WO2011051957A2

WO2011051957A2 - A process for the preparation of donepezil hydrochloride

Info

Publication number: WO2011051957A2
Application number: PCT/IN2009/000615
Authority: WO
Inventors: Arul Ramakrishnan; Guruswamy Batthini
Original assignee: Neuland Laboratories Ltd.
Priority date: 2009-10-30
Filing date: 2009-10-30
Publication date: 2011-05-05
Also published as: WO2011051957A3

Abstract

The present invention is directed to an improved industrially viable, cost effective process for manufacturing 1 -benzyl-4-(5,6,-dimethoxyindanone-2-yl)methylpiperidine hydrochloride commonly known as donepezil hydrochloride in a substantially pure form with a purity level of greater than 99.9% and a novel crystalline form of 1- benzyl-4-(5,6,-dimethoxyindanone-2-yI)methylpiperidine in a substantially pure form.

Description

A PROCESS FOR THE PREPARATION OF DONEPEZIL

HYDROCHLORIDE

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to an improved industrially viable, cost effective process for manufacturing racemic ( l -benzyl-4-(5,6,-dimethoxyindanone-2- yl)methylpiperidine)hydrochloride commonly known as donepezil hydrochloride in a substantially pure form with a purity level of greater than 99.9% and a novel polymorphic form of racemic ( l -benzyl-4-(5,6,-dimethoxyindanone-2- yl)methylpiperidine) i.e. Donepezil free base.

BACKGROUND OF THE INVENTION

Donepezil hydrochloride ( 1 -benzyl-4-(5,6,-dimethoxyindanone-2-yl)methyl piperidine) hydrochloride of formula-I

Formu!a-I

belongs to a group of selective acetylcholine esterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. Donepezil hydrochloride is a white crystalline powder. It is freely soluble in chloroform, water and glacial acetic acid, slightly soluble in ethanol and acetonitrile and insoluble in ethyl acetate and n-hexane.

Donepezil hydrochloride is produced by first producing Donepezil free base and then converting it into hydrochloride. Donepezil itself is a excellent medicament but it is also used as precursor for production of Donepezil hydrochloride. US4895841 describes the process for the preparation of Donepezil hydrochloride by

• condensation of pyridine carboxaldehyde analog of Formula III with an indanone derivative of formula II as shown in scheme l a Scheme ia

I

• or condensation of pyridine carboxaldehyde analogue of formula III with an indanone derivative of formula V as in scheme lb,

Scheme lb

in the presence of a strong base such as NaH or LDA to give a compound of Formula IV, which on further reduction gives a compound of Formula I.

The above reaction uses multiple solvents for the condensation of 5,6-dimethoxy- 1 -indanone and 2-benzylpiperidine-4-carboxaldehyde. These methods are not industrially viable because hazardous reagents like lithium diisopropyl amine and sodium hydride have been used for condensation, the reagents are highly moisture sensitive and the reaction requires very low temperature and anhydrous condition, which is difficult to handle at commercial scale, moreover the yield is very low (62%).

US5606064 and EP71 1 756 describe a process for preparation of donepezil by the reduction of pyridinium salt of Formula VII in the presence of platinum dioxide. The reaction can be described by the scheme II given below:

Scheme II

The formation of the pyridinium ring and reduction of the olefinic bond is time consuming, lengthy and difficult to achieve. This reaction leads to the formation of unwanted impurities and very low yields (58.5%).

W09722984 describes the synthesis of donepezil hydrochloride by reduction of 4-[(5,6-dimethoxy- l-indanone-2-ylidene)methyl]pyridine using noble metal oxide catalyst platinum oxide or platinum in a mixture of solvents followed by alkylation. The reaction leads to the formation of impurities, which are difficult to separate and inturn result less yield and low purity. The reaction can be illustrated by the scheme III given below:

WO9936405 discloses a process for the preparation of donepezil hydrochloride by the reaction of indanone derivative with a carbonate ester to give 2-alkoxycarbonyl indanone derivative, which is further condensed with halogenated pyridyl derivative and decarboxylated to give pyridyl indanone derivative. The pyridyl indanone derivative is reacted with substituted benzyl and reduced to give a compound of Formula 1. This reaction is time consuming due to additional step of decarboxylation and the overall yield is very low. This process can be illustrated by the below scheme IV:

Scheme IV

VII EP1386607 discloses the reaction of 5, 6-dimethoxyindanone ester with an N- protected piperidinyl derivative to give N-protected piperidinyl-5,6- dimethoxyindanone methyl ester followed by deprotection and substitution on the piperidine, hydrolysis and decarboxylation. The process is time consuming and requires extra steps of deprotection and decarboxylation making the overall yield very low. This process can be represented by the following scheme V:

Scheme V

US6492522 discloses a process which comprises hydrolysis of the compound of formula XIV to give compound of formula XV followed by cyclisation to give compound of formula I. An alternate method disclosed in this patent comprises hydrolysis of compound of formula XVI to give compound of formula XVII and cyclisation to form a compound of formula I. This process can be illustrated by the scheme VI given below:

Scheme VI

XV US624591 1 discloses and characterises three different polymorphic form of Donepezil free base named as polymorphic crystal A (or Type A), polymorphic crystal B (or Type B) and polymorphic crystal C (or Type C).

WO2008050351 discloses two forms, Form-D and Form-E of Donepezil base. This patent also characterises them by infrared absorption spectrum, X-ray powder diffraction pattern, thermogravimitric analysis (TGA), DSC and/or melting point.

US5985864, US6140321 , WO2004099142, US2004229914, US6649765, WO2004087660 and WO2004092137 are some of the patents which disclose the different polymorphic form of donepezil hydrochloride namely Form I, II, IV, V, VI, H I , H2, monohydrate, sesquihydrate and the amorphous form.

US624591 1 mentions that Donepezil being an excellent medicament, it should have such physical properties as to allow it to occur in the form of crystals not being sticky but being dry in order to achieve excellent filtering properties after crystalisation and to facilitate recovery of its filter cake by scrapping.

Therefore there is a need to find a crystal of Donepezil base, which is excellent in handling properties and has better stability. It is also apparent from the most of prior art that the preparation of Donepezil has certain disadvantages such as use of multiple solvent system for the condensation, hazardous raw materials like lithium diisopropyl amine and n-butyllithium, costly raw materials like platinum oxide, unviable reaction conditions like temperature below -80°C, low yields i.e. 62%, and presence of decarboxylation and hydrolysis steps. All these lead to the low yield of the desired molecule. Therefore, there is a continuing need for developing a new process for the manufacturing of Donepezil and salt thereof which is cost effective and industrially viable.

SUMMARY OF THE INVENTION

The principal aspect of present invention is to provide a novel polymorphic form of l-Benzyl-4-(5,6-dimethoxy- l-indanone)-2-ylidenyl)methylpiperidine i.e. donepezil free base having adequate stability and good dissolution property. In another aspect of the invention, the novel polymorphic form of Donepezil base is characterised by a powder X-Ray diffraction pattern with peaks at 5.76, 1 1 .53, 12.28, 13.31 , 13.9, 14.31 , 14.82, 15.44, 16.24, 16.7, 17.33, 18.65, 19.69, 20.76, 21 .62, 21 .99, 22.88, 23.1 7, 23.45, 23.77, 24.27, 24.65, 25.58, 28.07, 28.78, 29.85, 30.58 ± 0.2 degree 2Θ or substantially as indicated in figure 1.

In another aspect, this invention provides an improved process for the preparation of l -Benzyl-4-(5, 6 dimethoxy- l -indanone)-2-ylidenyl) methyl piperidine i.e. donepezil free base having HPLC purity of greater than 99.5% comprising:

a. condensation of 5,6-dimethoxy- l -indanone with l -benzyl-4-piperidine carboxaldehyde in halogenated organic solvent using a base dissolved in an alcoholic solvent to obtain l -Benzyl-4-(5, 6 dimethoxy- 1 -indanone)-2-ylidenyl) methyl piperidine hydrochloride;

b. reduction of the obtained l -Benzyl-4-(5, 6 dimethoxy- l -indanone)-2-ylidenyl) methyl piperidine hydrochloride in presence of a suitable metal catalyst under reduced pressure below 3 kg/cm² in a mixture of acetic acid and an alcoholic solvent to obtain a residue;

c. dissolving the residue in an suitable organic solvent followed by neutralization with a suitable base;

d. acidification of the organic layer with alcoholic hydrogen chloride and removal of solvent by distillation;

e. dissolving the residue in an alcoholic solvent selected from a group comprising methanol, ethanol and isopropanol and precipitating the solid by ketonic solvent; and

f. dissolving the compound obtained in step (e) in a mixture of purified water and an alcoholic solvent, adjusting the pH to 12- 13.5 with a suitable base, isolation of compound, washing with water to obtain a novel crystalline l -Benzyl-4-(5, 6 dimethoxy- l -indanone)-2-yl) methyl piperidine (donepezil free base) having HPLC purity level of greater than 99.5%.

Yet another aspect of the present invention is to provide an industrially viable process for manufacturing (l -benzyl-4-(5,6,-dimethoxyindanone-2yl)methylpiperidine) hydrochloride Form I with a purity level of greater than 99.9% from novel crystaline form of Donepezil base (Scheme VII). Scheme VII

yhdenyl methyl piperidine hydrochloride

reduction

Racemic-Donepezil hydrochloride Form-I Raceniic free base- Donepezil

Yet another aspect of the present invention is to provide an industrially viable insitu process for manufacturing (l -benzyI-4-(5,6,-dimethoxyindanone-2- yl)methylpiperidine) hydrochloride Form I with a purity level of greater than 99.9% without isolating the Donepezil base.

DESCRITPON OF THE FIGURES

FIGURE 1: XRPD novel crystalline Donepezil free base obtained by this invention FIGURE II: DSC novel crystalline Donepezil free base obtained by this invention FIGURE III: IR novel crystalline Donepezil free base obtained by this invention FIGURE IV: XRPD of crystalline Donepezil hydrochloride Form I

DETAILED DESCRIPTION OF THE INVENTION

Accordingly in an embodiment, the present invention provides a novel polymorphic form of l -Benzyl-4-(5,6-dimethoxy- l -indanone)-2-ylidenyl)methyl piperidine i.e. donepezil free base having adequate stability, handling and dissolution properties.

In an embodiment of the invention, the novel polymorphic form of Donepezil base is characterised by a powder X-Ray diffraction pattern with peaks at 5.76, 1 1.53, 12.28, 13.3 1 , 13.9, 14.3 1 , 14.82, 15.44, 16.24, 16.7, 1 7.33, 18.65, 19.69, 20.76, 21.62, 21 .99, 22.88, 23.17, 23.45, 23.77, 24.27, 24.65, 25.58, 28.07, 28.78, 29.85, 30.58 ± 0.2 degree 2Θ or substantially as indicated in figure 1.

In another embodiment of the invention, the novel polymorphic form of Donepezil base is characterised by XRPD monoclinical crystal lattice parameters having a=16.599A, b=9.499A, c=14.392A, <x=90°, β=1 12.62°, γ=90° and V=2094.758A³.

In another embodiment of the invention, in the condensation step of 5,6- dimethoxy- l-indanone with l -benzyl-4-piperidine carboxaldehyde, the halogenated organic solvent is selected from a group consisting of methylene chloride, ethylene chloride or a chloroform, preferably methylene chloride. The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sec-butoxide, and potassium ter-butoxide, preferably potassium hydroxide. The alcoholic solvent for dissolution of base is selected from the group consisting of methanol, ethanol and isopropanol, preferably in methanol. The condensation is followed by neutralization with hydrochloric acid, carbon treatment, acidification with an alcoholic hydrochloric acid preferably isopropanolic hydrochloric acid and removal of solvent. The compound thus obtained is dissolved in suitable alcoholic solvent, preferably methanol and precipitated by addition of an antisolvent, preferably ketonic solvent more preferably acetone to give l-Benzyl-4-(5,6-dimethoxy- l-indanone)-2-ylidenyl) methyl piperidine hydrochloride of formula IV.

In another embodiment of the invention, l -benzyl-4-(5,6-dimethoxy- l- indanone)-2-ylidenyl)methyl piperidine hydrochloride of formula IV is reduced under pressure below 3 kg/cm², preferably between 1.5 to 2 kg/cm² in presence of a metal catalyst selected from Raney nickel or palladium on carbon preferably palladium on carbon in a mixture of acetic acid and an alcoholic solvent preferably methanol, more preferably a mixture of acetic acid and methanol in the ratio 1 : 1. The compound is dissolved in halogenated organic solvent preferably methylene chloride, neutralized with a base preferably saturated sodium bicarbonate solution and treated with activated carbon. The organic layer is further acidified with an alcoholic, preferably isopropanolic hydrogen chloride and the solvent is removed by distillation. The compound thus obtained is dissolved in alcoholic solvent selected from methanol, ethanol and isopropanol, preferably methanol and the solid is isolated by addition of ketonic antisolvent preferably, acetone. The precipitated solid was taken in mixture of water and suitable alcoholic solvent and basified to isolate novel crystalline 1 -Benzyl- 4-(5, 6 dimethoxy- 1 -indanone)-2-yl) methyl piperidine.

In another embodiment of the invention, the obtained novel crystalline 1 - Benzyl-4-(5,6-dimethoxy- l -indanone)-2-yl)methyl piperidine is converted to Donepezil hydrochloride Form I. This conversion comprises dissolving crystalline donepezil free base obtained above in a suitable halogenated organic solvent preferably methylene chloride, optionally treating it with activated carbon and adjusting pH to below 2.0 with an alcoholic hydrochloric acid preferably isopropanolic hydrochloric acid. The organic layer is distilled and swapped with a suitable alcoholic solvent preferably with methanol. The obtained residue is further crystallized in suitable ethereal solvent preferably diethyl ether to obtain donepezil hydrochloride form I as illustrated in Fig. IV.

In yet another embodiment of the invention, ( l -benzyl-4-(5,6,- dimethoxyindanone-2-yl)methylpiperidine) hydrochloride Form I having a purity level of greater than 99.9%, is obtained from l -benzyl-4-(5,6-dimethoxy- l -indanone)-2- ylidenyl)methyl piperidine hydrochloride of formula IV without isolating the Donepezil base. This process reduces the work up and the reaction time, which in turn reduces the cost of the production.

The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLES

Example 1: Preparation of l-Benzyl-4-(5,6-Dimethoxy-l-indanone)-2- ylidenyl) methyl piperidine hydrochloride

1 -Benzyl piperidine-4-carboxaldehyde (150.0 g) was added to 5, 6-dimethoxy- l - indanone (l OOg) dissolved in methylene chloride (1000 mL) and the reaction mixture was stirred for 15 minutes at 25-30°C for dissolution. The reaction mixture was cooled to 0-5°C, potassium hydroxide dissolved in methanol solution (48.0 g in 200 ml methanol) was added to it over a period of 30-60 minutes and stirred for 30 minutes at 0-5°C. The temperature of the reaction mass was raised to 25-30°C and the stirring was continued for 2 hours. After the completion of the reaction, purified water (300mL) was added and the mixture was stirred for 15 minutes. The pH of the reaction mass was adjusted to 6.5-7.5 with concentrated hydrochloric acid at 25-30°C and stirred for 30 minutes. The layers were separated and the organic layer was extracted with methylene chloride. The methylene chloride layer was washed with purified water, treated with activated carbon ( l Og) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloric acid. The organic layer was distilled under vacuum, methanol (200 mL) was added to the residue and stirred for 15 minutes followed by the addition of acetone (1000 mL) and the stirring was continued for 3 hours at 25-30°C. The compound was filtered and washed with acetone to obtain a wet cake, which was dissolved in methanol (200 mL), followed by the addition of acetone (600 mL) and stirring was continued for 3 hours. The mixture was filtered, washed with acetone (200 mL) and dried at 60-65°C to obtain the title compound/ Dry weight: 195.g)(% Yield: 91.3%)

Example 2: Preparation of substantially pure novel crystalline l-Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-yl) methyl piper idine i.e. Donepezil free base

1 -Benzyl-4-(5,6-Dimethoxy- 1 -indanone)-2-ylidenyl)methy 1 piperidine hydrochloride. (50g) obtained above was taken in a mixture of acetic acid (650 mL) and methanol (650 mL) and stirred at 25-30°C for 15 minutes. The reaction content was heated to 40- 45°C. After complete dissolution it was cooled to 28-33°C and 5% Pd-C(50% wet) (2.5g) was added to it to hydrogenate under 1 .5-2.0 Kg/cm² pressure. The reaction mixture was filtered and the solvent was distilled under vacuum below 60°C & cooled to 25-30°C. The residue was taken in methylene chloride (500 mL) and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution (500 mL-50g Na₂C0₃ in 500 mL of purified water), the organic layer was separated and the aqueous layer was extracted with methylene chloride, both the methylene chloride layers were combined, washed with water, treated with activated carbon (5.0g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride at 25-30°C. The solvent was distilled under vacuum below 40°C and cooled to 25-30°C, methanol (550mL) was added to the residue, stirred for 10 minutes followed by the addition of acetone (250mL) and the stirring was continued for 3 hours at 25-30°C. The compound was filtered and washed with acetone. Purified water (80mL) and methanol (240mL) was added to the wet compound and content was stirred at 25-30°C for 15 minutes for complete dissolution. The pH was adjusted to 12.5-13 with 20% sodium hydroxide solution (20.0mL) and stirred for 5 minutes at 25-30°C followed by further addition of purified water (600mL) and the stirring was continued for 2 hrs at 25-30°C. The compound was filtered, washed with purified water (50mL) and dried for 30 minutes to yield crystalline donepezil free base. (Dry weight: 37g, HPLC: 99.5 %, % Yield: 80%)

Example 3: Preparation of substantially pure crystalline solid of Donepezil

Hydrochloride Form I

Donepezil free base (35g) obtained from the step 2 was taken in methylene chloride (350 mL), stirred for complete dissolution, treated with activated carbon (1.75g) and filtered. The pH of the filtrate was adjusted to <2.0 with isopropanolic hydrochloride at 25-30°C and the organic layer was distilled and swapped with methanol (1 75 mL). The residue was dissolved in methanol (350 mL), cooled to 0-5°C and diethyl ether (700 mL) was added to it over a period of 30-60 minutes to obtain Form 1 of Donepezil hydrochloride. The crystals were filtered and washed with diethyl ether (70 mL) and dried to get hydrochloride salt of Donepezil Form I. (Dry weight: 32g, HPLC: 99.9 %, % Yield: 85%)

Example 4: Insitu preparation of substantially pure crystalline solid of

Donepezil Hydrochloride Form I from l-Benzyl-4-(5, 6- Dimetlwxy-l-indanone)-2-ylidenyl)methyl piperidine

hydrochloride

l-Benzyl-4-(5,6-Dimethoxy- l-indanone)-2-ylidenyl)methyl piperidine hydrochloride (50g) obtained above was taken in a mixture of acetic acid (650 mL) and methanol (650 mL) and stirred at 25-30°C for 15 minutes. The reaction content was heated to 40-45°C. After complete dissolution it was cooled to 28-33°C and 2.5 g of 5% Pd-C (50% wet) was added to it to hydrogenate under 1.5-2.0 Kg reduced pressure. The reaction mixture was filtered and the solvent was distilled under vacuum below 60°C & cooled to 25-30°C. The residue was taken in methylene chloride (500 mL) and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution (500 mL-50g Na₂C0₃ in 500 mL of purified water), the organic layer was separated and the aqueous layer was extracted with methylene chloride, both the methylene chloride layers were combined, washed with water, treated with activated carbon (5.0g) and filtered. The pH of the filtrate was acidified to <2.0 with isopropanolic hydrochloride at 25-30°C. The solvent was distilled under vacuum below 40°C and cooled to 25-30°C, methanol (550mL) was added to the residue, stirred for 10 minutes followed by the addition of acetone (250mL) and the stirring was continued for 3 hours at 25-30°C. The compound was filtered and washed with acetone. Purified water (80mL) and methanol (240mL) was added to the wet compound and content was stirred at 25-30°C for 15 minutes for complete dissolution. The pH was adjusted to 12.5-13 with 20% sodium hydroxide solution (20.0mL) and stirred for 5 minutes. MDC was added, the compound was extracted into MDC and the MDC layer was washed with water. The separated MDC layer was treated with activated charcoal and filtered. The pH of the filtrate was adjusted to <2.0 with isopropanolic hydrochloride at 25-30°C and the organic layer was distilled and swapped with methanol ( 175 mL). The residue was dissolved in methanol (350 mL), cooled to 0-5°C and diethyl ether (700 mL) was added to it over a period of 30-60 minutes to obtain Form I of Donepezil hydrochloride. The crystals were filtered and washed with diethyl ether (70 mL) and dried to get hydrochloride salt of Donepezil Form 1. (Dry weight: 32g, HPLC: 99.9 %, % Yield: 85%)

Claims

CLAIMS:

1. A crystalline form of l-Benzyl-4-(5,6-dimethoxy- l -indanone)-2-ylidenyl) methyl piperidine characterised by a powder X-Ray diffraction pattern with peaks at 5.76, 1 1.53, 12.28, 13.31, 13.9, 14.31, 14.82, 15.44, 16.24, 16.7, 17.33, 18.65, 19.69, 20.76, 21.62, 21.99, 22.88, 23.17, 23.45, 23.77, 24.27, 24.65, 25.58, 28.07, 28.78, 29.85, 30.58 ± 0.2 degree 2Θ or substantially as indicated in figure 1.

2. A crystalline form of l -Benzyl-4-(5,6-dimethoxy-l -indanone)-2-ylidenyl) methyl piperidine having a monoclinic crystal lattice with the parameters as a =16.599A, b =9.499A, c =14.392A, a =90°, β =1 12.62°, γ =90° and V =2094.758A³, determined by X-ray structural analysis.

3. A crystalline form of l -Benzyl-4-(5,6-dimethoxy-l -indanone)-2-ylidenyl)methyl piperidine i.e. donepezil free base according to claim 1 or 2 having a purity of 99.5% or more.

4. A process for the preparation of l -Benzyl-4-(5,6-dimethoxy- l -indanone)-2- ylidenyl)methyl piperidine i.e. donepezil free base according to any one of the claim 1 to 3, which comprises:

a. condensation of 5,6-dimethoxy- l -indanone with l -benzyl-4-piperidine carboxaldehyde in halogenated organic solvent using a base dissolved in an alcoholic solvent to obtain l-Benzyl-4-(5, 6 dimethoxy- l -indanone)-2-ylidenyl) methyl piperidine hydrochloride;

b. reduction of the obtained l-Benzyl-4-(5, 6 dimethoxy- l-indanone)-2-ylidenyl) methyl piperidine hydrochloride in presence of a metal catalyst under pressure below 3 kg/cm² in a mixture of acetic acid and an alcoholic solvent to obtain a residue;

c. dissolving the residue in an halogenated organic solvent followed by neutralization with a base;

f. dissolving the compound obtained in step (e) in a mixture of water and an organic solvent, adjusting the pH to basic with a suitable base, isolation of compound, washing with water and drying to obtain a crystalline form of 1 - Benzyl-4-(5, 6 dimethoxy- l-indanone)-2-yl) methyl piperidine (donepezil free base) having HPLC purity level of 99.5% or more.

5. The process according to claim 4, wherein the halogenated organic solvent is selected from a group comprising methylene chloride, ethylene chloride and chloroform and ketonic solvent is acetone.

6. The process according to claim 4, wherein in step (b) the metal catalyst is selected from Raney nickel and palladium on carbon and alcoholic solvent is selected from a group comprising of ethanol, ethanol and isopropanol.

7. A process according to claim 4, wherein the reduction is carried out in presence of Raney nickel and in a mixture of acetic acid and methanol in 1 : 1 ratio at a pressure between 1.5 to 2 kg/cm².

8. A process for industrial manufacture of l -benzyl-4-(5,6-dimethoxy- l -indanone)- 2-ylidenyl)methyl piperidine hydrochloride i.e. donepezil hydrochloride Form I comprising:

a. dissolving donepezil free base according to the any one of the claim 1 to 3, in a an halogenated organic solvent and optionally treating with activated carbon;

b. acidification of the organic layer with an alcoholic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent; and

c. isolating l-benzyl-4-(5,6-dimethoxy- l-indanone)-2-yl)methyl piperidine hydrochloride by addition of ethereal antisolvent in the solvent layer obtained from the step (b) above.

9. The process according to claim 8, wherein the organic solvent for dissolving donepezil free base is selected from a group comprising methylene chloride, ethylene chloride and chloroform and the alcoholic hydrogen chloride is methanolic, ethanolic or isopropanolic hydrogen chloride.

10. The process according to claim 8, wherein solvent used for swapping is selected from a group comprising of ethanol, methanol and isopropanol; and antisolvent is selected from diethyl ether, diisopropyl ether or ter-butyl methyl ether.

1 1. The process according to any of the claims 8 to 10, wherein the halogenated organic solvent for dissolving donepezil free base is methylene chloride, the alcoholic hydrogen chloride is isopropanolic hydrogen chloride and methanol is used as a solvent for swapping and diethyl ether is used as an antisolvent.

12. A process for industrial manufacture of l-benzyl-4-(5,6-dimethoxy- l -indanone)- 2-yIidenyl)methyl piperidine hydrochloride i.e. donepezil hydrochloride Form I comprising:

a) reduction of l -Benzyl-4-(5, 6 dimethoxy-l-indanone)-2-ylidenyl) methyl piperidine hydrochloride in presence of a metal catalyst under pressure below 3kg/cm2 in a mixture of acetic acid and an alcoholic solvent to obtain a residue; b) dissolving the residue in an organic solvent followed by neutralization with a base;

c) acidification of the organic layer with alcoholic hydrogen chloride and removal of solvent by distillation;

d) dissolving the residue in an alcoholic solvent selected from a group comprising methanol, ethanol and isopropanol and precipitating the solid by ketonic solvent;

e) dissolving the compound obtained above in a mixture of water and an organic solvent, adjusting the pH to 12- 13.5 with a suitable base;

f adding a chlorinated solvent and extracting with it optionally treating with activated carbon;

g) acidification of the organic layer with an alcoholic hydrogen chloride and removal of solvent by distillation followed by swapping with a suitable alcoholic solvent; and

h) isolating l-benzyl-4-(5,6-dimethoxy- l -indanone)-2-yl)methyl piperidine hydrochloride by addition of ethereal antisolvent in the solvent layer obtained above.

13. The process according to claim 12, wherein in the metal catalyst is selected from Raney nickel and palladium on carbon and alcoholic solvent is selected from a group comprising of ethanol, ethanol and isopropanol.

14. A process according to claim 12, wherein the halogenated organic solvent is selected from methylene chloride, ethylene chloride, and chloroform.

15. A process according to claims 13, wherein the halogenated organic solvent is methylene chloride.