Orphenadrine 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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C₁₈H₂₃NO · C₆H₈O₇ 461.50

Ethanamine, N,N-dimethyl-2-[(2-methylphenyl)phenylmethoxy]-, (±)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1);

(±)-N,N-Dimethyl-2-[(o-methyl-α-phenylbenzyl)oxy]ethylamine citrate (1:1) CAS RN

®: 4682-36-4; UNII: X0A40N8I4S.

1 DEFINITION

Orphenadrine Citrate contains NLT 98.0% and NMT 101.5% of orphenadrine citrate (C₁₈H₂₃NO · C₆H₈O₇), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M (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〉: Meets the requirements

3 ASSAY

3.1 Procedure

Buffer: 5.8 g/L of monobasic ammonium phosphate in water. Adjust with ammonium hydroxide or phosphoric acid to a pH of 7.9.

Mobile phase: Methanol, acetonitrile, and Buffer (45:15:40)

System suitability solution: 0.01 mg/mL each of USP Orphenadrine Related Compound B RS, USP Orphenadrine Related Compound C RS, and USP Methylbenzhydrol RS and 1.0 mg/mL of USP Orphenadrine Citrate RS in Mobile phase

Standard solution: 1.0 mg/mL of USP Orphenadrine Citrate RS in Mobile phase

Sample solution: 1.0 mg/mL of Orphenadrine Citrate in Mobile phase

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-μm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 2.5 times the retention time of orphenadrine

3.3 System suitability

Samples: System suitability solution and Standard solution

[Note - See Table 1 for the relative retention times.]

3.4 Suitability requirements

Resolution: NLT 3.0 between orphenadrine related compound B and C; NLT 3.0 between orphenadrine related compound C and methylbenzhydrol, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 0.73%, Standard solution

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of orphenadrine citrate (C₁₈H₂₃NO · C₆H₈O₇) in the portion of Orphenadrine Citrate taken:

Result = (r_U/r_S) × (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 Orphenadrine Citrate RS in the Standard solution (mg/mL)

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

Acceptance criteria: 98.0%–101.5% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

4.1 Organic Impurities, Procedure 1

[Note - If methyl orphenadrine is a known manufacturing impurity, Procedure 1 and the test for Isomer Content are recommended. If diphenhydramine and didesmethyl orphenadrine are known manufacturing process impurities, Procedure 2 is recommended.]

Buffer, Mobile phase, System suitability solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.001 mg/mL of USP Orphenadrine Citrate RS in Mobile phase

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

Sample solution: 1 mg/mL of Orphenadrine Citrate in Mobile phase

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note - See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 3.0 between orphenadrine related compound B and C; NLT 3.0 between orphenadrine related compound C and 2- methylbenzhydrol, System suitability solution

Tailing factor: NMT 2, Standard 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 impurity in the portion of Orphenadrine Citrate taken:

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

r_U = peak area of each impurity from the Sample solution

r_S = peak area of Orphenadrine Citrate from the Standard solution

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

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

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. Disregard any peak less than 0.05%.

Table 1

^a Counter ion peak; not to be reported; not to be included in total impurities.

^b 2-(Di-o-tolylmethoxy)-N,N-dimethylethan-1-amine.

^c Excluding orphenadrine related compound E and orphenadrine related compound F from the Isomer Content test.

4.2 Organic Impurities, Procedure 2

[Note - If didesmethyl orphenadrine is a known manufacturing process impurity, Procedure 2 is recommended. The labeling indicates that the article complies with Organic Impurities, Procedure 2.]

System suitability solution: 0.3 mg/mL each of USP Orphenadrine Citrate RS, USP Diphenhydramine Citrate RS, USP Methylbenzhydrol RS, USP Orphenadrine Related Compound E RS, and USP Orphenadrine Related Compound F RS in toluene prepared as follows. Dissolve 6 mg each of the USP Reference Standards in 10 mL of water. Add 0.2 mL of ammonium hydroxide and shake with 3 mL of toluene. Separate the organic layer. Repeat the extraction of the aqueous layer two more times with 3 mL of toluene. To the combined organic layer add anhydrous sodium sulfate, shake, and filter. Evaporate the filtrate at NMT 50° using a rotary evaporator. Dissolve the residue in 20 mL of toluene.

Sample solution: 25 mg/mL of Orphenadrine Citrate in toluene prepared as follows. Dissolve 500 mg of Orphenadrine Citrate in 50 mL of water. Add 2 mL of ammonium hydroxide and shake with 10 mL of toluene. Separate the organic layer. Repeat the extraction of the aqueous layer two more times with 10 mL of toluene. To the combined organic layers add anhydrous sodium sulfate, shake, and filter.

Evaporate the filtrate at NMT 50° using a rotary evaporator. Dissolve the residue in 20 mL of toluene.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.32-mm × 60-m; 1-μm thick coating of phenyl methylpolysiloxane, phase G27

Carrier gas: Helium at 1 mL/min

Temperatures

Injection port: 290°

Detector: 290°

Column: 240°

Injection volume: 2 μL

Injection type: Split ratio, 1:25

Run time: 1.3 times the retention time of orphenadrine

System suitability

Sample: System suitability solution

[Note - Relative retention times for the peaks are given in Table 2.]

Suitability requirements

Resolution: NLT 1.5 between orphenadrine related compound E and orphenadrine; NLT 2.0 between orphenadrine and orphenadrine related compound F

Analysis

Sample: Sample solution

Calculate the sum of the percentage of any individual impurity in the portion of Orphenadrine Citrate taken:

Result = (r_U/r_T) × 100

r_U = peak response of the impurity from the Sample solution

r_T = sum of all peak responses from the Sample solution

Acceptance criteria: See Table 2. Disregard any peak less than 0.05%.

Table 2

^a Phenyl(o-tolyl)methanone.

^b 2-[Phenyl(o-tolyl)methoxy]ethanamine.

4.3 Isomer Content

If methyl orphenadrine is a known manufacturing impurity, the test for Isomer Content is to be performed.

System suitability solution: 0.3 mg/mL each of USP Orphenadrine Citrate RS, USP Orphenadrine Related Compound E RS, and USP Orphenadrine Related Compound F RS in toluene prepared as follows. Dissolve 6 mg each of the USP Reference Standards in 10 mL of water. Add 0.2 mL of ammonium hydroxide and shake with 3 mL of toluene. Separate the organic layer. Repeat the extraction of the aqueous layer two more times with 3 mL of toluene. To the combined organic layer add anhydrous sodium sulfate, shake, and filter.

Evaporate the filtrate at NMT 50° using a rotary evaporator. Dissolve the residue in 20 mL of toluene.

Sample solution and Chromatographic system: Proceed as directed in Organic Impurities, Procedure 2.

System suitability

Sample: System suitability solution

[Note - The relative retention times of orphenadrine related compound E, orphenadrine, and orphenadrine related compound F are about 0.98, 1.0, and 1.1, respectively.]

Suitability requirements

Resolution: NLT 1.5 between orphenadrine related compound E and orphenadrine; NLT 2.0 between orphenadrine and orphenadrine related compound F

Analysis

Sample: Sample solution

Calculate the percentage of orphenadrine related compound E and orphenadrine related compound F in the portion of Orphenadrine Citrate taken:

Result = (r_U/r_T) × 100

r_U = peak response of orphenadrine related compound E or orphenadrine related compound F from the Sample solution

r_T = sum of all peak responses from the Sample solution

Acceptance criteria: NMT 0.3% each of orphenadrine related compound E and orphenadrine related compound F

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

Labeling: The label states with which Organic Impurities procedure the article complies if Organic Impurities, Procedure 1, is not used.

USP Reference Standards 〈11〉

USP Diphenhydramine Citrate RS

USP Methylbenzhydrol RS

2-Methylbenzhydrol;

Also known as Phenyl(o-tolyl)methanol.

C₁₄H₁₄O 198.26

USP Orphenadrine Citrate RS

USP Orphenadrine Related Compound B RS

N-Ethyl-N,N-dimethyl-2-[phenyl(o-tolyl)methoxy]ethanaminium chloride.

C₂₀H₂₈ClNO 333.90

USP Orphenadrine Related Compound C RS

N-Methyl-2-[phenyl(o-tolyl)methoxy]ethanamine hydrochloride.

C₁₇H₂₁NO · HCl 291.82

USP Orphenadrine Related Compound E RS

N,N-Dimethyl-2-[phenyl(m-tolyl)methoxy]ethanamine.

C₁₈H₂₃NO 269.38

USP Orphenadrine Related Compound F RS

N,N-Dimethyl-2-[phenyl(p-tolyl)methoxy]ethanamine.

C₁₈H₂₃NO 269.38