Donepezil Hydrochloride
C24H29NO3·HCl 415.95
(±)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride
[120011-70-3].
197K
[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. ]
(RB 1-May-2011)
Procedure 1
(RB 1-May-2011)
• Organic Impurities, Procedure 2
(RB 1-May-2011)
921:
NMT 0.4% for the anhydrous form; NMT 7.0% for the monohydrate form(RB 1-May-2011)
• Labeling:
Label to indicate whether it is the monohydrate form. If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.(RB 1-May-2011)
11
(doe nep' e zil hye'' droe klor' ide).
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C24H29NO3·HCl 415.95
(±)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride
[120011-70-3].DEFINITION
Donepezil Hydrochloride contains NLT 98.0% and NMT 102.0% of C24H29NO3·HCl, calculated on the anhydrous basis.
IDENTIFICATION
Change to read:
• A. Infrared Absorption 197K
[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. ]
(RB 1-May-2011)
• 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
191
Sample solution:
10 mg/mL
Acceptance criteria:
Meets the requirements
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
Mode:
LC
Detector:
UV 271 nm
Column:
4.6-mm × 15-cm; 5-µm packing L1
Column temperature:
35
Flow rate:
1.4 mL/min
Injection size:
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 sample taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of donepezil hydrochloride from the Sample solution |
| rS | = | = peak response of donepezil hydrochloride from the Standard solution |
| CS | = | = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0% on the anhydrous basis
IMPURITIES
• Heavy Metals, Method II 231:
NMT 20 ppm
231:
NMT 20 ppm
• Residue on Ignition 281:
NMT 0.1%
281:
NMT 0.1%
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 3 are potential related compounds. ]
(RB 1-May-2011)
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:
NLT 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 = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of any individual impurity from the Sample solution |
| rS | = | = peak response of donepezil hydrochloride from the Standard solution |
| CS | = | = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
See Table 1.
Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Desbenzyl donepezila | 0.33 | 0.2 |
| Hydroxydonepezilb | 0.54 | 0.2 |
| Donepezil related compound Ac | 0.92 | 0.1 |
| Donepezil hydrochloride | 1.0 | — |
| Any individual unspecified impurity | — | 0.1 |
| Total impurities | — | 1.0 |
|
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.
|
||
Add the following:
• 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 filter of 0.45-µm or finer pore size.
Solution B:
Acetonitrile
Mobile phase:
See Table 2.
Table 2
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 75 | 25 |
| 10 | 40 | 60 |
| 40 | 40 | 60 |
| 41 | 75 | 25 |
| 50 | 75 | 25 |
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
Mode:
LC
Detector:
UV 286 nm
Column:
4.6-mm × 25-cm; 5-µm packing L1
Column temperature:
50
Flow rate:
1.5 mL/min
Injection size:
20 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 40,000 theoretical plates
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 any individual impurity in the portion of Donepezil Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of any individual impurity from the Sample solution |
| rS | = | = peak response of donepezil hydrochloride from the Standard solution |
| CS | = | = concentration of USP Donepezil Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Donepezil Hydrochloride in the Sample solution (mg/mL) |
| F | = | = relative response factor for the corresponding impurity peak from Table 3 |
Acceptance criteria:
See Table 3.
Table 3
| Name | Relative Retention Time* |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Desbenzyl donepezila | 0.23 | 1.5 | 0.15 |
| Donepezil pyridine analog (DPMI)b |
0.49 | 1.9 | 0.15 |
| Donepezilbenzyl bromidec | 0.68 | 0.73 | 0.15 |
| Donepezil hydrochloride |
1.0 | 1.0 | — |
| Dehydrodeoxy donepezild | 1.72 | 2.0 | 0.15 |
| Deoxydonepezile | 2.12 | 0.67 | 0.15 |
| Any individual unspecified impurity | — | 1.0 | 0.1 |
| Total impurities | — | — | 0.5 |
|
*
Relative retention times are based on 1-mL gradient delay volume.
a
5,6-Dimethoxy-2-(piperidin-4-ylmethyl)indan-1-one.
b
5,6-Dimethoxy-2-(pyridin-4-ylmethyl)indan-1-one.
c
1,1-Dibenzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium.
d
1-Benzyl-4-[(5,6-dimethoxyinden-2-yl)methyl]piperidine.
e
1-Benzyl-4-[(5,6-dimethoxyindan-2-yl)methyl]piperidine.
|
|||
(RB 1-May-2011)SPECIFIC TESTS
Change to read:
• Water Determination, Method Ia 921:
NMT 0.4% for the anhydrous form; NMT 7.0% for the monohydrate form(RB 1-May-2011)
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers. Store at controlled room temperature.
Add the following:
• Labeling:
Label to indicate whether it is the monohydrate form. If a test for Organic Impurities other than Procedure 1 is used, the labeling states the test with which the article complies.(RB 1-May-2011)
Change to read:
• USP Reference Standards 11
USP Donepezil Hydrochloride RS 
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USP Donepezil Related Compound A RS
(E)-2-[(1-Benzylpiperidin-4-yl)methylene]-5,6-dimethoxyindan-1-one.(RB 1-May-2011)
C24H27NO3 377.48
(E)-2-[(1-Benzylpiperidin-4-yl)methylene]-5,6-dimethoxyindan-1-one.(RB 1-May-2011)
C24H27NO3 377.48
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2967
Pharmacopeial Forum: Volume No. 36(1) Page 97