FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION
A PROCESS FOR THE PURIFICATION OF DONEPEZIL HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for purification of donepezil hydrochloride.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for the purification of donepezil hydrochloride.
Donepezil is chemically known as 2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one and is represented by following formula (I).

Donepezil, marketed under the name ARICEPT, is a reversible inhibitor of the enzyme acetylcholinesterase and is commonly referred to in the pharmacological literature as E2020. ARICEPT is indicated for the treatment of mild to moderate dementia of the Alzheimers type.
There are several patents and patent applications cited in the literature, which refer to process for the preparation of donepezil such as U.S. Patent No. 7,148,354, U.S. Patent No. 6,953,856, U.S. Patent No. 6,649,765, WO 2005/076749, WO 2007/108011 and WO 2007/057226. The polymorphs of donepezil are disclosed in U.S. Patent No. 5,985,864, U.S. Patent No. 6,140,321, U.S. Patent No. 7,186,842 and WO 2006/111983. Further, U.S. Patent No. 6,492,522 provides a process for preparing intermediates of donepezil.
The present inventors have developed an easy process of purification of donepezil hydrochloride by adjusting the specific pH of solution. The present inventors have found that Donepezil hydrochloride obtained by this method has purity of 99% or above when measured by HPLC.


In one aspect of the present invention there is provided a process for the purification of donepezil hydrochloride. The process includes steps of;
(a) adjusting the pH between 8-10 of donepezil hydrochloride solution,
(b) separating the organic layer,
(c) adjusting the pH between 2-4 of organic layer,
(d) isolating the pure donepezil hydrochloride from the reaction mixture thereof.
The process of present invention involves dissolving donepezil hydrochloride in a mixture of water and an organic solvent. The reaction mixture is treated with base to adjust pH between 8-10. The organic layer is separated and treated with concentrated hydrochloric acid to adjust pH between 2-4. The acidic aqueous layer is separated and cooled to 0-5 °C to obtain donepezil hydrochloride. The donepezil hydrochloride obtained from the reaction mixture thereof is then added in methanol and refluxed. The clear reaction mixture is then cooled and methyl tertiary butyl ether is added to it under stirring. The reaction mass is further cooled to 0-5°C and pure crystalline donepezil hydrochloride was isolated from the reaction mass thereof. The so obtained donepezil hydrochloride has purity of 99% or above.
The non-limiting examples of organic solvent include toluene, methyl acetate, ethyl acetate, chloroform, carbon tetrachloride, dichloromethane, hexane, cyclohexane, 1,2-dichloroethane, diethyl ether, dimethyl formamide, heptane, methyl-tert-butyl ether, pentane, 2,2,4-trimethylpentane and the like. The non-limiting examples of base include ammonia, methyl amine, dimethyl amine, triethyl amine, pyridine, N,N-dimethylaniline, 2,6-dimethylpyridine, 4-methylpyridine, 4-dimethylamino pyridine, dicyclohexyl amine sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like.
In another aspect of the present invention there is provided pure donepezil hydrochloride.


In this disclosure, pure donepezil hydrochloride means donepezil hydrochloride having purity of 99% or more when measured by HPLC.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES Purification of donepezil hydrochloride
Donepezil hydrochloride (240 gm) was added in mixture of water (600 ml) and ethyl acetate (1.2 litre). To the reaction mixture obtained thereof ammonia solution (100 ml) was added to adjust pH between 9-10. Ethyl acetate layer was separated and aqueous layer was extracted with fresh ethyl acetate (0.6 litre). Combined ethyl acetate extract was stirred with water (550 ml) followed by addition of concentrated hydrochloric acid to adjust pH between 2-3. Acidic aqueous layer was cooled to 0-5 °C. The donepezil hydrochloride (230 gm) obtained from the reaction mixture thereof was added in methanol (2.0 litre) and refluxed for 30 minutes. The clear reaction mixture was then cooled and methyl tertiary butyl ether (4.0 litre) was added to it under stirring. The reaction mass was further cooled to 0-5°C and pure crystalline donepezil hydrochloride was isolated from the reaction mass thereof.
Yield : 210 gm
HPLC purity : 99.8 %


We claim:
1. A process for the purification of donepezil hydrochloride. The process
comprises steps of;
(a) adjusting the pH between 8-10 of donepezil hydrochloride solution,
(b) separating the organic layer,
(c) adjusting the pH between 2-4 of organic layer,
(d) isolating the pure donepezil hydrochloride from the reaction mixture thereof.
2. The process of claim 1, wherein solution of donepezil hydrochloride is
prepared in mixture of water and organic solvent.
3. A process of claim 2, wherein an organic solvent is selected from the group of toluene, methyl acetate, ethyl acetate, chloroform, carbon tetrachloride, dichloromethane, hexane, cyclohexane, 1,2-dichloroethane, diethyl ether, dimethyl formamide, heptane, methyl-tert-butyl ether, pentane and 2,2,4-trimethylpentane.
4. A process of claim 1, wherein the pH between 8-10 is adjusted by adding base
5. A process of claim 4, wherein the base is selected from the group of ammonia, methyl amine, dimethyl amine, triethyl amine, pyridine, N,N-dimethylaniline, 2,6-dimethylpyridine, 4-methylpyridine, 4-dimethylamino pyridine, dicydohexyl amine sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
6. A process of claim 1, wherein hydrochloric acid is used to adjust pH between 2-4.


7. A process of claim 1, wherein the pure donepezil hydrochloride was isolated by treating the reaction mixture with methyl tertiary butyl ether.
8. Donepezil hydrochloride having the purity of 99.0% or more when measured by HPLC.



Abstract
The present invention provides a process for the purification of donepezil hydrochloride.