FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2005
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
" Process for Producing Form (I), a polymorph ol'(l-Benzyl-4-[(5, 6-Dimethoxy-l-
Indanone)-2-yl] Methyl Piperidine Hydrochloride (Donepezil Hydrochloride)"

2. APPLICANT (S)
NAME

NATIONALITY

ADDRESS

USV LIMITED

INDIAN

B.S.D. MARG
STATION ROAD, GOVANDI, MUMBAI 400 088

3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which
it is performed.

Process for Producing Form (I), a polymorph of (l-Benzyl-4-[(5, 6-Dimethoxy-l-Indanone)-2-yl] Methyl Piperidine Hydrochloride (Donepezil Hydrochloride)
RELATED APPLICATIONS
This application claims priority from US Patent Application Serial No. 11/072,169 5 filed on 4th March 2005.
TECHNICAL FIELD
The present invention relates to industrial processes of producing a stable and substantially pure polymorph of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl] methyl piperidine hydrochloride, a compound commonly known as Donepezil Hydrochloride
10 form l.

Donepezil Hydrochloride form 1
BACKGROUND
Donepezil hydrochloride has excellent action as a prophylactic and a therapeutic
15 agent for senile dementia, and in particular as a prophylactic and therapeutic agent for Alzheimer's disease and an industrial process for producing the same has been reported. The process for the preparation of l-benzyl-4-[(5,6-dimethoxy-l-indanone)-2-yl] methyl piperidine has been described in JP A-64-79151 (US-4895841, EP 296560), United States Patent Nos. 5,985,864 and 6,140,321. Moreover, United States Patent Nos. 5,985,864 and
20 6,140,321 also disclose various polymorphic forms of Donepezil hydrochloride.
WO 9746527 (US Patent No. 6953856- USV's Donepezil HCI process pat)
discloses certain forms (I, II, III, IV & V) of Donepezil Hydrochloride, (l-Benzyl-4-[(5,
6-Dimethoxy-l-Indanone)-2-yl] Methyl Piperidine Hydrochloride. The invention offers
five forms or species of novel polymorphs of Donepezil Hydrochloride and industrially
25 excellent processes for producing them. A therapeutical composition to treat Alzheimer's
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disease is also disclosed by the present invention. Example 7 of W09746527 describes the
synthesis of Donepezil Hydrochloride (1) using ethanol and diisopropyl ether. The yield
obtained in W09746527 is 85.4 % only. Also, the patent does not teach purity level of the
Donepezil hydrochloride obtained in that process.
5 However, applicant in the present application obtained surprising results in terms
of yield up to 94 % with a purity level of >99.5 %. Donepezil Hydrochloride, when n-hexane is used in combination with ethanol and dichloromethane which is useful for the industrial application.
OBJECT OF THE INVENTION
10 The main object of the present invention is to provide an industrial process of
producing a stable and substantially pure polymorph of l-benzyl-4-[(5, 6-dimethoxy-l-indanone)-2-yl] methyl piperidine hydrochloride, a compound commonly known as Donepezil Hydrochloride form I.
Another object of the invention is to provide an-industrial process for the synthesis
15 of Donepezil Hydrochloride form I with higher yield.
SUMMARY OF THE INVENTION
Accordingly, the present invention encompasses the polymorphic form of Donepezil hydrochloride form (I) isolated in a substantially pure pharmaceutically-acceptable form, especially in bulk quantities, having good flow properties, especially
20 good bulk flow properties. The process for making Donepezil Hydrochloride Form (I) from Donepezil Oxalate and Donepezil Hydrochloride Form (VI) is disclosed herein. Donepezil hydrochloride (I) in the present invention is characterized by powder X-ray diffraction or infrared absorption peaks recorded in potassium bromide.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINCS
25 Figure 1 shows a powder X-ray diffraction pattern for Donepezil hydrochloride form (I). Figure 2 shows an infrared absorption spectrum for Donepezil hydrochloride form (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a process for the preparation of stable and substantially pure polymorph form (1) of Donepezil Hydrochloride. The form (I) salt can
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be prepared by an efficient, economic and reproducible process and particularly suited to large-scale preparation. The sails of Donepezil are therefore surprisingly amenable to large scale pharmaceutical processing and formulation.
The present invention specifically relates to the polymorphic form (I) of Donepezil
5 hydrochloride, which is characterized by powder X-ray diffraction or infrared absorption peaks recorded in potassium bromide.
The Donepezil Hydrochloride form (I) is characterized by decomposition at M.P. intherangeof220to223°C.
The present invention encompasses the polymorphic form of Donepezil 10 hydrochloride form (I) isolated in a purified form.
Also, the invention provides this polymorphic form (1) of Donepezil hydrochloride in a pharmaceutically-acceptable form, especially in bulk quantity having good flow properties, especially good bulk flow properties.
The invention provides a process for the preparation of Donepezil hydrochloride
15 form (I), which comprises the steps, dissolving Donepezil salt such as Donepezil oxalate or Donepezil hydrochloride form (VI), in water and basifying it. The Donepezil base thus obtained is extracted in a suitable solvent and acidified with aqueous hydrochloric acid. The first solvent is evaporated and the remaining portion is co-distilled with a second solvent. Further, the second solvent is cooled and / or mixed with an anti-solvent, to
20 obtain Donepezil hydrochloride form (I). Applicants have disclosed the method for preparing Donepezil Oxalate in earlier Application No. US 10/879,816 and method for preparation of Donepezil Hydrochloride form (VI) is disclosed in earlier PCT Application no. PCT/rN04/00227 (not published).
The base used is an inorganic base selected from ammonia, sodium hydroxide,
25 potassium hydroxide, sodium carbonate and sodium bicarbonate, preferably ammonia.
A suitable solvent may be a hydrocarbon, such as toluene, or ethyl acetate, or a halogenated hydrocarbon such as dichloromethane and chloroform, preferably dichloromethane used for extraction.
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The second solvent used is an alcoholic solvent such as isopropanol, ethanol and methanol preferably methanol. The anti solvent used is a hydrocarbon solvent like toluene, o-xylene, ether such as diethyl ether, diisopropyl ether or n-hexane. The anti solvent used is more preferably diisopropyl ether and most preferably n-hexane.
5 The concentration of Donepezil oxalate solution in water is in the range of about 5
to 25% weight/volume, preferably in the range of 5-15 % weight/volume.
The dissolution of Donepezil oxalate in water is usually earned out at an ambient temperature or at an elevated temperature, although any convenient temperature that provides the required product may be employed. A preferred temperature is in the range of
10 roughly 20-80 °C, such as 35 to 60 °C, or more preferably 50 °C.
Evaporation is usually carried out at in the temperature range of about 60 to 80°C, such as 60 to 70°C
The addition of anti-solvent is usually earned out at in the temperature range of 5 to 30 °C, preferably 5 to 20 °C or more preferably 5 to 10 °C.
15 The following powder XRD data provides characteristic peaks of Donepezil hydrochloride form (I) prepared form Ethanol/n-hexane.

S.No. Diffraction Angle(26") Intensity % (I/Io)
1. 5.10 100.00
2. 10.03 18.81
3. 10.67 3.51
4. 12.73 19.69
5. 13.19 15.27
6. 13.74 8.49
7. 13.97 6.88
8. 14.99 36.89
9. 15.36 3.32
10. 16.18 5.95
11. 16.96 5.89
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12. 17.70 16.62
13. 18.64 2.29
14. 19.38 2.88
15. 19.98 24.64
16. 21.42 20.07
17. 22.11 12.07
18. 22.57 11.47
19. 23.13 9.56
20. 23.79 7.46
2!. 24.06 17.96
22. 25.04 6.87
23. 25.80 2.60
24. 26.43 5.62
25. 26.87 7.42
26. 27.49 4.68
27. 28.06 3.38
28. 29.22 17.33
.29. 29.61 10.18
30. 30.0S 12.63
31. 30.75 5.48
32. 31.54 8.23
33. 32.92 3.07
34. 34.03 1.60
35. 35.24 30.32
36. 39.06 4.98
37. 40.00 5.35
38. 41.11 5.52
39. 42.86 1.18
40. 43.81 1.78
41. 44.86 4.73
42. 47.96 1.04
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Wave numbers (cm"1) of infrared absorption spectra recorded in potassium bromide are: 430.1, 461.0, 499.5, 565.1, 607.5, 651.9, 700.1, 727.1, 752.2, 804.3, 837.0, 862.1, 894.9, 920.0, 948.9, 974.0, 1037.6, 1072.3, 1122.5, 1195.8, 1224.7, 1249.8, 1286.4, 1334.6,
5 1407.9, 1437.9, 1452.3, 1502.4, 1595.0, 1643.2, 1685.7, 2391.6, 2530.4, 2561.3, 2636.5, 2700.2, 2860.2, 2937.4, 3003.0, 3070.5, 3 109.0, 3155.3, 3244.0, 3365.6, 3487.1, 3516.0, 3587.4,3635.6
EXAMPLES
The present invention will now be described in more detail with reference to the
10 following examples. It is needless to say that the technical scope of the present invention is not limited to these examples:
Example 1
Donepezil oxalate (5 gm) was dissolved in water 50 ml under heating at 50 °C. Stirring was continued for I hour with gradual cooling to room temperature. At room
15 temperature, dichloromethane 50 ml was added and stirred for 10 minutes. Liquid ammonia 5 ml was then added slowly with stirring. The dichloromethane layer was separated and 50 ml water was added to it. Further, Analytical grade concentrated hydrochloric acid 1.5 ml was slowly added and stirred for 10 minutes. Again Dichloromethane layer was separated and washed with 2x 10 ml water. Dichloromethane
20 was evaporated; methanol 25 ml was added to the mass and cooled to 10 °C. Diisopropyl ether was added to the methanol solution, solid precipitated was filtered and dried at 30 to 35 °C to obtain the Donepezil hydrochloride form (I) with a yield of 3.9 gm (95 % yield) with purity level of >99.5 %.
Example 2
25 Donepezil Hydrochloride Form (VI) (5 gm) was dissolved in water 50 ml under
heating at 50 °C. Stirring was continued for 1 hour with gradual cooling. At room temperature, dichloromethane 50 ml was added and stirred for 10 minutes. Liquid Ammonia 5 ml was added slowly with stirring. The dichloromethane layer was separated and 50 ml water was added to it. Further Analytical grade concentrated hydrochloric acid
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1.5 ml was slowly added and stirred for 10 minutes. Again Dichloromethane layer was separated and washed with 2x 10 ml water. Dichloromethane was evaporated; methanol 25 ml was added to the mass and cooled to 10 °C. Diisopropyl ether was added to the methanol solution, solid precipitated was filtered and dried at 30 to 35 °C to obtain the
5 polymorphic form of Donepezil hydrochloride created by our new process, with a yield of 4.5 gm (90 % yield) with purity level of >99.5 %.
Example 3:
Donepezil oxalate (5 gm) was dissolved in water 50 ml under heating at 50 °C. Stirring was continued for 1 hour with gradual cooling. At room temperature,
10 dichloromethane 50 ml was added and stirred for 10 mins liq. Ammonia 5 ml was added slowly with stirring. The dichloromethane layer was separated and 50 ml water was added to it. Further Analytical grade concentrated hydrochloric acid 1.5 ml was slowly added and stirred for 10 min. Again Dichloromethane layer was separated and washed with 2 x 10 ml water. Dichloromethane was evaporated; ethanol 25 ml was added to the mass and
15 cooled to 10 °C. n-Hexane was added to the ethanol solution, solid precipitated was filtered and dried at 30 to 35 °C to obtain Donepezil hydrochloride form (I) with a yield of 3.8 gm (94%) with purity level of >99.5%.
Example 4:
Donepezil Hydrochloride form (VI) (5 gm) was dissolved in water 50 ml under
20 heating at 50 °C. Stirring was continued for 1 hour with gradual cooling. At room temperature, dichloromethane 50 ml was added and stirred for 10 mins. Liq. Ammonia 5 ml was added slowly with stirring. The dichloromethane layer was separated and 50 ml water was added to it. Further Analytical grade concentrated hydrochloric acid 1.5 ml was slowly added and stirred for 10 mins. Again Dichloromethane layer was separated and
25 washed with 2 x 10 ml water. Dichloromethane was evaporated; ethanol 25 ml was added to the mass and cooled to 10 °C. n-Hexane was added to the ethanol solution, solid precipitated was filtered and dried at 30 to 35 °C to obtain Donepezil hydrochloride form (I) with a yield of 4.5 gm (90 %) with purity level of >99.5 %.
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ADVANTAGES OF THE PRESENT INVENTION
1. Diisopropyl ether is a solvent which has no limits set by ICH. The limits are essential
for industrial production. The absence of set limits poses problem in commercial
5 production, whereas hexane has set limits and eases the process of industrial
production.
2. The present invention provides substantially pure Donepezil hydrochloride form (I) in
higher yield.
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I/We Claim:
1. A process for the preparation of substantially pure Donepezil Hydrochloride Form
(I) from Donepezil oxalate comprising the steps of:
a) dissolving a Donepezil salt in water and basifying the solution;
5 b) extracting the Donepezil base with a halogenated organic solvent and
acidifying with aqueous hydrochloride;
c) evaporating the contents of step (b) and subsequently adding a suitable alcoholic solvent;
d) cooling the solution containing the alcoholic solvent;
10 e) adding n-hexane as an anti-solvent to precipitate the Donepezil Hydrochloride
form (I); and f) drying the product to obtain substantially pure Donepezil Hydrochloride Form
(i).
2. A process for preparation of substantially pure Donepezil Hydrochloride Form (I)
15 from Donepezil hydrochloride Form (VI) comprising the steps of:
a) dissolving a Donepezil salt in water and basifying the solution;
b) extracting the Donepezil base with a halogenated organic solvent and acidifying with aqueous hydrochloride;

c) evaporating the contents of step (b) and subsequently adding a suitable
20 alcoholic solvent;
d) cooling the solution containing the alcoholic solvent;
e) adding n-hexane as an anti-solvenl to precipitate the Donepezil Hydrochloride
form (I); and
f) drying the product to obtain substantially pure Donepezil Hydrochloride Form
25 (I).
3. The process as claimed in claims I and 2, wherein the purity of Donepezil Hydrochloride form (I) is >99.5 %.
4. The process as claimed in claims 1 and 2, wherein the yield of Donepezil Hydrochloride form (I) is >99.5 %.
30 5. The process as claimed in claims 1 and 2, wherein said salt is dissolved in water at a
temperature range of about 40 to 60 0C.
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6. The process as claimed in claims 1 and 2, wherein the base is selected from a group
consisting of ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate
and sodium bicarbonate.
7. The process as claimed in claims 1 and 2, wherein the solvent in step (b) is selected
5 from a group consisting of dichloromethane and chloroform.
8. The process as claimed in claims 1 and 2, wherein the solvent in step (b) is dichloromethane.
9. The process as claimed in claims I and 2, wherein the alcoholic solvent in step (c) is selected from a group consisting of methanol and ethanol,
10 10. The process as claimed in claims 1 and 2, wherein the alcoholic solvent in step fc) is
ethanol.
11. The process as claimed in claims 1 and 2, wherein in step (d) the solution
containing alcoholic solvent is cooled at about 0 to 15 UC.
12. The process as claimed in claim claims 1 and 2, wherein the anti-solvent in step (e)
15 is selected from an organic solvent group consisting of toluene, o-xylene, diethyl
ether, diisopropyl ether and n-hexane,
13. The process as claimed in claims 1 and 2, wherein the anti-solvent is added at a
temperature of about 5 to 15 °C.
14. The process as claimed in claims 1 and 2, wherein the product is dried at about 30
20 to 80 °C.
15. The process as claimed in claims 1 and 2, wherein the product is dried at about 30
to 35 °C.

DATED THIS...23...DAY OF DECEMBER, 2005
25 T.SRINIVASAN
AGENT FOR THE APPLICANT
TO
THE CONTROLLER OF PATENTS
PATENT OFFICE
30 AT MUMBAI

ABSTRACT
The present invention provides processes for making substantially pure Donepezil
Hydrochloride Form (I) from Donepezil Oxalate and Donepezil Hydrochloride Form
(VI) comprising dissolving a Donepezil salt in water and basifying the solution;
5 extracting the Donepezil base with a halogenaled organic solvent and acidifying with
aqueous hydrochloride; evaporating and subsequently adding a suitable alcoholic solvent; cooling the solution containing the alcoholic solvent; adding n-hexane as an anti-solvent to precipitate; and drying the product to obtain Donepezil Hydrochloride Form (I).
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