WO2004092137A1 - Novel crystalline forms of donepezil hydrochloride - Google Patents

Novel crystalline forms of donepezil hydrochloride Download PDF

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Publication number
WO2004092137A1
WO2004092137A1 PCT/IN2003/000158 IN0300158W WO2004092137A1 WO 2004092137 A1 WO2004092137 A1 WO 2004092137A1 IN 0300158 W IN0300158 W IN 0300158W WO 2004092137 A1 WO2004092137 A1 WO 2004092137A1
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Prior art keywords
donepezil hydrochloride
donepezil
solvent
ray powder
powder diffraction
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PCT/IN2003/000158
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French (fr)
Inventor
Reddy Bandi Parthasaradhi
Reddy Kura Rathnakar
Reddy Rapolu Raji
Reddy Dasari Muralidhara
Reddy Kesireddy Subash Chander
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Hetero Drugs Limited
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Priority to US10/511,735 priority Critical patent/US7560560B2/en
Priority to AU2003245029A priority patent/AU2003245029A1/en
Priority to PCT/IN2003/000158 priority patent/WO2004092137A1/en
Priority to ARP030103825A priority patent/AR041678A1/en
Publication of WO2004092137A1 publication Critical patent/WO2004092137A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention provides novel crystalline forms of donepezil hydrochloride, processes for their preparation and pharmaceutical compositions containing them.
  • US 6,140,321 disclosed four crystalline forms of donepezil hydrochloride, polymorph (I), polymorph (II), polymorph (III) and polymorph (IV) and processes for preparation thereof. It has now been discovered that donepezil hydrochloride can be prepared in four stable crystalline forms having good dissolution characteristics.
  • the object of the present invention is to provide stable novel crystalline forms of donepezil hydrochloride, processes for preparing these forms and pharmaceutical compositions containing them.
  • a novel crystalline form of donepezil hydrochloride designated as form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 15.2, 18.7, 20.6, 22.3, 23.5, 24.0, 24.6, 27.0, 29.0 and 30.5 degrees.
  • Figure 1 shows typical form H1 x-ray powder diffraction spectrum.
  • a process for preparation of donepezil hydrochloride form H1 which comprises: a) dissolving donepezil free base in methylene dichloride; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride form H1 from the solution formed in (b) by adding an anti-solvent.
  • the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
  • the anti-solvent should be added in the quantity that causes the precipitation of donepezil hydrochloride under the conditions of experiment.
  • Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
  • an another process for preparation of donepezil hydrochloride form H1 , which comprises: a) dissolving donepezil hydrochloride in methylene dichloride; and b) precipitating donepezil hydrochloride form H1 from the solution formed in (a) by adding an anti-solvent.
  • Donepezil hydrochloride in any form, crystalline, amorphous or solvated form, may be used in (a).
  • the anti-solvent should be added in a quantity thai causes the precipitation of donepezil hydrochloride under the conditions of experiment.
  • Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
  • a novel crystalline form of donepezil hydrochloride designated as form H2 characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 6.6, 6.8, 10.1, 12.8, 13.7, 15.0, 15.6, 16.5, 17.3, 18.4, 19.5, 19.8, 20.0, 21.6, 21.9, 22.3, 23.9, 24.2, 24.7, 25.3, 26.0, 26.9 and 28.2 degrees.
  • Figure 2 shows typical form H2 x-ray powder diffraction spectrum.
  • a process for preparation of donepezil hydrochloride form H2 which comprises: a) dissolving donepezil free base in toluene; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride form H2 by filtration or centrifugation.
  • the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
  • a novel crystalline form of donepezil hydrochloride monohydrate characterized by an x- ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1, 23.9 and 25.3 degrees.
  • Figure 3 shows donepezil hydrochloride monohydrate x-ray powder diffraction spectrum.
  • a process for preparation of donepezil hydrochloride monohydrate which comprises: a) dissolving donepezil free base in a mixture of chloroform and water; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride monohydrate from the solution formed in (b) by adding an anti-solvent.
  • the water can be added directly or in the form of, for example, as an aqueous solution of hydrochloric acid.
  • the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
  • Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti- solvents may also be used.
  • an another process for preparation of donepezil hydrochloride monohydrate, which comprises: a) dissolving donepezil hydrochloride in a mixture of chloroform and water; and b) precipitating donepezil hydrochloride monohydrate from the solution formed in (a) by adding an anti-solvent.
  • Donepezil hydrochloride in any form, crystalline, amorphous or solvated form, may be used in (a).
  • the anti-solvent should be added in a quantity that causes the precipitation of donepezil hydrochloride under the conditions of experiment.
  • Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
  • a novel crystalline form of donepezil hydrochloride sesquihydrate characterized by an x- ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 5.1, 10.8, 12.8, 13.3, 13.9, 15.0, 16.3, 17.1, 17.7, 19.5, 20.1, 21.4, 23.2, 24.1, 26.6, 27.3, 28.2, 29.7, 31.9 and 35.3 degrees.
  • Figure 4 shows donepezil hydrochloride sesquihydrate x-ray powder diffraction spectrum.
  • a process for preparation of donepezil hydrochloride sesquihydrate which comprises: a) dissolving donepezil free base in a mixture of tert-butyl alcohol and water; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride sesquihydrate by filtration or centrifugation.
  • the water can be added directly or in the form of, for example, as an aqueous solution of hydrochloric acid.
  • the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
  • Donepezil free base and donepezil hydrochloride used in the above processes can be obtained from the previously known methods.
  • a pharmaceutical composition comprising donepezil hydrochloride form H1 and pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition comprising donepezil hydrochloride form H2 and pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition comprising donepezil hydrochloride monohydrate and pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition comprising donepezil hydrochloride sesquihydrate and pharmaceutically acceptable carrier or diluent.
  • Figure 1 is a x-ray powder diffraction spectrum of donepezil hydrochloride form I.
  • Figure 2 is a x-ray powder diffraction spectrum of donepezil hydrochloride form II.
  • Figure 3 is a x-ray powder diffraction spectrum of donepezil hydrochloride monohydrate.
  • Figure 4 is a x-ray powder diffraction spectrum of donepezil hydrochloride sesquihydrate. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-K radiation.
  • Example 1 Donepezil free base (4.0 gm) is dissolved in ethylene dichloride (20 ml) at 27°C, cone, hydrochloric acid (1.2 ml) is added to the solution and stirred for 2 hours at 25°C to 30°C. Then diisopropyl ether (75 ml) is added and the precipitated solid is filtered off and dried to give 3.0 gm of donepezil hydrochloride form H1.
  • Donepezil free base (10.0 gm) is dissolved in toluene (50 ml) at 25°C, cone, hydrochloric acid (2.8 ml) is added to the solution and stirred for 6 hours at 25°C to 30°C. The crystals formed are filtered and dried to give 8.2 gm of donepezil hydrochloride form H2.
  • Donepezil hydrochloride form H2 (5.0 gm) is added to ethylene dichloride (100 ml), the contents are heated to 55°C and stirred for 8 hours at 55°C to 60°C. The solution so obtained is cooled to 25°C, diisopropyl ether (100 ml) is added to the solution and precipitated solid is filtered and dried to give 4.3 gm of donepezil hydrochloride form H1.
  • Example 4 Donepezil free base (4.0 gm) is dissolved in a mixture of chloroform (20 ml) and water (1 ml) at 25°C, cone, hydrochloric acid (1.4 ml) is added to the solution and stirred for 3 hours at 25°C to 30°C. Then diisopropyl ether (100 ml) is added and precipitated solid is filtered off and dried to give 4.0 gm of donepezil hydrochloride monohydrate.
  • Example 5 Donepezil hydrochloride form H2 (5.0 gm) is added to a mixture of chloroform (100 ml) and water (1.5 ml), the contents are heated to 45°C and stirred for 8 hours at 45°C to 50°C. The solution so obtained is cooled to 25°C, diisopropyl ether (100 ml) is added to the solution and precipitated solid is filtered and dried to give 4.1 gm of donepezil hydrochloride monohydrate.
  • Example 6 Donepezil free base (4.0 gm) is dissolved in a mixture of tert-butyl alcohol (30 ml) and water (1.5 ml) at 27°C, cone, hydrochloric acid (1.2 ml) is added to the solution and stirred for 3 hours at 25°C to 30°C. The crystals so obtained are filtered and dried to give 3.5 gm of donepezil hydrochloride sesquihydrate.

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Abstract

The present invention provides novel crystalline forms of donepezil hydrochloride, processes for their preparation and pharmaceutical compositions containing them.

Description

NOVEL CRYSTALLINE FORMS OF DONEPEZIL HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention provides novel crystalline forms of donepezil hydrochloride, processes for their preparation and pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Donepezil hydrochloride of formula (1)
Figure imgf000002_0001
or 2,3-Dihydro-5,6-dimethoxy-2-[[1 -(phenylmethyl)-4-piperidinyl]methyl]-1 H- inden-1-one hydrochloride is useful for prevention and treatment of alzheimer disease. The therapeutic uses of donepezil hydrochloride and related compounds are disclosed in EP 296560.
US 6,140,321 disclosed four crystalline forms of donepezil hydrochloride, polymorph (I), polymorph (II), polymorph (III) and polymorph (IV) and processes for preparation thereof. It has now been discovered that donepezil hydrochloride can be prepared in four stable crystalline forms having good dissolution characteristics. The object of the present invention is to provide stable novel crystalline forms of donepezil hydrochloride, processes for preparing these forms and pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel crystalline form of donepezil hydrochloride, designated as form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 15.2, 18.7, 20.6, 22.3, 23.5, 24.0, 24.6, 27.0, 29.0 and 30.5 degrees. Figure 1 shows typical form H1 x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of donepezil hydrochloride form H1, which comprises: a) dissolving donepezil free base in methylene dichloride; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride form H1 from the solution formed in (b) by adding an anti-solvent.
Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil. The anti-solvent should be added in the quantity that causes the precipitation of donepezil hydrochloride under the conditions of experiment. Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
In accordance with the present invention, an another process is provided for preparation of donepezil hydrochloride form H1 , which comprises: a) dissolving donepezil hydrochloride in methylene dichloride; and b) precipitating donepezil hydrochloride form H1 from the solution formed in (a) by adding an anti-solvent.
Donepezil hydrochloride in any form, crystalline, amorphous or solvated form, may be used in (a). The anti-solvent should be added in a quantity thai causes the precipitation of donepezil hydrochloride under the conditions of experiment. Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
In accordance with the present invention, there is provided a novel crystalline form of donepezil hydrochloride, designated as form H2, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 6.6, 6.8, 10.1, 12.8, 13.7, 15.0, 15.6, 16.5, 17.3, 18.4, 19.5, 19.8, 20.0, 21.6, 21.9, 22.3, 23.9, 24.2, 24.7, 25.3, 26.0, 26.9 and 28.2 degrees. Figure 2 shows typical form H2 x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of donepezil hydrochloride form H2, which comprises: a) dissolving donepezil free base in toluene; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride form H2 by filtration or centrifugation.
Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
In accordance with the present invention, there is provided a novel crystalline form of donepezil hydrochloride monohydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1, 23.9 and 25.3 degrees. Figure 3 shows donepezil hydrochloride monohydrate x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of donepezil hydrochloride monohydrate, which comprises: a) dissolving donepezil free base in a mixture of chloroform and water; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride monohydrate from the solution formed in (b) by adding an anti-solvent.
The water can be added directly or in the form of, for example, as an aqueous solution of hydrochloric acid. Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil. Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti- solvents may also be used.
In accordance with the present invention, an another process is provided for preparation of donepezil hydrochloride monohydrate, which comprises: a) dissolving donepezil hydrochloride in a mixture of chloroform and water; and b) precipitating donepezil hydrochloride monohydrate from the solution formed in (a) by adding an anti-solvent.
Donepezil hydrochloride in any form, crystalline, amorphous or solvated form, may be used in (a). The anti-solvent should be added in a quantity that causes the precipitation of donepezil hydrochloride under the conditions of experiment. Preferable anti-solvents are diisopropyl ether, n-hexane, n-heptane and diethyl ether. A mixture of anti-solvents may also be used.
In accordance with the present invention, there is provided a novel crystalline form of donepezil hydrochloride sesquihydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.1, 10.8, 12.8, 13.3, 13.9, 15.0, 16.3, 17.1, 17.7, 19.5, 20.1, 21.4, 23.2, 24.1, 26.6, 27.3, 28.2, 29.7, 31.9 and 35.3 degrees. Figure 4 shows donepezil hydrochloride sesquihydrate x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of donepezil hydrochloride sesquihydrate, which comprises: a) dissolving donepezil free base in a mixture of tert-butyl alcohol and water; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride sesquihydrate by filtration or centrifugation.
The water can be added directly or in the form of, for example, as an aqueous solution of hydrochloric acid. Preferably, the quantity of hydrochloric acid is 0.5 to 2.0 mole per mole of donepezil.
Donepezil free base and donepezil hydrochloride used in the above processes can be obtained from the previously known methods.
In accordance with the present invention, there is provided a pharmaceutical composition comprising donepezil hydrochloride form H1 and pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising donepezil hydrochloride form H2 and pharmaceutically acceptable carrier or diluent. In accordance with the present invention, there is provided a pharmaceutical composition comprising donepezil hydrochloride monohydrate and pharmaceutically acceptable carrier or diluent.
In accordance with the present invention, there is provided a pharmaceutical composition comprising donepezil hydrochloride sesquihydrate and pharmaceutically acceptable carrier or diluent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of donepezil hydrochloride form I. Figure 2 is a x-ray powder diffraction spectrum of donepezil hydrochloride form II.
Figure 3 is a x-ray powder diffraction spectrum of donepezil hydrochloride monohydrate. Figure 4 is a x-ray powder diffraction spectrum of donepezil hydrochloride sesquihydrate. x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-K radiation.
The following examples further illustrate the present invention.
Example 1 Donepezil free base (4.0 gm) is dissolved in ethylene dichloride (20 ml) at 27°C, cone, hydrochloric acid (1.2 ml) is added to the solution and stirred for 2 hours at 25°C to 30°C. Then diisopropyl ether (75 ml) is added and the precipitated solid is filtered off and dried to give 3.0 gm of donepezil hydrochloride form H1.
Example 2
Donepezil free base (10.0 gm) is dissolved in toluene (50 ml) at 25°C, cone, hydrochloric acid (2.8 ml) is added to the solution and stirred for 6 hours at 25°C to 30°C. The crystals formed are filtered and dried to give 8.2 gm of donepezil hydrochloride form H2. Example 3
Donepezil hydrochloride form H2 (5.0 gm) is added to ethylene dichloride (100 ml), the contents are heated to 55°C and stirred for 8 hours at 55°C to 60°C. The solution so obtained is cooled to 25°C, diisopropyl ether (100 ml) is added to the solution and precipitated solid is filtered and dried to give 4.3 gm of donepezil hydrochloride form H1.
Example 4 Donepezil free base (4.0 gm) is dissolved in a mixture of chloroform (20 ml) and water (1 ml) at 25°C, cone, hydrochloric acid (1.4 ml) is added to the solution and stirred for 3 hours at 25°C to 30°C. Then diisopropyl ether (100 ml) is added and precipitated solid is filtered off and dried to give 4.0 gm of donepezil hydrochloride monohydrate. Example 5 Donepezil hydrochloride form H2 (5.0 gm) is added to a mixture of chloroform (100 ml) and water (1.5 ml), the contents are heated to 45°C and stirred for 8 hours at 45°C to 50°C. The solution so obtained is cooled to 25°C, diisopropyl ether (100 ml) is added to the solution and precipitated solid is filtered and dried to give 4.1 gm of donepezil hydrochloride monohydrate.
Example 6 Donepezil free base (4.0 gm) is dissolved in a mixture of tert-butyl alcohol (30 ml) and water (1.5 ml) at 27°C, cone, hydrochloric acid (1.2 ml) is added to the solution and stirred for 3 hours at 25°C to 30°C. The crystals so obtained are filtered and dried to give 3.5 gm of donepezil hydrochloride sesquihydrate.

Claims

We claim:
1. A crystalline donepezil hydrochloride form H1 , characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 15.2, 18.7, 20.6, 22.3, 23.5, 24.0, 24.6, 27.0, 29.0 and 30.5 degrees.
2. A crystalline donepezil hydrochloride form H1 , further characterized by an x- ray powder diffraction spectrum as in figure 1.
3. A process for preparation of donepezil hydrochloride form H1 as defined in claim 1 , which comprises the steps of: a) dissolving donepezil free base in methylene dichloride; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride form H1 from the solution formed in (b) by adding an anti-solvent.
4. A process according to claim 3, wherein the anti-solvent is diisopropyl ether, n-hexane, n-heptane or diethyl ether.
5. A process according to claim 3, wherein the anti-solvent is diisopropyl ether.
6. An another process for preparation of donepezil hydrochloride form H1 as defined in claim 1 , which comprises the steps of: a) dissolving donepezil hydrochloride in methylene dichloride; and b) precipitating donepezil hydrochloride form H1 from the solution formed in (a) by adding an anti-solvent.
7. A process according to claim 6, wherein the anti-solvent is diisopropyl ether, n-hexane, n-heptane or diethyl ether.
8. A process according to claim 6, wherein the anti-solvent is diisopropyl ether. 9. A crystalline donepezil hydrochloride form H2, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 6.6, 6.8, 10.1 , 12.8, 13.7, 15.0, 15.6, 16.5, 17.3, 18.4, 19.5, 19.8, 20.0, 21.6, 21.9, 22.3, 23.9, 24.2, 24.7, 25.3, 26.0, 26.
9 and 28.2 degrees.
10. A crystalline donepezil hydrochloride form H2 as defined in claim 9, further characterized by an x-ray powder diffraction spectrum as in figure 2.
11. A process for preparation of donepezil hydrochloride form H2 as defined in claim 9, which comprises the steps of: a) dissolving donepezil free base in toluene; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride form H2 by filtration or centrifugation.
12. A crystalline donepezil hydrochloride monohydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.0, 10.0, 12.7, 13.2, 16.2, 20.0, 21.3, 23.1, 23.9 and 25.3 degrees.
13. A crystalline donepezil hydrochloride monohydrate as defined in claim 12, further characterized by an x-ray powder diffraction spectrum as in figure 3.
14. A process for preparation of donepezil hydrochloride monohydrate as defined in claim 12, which comprises the steps of: a) dissolving donepezil free base in a mixture of chloroform and water; b) adding hydrochloric acid; and c) precipitating donepezil hydrochloride monohydrate from the solution formed in (b) by adding an anti-solvent.
15. A process according to claim 14, wherein the anti-solvent is diisopropyl ether, n-hexane, n-heptane or diethyl ether.
16. A process according to claim 14, wherein the anti-solvent is diisopropyl ether.
17. An another process for preparation of donepezil hydrochloride monohydrate as defined in claim 12, which comprises the steps of: a) dissolving donepezil hydrochloride in a mixture of chloroform and water; and b) precipitating donepezil hydrochloride monohydrate from the solution formed in (a) by adding an anti-solvent.
18. A process according to claim 17, wherein the anti-solvent is diisopropyl ether, n-hexane, n-heptane or diethyl ether.
19. A process according to claim 17, wherein the anti-solvent is diisopropyl ether.
20. A crystalline donepezil hydrochloride sesquihydrate, characterized by an x- ray powder diffraction spectrum having peaks expressed as 20 at about 5.1 , 10.8, 12.8, 13.3, 13.9, 15.0, 16.3, 17.1 , 17.7, 19.5, 20.1 , 21.4, 23.2, 24.1 , 26.6, 27.3, 28.2, 29.7, 31.9 and 35.3 degrees.
21. A crystalline donepezil hydrochloride sesquihydrate as defined in claim 20, further characterized by an x-ray powder diffraction spectrum as in figure 4.
22. A process for preparation of donepezil hydrochloride sesquihydrate as defined in claim 20, which comprises the steps of: a) dissolving donepezil free base in a mixture of tert-butyl alcohol and water; b) adding hydrochloric acid; and c) isolating donepezil hydrochloride sesquihydrate by filtration or centrifugation.
23. A pharmaceutical composition comprising donepezil hydrochloride form H1 of claim 1 and a pharmaceutically acceptable carrier or diluent.
24. A pharmaceutical composition comprising donepezil hydrochloride form H2 of claim 9 and a pharmaceutically acceptable carrier or diluent.
25. A pharmaceutical composition comprising donepezil hydrochloride monohydrate of claim 12 and a pharmaceutically acceptable carrier or diluent.
26. A pharmaceutical composition comprising donepezil hydrochloride sesquihydrate of claim 20 and a pharmaceutically acceptable carrier or diluent.
PCT/IN2003/000158 2003-04-16 2003-04-16 Novel crystalline forms of donepezil hydrochloride WO2004092137A1 (en)

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AU2003245029A AU2003245029A1 (en) 2003-04-16 2003-04-16 Novel crystalline forms of donepezil hydrochloride
PCT/IN2003/000158 WO2004092137A1 (en) 2003-04-16 2003-04-16 Novel crystalline forms of donepezil hydrochloride
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WO2006011154A1 (en) * 2004-07-28 2006-02-02 Usv Limited A novel polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine hydrochloride (donepezil hydrochloride) and a process for producing thereof
WO2006090263A1 (en) * 2005-02-28 2006-08-31 Ranbaxy Laboratories Limited Stable form i donepezil hydrochloride and process for its preparation and use in pharmaceutical compositions
WO2006097341A1 (en) * 2005-03-17 2006-09-21 Synthon B.V. Process for making crystalline donepezil hydrochloride monohydrate
WO2006111983A2 (en) * 2005-04-21 2006-10-26 Jubilant Organosys Limited NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME
WO2007015052A1 (en) * 2005-07-30 2007-02-08 Pliva Istrazivanje I Razvoj D.O.O. Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil
US7186842B2 (en) 2003-02-12 2007-03-06 Usv, Ltd. Polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-y1] methyl piperidine hydrochloride (Donepezil hydrochloride) and a process for producing thereof
WO2008012495A1 (en) * 2006-07-22 2008-01-31 Pliva Hrvatska D.O.O. Pharmaceutical formulation comprising donepezil
DE102007037932A1 (en) 2007-08-11 2009-02-12 Alfred E. Tiefenbacher Gmbh & Co.Kg Donepezil hydrochloride in amorphous form containing tablet
WO2011061591A1 (en) * 2009-11-18 2011-05-26 Jubilant Life Sciences Limited Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii
JP2012512133A (en) * 2008-12-17 2012-05-31 エーザイ・アール・アンド・ディー・マネジメント株式会社 Donepezil polymorph crystal and process for producing the same
CN103694164A (en) * 2014-01-23 2014-04-02 天津大学 New crystal form of donepezil hydrochloride and preparation method
CN106397306A (en) * 2016-10-20 2017-02-15 山东罗欣药业集团股份有限公司 Donepezil hydrochloride crystal form compound and preparation method thereof

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EP2366378A1 (en) 2010-03-01 2011-09-21 Dexcel Pharma Technologies Ltd. Sustained-release donepezil formulations

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EP1323712A1 (en) * 2000-09-25 2003-07-02 Eisai Co., Ltd. Process for producing multiform crystal of donepezil hydrochloride

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7186842B2 (en) 2003-02-12 2007-03-06 Usv, Ltd. Polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-y1] methyl piperidine hydrochloride (Donepezil hydrochloride) and a process for producing thereof
WO2006011154A1 (en) * 2004-07-28 2006-02-02 Usv Limited A novel polymorph of (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl] methyl piperidine hydrochloride (donepezil hydrochloride) and a process for producing thereof
WO2006090263A1 (en) * 2005-02-28 2006-08-31 Ranbaxy Laboratories Limited Stable form i donepezil hydrochloride and process for its preparation and use in pharmaceutical compositions
WO2006097341A1 (en) * 2005-03-17 2006-09-21 Synthon B.V. Process for making crystalline donepezil hydrochloride monohydrate
WO2006111983A3 (en) * 2005-04-21 2007-03-22 Jubilant Organosys Ltd NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME
WO2006111983A2 (en) * 2005-04-21 2006-10-26 Jubilant Organosys Limited NOVEL POLYMORPHIC FORM OF (l-BENZYL-4-[(5,6-DIMETHOXY-l- INDANONE)-2-YL]METHYL PIPERIDINE HYDROCHLORIDE AND PROCESS FOR PREPARING THE SAME
WO2007015052A1 (en) * 2005-07-30 2007-02-08 Pliva Istrazivanje I Razvoj D.O.O. Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil
WO2008012495A1 (en) * 2006-07-22 2008-01-31 Pliva Hrvatska D.O.O. Pharmaceutical formulation comprising donepezil
DE102007037932A1 (en) 2007-08-11 2009-02-12 Alfred E. Tiefenbacher Gmbh & Co.Kg Donepezil hydrochloride in amorphous form containing tablet
JP2012512133A (en) * 2008-12-17 2012-05-31 エーザイ・アール・アンド・ディー・マネジメント株式会社 Donepezil polymorph crystal and process for producing the same
WO2011061591A1 (en) * 2009-11-18 2011-05-26 Jubilant Life Sciences Limited Improved process for the preparation of 1-benzyl-4-(5,6-dimethoxy-1-indanone)-2-yl)methyl piperidine hydrochloride form-iii
CN103694164A (en) * 2014-01-23 2014-04-02 天津大学 New crystal form of donepezil hydrochloride and preparation method
CN106397306A (en) * 2016-10-20 2017-02-15 山东罗欣药业集团股份有限公司 Donepezil hydrochloride crystal form compound and preparation method thereof
CN106397306B (en) * 2016-10-20 2019-03-08 山东罗欣药业集团股份有限公司 A kind of Donepezil hydrochloride Form compound and preparation method thereof

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