: 2.5 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

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

3.1.3 Suitability requirements

Resolution: NLT 2.0 between benzhydrol and diphenhydramine related compound A; NLT 2.0 between diphenhydramine related compound A and diphenhydramine, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT ^▲1.0%, _{▲(USP 1-Dec-2022)} Standard solution

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO · HCI) in the portion of Oral Powder taken:

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

r_U = peak response of diphenhydramine 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 = nominal concentration of diphenhydramine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

UNIFORMITY OF DOSAGE UNITS (905): Meets the requirements

5 IMPURITIES

Change to read:

5.1 ORGANIC IMPURITIES

Buffer, Solution A, Solution B, Mobile phase, Diluent, System suitability solution,^▲_{▲ (USP 1-Dec-2022)} and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.5 µg/ml. each of USP Diphenhydramine Hydrochloride RS and USP Benzophenone RS, ^▲1.25 µg/mL _{▲(USP 1-Dec-2022)} of USP Diphenhydramine Related Compound A RS, and ^▲2.5 µg/mL _{▲(USP 1-Dec-2022)} each of USP Benzhydrol RS and USP Diphenhydramine N-Oxide RS in Diluent

Sample solution: Nominally 250 µg/mL of diphenhydramine hydrochloride in Diluent from Oral Powder, prepared as directed in the Assay _{▲(USP 1-Dec-2022)}

5.1.1 System suitability

Samples: System suitability solution and Standard solution

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

5.1.2 Suitability requirements

Resolution: NLT 2.0 between benzhydrol and diphenhydramine related compound A; NLT 2.0 between diphenhydramine related compound A and diphenhydramine, System suitability solution

Relative standard deviation: NMT 5.0% for each peak, Standard solution

5.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diphenhydramine related compound A, benzhydrol, benzophenone, or diphenhydramine N-oxide in the portion of Oral Powder taken:

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

r_U = peak response of diphenhydramine related compound A, benzhydrol, benzophenone, or diphenhydramine N-oxide from the Sample solution

r_S = peak response of diphenhydramine related compound A, benzhydrol, benzophenone, or diphenhydramine N-oxide from the Standard solution

C_S = concentration of USP Diphenhydramine Related Compound A RS, USP Benzhydrol RS, USP Benzophenone RS, or USP Diphenhydramine N-Oxide RS in the Standard solution (^▲µg/mL _{▲(USP 1-Dec-2022)})

C_S = nominal concentration of diphenhydramine hydrochloride in the Sample solution (^▲µg/mL _{▲(USP 1-Dec-2022)})

Calculate the percentage of any unspecified degradation product in the portion of Oral Powder taken:

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

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

r_S = peak response of diphenhydramine from the Standard solution s

C_S = concentration of USP Diphenhydramine Hydrochloride RS in the Standard solution (^▲µg/mL _{▲(USP 1-Dec-2022)})

C_U = nominal concentration of diphenhydramine hydrochloride in the Sample solution (^▲µg/mL _{▲(USP 1-Dec-2022)})

Acceptance criteria: See Table 2.

Table 2 
 

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, unit-dose containers. Store at controlled room temperature.

Change to read:

USP REFERENCE STANDARDS (11)

USP Benzhydrol RS

Diphenylmethanol.

C₁₃H₁₂O         ^▲184.24 _{▲(USP 1-Dec-2022)}

USP Benzophenone RS

Benzophenone; also known as _{▲(USP 1-Dec-2022)} diphenylmethanone.

C₁₃H₁₀O          182.22

USP Diphenhydramine Hydrochloride RS

USP Diphenhydramine Related Compound A RS

2-(Diphenylmethoxy)-N-methylethanamine hydrochloride.

C₁₆H₁₉NO · HCI                  277.79

USP Diphenhydramine N-Oxide RS

2-(Benzhydryloxy)-N,N-dimethylethan-1-amine oxide hydrochloride.

C₁₇H₂₁NO₂ · HCI               307.82