The present invention relates to a process for the preparation of Donepezil hydrochloride. More particularly, the present invention relates to a simple, economical and industrially efficient process for the preparation of Donepezil hydrochloride monohydrate of Formula I.

.HC1.H20 Formula I
H3CO H3CO
BACKGROUND OF THE INVENTION
Donepezil hydrochloride is chemically known as 1 -benzyl-4-[(5,6-dimethoxy-l-indanon-2-yl)methyl]piperidine hydrochloride and it is structurally represented by the following Formula II. It is an active ingredient of Aricept(R), which is available in the market for oral administration as a film coated tablets.

.HC1 Formula II
Donepezil hydrochloride is a white crystalline powder freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and acetonitrile and practically insoluble in ethyl acetate and in n-hexane.
Donepezil is used to treat dementia associated with Alzheimer's disease, which is a brain disorder that affects the ability to remember, think clearly, communicate, and

perform daily activities and may cause changes in mood and personality. Donepezil belongs to a class of acetylcholinesterase inhibitors, which improves mental function such as memory, attention, social interaction, reasoning and language abilities and ability to perform activities of daily living, by increasing the amount of a certain naturally occurring substance in the brain. Donepezil improves the ability to think and remember or slow the loss of these abilities in people who have Alzheimer's disease.
The preparation of Donepezil hydrochloride was first disclosed in US Patent No. 4,895,841. The process in said patent involves condensation of substituted 1-indanone-2-phosphonate of Formula X with pyridine carboxaldehyde analog of Formula Y in presence of a strong base, such as lithium diisopropylamide (LDA), followed by catalytic reduction using palladium on carbon in tetrahydrofuran (40 volumes) to yield Donepezil with an overall yield of 50.8% as per the Scheme 1.

o
-YYV5 .TI
base M8VYN^VN1 reductior] MeCX^
MeoK/ \" N,- MeO ^ ^v MeO ^ \/ x/
Formula X Formula Y Formula Z Donepezil
Scheme 1
Process of US'841, have certain drawbacks such as employment of hazardous reagent like lithium diisopropylamide (LDA) in the condensation reaction which is a highly moisture sensitive reagent and the reaction requires very low temperature and anhydrous condition which is difficult to handle on the commercial scale. Further, the process makes use of tetrahydrofuran solvent which is highly flammable and may form explosive peroxide vapors. Beside this, the resulting Donepezil obtained after reduction was purified via column chromatography which requires large amount of solvents which is discarded after use or its recyclability requires purification of the recovered solvent which substantially affect the economic viability. Thus, the process is not only expensive but difficult to use on the industrial scale.

US Patent No. 6,252,081 discloses process, which involves the selective reduction of pyridinium ring of l-benzyl-4-[(5,6-dimethoxy-l-indanon-2-yl)methyl]pyridinium salt using platinum oxide as catalyst and methanol as a solvent. This process also leads to the formation of impurities, which are difficult to separate and affects the overall yield along with the purity of the final compound (Scheme 2).




Br

Scheme 2
US Patent No. 7,560,560 discloses process for the preparation of Donepezil hydrochloride monohydrate by dissolving Donepezil free base in mixture of chloroform and water, adding hydrochloric acid and then adding an anti-solvent.
PCT patent application WO2007015052A1 discloses process for the preparation of Donepezil hydrochloride monohydrate in which Donepezil hydrochloride was suspended in methanol and deionized water. The suspension was then heated at 40°C and after filtration, cooled down at 0-5°C and finally tert-butyl methyl ether was added. The yield in this process is very low.
The processes disclosed in the above mentioned prior art(s) have several limitations like multiple chemical steps, overall low yields, use of expensive or hazardous reagents yield and cumbersome purification by column chromatography. Furthermore,

the other drawbacks are use of very large volume of solvent as well as high loading of noble metal catalyst in the hydrogenation step which is not only expensive but also subsequently large volume of solvents has to be distilled off to isolate the hydrogenated product. Further, handling of large volume of solvent leads to the generation of significant amount of effluents which makes the process operationally time consuming and uneconomical on industrial scale.
In view of the same, there is a need for simple, industrially feasible, cost effective and environmentally-friendly processes for the preparation of Donepezil hydrochloride monohydrate that is free from above mentioned drawbacks and achieves high yield and purity.
Therefore, a method which has a simple process with low cost, beneficial for synthesizing high-purity product and is suitable for industrial production still needs to be found.
The problem has been solved by providing an improved process with the use of ternary solvent system in specific ratio, which allows a convenient and efficient isolation of Donepezil hydrochloride monohydrate. By using this ternary solvent system in specific ratio, high yield and high purity of Donepezil hydrochloride monohydrate is achieved.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations in the prior arts by providing an efficient process for the preparation of Donepezil hydrochloride monohydrate.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing Donepezil hydrochloride monohydrate, in high yield and purity.

It is still another object of the present invention to provide an improved and commercially viable process for the isolation of Donepezil hydrochloride monohydrate, using ternary solvent system in specific ratio.
It is still another object of the present invention to provide an improved and commercially viable process for the isolation of Donepezil hydrochloride monohydrate, using ternary solvent system (alcohol, water and ether) in specific ratio.
It is still another object of the present invention to provide an improved and commercially viable process for the isolation of Donepezil hydrochloride monohydrate, using ternary solvent system (alcohol, water and ether) in ratio from 1: 0.2: 4 to 5: 1:20.
It is still another object of the present invention to provide an improved and commercially viable process for the isolation of Donepezil hydrochloride monohydrate, using ternary solvent system (methanol, water and methyl tert-butyl ether) in specific ratio.
It is still another object of the present invention to provide an improved and commercially viable process for the isolation of Donepezil hydrochloride monohydrate, using ternary solvent system (methanol, water and methyl tert-butyl ether) in ratio from 1: 0.2: 4 to 5: 1: 20.
It is still another object of the present invention to provide Donepezil hydrochloride monohydrate substantially free from impurities.
SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided an efficient and cost effective process for the preparation of Donepezil hydrochloride monohydrate of Formula I, as shown in scheme 3.

o CHO

A^-V l J Reflux,
HjCO^^ V ReflUX' 105"110°C H3CO^^ ^ ^f 40-45°C
Formula A Formula B Formulae Formula D
Pd/C, MeOH, AcOH H2 (8-10Kg/cm2) 75-80°C

H3COy^A^N^s ^N ?mZyl^1°ii-d.e
:13cu H3CO'
U0-
^
Toluene/H,0/K.,CO, H;iC0-

0 0
H,CO^^ ^»^^ 85-90°C H3C(A^ ^NH
Formula F Formula E

Cone. HC1/DM water MeOH/Acetone
O
^VVW^I f^ MeOH, Purified water. ' TYjY^ C]
H3C0XXJ Xjjj MTBE^C H3C to 6.0%> w/w, as per European Pharmacopoeia 10.1.

In an another embodiment, the present invention (Scheme 3) relates to a process for the preparation of Donepezil hydrochloride monohydrate of Formula I

Formula I
comprising the steps of:
(a) refluxing a mixture of 5,6-dimethoxy indanone of the Formula A and pyridine-4-
carboxaldehyde of the Formula B to obtain compound of Formula C;



H3CO H3CO
Formula A

O

CHO

N Formula B

Formula C

SOoH

(b) treating the compound of Formula C with an aqueous basic solution to obtain compound of Formula D;

Formula D
(c) reducing the compound of the Formula D to obtain compound of Formula E;


NH

Formula E

(d) reacting the compound of the Formula E with benzyl halide to obtain Donepezil of the Formula F;

H3CO

Formula F
(e) converting Donepezil to Donepezil hydrochloride of Formula II; and

(f) treating Donepezil hydrochloride of formula II with ternary solvent system to obtain Donepezil hydrochloride monohydrate of Formula I.
In step (a) of scheme 3, reaction is carried out in presence of toluene and p-toluene sulfonic acid.
In step (b) of scheme 3, aqueous basic solution is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate solution and the like; preferably aqueous sodium carbonate solution.
In step (c) of scheme 3, reduction is carried out in alcoholic solvent selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol or tertiary butanol and the like; preferably methanol.

In step (d) of scheme 3, reaction is carried out in solvent selected from the group comprising of toluene, methanol, ethanol isopropanol, butanol, acetone, ethyl methyl ketone, 2-butanone and the like.
In step (d) of scheme 3, benzyl halide is selected from the group comprising of benzyl chloride, benzyl bromide and the like; preferably benzyl chloride.
In step (d) of scheme 3, reaction is carried out in presence of base selected from the group comprising of inorganic or organic base. Inorganic base is selected from the group comprising of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like. Organic base is selected from the group comprising of triethyl amine, tributyl amine, tertiary butyl amine, pyridine and the like. In step (d) of scheme 3, reaction is preferably carried out in presence of potassium carbonate.
In step (e) of scheme 3, reaction is carried out in presence of hydrochloric acid.
In step (f) of scheme 3, ternary solvent system includes alcohol, water and ether. Alcohol in ternary solvent is C1-C5 alcohol selected from the group comprising of methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, isobutyl alcohol and tert-butanol and the like and mixture thereof. Alcohol in ternary solvent is preferably methanol. Ether in ternary solvent is selected from the group comprising of dimethyl ether, diethyl ether, dimethoxy ethane, tetrahydrofuran, dioxane, anisole, methyl tert-butyl ether, ethyl tert-butyl ether and the like and mixture thereof. Ether in ternary solvent is preferably methyl tert-butyl ether.
Use of this ternary solvent system in specific ratio helps in achieving Donepezil hydrochloride monohydrate in high yield and high purity. Accordingly, this specific ternary solvent system in specific ratio plays a vital role in achieving better yield and high purity of Donepezil hydrochloride monohydrate.

In an another embodiment, the present invention relates to an improved process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20 Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with methanol;

.HC1 Formula II
(ii) adding water to the reaction mixture;
(iii) adding methyl tert-butyl ether solvent to the reaction mixture; and
(iv) isolating Donepezil hydrochloride monohydrate,
wherein ratio of alcohol: water: ether is selected from the range comprising of 1: 0.2: 4
to 5: 1:20.
In an another embodiment, the present invention relates to an improved process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20 Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with alcohol;

uo
o H3co
H3C0
.HC1
Formula II
(ii) heating the reaction mixture;
(iii) adding water to the reaction mixture;
(iv) adding ether solvent to the reaction mixture;
(v) cooling the reaction mixture; and
(vi) isolating Donepezil hydrochloride monohydrate,
wherein ratio of alcohol: water: ether is selected from the range comprising of 1: 0.2: 4
to 5: 1:20.
In step (i), alcohol is C1-C5 alcohol selected from the group comprising of methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, isobutyl alcohol and tert-butanol and the like and mixture thereof. Alcohol in step (i) is preferably methanol.
In step (ii), heating is performed at temperature selected from the group comprising of 30°C to 60°C and preferably at 45°C to 55°C.
In step (iii), water is added to the reaction mixture.
In step (iv), ether is selected from the group comprising of dimethyl ether, diethyl ether, dimethoxy ethane, tetrahydrofuran, dioxane, anisole, methyl tert-butyl ether, ethyl tert-butyl ether and the like and mixture thereof. Ether in step (iv) is preferably methyl tert-butyl ether.
In step (v), cooling is performed at the temperature selected from the group comprising of -10°C to 10°C and preferably at 0°C to 5°C.

This ternary solvent system includes alcohol, water and ether. Use of this ternary solvent system in specific ratio helps in achieving Donepezil hydrochloride monohydrate in high yield and high purity. Accordingly, this specific ternary solvent system in specific ratio plays a vital role in achieving Donepezil hydrochloride monohydrate in high yield and high purity.
The specific ratio of ternary solvent system alcohol: water: ether is comprising of 1: 0.2: 4 to 5: 1: 20; preferably 2: 0.3: 6 to 4: 0.7: 12 and more preferably 2: 0.4: 7 to 3: 0.6: 10. The most preferable ratio of ternary solvent system of alcohol: water: ether is 2.5:0.5: 8.
In an another embodiment, the present invention relates to an improved process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20 Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with methanol;

.HC1 Formula II
(ii) heating the reaction mixture;
(iii) adding water to the reaction mixture;
(iv) adding methyl tert-butyl ether solvent to the reaction mixture;
(v) cooling the reaction mixture; and
(vi) isolating Donepezil hydrochloride monohydrate,

wherein ratio of methanol: water: methyl tert-butyl ether is selected from the range comprising of 1: 0.2: 4 to 5: 1: 20.
In step (ii), heating is performed at temperature selected from the group comprising of 30°C to 60°C and preferably at 45°C to 55°C.
In step (v), cooling is performed at the temperature selected from the group comprising of -10°C to 10°C and preferably at 0°C to 5°C.
The specific ratio of ternary solvent system alcohol: water: ether is comprising of 1: 0.2: 4 to 5: 1: 20; preferably 2: 0.3: 6 to 4: 0.7: 12 and more preferably 2: 0.4: 7 to 3: 0.6: 10. The most preferable ratio of ternary solvent system of alcohol: water: ether is 2.5:0.5: 8.
In yet another embodiment, the present invention relates to an improved process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20
Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with methanol;

.HC1 Formula II
(ii) heating the reaction mixture at 30°C to 60°C; (iii) adding water to the reaction mixture;

(iv) adding methyl tert-butyl ether solvent to the reaction mixture;
(v) cooling the reaction mixture to -10°C to 10°C; and
(vi) isolating Donepezil hydrochloride monohydrate,
wherein ratio of methanol: water: methyl tert-butyl ether is 2.5: 0.5: 8.
Donepezil hydrochloride monohydrate obtained by the process of the invention is in fact substantially pure, and in particular substantially free from the impurities. The expression "substantially pure" means having a purity degree equal to or higher than 99.7%.
According to the present invention Donepezil hydrochloride monohydrate is isolated from the reaction mixture by conventional methods like filtration and the like, as reported in the literature.
The problem has been solved by providing an improved process with the use of ternary solvent system in specific ratio, which allows a convenient and efficient isolation of Donepezil hydrochloride monohydrate. By using this ternary solvent system in specific ratio, high yield and high purity of Donepezil hydrochloride monohydrate is achieved.
Donepezil hydrochloride monohydrate is efficiently prepared from Donepezil hydrochloride using ternary solvent system (methanol, water and methyl tert-butyl ether) in ratio from 1: 0.2: 4 to 5: 1: 20. Use of this ternary solvent system in specific ratio helps in achieving better yield and high purity of Donepezil hydrochloride monohydrate. Each solvent with specific ratio in ternary solvent system plays a vital role in achieving better yield and high purity of Donepezil hydrochloride monohydrate.
Several experiments have been carried out to find impact of solvent volume/ratio on yield and purity of Donepezil hydrochloride monohydrate.

Table 1

Change in Methanol volume
S.No. Methanol volume Water volume Methyl tert-butyl ether volume Yield (%) Purity (%)
1 2.0 0.50 8.0 97.46 100.0
2 2.5 0.50 8.0 97.0 100.0
3 3.0 0.50 8.0 91.46 100.0
4 5.0 0.50 8.0 76.3 100.0
Table 1 shows impact of methanol volume. Due to increase in methanol volume, yield of Donepezil hydrochloride monohydrate decreases.
Table 2

Change in Water volume
S.No. Methanol volume Water volume Methyl tert-butyl ether volume Yield (%) Purity (%)
1 2.5 0.3 8.0 97.40 100.0
2 2.5 0.5 8.0 97.0 100.0
3 2.5 0.8 8.0 75 100.0
4 2.5 1.0 8.0 78.33 100.0
Table 2 shows impact of water volume. Due to increase in water volume, yield of Donepezil hydrochloride monohydrate decreases.
Table 3

Change in Methyl tert-butyl ether volume
S.No. Methanol volume Water volume Methyl tert-butyl ether volume Yield (%) Purity (%)
1 2.5 0.5 4.0 89.6 99.98
2 2.5 0.5 6.0 94.8 100.0
3 2.5 0.5 8.0 97.0 100.0
4 2.5 0.5 15.0 97.0 100.0
Table 3 shows impact of methyl tert-butyl ether volume. When less volume of methyl tert-butyl ether was used then less yield of Donepezil hydrochloride monohydrate obtained. Moreover, higher volume of methyl tert-butyl ether volume has no positive impact on yield and purity.
Use of this ternary solvent system (methanol, water and methyl tert-butyl ether) in specific ratio helps in achieving higher yield with high purity of Donepezil hydrochloride monohydrate.
The process for the preparation of Donepezil hydrochloride monohydrate as described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example 1: Preparation of compound of Formula D
5,6-dimethoxy indan-1-one of Formula A (100.Og), Pyridine-4-carboxaldehyde of Formula B (61.3g) and p-toluene sulfonic acid (128.6g) were suspended in 1000.0 mL of toluene and heated to reflux at 105-110°C to azeotropically remove the water. After reaction completion reaction, the resulting mass was cooled to 25-40°C and the solid was filtered off under suction and washed with toluene. Further the wet solid was suspended in aqueous 10% sodium carbonate solution (1200 mL). The resulting solid

was filtered off under suction and then again wet solid taken in DM water (HOOmL) and stirred at 25-30°C for 30-60 min. The resulting solid was filtered off under suction and dried in VTD at 60-70°C for 12-18h to afford compound of Formula D. Yield: 138 g; Yield (%): 94.29 Purity by HPLC: 99.30
Example 2: Preparation of Donepezil hydrochloride of Formula II
Compound of Formula D (lOO.Og) is reduced with 10% Pd/C (lO.Og) in methanol (800 mL) at 70-80°C and at 8-10kg/cm2 hydrogen pressure. After reaction completion, the reaction mixture was cooled to 25-30°C. Filtered the reaction mixture, washed the bed with methanol (200 mL) and solvent is removed via distillation under vacuum at 50-55°C. Chased out of Methanol/Acetic acid with toluene (200 mL) under vacuum at 50-55°C. Oil was degassed at 60-65°C for l-2h to obtain compound of Formula E. Benzylation of compound of Formula E with benzyl chloride (49.50 g ) is performed in toluene/water (600mL/300mL) in presence of potassium carbonate (147.38 g) and heated to 85-95°C. After reaction completion in 6-8h, the reaction mixture was cooled to 25-30°C and filtered. Further, organic layer was separated out and washed with DM water and cooled to 5-10°C and pre-chilled diluted aqueous HC1 solution was added to it at 5-15°C. Stirred the reaction mixture at 5-15°C for 10-15 min. Settled and separated the lower acidic aqueous layer at 5-10°C. After addition of chilled methanol (100 mL), acetone (1500 mL) was added to it. Reaction mixture was stirred at 25-30°C for 8-10h. Then reaction mixture was cooled to 0-5°C, stirred for 2-3h, filtered and finally dried under vacuum at 50-55°C for 6-8h. Yield: 111 g; Yield (%): 75% Purity by HPLC: 99.80%
Example 3: Preparation of Donepezil hydrochloride monohydrate
Methanol (2.0V) (160 mL) was added to Donepezil hydrochloride (80.0 g) at 25-30°C. Reaction mass was heated to 45-55°C. Then purified water (0.5V) was added drop-wise to it at 45-55°C. Reaction mass filtered through 0.45-micron filter at 25-30°C and washed with methanol (0.5 V) (40 mL). Then methyl tert-butyl ether (8V) (640 mL)

was added to it drop-wise at 25-30°C. Slowly cooled the reaction mixture to 0-5°C. Reaction mixture was stirred at 0-5°C for l-3h. Then the reaction mixture was filtered and washed with MTBE (80.0 mL) suck dried for 25-30 min and finally dried at 50-55°C for 4-6h. The product is exposed to atmosphere at 25-30°C for l-3h. Yield: 80.8 g; Yield: 97% Purity: 100%
Example 4: Preparation of Donepezil hydrochloride monohydrate
Methanol (2.0V) (20.0 mL) was added to Donepezil hydrochloride (10.0 g) at 25-30°C. Reaction mass was heated to 45-55°C. Then purified water (0.8V) (8.0 mL) was added drop-wise to it at 45-55°C. Reaction mass filtered through 0.45-micron filter at 25-30°C and washed with methanol (0.5 V) (5.0 mL). Then methyl tert-butyl ether (8V) (80.0 mL) was added to it drop-wise at 25-30°C. Slowly cooled the reaction mixture to 0-5°C. Reaction mixture was stirred at 0-5°C for l-3h. Then the reaction mixture was filtered and washed with MTBE (10.0 mL) suck dried for 25-30 min and finally dried at 50-55°C for 4-6h. The product is exposed to atmosphere at 25-30°C for l-3h.
Yield: 7.8 g; Yield: 75% Purity: 100%
Example 5: Preparation of Donepezil hydrochloride monohydrate
Methanol (2.0V) (30.0 mL) was added to Donepezil hydrochloride (15.0 g) at 25-30°C. Reaction mass was heated to 45-55°C. Then purified water (0.5V) (7.5 mL) was added drop-wise to it at 45-55°C. Reaction mass filtered through 0.45-micron filter at 25-30°C and washed with methanol (7.5 mL). Then methyl tert-butyl ether (15V) (225 mL) was added to it drop-wise at 25-30°C. Slowly cooled the reaction mixture to 0-5°C. Reaction mixture was stirred at 0-5°C for l-3h. Then the reaction mixture was filtered and washed with MTBE (15.0 mL) suck dried for 25-30 min and finally dried at 50-55°C for 6h. The product is exposed to atmosphere at 25-30°C for l-3h. Yield: 15.15 g; Yield: 97% Purity: 99.92%

Example 6: Preparation of Donepezil hydrochloride monohydrate
Ethanol (2.0V) (20.0 mL) was added to Donepezil hydrochloride (10.0 g) at 25-30°C. Reaction mass was heated to 45-55°C. Then purified water (0.5V) (5.0 mL) was added drop-wise to it at 45-55°C. Reaction mass filtered through 0.45-micron filter at 25-30°C and washed with ethanol ( 5.0mL). Then methyl tert-butyl ether (8V) (80.0 mL) was added to it drop-wise at 25-30°C. Slowly cooled the reaction mixture to 0-5°C. Reaction mixture was stirred at 0-5°C for l-3h. Then the reaction mixture was filtered and washed with MTBE (10.0 mL) suck dried for 25-30 min and finally dried at 50-55°C for 6h. The product is exposed to atmosphere at 25-30°C for l-3h. Yield: 10.1 g; Yield: 97% Purity: 99.98%
Example 7: Preparation of Donepezil hydrochloride monohydrate
Methanol (2V) (60.0 mL) was added to Donepezil hydrochloride (30.0g) at 25-30°C. Reaction mass was heated to 45-55°C. Then purified water (0.5V) (15.0 mL) was added drop-wise to it at 45-55°C. Reaction mass filtered through 0.45-micron filter at 25-30°C and washed with methanol (15.0 mL). Then di-isopropyl ether (8V) (240.0 mL) was added to it drop-wise at 25-30°C. Slowly cooled the reaction mixture to 0-5°C. Reaction mixture was stirred at 0-5°C for 2-3h. Then the reaction mixture was filtered and suck dried for 25-30 min and finally dried at 50-55°C for 6h. Yield: 29.4 g; Yield: 94% Purity: 99.86

WE CLAIM:

1. A process for the preparation of Donepezil hydrochloride monohydrate of Formula I
X)
O H3CO
H3CO
.HC1.H20
Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with alcohol;
uo
o H3CO
H3CO
.HC1
Formula II
(ii) adding water to the reaction mixture;
(iii) adding ether solvent to the reaction mixture; and
(iv) isolating Donepezil hydrochloride monohydrate,
wherein ratio of alcohol: water: ether is selected from the range comprising of 1: 0.2: 4
to 5: 1:20.
2. The process as claimed in claim 1, wherein alcohol in step (i) is selected from the group comprising of methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, isobutyl alcohol andtert-butanol.
3. The process as claimed in claim 1, wherein alcohol is methanol.
4. The process as claimed in claim 1, wherein ether in step (iii) is selected from the group comprising of dimethyl ether, diethyl ether, dimethoxy ethane, tetrahydrofuran, dioxane, anisole, methyl tert-butyl ether and ethyl tert-butyl ether.

5. The process as claimed in claim 1, wherein ether is methyl tert-butyl ether.
6. The process as claimed in claim 1, wherein ratio of alcohol: water: ether is selected from the range comprising of 2: 0.3: 6 to 4: 0.7: 12.
7. The process as claimed in claim 1, wherein ratio of alcohol: water: ether is selected from the range comprising of 2: 0.4: 7 to 3: 0.6: 10.
8. The process as claimed in claim 1, wherein ratio of alcohol: water: ether is 2.5: 0.5: 8.
9. The process as claimed in claim 1, wherein process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20 Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with methanol;

.HC1 Formula II
(ii) adding water to the reaction mixture;
(iii) adding methyl tert-butyl ether to the reaction mixture; and
(iv) isolating Donepezil hydrochloride monohydrate,
wherein ratio of methanol: water: methyl tert-butyl ether is selected from the range
comprising of 1: 0.2: 4 to 5: 1:20.

10. A process for the preparation of Donepezil hydrochloride monohydrate of Formula I

.HC1.H20 Formula I
comprising the steps of:
(i) mixing Donepezil hydrochloride of Formula II with methanol;

.HC1 Formula II
(ii) heating the reaction mixture from 30°C to 60°C;
(iii) adding water to the reaction mixture;
(iv) adding methyl tert-butyl ether to the reaction mixture;
(v) cooling the reaction mixture from -10°C to 10°C; and
(vi) isolating Donepezil hydrochloride monohydrate,
wherein ratio of methanol: water: methyl tert-butyl ether is 1: 0.2: 4 to 5: 1: 20.