Diphenoxylate 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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C₃₀H3₂N₂O₂ · HCI             489.05

4-Piperidinecarboxylic acid, 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-, ethyl ester, hydrochloride;

Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride CAS RN^®: 3810-80-8; UNII: W240D7YW48.

1 DEFINITION

Diphenoxylate Hydrochloride contains NLT 98.0% and NMT 102.0% of diphenoxylate hydrochloride (C₃₀H3₂N₂O₂ · HCI), calculated on the dried basis.

2 IDENTIFICATION

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

B. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Chloride: A saturated solution meets the requirements.

Add the following:

C. The retention time of the diphenoxylate peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay _{▲(USP 1-Dec-2021)}

3 ASSAY

Change to read:

3.1 PROCEDURE

Solution A: Adjust 900 mL of water with phosphoric acid to a pH of 2.3, and dilute with water to 1000 mL.

Solution B: Acetonitrile

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the system for NLT 5 min.

Table 1

Diluent: Acetonitrile and Solution A (50:50)

System suitability solution: 1.0 mg/mL of USP Diphenoxylate Hydrochloride RS and 0.005 mg/mL of USP Diphenoxylate Related Compound A RS in Diluent. Sonicate to dissolve, if necessary.

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

Sample solution: 0.05 mg/mL of Diphenoxylate Hydrochloride in Diluent, Sonicate to dissolve, if necessary.

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 25-cm; 5-µm packing 11

Flow rate: 2 mL/min

Injection volume: 20 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for diphenoxylate related compound A and diphenoxylate are about 0.8 and 1.0, respectively.]

3.1.3 Suitability requirements

Resolution: NLT 5.0 between diphenoxylate related compound A and diphenoxylate, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 0.73%, Standard solution

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diphenoxylate hydrochloride (C₃₀H3₂N₂O₂ · HCI) in the portion of Diphenoxylate Hydrochloride taken:

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

r_U = peak response of diphenoxylate from the Sample solution

r_S = peak response of diphenoxylate from the Standard solution

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

C_U = concentration of Diphenoxylate Hydrochloride in the Sample solution (mg/mL) _{▲(USP 1-Dec-2021)}

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

4 IMPURITIES

Change to read:

4.1 ORGANIC IMPURITIES

Solution A, Solution B, Mobile phase, Diluent, System suitability solution, and Chromatographic system: Proceed as directed in the Assay _{▲(USP 1-Dec-2021)}

Standard solution: ^▲0.001 mg/mL _{▲(USP 1-Dec-2021)} of USP Diphenoxylate Hydrochloride RS in Diluent

Sensitivity solution: 0.5 µg/mL of USP Diphenoxylate Hydrochloride RS from Standard solution in Diluent

Sample solution: 1.0 mg/mL of Diphenoxylate Hydrochloride in Diluent. Sonicate for about 2 min to dissolve.

(USP 1-Dec-2021)

4.1.1 System suitability

Samples: System suitability solution, ^▲Standard solution _{▲(USP 1-Dec-2021)} and Sensitivity solution

4.1.2 Suitability requirements

Resolution: NLT 5.0 between diphenoxylate related compound A and diphenoxylate, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution _{▲(USP 1-Dec-2021)}

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

4.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Diphenoxylate Hydrochloride taken:

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

r_U = peak response of each individual (USP 1-Dec-2021) impurity from the Sample solution

r_S = peak response of diphenoxylate from the Standard solution

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

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

Acceptance criteria: See Table 2. ^▲The reporting threshold is _{▲(USP 1-Dec-2021)} 0.05%.

Table 2

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry at 105° for 2 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers, protected from light. Store at room temperature.

USP REFERENCE STANDARDS (11)

USP Diphenoxylate Hydrochloride RS

USP Diphenoxylate Related Compound A RS

Diphenoxylic acid;

1-(3-Cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid.

C₂₈H₂₈N₂O₂             424.53