WO2004099142A1 - Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs - Google Patents

Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs Download PDF

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Publication number
WO2004099142A1
WO2004099142A1 PCT/IB2004/001348 IB2004001348W WO2004099142A1 WO 2004099142 A1 WO2004099142 A1 WO 2004099142A1 IB 2004001348 W IB2004001348 W IB 2004001348W WO 2004099142 A1 WO2004099142 A1 WO 2004099142A1
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donepezil
hydrobromide
process according
donepezil hydrobromide
salt
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PCT/IB2004/001348
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French (fr)
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Yatendra Kumar
Mohan Prasad
Asok Nath
Nitin Maheshwari
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Ranbaxy Laboratories Limited
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Publication of WO2004099142A1 publication Critical patent/WO2004099142A1/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

  • a hydrobromide salt of donepezil which is l-[benzyl-4-(5,6 dimethoxy-1- indanon)-2-yl] methyl piperidine, is provided. Also crystalline polymorphic forms I and II of hydrobromide salt of donepezil are provided. Further, processes for preparing the polymorphic forms, pharmaceutical compositions comprising the salts, and methods of treatment comprising administration of the salts are provided.
  • Benzyl-piperidylmethyl-indanones such as donepezil have an excellent pharmacological action as prophylatic or medicament for senile dementia especially for Alzheimer's Disease.
  • UnitediStates Patent No. 4,895,841 discloses several substituted piperidylalkyl indanones including l-[benzyl-4-(5,6 dimethoxy-l-indanon)-2-yl]methyl piperidine, that is, donepezil.
  • donepezil hydrobromide The hydrobromide salt of donepezil, that is, donepezil hydrobromide.
  • donepezil hydrobromide in a solid state is provided
  • donepezil hydrobromide in a crystalline form is provided.
  • crystalline polymorphic forms I and II of donepezil hydrobromide are provided.
  • Process for preparing donepezil hydrobromide comprising contacting donepezil free base with hydrogen bromide in a suitable solvent and precipitating donepezil hydrobromide.
  • Further aspects include methods for treating or preventing a disease caused by acetylcholinesterase activity, comprising administering donepezil hydrobromide, or a pharmaceutical composition that comprises donepezil hydrobromide along with pharmaceutically acceptable excipients.
  • Fig. 1 is a powder X-ray diffraction pattern of donepezil hydrobromide Form I crystals.
  • Fig. 2 s a powder X-ray diffraction pattern of donepezil hydrobromide Form II crystals.
  • Fig. 3 is an infrared absorption spectrum of donepezil hydrobromide Form I crystals.
  • Fig. 4 is an infrared absorption spectrum of donepezil hydrobromide Form II crystals.
  • form I of donepezil hydrobromide can be characterized by X-ray peaks at about 10.2, 12.5, 13.5, 20.46, 20.82, 23.52, and 27.22 ⁇ 0.2 degrees two-theta; and medium peaks at about 19.16, 20.14, 25.20, 26.86 and 28.76 ⁇ 0.2 degrees two-theta.
  • form II of donepezil hydrobromide can be characterized by strong X-ray peaks at about 21.46 ⁇ 0.2, 10.2 , 18.2 and 24.42 ⁇ 0.2 degrees two-theta and medium-peaks at about 19.64, 20.36, 23.72 ,24.92, and 27.82 ⁇ 0.2 degrees two-theta.
  • donepezil hydrobromide having form I can be characterized by the X-ray powder diffraction pattern given in Fig.l, and IR spectrum given in Fig.3.
  • donepezil hydrobromide having form II can be characterized by the X-ray powder diffraction pattern given in Fig. 2, and IR spectrum given in Fig. 4.
  • the donepezil free base to be used in the preparation processes can be obtained by methods known in the art, including those described in, for example, United States Patent Nos. 4,895,841 and 5,606,064; in International Applications WO 97/22584, WO 2000/9483 WO 99/36405, and WO 99/29668; in the publication J Med Chem., 1995, 38 (24), 4821-4829, and pending Indian application 352/DEL/2003.
  • the starting donepezil free base may be obtained as a solution directly from a reaction in which donepezil is formed and used as such without isolation.
  • Hydrogen bromide used in the salt-formation process may be an aqueous solution or in gaseous form.
  • Aqueous solution of hydrogen bromide is commercially available.
  • Gaseous hydrogen bromide may be obtained commercially, or prepared by methods known in the art.
  • the precipitation of donepezil hydrobromide may be spontaneous, depending upon the solvent used and the conditions. Precipitation may otherwise occur on addition of an antisolvent, that is, a solvent in which donepezil hydrobromide is insoluble or sparingly soluble, to the solvent in which donepezil hydrobromide is prepared. Alternatively, precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature is elevated. The precipitation may also be facilitated by adding seed of donepezil hydrobromide, or by reducing the volume of the solution.
  • an antisolvent that is, a solvent in which donepezil hydrobromide is insoluble or sparingly soluble
  • Suitable solvents for preparing donepezil hydrobromide are the customary inert solvents that do not change under the reaction conditions.
  • suitable solvents for carrying out the process include water, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, chlorinated hydrocarbons such as methylene chloride,ethylenedichloride, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, esters such as ethylacetate and isopropylacetate, cyclic ethers such as dioxane and tetrahydrofuran and mixtures thereof.
  • the amount of the solvent used is not critical, and can be varied depending on the type of solvent, lot size etc.
  • the operation conditions, for example stirring, are not critical, and crystallization may be conducted with or without stirring. Addition of seed crystals is optional and may be used for obtaining the desired polymo ⁇ hic crystals in a shorter time.
  • the crystallization time is also varied depending on these operation conditions, but may be usually 30 minutes to 2 hours or so.
  • the crystallization temperature is specific for precipitation of each polymorph.
  • Donepezil hydrobromide in form I crystallizes at ambient or lower temperatures, for example, at about 0°C to about 25°C
  • donepezil hydrobromide in form II crystallizes above ambient temperature, for example at about 25°C to about 60°C.
  • the precipitated polymorphic crystals may be isolated by conventional methods such as filtration or centrifugation, optionally followed by washing, and drying.
  • Donepezil hydrobromide, in forms I and/or II crystals is non sticky and has excellent filtering properties, enabling easy scraping and handling of filter cake. Crystalline polymorphic forms I and/or II of donepezil hydrobromide have good flowability and is thus suitable for formulation into pharmaceutical dosage forms.
  • Donepezil hydrobromide has strong and highly selective antiacetylcholinesterase activity. Accordingly, there is provided a method of producing acetylcholinesterase inhibitory action, comprising administering donepezil hydrobromide.
  • donepezil hydrobromide can be used for the treatment of Huntington's chorea, Pick's disease and delayed ataxia and tardive dyskinesia other than senile dementia of the Alzheimer type.
  • senile dementia diseases such as dementia of Alzheimer type; cerebro vascular diseases accompanying cerebral apoplexy such as cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis and head injury; and aprosexia, disturbance of speech, hypobulia, emotional changes, attention deficit/hyperactivity disorder, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes accompanying encephalitis and cerebral palsy.
  • the salt can be administered as part of a pharmaceutical composition.
  • a pharmaceutical composition comprising donepezil hydrobromide and pharmaceutically acceptable carriers, diluents or excipient and optionally other therapeutic ingredients.
  • the salt may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example peroral or parental.
  • X-Ray Diffractograms were taken with a diffractometer manufactured by Rigaku Corporation, specifically the model RU-H3R.
  • the goniometer was a CN2155A3, and the X-Ray tube was equipped with a Cu target anode.
  • the settings for the divergence slits was 1 0, with the receiving slit 0.15mm, and the scatter slit 1 0.
  • the operating power was 40 KV, 100 niA, the scanning speed was 2 deg/min step: 0.02 deg, and the wave length was 1.5406 A.
  • Moisture content (KF) 4.03% w/w
  • Bromide content 17.56% W/W
  • XRD and IR spectra were similar to those of Fig. 1 and Fig. 3.

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Abstract

A hydrobromide salt of donepezil, which is 1-[benzyl-4-(5,6 dimethoxy-1-indanon)-2-yl] methyl piperidine, is provided. Also crystalline polymorphic forms I and II of hydrobromide salt of donepezil are provided. Further, processes for preparing the polymorphic forms, pharmaceutical compositions comprising the salts, and methods of treatment comprising administration of the salts are provided.

Description

HYDROBROMIDE SALT OF BENZYL-PIPERIDYLMETHYL-INDANONE AND
ITS POLYMORPHS
Field of the Invention
A hydrobromide salt of donepezil, which is l-[benzyl-4-(5,6 dimethoxy-1- indanon)-2-yl] methyl piperidine, is provided. Also crystalline polymorphic forms I and II of hydrobromide salt of donepezil are provided. Further, processes for preparing the polymorphic forms, pharmaceutical compositions comprising the salts, and methods of treatment comprising administration of the salts are provided.
Background of the Invention
Benzyl-piperidylmethyl-indanones such as donepezil have an excellent pharmacological action as prophylatic or medicament for senile dementia especially for Alzheimer's Disease. UnitediStates Patent No. 4,895,841 discloses several substituted piperidylalkyl indanones including l-[benzyl-4-(5,6 dimethoxy-l-indanon)-2-yl]methyl piperidine, that is, donepezil.
While the patent mentions that some of the disclosed compounds which can form a salt with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, as well as, organic salts like formate, acetate, triflouroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate, only the hydrochloride salts of the disclosed compounds have been prepared. Thus, no hydrobromide salt of donepezil has been isolated or characterized.
Summary of the Invention
The hydrobromide salt of donepezil, that is, donepezil hydrobromide, is provided. In one aspect, donepezil hydrobromide in a solid state is provided, hi yet another aspect, donepezil hydrobromide in a crystalline form is provided. In a further aspect, crystalline polymorphic forms I and II of donepezil hydrobromide are provided.
Process for preparing donepezil hydrobromide is also provided, comprising contacting donepezil free base with hydrogen bromide in a suitable solvent and precipitating donepezil hydrobromide.
Further aspects include methods for treating or preventing a disease caused by acetylcholinesterase activity, comprising administering donepezil hydrobromide, or a pharmaceutical composition that comprises donepezil hydrobromide along with pharmaceutically acceptable excipients.
Brief Description of the Figures
Fig. 1 is a powder X-ray diffraction pattern of donepezil hydrobromide Form I crystals.
Fig. 2 s a powder X-ray diffraction pattern of donepezil hydrobromide Form II crystals.
Fig. 3 is an infrared absorption spectrum of donepezil hydrobromide Form I crystals.
Fig. 4 is an infrared absorption spectrum of donepezil hydrobromide Form II crystals.
In general, form I of donepezil hydrobromide can be characterized by X-ray peaks at about 10.2, 12.5, 13.5, 20.46, 20.82, 23.52, and 27.22 ± 0.2 degrees two-theta; and medium peaks at about 19.16, 20.14, 25.20, 26.86 and 28.76 ± 0.2 degrees two-theta. In general, form II of donepezil hydrobromide can be characterized by strong X-ray peaks at about 21.46 ± 0.2, 10.2 , 18.2 and 24.42 ± 0.2 degrees two-theta and medium-peaks at about 19.64, 20.36, 23.72 ,24.92, and 27.82 ± 0.2 degrees two-theta.
In one embodiment, donepezil hydrobromide having form I can be characterized by the X-ray powder diffraction pattern given in Fig.l, and IR spectrum given in Fig.3.
In another embodiment donepezil hydrobromide having form II can be characterized by the X-ray powder diffraction pattern given in Fig. 2, and IR spectrum given in Fig. 4.
The donepezil free base to be used in the preparation processes can be obtained by methods known in the art, including those described in, for example, United States Patent Nos. 4,895,841 and 5,606,064; in International Applications WO 97/22584, WO 2000/9483 WO 99/36405, and WO 99/29668; in the publication J Med Chem., 1995, 38 (24), 4821-4829, and pending Indian application 352/DEL/2003. The starting donepezil free base may be obtained as a solution directly from a reaction in which donepezil is formed and used as such without isolation.
Hydrogen bromide used in the salt-formation process may be an aqueous solution or in gaseous form. Aqueous solution of hydrogen bromide is commercially available. Gaseous hydrogen bromide may be obtained commercially, or prepared by methods known in the art.
The precipitation of donepezil hydrobromide may be spontaneous, depending upon the solvent used and the conditions. Precipitation may otherwise occur on addition of an antisolvent, that is, a solvent in which donepezil hydrobromide is insoluble or sparingly soluble, to the solvent in which donepezil hydrobromide is prepared. Alternatively, precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature is elevated. The precipitation may also be facilitated by adding seed of donepezil hydrobromide, or by reducing the volume of the solution.
Suitable solvents for preparing donepezil hydrobromide are the customary inert solvents that do not change under the reaction conditions. Examples of suitable solvents for carrying out the process include water, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, chlorinated hydrocarbons such as methylene chloride,ethylenedichloride, dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide, esters such as ethylacetate and isopropylacetate, cyclic ethers such as dioxane and tetrahydrofuran and mixtures thereof.
Examples of antisolvents that may be added to precipitate out donepezil hydrobromide include hydrocarbons such as hexane, cyclohexane, toluene, heptane and octane; lower alkyl ethers such as diethylether and dusopropylether and mixtures thereof.
The amount of the solvent used is not critical, and can be varied depending on the type of solvent, lot size etc. The operation conditions, for example stirring, are not critical, and crystallization may be conducted with or without stirring. Addition of seed crystals is optional and may be used for obtaining the desired polymoφhic crystals in a shorter time. The crystallization time is also varied depending on these operation conditions, but may be usually 30 minutes to 2 hours or so.
The crystallization temperature is specific for precipitation of each polymorph. Donepezil hydrobromide in form I crystallizes at ambient or lower temperatures, for example, at about 0°C to about 25°C, whereas donepezil hydrobromide in form II crystallizes above ambient temperature, for example at about 25°C to about 60°C. The precipitated polymorphic crystals may be isolated by conventional methods such as filtration or centrifugation, optionally followed by washing, and drying. Donepezil hydrobromide, in forms I and/or II crystals, is non sticky and has excellent filtering properties, enabling easy scraping and handling of filter cake. Crystalline polymorphic forms I and/or II of donepezil hydrobromide have good flowability and is thus suitable for formulation into pharmaceutical dosage forms.
Donepezil hydrobromide has strong and highly selective antiacetylcholinesterase activity. Accordingly, there is provided a method of producing acetylcholinesterase inhibitory action, comprising administering donepezil hydrobromide. Thus, donepezil hydrobromide can be used for the treatment of Huntington's chorea, Pick's disease and delayed ataxia and tardive dyskinesia other than senile dementia of the Alzheimer type. Furthermore, it is a useful therapeutic agent in the treatment or prevention of various kinds of senile dementia diseases such as dementia of Alzheimer type; cerebro vascular diseases accompanying cerebral apoplexy such as cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis and head injury; and aprosexia, disturbance of speech, hypobulia, emotional changes, attention deficit/hyperactivity disorder, recent memory disturbance, hallucinatory-paranoid syndrome, behavioral changes accompanying encephalitis and cerebral palsy.
The salt can be administered as part of a pharmaceutical composition. Accordingly, in a further aspect, there is provided a pharmaceutical composition comprising donepezil hydrobromide and pharmaceutically acceptable carriers, diluents or excipient and optionally other therapeutic ingredients. The salt may be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed for example peroral or parental.
In the following section, embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.
Examples General Experimental Methods - Powder X-Ray Diffraction
X-Ray Diffractograms were taken with a diffractometer manufactured by Rigaku Corporation, specifically the model RU-H3R. The goniometer was a CN2155A3, and the X-Ray tube was equipped with a Cu target anode. The settings for the divergence slits was 1 0, with the receiving slit 0.15mm, and the scatter slit 1 0. The operating power was 40 KV, 100 niA, the scanning speed was 2 deg/min step: 0.02 deg, and the wave length was 1.5406 A.
General Experimental Methods - FT-Infrared
Infrared spectra were taken on a Perkin Elmer, 16 PC, with scan settings of 16 scans, 4.0 cm.'1, according to the USP 25, general test methods page 1920. Infrared absorption spectrum were taken by the potassium bromide pellet method. Example A: Preparation of donepezil free base by Preparation I
To a stirred mixture of 2,3-dihydro-5,6-dimethoxy-2-(4-piperidinyl)methyl-indan- 1-one hydrochloride (lOg), tetra butylammonium bromide(lg), potassium carbonate (9g) in water (40 ml) and methylene chloride (50ml), benzylbromide (5.3gm) was added at 20- 25°C over 30 minutes. After addition, the reaction mixture was stirred at the same temperature for 30 minutes. The two layers were separated and the organic layer was stirred with a mixture of concentrated hydrochloride (6.4g) and water (20ml) at 20-25°C for 15 minutes. The two layers were separated and organic layer was concentrated. After dissolving the residue in water(lθθml) followed by washing of aqueous solution with ethyl acetate (50ml), pH of the aqueous solution was adjusted to 9.5 with aqueous ammonia solution (3.5ml). The aqueous solution was then extracted twice with ethyl acetate (50ml). The combined ethyl acetate extract was washed with water. The organic layer was then treated with activated carbon(lg) at room temperature for 15 minutes and then filtered. Concentration of the combined filtrate afforded a residue of the title compound.
Example 1 : Preparation of donepezil hydrobromide Form I
The residue from preparation I (Example A) was dissolved in methanol (50ml). To the solution was added aqueous hydrobromide solution, (50 %, 6.5g) diluted with methanol (10ml). Diisopropyl ether (120ml) was then added to the solution at 25°C. Stirring at 5-10°C for 30 minutes afforded the crystals. Filtration of the crystals followed by drying produced title compound (12g).
Moisture content (KF) : 4.03% w/w, Bromide content: 17.56% W/W; XRD and IR spectra were similar to those of Fig. 1 and Fig. 3.
Example 2: Preparation of donepezil hydrobromide Form II
The residue from Preparation 1 (Example A) was dissolved in methanol (50ml). To the solution was added aqueous hydrobromide solution (50 %, 6.5gm) diluted with methanol (10ml). Diisopropyl ether (120ml) was then added to the solution at 40°C. Stirring at 40-45°C for 60 minutes afforded the crystals. Filtration of the crystals followed by drying produced title compound (12g).
Moisture content (KF): 0.7% w/w, Bromide content: 17.36% W/W; XRD and IR spectra were similar to those of Fig. 2 and Fig. 4

Claims

We Claim:
1. A hydrobromide salt of donepezil .
2. The salt according to claim 1, which is in a solid state.
3. The salt according to claim 2, which is in a crystalline form.
4. The salt according to claim 3, which is in polymorphic form I.
5. The salt according to claim 3, which is in polymorphic form II.
6. A process for preparing donepezil hydrobromide which comprises contacting donepezil free base with hydrogen bromide in a suitable solvent, and precipitating donepezil hydrobromide.
7. The process according to claim 6, wherein the solvent is selected from the group consisting of water, ketones, alcohols, esters, nitriles, chlorinated hydrocarbons, cyclic ethers and dipolar aprotic solvents.
8. The process according to claim 7, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
9. The process according to claim 6, wherein an antisolvent is added to precipitate donepezil hydrobromide.
10. The process according to claim 9, wherein the antisolvent is selected from the group consisting of lower alkyl ethers ,hydrocarbons and mixtures thereof.
11. The process according to claim 10, wherein the lower alkyl ethers are selected from the group consisting of diethylether , dusopropylether and mixtures thereof.
12. The process according to claim 6, wherein a seed of donepezil hydrobromide is used.
13. The process according to claim 6, wherein crystalline form of donepezil hydrobromide is obtained.
14. The process according to claim 6 or 13, wherein precipitation is performed at ambient or lower temperature to obtain donepezil hydrobromide in form I.
15. The process according to claim 14 ,wherein the temperature is from about 0°C to about 25°C.
16. The process according to claim 6 or 13, wherein precipitation is performed above ambient temperature to obtain donepezil hydrobromide in form II.
17. The process according to claim 16,wherein the temperature is from about 25°C to about 60°C.
18. A method of producing acetylcholinesterase inhibitory action in mammals comprising administering donepezil hydrobromide.
19. A method of treating or preventing various kinds of senile dementia diseases such as dementia of Alzheimer type; cerebrovascular diseases accompanying cerebral apoplexy such as cerebral hemorrhage or cerebral infarcts, cerebral arteriosclerosis and head injury; and aprosexia, disturbance of speech, hypobulia, emotional changes, attention deficit/hyperactivity disorder, recent memory disturbance, hallucinatory- paranoid syndrome, behavioral changes accompanying encephalitis and cerebral palsy; which comprises administering donepezil hydrobromide.
20. A method of treating various kind of diseases like Huntington's chorea, Pick's disease and delayed ataxia, and tardive dyskinesia other than senile dementia of the Alzheimer type.
21. The method according to claim 18, 19 or 20, wherein crystalline form of donepezil hydrobromide is used.
22. The method according to claim 21, wherein polymorphic form I of donepezil hydrobromide is used.
23. The method according to claim 21, wherein polymorphic form II of donepezil hydrobromide is used.
24. A pharmaceutical composition comprising donepezil hydrobromide and pharmaceutically acceptable carriers, diluents or exipients for use in the treatment or prevention of a disease caused by acetylcholinsterase activity.
25. The pharmaceutical composition according to claim 24, wherein crystalline form of donepezil hydrobromide is used.
26. The pharmaceutical composition according to claim 25, wherein polymorphic form
I of donepezil hydrobromide is used.
27. The pharmaceutical composition according to claim 25, wherein polymorphic form
II of donepezil hydrobromide is used.
PCT/IB2004/001348 2003-05-05 2004-05-03 Hydrobromide salt of benzyl-piperidylmethyl-indanone and its polymorphs WO2004099142A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1669349A1 (en) * 2004-12-08 2006-06-14 Chemagis Ltd. New crystalline forms of donepezil base
WO2006015338A3 (en) * 2004-07-30 2006-07-20 Reddys Lab Ltd Dr Crystalline form of donepezil hydrochloride
WO2007013922A1 (en) * 2005-07-20 2007-02-01 Eisai R & D Management Co., Ltd. 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine hydrobromide or crystals thereof
US20080306271A1 (en) * 2005-12-20 2008-12-11 Jozsef Neu Novel Process for Production of Highly Pure Polymorph (I) Donepezil Hydrochloride
US7592459B2 (en) 2004-09-29 2009-09-22 Chemagis Ltd. Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022584A1 (en) * 1995-12-15 1997-06-26 Pfizer Inc. Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine
WO1997046526A1 (en) * 1996-06-07 1997-12-11 Eisai Co., Ltd. Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production
WO1999036405A1 (en) * 1998-01-16 1999-07-22 Eisai Co., Ltd. Process for production of donepezil derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022584A1 (en) * 1995-12-15 1997-06-26 Pfizer Inc. Processes and intermediates for preparing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine
WO1997046526A1 (en) * 1996-06-07 1997-12-11 Eisai Co., Ltd. Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production
WO1999036405A1 (en) * 1998-01-16 1999-07-22 Eisai Co., Ltd. Process for production of donepezil derivative

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015338A3 (en) * 2004-07-30 2006-07-20 Reddys Lab Ltd Dr Crystalline form of donepezil hydrochloride
US7592459B2 (en) 2004-09-29 2009-09-22 Chemagis Ltd. Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride
EP1669349A1 (en) * 2004-12-08 2006-06-14 Chemagis Ltd. New crystalline forms of donepezil base
EP1935884A3 (en) * 2004-12-08 2008-07-09 Chemagis Ltd. New crystalline forms of donepezil base
WO2007013922A1 (en) * 2005-07-20 2007-02-01 Eisai R & D Management Co., Ltd. 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl] methylpiperidine hydrobromide or crystals thereof
US20080306271A1 (en) * 2005-12-20 2008-12-11 Jozsef Neu Novel Process for Production of Highly Pure Polymorph (I) Donepezil Hydrochloride

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