Donepezil Hydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₂₄H₂₉NO₃ · HCl                    415.95

C₂₄H₂₉NO₃ · HCl · H₂O          433.97

5,6-Dimethoxyindan-1-one, 2-[(1-benzyl-4-piperidyl)methyl]-, (±)-, hydrochloride;

(±)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride CAS RN: 120011-70-3; UNII: 3O2T2PJ89D.

Monohydrate CAS RN: 884740-09-4.

1 DEFINITION

Donepezil Hydrochloride contains NLT 98.0% and NMT 102.0% of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A.SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K _{(CN 1-MAY-2020)}

[NOTE-If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the USP Donepezil Hydrochloride RS separately in dichloromethane, evaporate to dryness, and record new spectra using the residues.]

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, Chloride (191)

Sample solution: 10 mg/mL

Acceptance criteria: Meets the requirements

3 ASSAY

PROCEDURE

Buffer: 3.9 g/L of sodium 1-decane sulfonate in water

Mobile phase: Acetonitrile and Buffer (35:65), Adjust with perchloric acid to a pH of 1.8.

System suitability solution: 0.4 mg/mL of USP Donepezil Hydrochloride RS and 0.016 mg/mL of USP Donepezil Related Compound A RS prepared as follows. Dissolve suitable quantities of USP Donepezil Hydrochloride RS and USP Donepezil Related Compound A RS using 40% of the flask volume of methanol, and dilute with water to volume.

Standard solution: 0.4 mg/mL of USP Donepezil Hydrochloride RS in Mobile phase

Sample solution: 0.4 mg/mL of Donepezil Hydrochloride in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 271 nm

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

Column temperature: 35^o

Flow rate: 1.4 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-Refer to Table 1 under Organic Impurities, Procedure 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between donepezil related compound A and donepezil, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the portion of Donepezil Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak response of donepezil hydrochloride from the Sample solution

r_s = peak response of donepezil hydrochloride from the Standard solution

C_s = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the anhydrous basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

4.1 ORGANIC IMPURITIES, PROCEDURE 1

[NOTE-On the basis of the synthetic route, perform either Procedure 1 or Procedure 2. Procedure 2 is recommended if any of the impurities

included in Table 3 are potential related compounds.]

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

Standard solution: 0.8 µg/mL of USP Donepezil Hydrochloride RS in Mobile phase

System suitability

Samples: System suitability solution and Standard solution

[NOTE-Refer to Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between donepezil related compound A and donepezil, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Donepezil Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak response of any individual impurity from the Sample solution

r_s = peak response of donepezil hydrochloride from the Standard solution

C_s = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: See Table 1.

Table 1

^a 5,6-Dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one.

^b 2-[(1-Benzylpiperidin-4-yl)(hydroxy)methyl]-5,6-dimethoxyindan-1-one.

^c (E)-2-[(1-Benzylpiperidin-4-yl)methylene]-5,6-dimethoxyindan-1-one.

4.2 ORGANIC IMPURITIES, PROCEDURE 2

Solution A: Add 1 mL of phosphoric acid in 1 L of water. Adjust with triethylamine to a pH of 6.6 ± 0.1. Pass through a lter of 0.45-µm or ner pore size.

Solution B: Acetonitrile

Mobile phase: See Table 2.

Table 2

[NOTE-The gradient was established on an HPLC system with a dwell volume of approximately 0.65 mL.]

Diluent: Acetonitrile and water (25:75)

System suitability solution: 1 mg/mL of USP Donepezil Hydrochloride RS and 0.002 mg/mL of USP Donepezil Related Compound A RS in

Diluent

Sensitivity solution: 0.0015 mg/mL of USP Donepezil Hydrochloride RS in Diluent

Standard solution: 0.01 mg/mL of USP Donepezil Hydrochloride RS in Diluent. Sonication may be used to aid the dissolution.

Sample solution: 1.0 mg/mL of Donepezil Hydrochloride in Diluent. Sonication may be used to aid the dissolution.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 286 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

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

Suitability requirements

Resolution: NLT 2.0 between donepezil and donepezil related compound A, System suitability solution

Tailing factor: NMT 1.5 for donepezil, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Donepezil Hydrochloride taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

r_u = peak response of any individual impurity from the Sample solution

r_s = peak response of donepezil hydrochloride from the Standard solution

C_s = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL)

C_u = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL)

F = relative response factor for the corresponding impurity peak (see Table 3)

Acceptance criteria: See Table 3. Disregard peaks less than 0.03%.

Table 3

^a 5,6-Dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one.

^b (E)-4-[(5,6-Dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl]pyridine 1-oxide.

^c 1-Benzyl-4-[(5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl]piperidine 1-oxide.

^d 5,6-Dimethoxy-2-(pyridin-4-ylmethyl)indan-1-one.

^e 2-[(1-Benzylpiperidin-4-yl)methyl]-3-hydroxy-5,6-dimethoxy-1H-indan-one.

^f 2-[(1-Benzylpiperidin-4-yl)(hydroxy)methyl]-5,6-dimethoxyindan-1-one.

^g 1,1-Dibenzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium.

^h 1-Benzyl-4-[(5,6-dimethoxyinden-2-yl)methyl]piperidine.

ⁱ 1-Benzyl-4-[(5,6-dimethoxyindan-2-yl)methyl]piperidine.

5 SPECIFIC TESTS

WATER DETERMINATION, Method la (921)

Acceptance criteria

Anhydrous form: NMT 0.4%

Anhydrous form-I: NMT 7.0%

Monohydrate form: NMT 7.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers. Store at controlled room temperature.

LABELING: Where it is the anhydrous form-l or the hydrated form, the label so indicates. If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.

USP REFERENCE STANDARDS (11)

USP Donepezil Hydrochloride RS

USP Donepezil Related Compound A RS

(E)-2-[(1-Benzylpiperidin-4-yl)methylene]-5,6-dimethoxyindan-1-one.

C₂₄H₂₇NO₃                     377.48