Donepezil Hydrochloride Tablets

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

Donepezil Hydrochloride Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of donepezil hydrochloride  (C₂₄H₂₉NO₃ · HCl).

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 1970 _{(CN 1-May-2020)}

Wavelength range: 220-360 nm

Sample solution: Crush a suitable number of Tablets, and transfer an amount of powder, equivalent to 10 mg of donepezil hydrochloride, to a 100-mL volumetric flask. Add 80 mL of 0.1 N hydrochloric acid VS, and sonicate for 5 min. Cool the solution to room temperature, and dilute with 0.1 N hydrochloric acid VS to volume. Transfer a portion of this solution to a centrifuge tube, and centrifuge for 15 min. Transfer 5 mL of the clear supernatant to a 25-mL volumetric flask, and dilute with 0.1 N hydrochloric acid VS to volume.

Analysis: Using a 1-cm cell, record the UV spectrum of the Sample solution.

Acceptance criteria: The solution exhibits absorption maxima at 230, 271, and 315 nm.

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

3 ASSAY

PROCEDURE

Diluent: Methanol and 0.1 N hydrochloric acid VS (75:25)

Mobile phase: Dissolve 2.5 g of sodium 1-decanesulfonate in 650 mL of water, and add 1.0 mL of perchloric acid and 350 mL of acetonitrile. If necessary, adjust with an additional 0.5 mL of perchloric acid to a pH of about 1.8.

System suitability solution: 0.2 mg/mL of USP Donepezil Hydrochloride RS and 0.008 mg/mL of USP Donepezil Related Compound A RS.

[NOTE-Dissolve in 40% of the flask volume of methanol, swirl, and dilute with water to volume.]

Standard solution: 0.4 mg/mL of USP Donepezil Hydrochloride RS in Diluent. [NOTE-Dissolve in 60% of the flask volume of Diluent, swirl, and dilute with Diluent to volume.]

Sample solution: Nominally 0.4 mg/mL of donepezil hydrochloride prepared as follows. Dissolve a suitable number of Tablets in 75% of the flask volume of Diluent, and sonicate in an ultrasonic bath for 20 min. Swirl the mixture for 30 s, allow to cool to room temperature, and dilute with Diluent to volume. [NOTE-If necessary, add a magnetic stirring bar to the flask, and mix for 10 min on the magnetic stirrer, to aid in dissolution.) Allow a few min for the solids to settle. Pass through a suitable filter, discarding the first 2-3 mL of the filtrate.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 271 nm

Column: 4.6-mm x 15-cm; 5-um packing 11

Column temperature: 35°

Flow rate: 1.4 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for donepezil related compound A and donepezil are about 0.92 and 1.0, respectively.]

Suitability requirements

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

Tailing factor: NMT 1.5 for the donepezil peak, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the portion of Tablets 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 = nominal concentration of donepezil hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Test 1

Medium: 0.1 N hydrochloric acid VS: 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Analytical procedure: Determine the amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved, by using one of the following methods.

Chromatographic method

Diluent: Methanol and 0.1 N hydrochloric acid VS (75:25)

Mobile phase: Acetonitrile, water, and perchloric acid (35: 65:0.1)

Standard stock solution A: 1.1 mg/mL of USP Donepezil Hydrochloride RS in Diluent

Standard stock solution B: 0.11 mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution A in Medium

Standard solution: (L/1000) mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution B in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first few mL of the filtrate.

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: 1.0 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Column efficiency: NLT 5000 theoretical plates

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved:

Result = (r_u /r_s ) × (C_s /L) × V × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Spectrometric method

Standard stock solution: 0.11 mg/mL of USP Donepezil Hydrochloride RS in water

Standard solution: (L/900) mg/mL of USP Donepezil Hydrochloride RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable lter of 0.45-µm pore size.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 230 nm

Blank: Medium

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved:

Result = (A_u /A_s ) × (C_s /L) × V × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of donepezil hydrochloride is dissolved.

For Tablets which contain 23 mg of donepezil hydrochloride

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: pH 6.8 phosphate buffer, 900 mL

Apparatus 2: 50 rpm

Times: 1, 3, and 8 h

Buffer: 5.0 g/L of monobasic ammonium phosphate in water adjusted with phosphoric acid to a pH of 2.3

Mobile phase: Acetonitrile and Buffer (25:75)

Standard stock solution: 0.26 mg/mL of USP Donepezil Hydrochloride RS prepared as follows. Transfer a suitable quantity of USP

Donepezil Hydrochloride RS to an appropriate volumetric flask. Add 70% of the flask volume of Medium. Sonicate to dissolve and dilute

with Medium to volume.

Standard solution: (L/900) mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution in Medium, where L is the label claim in mg/Tablet. Pass the solution through a suitable filter, discarding the first 3 mL of the filtrate.

Sample solution: Pass a portion of the solution under test through a suitable filter, discarding the first 3 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 15-cm; 5-um packing 11

Column temperature: 35°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

Run time: NLT 1.7 times the retention time of donepezil

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation : NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the sample withdrawn from the vessel at each time point (1):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of donepezil from the Sample solution

r_s = peak response of donepezil from the Standard solution

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

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s)] + [C₁ × V_s ]} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C_i = concentration of donepezil hydrochloride in the portion of the sample withdrawn at the specied time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: pH 6.8 phosphate buffer; 900 mL

Apparatus 2: 50 rpm

Times: 1, 3, and 10 h

Standard stock solution: 0.25 mg/mL of USP Donepezil Hydrochloride RS prepared as follows. Transfer a suitable quantity of USP Donepezil Hydrochloride RS to an appropriate volumetric flask. Add 70% of the flask volume of water. Sonicate to dissolve and allow to cool to room temperature. Dilute with water to volume.

Standard solution: (L/900) mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy (857),)

Mode: UV-Vis

Analytical wavelength: 315 nm

Blank: Medium

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the sample withdrawn from the vessel at each time point (1):

Result_i = (A_u /A_s ) × C_s

A_u = absorbance of donepezil from the Sample solution

A_s = absorbance of donepezil from the Standard solution

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

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s)] + [C₁ × V_s ]} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C_i = concentration of donepezil hydrochloride in the portion of the sample withdrawn at the specied time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_s = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: 0.05 M sodium phosphate buffer, pH 6.8 [0.1 N hydrochloric acid VS and 76 g/L of tribasic sodiurn phosphate (25:75) adjusted with 2 N hydrochloric acid TS or 2 N sodium hydroxide TS to a pH of 6.8); 900 mL, degassed

Apparatus 2: 50 rpm, with sinkers; see Dissolution (711), Figure 2a.

Times: 1, 3, and 8 h

Buffer: 1.36 g/L of monobasic potassium phosphate prepared as follows. To each 1 L of 1.36 g/L of monobasic potassium phosphate in water, add 3 mL of triethylamine and adjust with phosphoric acid to a pH of 2.8.

Mobile phase: Methanol and Buffer (47:53)

Diluent: Methanol and water (50:50)

Standard stock solution: 0.53 mg/mL of USP Donepezil Hydrochloride RS in Diluent

Standard solution: 0.027 mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Replace the portion removed with the same volume of

Medium.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 268 nm

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

Flow rate: 1.3 mL/min

Injection volume: 20 µL

Run time: NLT 1.7 times the retention time of donepezil

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of donepezil from the Sample solution

r_s = peak response of donepezil from the Standard solution

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

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s)] + [C₁ × V_s ]} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C_i = concentration of donepezil hydrochloride in the portion of the sample withdrawn at time point i (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_s = volume of Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.

Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium: 0.05 M potassium phosphate buffer (6.8 g/L of monobasic potassium phosphate and 0.9 g/L of sodium hydroxide in water adjusted with dilute phosphoric acid in water or dilute sodium hydroxide in water to a pH of 6.80); 900 mL

Apparatus 2: 50 rpm, with suitable sinkers

Times: 1, 3, and 9 h

Buffer: 6.8 g/L of monobasic potassium phosphate in water; adjusted with phosphoric acid to a pH of 3.0

Mobile phase: Methanol and Buffer (40:60)

Diluent: Methanol and water (50:50)

Standard stock solution: 0.5 mg/mL of USP Donepezil Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Donepezil Hydrochloride RS to an appropriate volumetric flask and dissolve in 50% of the flask volume of Diluent. Sonicate for NLT 1 min to promote dissolution then dilute with Diluent to volume.

Standard solution: 0.025 mg/mL of USP Donepezil Hydrochloride RS from Standard stock solution in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter discarding the first NLT 3 mL of filtrate.

Chromatographic system

(See Chromatography (621) System Suitability.)

Mode: LC

Detector: UV 271 nm

Column: 4.6-mm x 15-cm; 5-µm packing 11

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 50 µL

Run time: NLT 1.5 times the retention time of donepezil

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_u /r_s ) × C_s

r_u = peak response of donepezil from the Sample solution

r_s = peak response of donepezil from the Standard solution

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

Calculate the percentage of the labeled amount of donepezil hydrochloride (C₂₄H₂₉NO₃ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_s)] + [C₁ × V_s ]} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_s )]} + [(C₂ + C₁ ) × V_s ]) × (1/L) × 100

C = concentration of donepezil hydrochloride in the portion of the sample withdrawn at the specied time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of donepezil hydrochloride (CHNO, HCI) dissolved at the times specified conform to

Dissolution (711), Acceptance Table 2 (RB 1-May-2020)

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

5 IMPURITIES

Change to read:

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 Z _{(RB 1-May-2020)} are potential degradation products.)

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

Standard solution: 0.0008 mg/mL of USP Donepezil Hydrochloride RS in Diluent

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for donepezil related compound A and donepezil are about 0.92 and 1.0, respectively.]

Suitability requirements

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

Relative standard deviation: NMT 8.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

[NOTE-Identify the impurities using the relative retention times given in Table 5 _{(RB-1-May-2020)}]

Calculate the percentage of any individual impurity in the portion of Tablets taken:

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

r_u = peak response of each 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 = nominal concentration of donepezil hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 5) _{(RB 1-May-2020)}

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

^b 2-(3-(1-Benzylpiperidin-4-yl)-2-oxopropyl)-4,5-dimethoxybenzoic acid.

^c 2-[(1-Benzylpiperidin-4-yl)methyl]-5,6-dimethoxyindan-1-one N-oxide.

Change to read:

Organic Impurities, Procedure 2

Diluent: Acetonitrile and water (25:75)

Solution A: Add 1 mL of phosphoric acid in 1 L of water. Adjust with triethylamine to a pH of 6.5. Pass through a lter of 0.45-µm or ner pore size.

Solution B: Acetonitrile

Mobile phase: See Table 6.

Table 6

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

Sample solution: Nominally 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 11

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%, for five replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each specied impurity or any individual degradation product in the portion of Tablets taken:

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

r_u = peak response of each 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 = nominal concentration of donepezil hydrochloride in the Sample solution (mg/mL)

F = relative response factor for the corresponding impurity peak from Table 7 _{(RB 1-May-2020)}

Acceptance criteria: SeeTable 7.

Table 7 _{(RB 1-May-2020)}

^a Relative retention times are based on 1-mL gradient delay volume.

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

^c 5,6-Dimethoxy-2-(pyridin-4-ylmethyl)indan-1-one; also known as DPMI.

^d 1,1-Dibenzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium; also known as donepezil benzyl.

^e 1-Benzyl-4-[(5,6-dimethoxyinden-2-yl)methyl]piperidine; also known as dehydrodeoxy donepezil.

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

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

Labeling: If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies. If a test for Dissolution other than Test 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-dimeth oxyindan-1-one.

C₂₄H₂₇NO₃                377.48