WO2010071216A1 - Polymorphic crystal of donepezil and process for producing the same - Google Patents
Polymorphic crystal of donepezil and process for producing the same Download PDFInfo
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- WO2010071216A1 WO2010071216A1 PCT/JP2009/071198 JP2009071198W WO2010071216A1 WO 2010071216 A1 WO2010071216 A1 WO 2010071216A1 JP 2009071198 W JP2009071198 W JP 2009071198W WO 2010071216 A1 WO2010071216 A1 WO 2010071216A1
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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
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- 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 relates to a novel crystal polymorphism of donepezil that is an intermediate of donepezil hydrochloride as a therapeutic agent for Alzheimer-type dementia.
- the 10 present invention also relates to a process for producing the same.
- Donepezil hydrochloride (chemical name: 1- benzyl-4- [ (5, 6-dimethoxy-l-indanon) -2- yl]methylpiperidine hydrochloride) has an acetylcholinesterase inhibitory action and is useful as an agent for treating various types of dementia, and,
- Donepezil hydrochloride is produced by
- Crystals used as a pharmaceutical ingredient are required to have properties that they can be easily handled in industrial production.
- the present invention relates to a polymorphic crystal (F) of donepezil and a process for producing the same .
- the present invention includes the followings:
- a polymorphic crystal (F) of donepezil represented by the following chemical formula:
- a polymorphic crystal (F) of donepezil characterized by having peaks at chemical shifts: 132.3, 104.4, and 41.8 ppm in a 13 C solid NMR spectrum.
- a polymorphic crystal (F) of donepezil characterized by having peaks at wavenumbers: 3008,
- a process for producing a polymorphic crystal (F) of donepezil which comprises: suspending a polymorphic crystal (A) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
- a process for producing a polymorphic crystal (F) of donepezil which comprises: suspending a polymorphic crystal (B) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
- a process for producing a polymorphic crystal (F) of donepezil which comprises: suspending a polymorphic crystal (C) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
- a process for producing a polymorphic crystal (F) of donepezil which comprises: adding seed crystals of polymorphic crystal (F) to a donepezil solution, allowing precipitation to occur, and filtering off the polymorphic crystal (F) of donepezil from the obtained suspension.
- Fig. 1 shows a powder X-ray diffraction pattern of Type-F donepezil crystal.
- Fig. 2 shows an infrared absorption spectrum of Type-F donepezil crystal.
- Fig. 3 shows a 13 C solid NMR spectrum of Type-
- FIG. 4 shows results in differential scanning calorimetry (DSC) of Type-F donepezil crystal.
- Donepezil is used as a precursor for production of donepezil hydrochloride, and is an active principle exhibiting an acetylcholinesterase inhibitory action in vivo. Since donepezil itself has a poor water-solubility, it has not been used for oral drugs in its free form, but developed as oral drugs using donepezil hydrochloride having a high water-solubility. In relatively many cases, it is difficult to administer oral drugs to patients with Alzheimer's disease.
- transdermal systems such as a patch is significant for improving the compliance of not only patients but also care persons. It is known that a free form has higher skin permeability as compared with a salt thereof. In the development of transdermal systems, a free form itself is used in many cases. Thus, transdermal systems as a therapeutic agent for Alzheimer's disease, which contain donepezil as a main ingredient, are expected to be developed. [0009] Therefore, as the physical properties in the formulation of donepezil itself, in addition to such handling advantages in producing pharmaceutical ingredients that crystals are not sticky but dry and excellent in being filtered after crystallization, it is very important that the pharmaceutical ingredient is so stable that it is not converted into other crystal polymorphisms, not decomposed, and the like, during formulation.
- donepezil when supplied for formulation, from the viewpoint of stable supply, it is important to find a crystal polymorphism suitable for mass synthesis, that is, a crystal polymorphism capable of securing reproducibility in any producing scales. It has been reported that donepezil has polymorphism described in the above-mentioned Patent Literatures 2 to 5. However, it has not been known which polymorphic crystal of donepezil is suitable for formulation. [0010] The present inventors have extensively studied for searching polymorphic crystals of donepezil most suitable for formulation.
- the present inventors have found that the novel polymorphic crystal (F) of donepezil is dry, can be purified without using column chromatography, and has a very low content of residual solvents, and in addition, that the polymorphic crystal (F) of donepezil is a very preferable pharmaceutical ingredient because it is extremely stable, excellent in reproducibility in production, and suitable for mass synthesis. Thus, the present inventors have completed the present invention. [0012]
- the present invention provides a novel polymorphic crystal (F) of donepezil that is superior in stability to other crystal polymorphisms, and provides an industrial process for producing the same.
- the present invention provides the novel polymorphic crystal (F) of donepezil represented by the chemical formula shown below, and characterized by a powder X-ray diffraction pattern, an infrared absorption peak in potassium bromide and/or a 13 C solid NMR peak as follows.
- Apparatus AVANCE400 7 mm CP/MAS probe ( BRUKER)
- Chemical shift standard External standard when the chemical shift of carbonyl carbon of glycine is set as 176.03 ppm
- Peaks in the infrared absorption spectrum in potassium bromide are shown in Fig. 2. Peaks characteristic to the Type-F crystal are shown at the wavenumbers: 704, 747, 1498, 1591, 1688, 2918 and 3008 cm “1 .
- Peaks in the 13 C solid NMR spectrum are shown in Fig. 3. Peaks characteristic to the Type-F crystal are shown at the chemical shifts: 132.3, 104.4, and 41.8 ppm. [0018]
- polymorphic crystal (F) of donepezil of the present invention is different also in the results of differential scanning calorimetry (DSC) under the following conditions from other polymorphic crystals and has a completely different crystal form from the conventionally known polymorphic crystals (see Fig. 4).
- the Type-F crystal of donepezil according to the present invention can be obtained by a general crystallization method.
- seed crystals of the desired Type-F crystal are preferably added at the time of crystallization.
- the seed crystal means a very small amount of crystals whose crystal forms are known .
- the type-F crystal of donepezil can be produced by the methods described in Examples as follows:
- Type-F crystal of donepezil 1) a method of obtaining the Type-F crystal of donepezil by converting Types-A, B and C crystals of donepezil into the Type-F crystal; or 2) a method of obtaining the Type-F crystal of donepezil by dissolving donepezil in a solvent containing ethanol alone or an ethanol-water mixture solvent, followed by adding the Type-F seed crystals thereto.
- Donepezil used herein may be dry donepezil or may be donepezil containing a solvent such as ethanol and water.
- Stirring may or may not be carried out in crystallization. Crystallization can be carried out under standing still or under stirring. A crystallization temperature is not limited either, but preferable results can be obtained by carrying out crystallization usually at a temperature of ice-cold water bath, room temperature or a temperature of warm water bath. Addition of seed crystals is also arbitrary, but with the addition of them, the desired polymorphic crystals can be obtained reliably in a shorter time. [0025]
- the precipitated crystals can be collected by a usual filtration method, for example, natural filtration, filtration under suction (under reduced pressure) , and centrifugation.
- the novel polymorphic crystal (F) of the present invention is dry and can be therefore filtered off very easily in a short time.
- the crystal has excellent physical properties in handling and production efficiency.
- the filtered-off crystals can be reliably and easily made free of residual solvent by usual drying methods such as natural drying, drying under reduced pressure (under vacuum) , drying by heating, and drying by heating under reduced pressure.
- the novel crystal (F) of donepezil obtained by the present invention is extremely preferable as a pharmaceutical ingredient because it is excellent in handing properties, for example, it is not sticky but dry, excellent in filtering property after crystallization, and capable of easily being scraped in recovering its filter cake.
- Example 1 To 0.3 g of Type-A crystals, 3 ml of methanol was added. The Type-A crystals were dissolved in methanol under stirring at room temperature, followed by continuing stirring to precipitate crystals. Then, stirring was continued for six days, and precipitates were collected by filtration and dried at 50°C for one hour to give 0.074 g of Type-F crystals.
- Type-A crystals To 0.3 g of Type-A crystals, 1.5 ml of methanol was added. The Type-A crystals were suspended in methanol under stirring at room temperature for seven days. Then, crystals were collected by filtration and dried at 50 0 C for one hour to give 0.19 g of Type-F crystals. [0030]
- Type-A crystals To 0.3 g of Type-A crystals, 3 ml of 2- propanol was added. The Type-A crystals were suspended in 2-propanol under stirring at room temperature for eight days. Then, crystals were collected by filtration and dried at 50 0 C for one hour to give 0.22 g of Type-F crystals.
- Type-A crystals To 0.3 g of Type-A crystals, 3 ml of ethanol was added. The Type-A crystals were suspended in ethanol under stirring at room temperature for three days. Then, crystals were collected by filtration and dried at 50 0 C for one hour to give 0.20 g of Type-F crystals .
- Example 5 To 0.3 g of Type-B crystals, 3 ml of ethanol was added. The Type-B crystals were suspended in ethanol under stirring at room temperature for nine days. Then, crystals were collected by filtration and dried at 50°C for two hours and 45 minutes to give 0.19 g of Type-F crystals.
- Type-C crystals To 0.3 g of Type-C crystals, 3 ml of ethanol was added. The Type-C crystals were suspended in ethanol under stirring at room temperature for three days. Then, crystals were collected by filtration and dried at 5O 0 C for one hour to give 0.19 g of Type-F crystals .
- Example 8 77.0 g of the obtained donepezil wet body- was dissolved in 462 ml of ethanol, heated in a water bath at 50 0 C and then cooled, and the Type-F crystal obtained in Example 1 was added thereto at 26.4°C, then cooled to room temperature and stirred at room temperature for four days. Then, the precipitated crystals were filtrated and dried to give 58.7 g of Type-F white crystals. The obtained crystals were used as seed crystals in Examples 8 and 9 mentioned below. [0035] Example 8
- Example 9 155.8 g of donepezil wet body (dry donepezil amount: 120 g, water content: 13.5%) obtained by the similar method to that in Example 7 (1) was dissolved in a mixture solution of 720 ml of ethanol and 10 ml of water with heating at 50 0 C and then the solution was cooled to 40 0 C. 6.0 g of Type-F seed crystals were added thereto and then the mixture was gradually cooled to 8°C. 47 hours after the addition of the seed crystals, the abtained crystals were collected by filtration and dried to give 103.5 g of Type-F white crystals.
Abstract
[Problem] A novel polymorphic crystal (F) of donepezil that is a precursor for production of donepezil hydrochloride having an excellent effect as a medicine and is an active principle, which has excellent handling properties, and an industrial process for producing the novel polymorphic crystal (F). [Solution] The novel polymorphic crystal (F) of the present invention is characterized by a powder X-ray diffraction pattern, an IR absorption peak, a solid NMR spectrum, and the like, of donepezil represented by the following formula (I).
Description
DESCRIPTION
POLYMORPHIC CRYSTAL OF DONEPEZIL AND PROCESS FOR PRODUCING THE SAME
[Technical Field] 5 [0001]
The present invention relates to a novel crystal polymorphism of donepezil that is an intermediate of donepezil hydrochloride as a therapeutic agent for Alzheimer-type dementia. The 10 present invention also relates to a process for producing the same.
[Background Art] [0002]
15 Donepezil hydrochloride (chemical name: 1- benzyl-4- [ (5, 6-dimethoxy-l-indanon) -2- yl]methylpiperidine hydrochloride) has an acetylcholinesterase inhibitory action and is useful as an agent for treating various types of dementia, and,
20 in particular, very useful as an agent for preventing or treating Alzheimer-type dementia (Patent Document
1). [0003]
Donepezil hydrochloride is produced by
25 converting donepezil (chemical name: l-benzyl-4- [ (5, 6- dimethoxy-1-indanone) -2-yl]methylpiperidine) in a free form into its hydrochloride. Donepezil is used as a
precursor for production of donepezil hydrochloride. At present, ten kinds of crystal forms are known (see Patent Document 2 as to crystal forms A, B and C, Patent Document 3 as to crystal forms D and E, Patent Document 4 as to crystal forms III and IV, and Patent Document 5 as to crystal forms IV, V, VI and VII) .
[Citation List]
[Patent Literature] [PTL 1] JP-A-64-79151
[PTL 2] WO 99/29668 A
[PTL 3] WO 2008/050351 A
[PTL 4] WO 2005/089511 A
[PTL 5] EP 1669349 A
[Summary of Invention]
[Technical Problem]
[0004]
Crystals used as a pharmaceutical ingredient are required to have properties that they can be easily handled in industrial production.
[Solution to Problem] [0005] The present inventors have extensively studied. As a result, the present inventors have found novel and more stable crystals of donepezil described below, and completed the present invention. That is to
say, the present invention relates to a polymorphic crystal (F) of donepezil and a process for producing the same . [0006] That is to say, the present invention includes the followings:
(1) A polymorphic crystal (F) of donepezil represented by the following chemical formula:
and characterized by having peaks at the following diffraction angles expressed as 2θ in a powder X-ray diffraction pattern.
Diffraction angle (2 Θ , ° ) Intensity ( I / I 0)
7.859 10.0
9.023 4.6
10.615 2.1
11.982 4.3
13.108 1.9
15.625 40.6
16.186 4.8
16.899 2.3
17.633 12.3
18.237 39.0
18.98 100.0
19.852 4.2
20.707 64.3
21.061 7.7
22.005 91.6
22.525 8.5
22.917 14.4
23.463 6.1
23.790 3.1
23.951 2.8
24.517 3.3
24.789 4.4
24.959 4.1
25.499 2.3
26.298 4.8
26.824 6.8
27.720 26.9
(2) A polymorphic crystal (F) of donepezil characterized by having peaks at chemical shifts: 132.3, 104.4, and 41.8 ppm in a 13C solid NMR spectrum.
(3) A polymorphic crystal (F) of donepezil characterized by having peaks at wavenumbers: 3008,
2918, 1688, 1591, 1498, 747, and 704 cm'1 in an infrared absorption spectrum in potassium bromide.
(4) A process for producing a polymorphic
crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (A) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension. (5) A process for producing a polymorphic crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (B) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension. (6) A process for producing a polymorphic crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (C) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension. (7) A process for producing a polymorphic crystal (F) of donepezil, which comprises: adding seed crystals of polymorphic crystal (F) to a donepezil solution, allowing precipitation to occur, and filtering off the polymorphic crystal (F) of donepezil from the obtained suspension.
[Brief Description of the Drawings]
Fig. 1 shows a powder X-ray diffraction pattern of Type-F donepezil crystal. Fig. 2 shows an infrared absorption spectrum of Type-F donepezil crystal.
Fig. 3 shows a 13C solid NMR spectrum of Type-
F donepezil crystal.
Fig. 4 shows results in differential scanning calorimetry (DSC) of Type-F donepezil crystal.
[Description of Embodiment] [0007]
Hereinafter, polymorphic crystals (A, B, C, and F) of donepezil are also referred to as Type-A, Type-B, Type-C and Type-F crystals, respectively. [0008] Donepezil is used as a precursor for production of donepezil hydrochloride, and is an active principle exhibiting an acetylcholinesterase inhibitory action in vivo. Since donepezil itself has a poor water-solubility, it has not been used for oral drugs in its free form, but developed as oral drugs using donepezil hydrochloride having a high water-solubility. In relatively many cases, it is difficult to administer oral drugs to patients with Alzheimer's disease. Therefore, development of transdermal systems such as a patch is significant for improving the compliance of not only patients but also care persons. It is known that a free form has higher skin permeability as compared with a salt thereof. In the development of transdermal systems, a free form itself is used in many cases. Thus, transdermal systems as a therapeutic agent for Alzheimer's disease, which contain donepezil as a main ingredient, are expected to be developed. [0009]
Therefore, as the physical properties in the formulation of donepezil itself, in addition to such handling advantages in producing pharmaceutical ingredients that crystals are not sticky but dry and excellent in being filtered after crystallization, it is very important that the pharmaceutical ingredient is so stable that it is not converted into other crystal polymorphisms, not decomposed, and the like, during formulation. Furthermore, when donepezil is supplied for formulation, from the viewpoint of stable supply, it is important to find a crystal polymorphism suitable for mass synthesis, that is, a crystal polymorphism capable of securing reproducibility in any producing scales. It has been reported that donepezil has polymorphism described in the above-mentioned Patent Literatures 2 to 5. However, it has not been known which polymorphic crystal of donepezil is suitable for formulation. [0010] The present inventors have extensively studied for searching polymorphic crystals of donepezil most suitable for formulation. As a result, the present inventors have found that when polymorphic crystals A, B and C described in Patent Literature 2 (WO 99/29668 A) are stirred in a solvent such as ethanol for a long time, the polymorphic crystals are converted into a novel polymorphic crystal (F) that is more stable. The present inventors have further
succeeded in developing a simpler method for producing the novel polymorphic crystal (F) . [0011]
The present inventors have found that the novel polymorphic crystal (F) of donepezil is dry, can be purified without using column chromatography, and has a very low content of residual solvents, and in addition, that the polymorphic crystal (F) of donepezil is a very preferable pharmaceutical ingredient because it is extremely stable, excellent in reproducibility in production, and suitable for mass synthesis. Thus, the present inventors have completed the present invention. [0012]
That is to say, the present invention provides a novel polymorphic crystal (F) of donepezil that is superior in stability to other crystal polymorphisms, and provides an industrial process for producing the same. [0013] More specifically, the present invention provides the novel polymorphic crystal (F) of donepezil represented by the chemical formula shown below, and characterized by a powder X-ray diffraction pattern, an infrared absorption peak in potassium bromide and/or a 13C solid NMR peak as follows.
Measurement Method and Conditions for Powder X-ray Diffraction Pattern
(1) Measurement Method About 100 mg of sample was measured for its powder X-ray diffraction pattern under the following measurement conditions.
(2) Measurement Conditions
Target: Cu Filter: monochromator
Voltage: 35 KV Current: 40 mA Slit: DS 0.3 Scan speed: 2°/min Range: 5-30°
Wave length: 1.5406 A Sampling width: 0.020° [0015]
Measurement Method and Conditions for Infrared Absorption Spectrum
Measurement was carried out by FT-IR (SCAN: 2 mm/sec, 4.0 cm"1) according to the Japanese Pharmacopoeia, General Tests, Processes and Apparatus, Infrared Spectrophotometry, Potassium bromide disk method. [0016] Measurement Conditions for Solid NMR
Apparatus: AVANCE400 7 mm CP/MAS probe
( BRUKER)
Observation nucleus: 13C (100.6248425 MHz!
Chemical shift standard: External standard when the chemical shift of carbonyl carbon of glycine is set as 176.03 ppm
Pulse mode: CP-TOSS
Pulse waiting time: 10 seconds
Sample frequency: 5000 Hz
Temperature: room temperature [0017]
(1) Type-F Crystal
Peaks in the powder X-ray diffraction pattern are shown in Fig. 1.
Peaks in the infrared absorption spectrum in potassium bromide are shown in Fig. 2. Peaks characteristic to the Type-F crystal are shown at the wavenumbers: 704, 747, 1498, 1591, 1688, 2918 and 3008 cm"1.
Peaks in the 13C solid NMR spectrum are shown in Fig. 3. Peaks characteristic to the Type-F crystal are shown at the chemical shifts: 132.3, 104.4, and 41.8 ppm. [0018]
Furthermore, the polymorphic crystal (F) of donepezil of the present invention is different also in the results of differential scanning calorimetry (DSC) under the following conditions from other polymorphic crystals and has a completely different crystal form
from the conventionally known polymorphic crystals (see Fig. 4). [0019]
Method and Conditions for Differential Scanning Calorimetry (DSC)
Sample (1.04 mg) was weighed and subject to thermal analysis under the following conditions. Reference: empty Scan speed: 10°C/min Sampling: 1.0 sec
Upper limit: 3000C Lower limit: Room temperature Thermocouple: PL [0020] A process for actually producing the Type-F crystal of donepezil is specifically described below. Note here that the donepezil according to the present invention refers to a free form of donepezil hydrochloride described in Example 4 of JP-A-64-79151, that is, l-benzyl-4- [ (5, 6-dimethoxy-l-indanone) -2- yl ] methylpiperidine . [0021]
The Type-F crystal of donepezil according to the present invention can be obtained by a general crystallization method. However, in order to obtain the Type-F crystal more reliably, seed crystals of the desired Type-F crystal are preferably added at the time of crystallization. Hereupon, the seed crystal means a
very small amount of crystals whose crystal forms are known . [0022]
The type-F crystal of donepezil can be produced by the methods described in Examples as follows:
1) a method of obtaining the Type-F crystal of donepezil by converting Types-A, B and C crystals of donepezil into the Type-F crystal; or 2) a method of obtaining the Type-F crystal of donepezil by dissolving donepezil in a solvent containing ethanol alone or an ethanol-water mixture solvent, followed by adding the Type-F seed crystals thereto. [0023]
Donepezil used herein may be dry donepezil or may be donepezil containing a solvent such as ethanol and water. [0024] Stirring may or may not be carried out in crystallization. Crystallization can be carried out under standing still or under stirring. A crystallization temperature is not limited either, but preferable results can be obtained by carrying out crystallization usually at a temperature of ice-cold water bath, room temperature or a temperature of warm water bath. Addition of seed crystals is also arbitrary, but with the addition of them, the desired
polymorphic crystals can be obtained reliably in a shorter time. [0025]
The precipitated crystals can be collected by a usual filtration method, for example, natural filtration, filtration under suction (under reduced pressure) , and centrifugation. At this time, the novel polymorphic crystal (F) of the present invention is dry and can be therefore filtered off very easily in a short time. Thus, the crystal has excellent physical properties in handling and production efficiency. The filtered-off crystals can be reliably and easily made free of residual solvent by usual drying methods such as natural drying, drying under reduced pressure (under vacuum) , drying by heating, and drying by heating under reduced pressure. [0026]
The novel crystal (F) of donepezil obtained by the present invention is extremely preferable as a pharmaceutical ingredient because it is excellent in handing properties, for example, it is not sticky but dry, excellent in filtering property after crystallization, and capable of easily being scraped in recovering its filter cake. [0027]
Hereinafter, the present invention is described in more detail with reference to Examples below. Needless to say, the present invention is not
necessarily limited to these Examples .
[Examples]
[ 0028 ]
Example 1 To 0.3 g of Type-A crystals, 3 ml of methanol was added. The Type-A crystals were dissolved in methanol under stirring at room temperature, followed by continuing stirring to precipitate crystals. Then, stirring was continued for six days, and precipitates were collected by filtration and dried at 50°C for one hour to give 0.074 g of Type-F crystals.
[0029]
Example 2
To 0.3 g of Type-A crystals, 1.5 ml of methanol was added. The Type-A crystals were suspended in methanol under stirring at room temperature for seven days. Then, crystals were collected by filtration and dried at 500C for one hour to give 0.19 g of Type-F crystals. [0030]
Example 3
To 0.3 g of Type-A crystals, 3 ml of 2- propanol was added. The Type-A crystals were suspended in 2-propanol under stirring at room temperature for eight days. Then, crystals were collected by filtration and dried at 500C for one hour to give 0.22 g of Type-F crystals.
[0031]
Example 4
To 0.3 g of Type-A crystals, 3 ml of ethanol was added. The Type-A crystals were suspended in ethanol under stirring at room temperature for three days. Then, crystals were collected by filtration and dried at 500C for one hour to give 0.20 g of Type-F crystals .
[0032]
Example 5 To 0.3 g of Type-B crystals, 3 ml of ethanol was added. The Type-B crystals were suspended in ethanol under stirring at room temperature for nine days. Then, crystals were collected by filtration and dried at 50°C for two hours and 45 minutes to give 0.19 g of Type-F crystals.
[0033]
Example 6
To 0.3 g of Type-C crystals, 3 ml of ethanol was added. The Type-C crystals were suspended in ethanol under stirring at room temperature for three days. Then, crystals were collected by filtration and dried at 5O0C for one hour to give 0.19 g of Type-F crystals .
[0034] Example 7
(1) 100 g (240 mmol) of donepezil hydrochloride was dissolved in 900 ml of water and 600 ml of ethanol, and 38 g of 25% aqueous caustic soda was
dropped under heating at 400C until pH of the solution became about 10. One hour after the completion of the dropping, the solution was cooled to a temperature of 5°C, and allowed to stand under stirring over night. The next day, the resulting crystals were filtered to give 77.0 g of donepezil wet body.
(2) 77.0 g of the obtained donepezil wet body- was dissolved in 462 ml of ethanol, heated in a water bath at 500C and then cooled, and the Type-F crystal obtained in Example 1 was added thereto at 26.4°C, then cooled to room temperature and stirred at room temperature for four days. Then, the precipitated crystals were filtrated and dried to give 58.7 g of Type-F white crystals. The obtained crystals were used as seed crystals in Examples 8 and 9 mentioned below. [0035] Example 8
114.7 g of donepezil was dissolved in 688 ml of ethanol under heating at 5O0C and then the solution was cooled to 4O0C. 5.7 g of Type-F seed crystals were added thereto, maintained at 400C for 20 hours, then cooled to 300C at 2°C/hr, and then cooled to 80C at about 10°C/hr. 38 hours after the temperature reached 8°C, crystals were collected by filtration and dried to give 107.5 g of Type-F white crystals.
1H-NMR (600 MHz, CDCl3) : δ 7.31 (m, 4H), 7.24 (m, IH), 7.17 (s, IH), 6.85 (s, IH), 3.96 (s, 3H), 3.90 (s, 3H),
3.50 (s, 2H) , 3.23 (dd, IH) , 2.90 (m, IH) , 2.89 (m, IH) , 2.70 (m, 2H) , 1.98 (m, IH) , 1.96 (m, IH) , 1.92 (m, IH) , 1.73 (m, IH) , 1.66 (m, IH) , 1.49 (m, IH) , 1.38 (m, IH) , 1.32 (m, IH) , 1.31 (m, IH) . HRMS (ESI) Calculated for C24H29NO3: [M+H] + : 380.2220, Measured: 380.2215.
IR (KBr, cm'1) : 3008, 2918, 1688, 1591, 1498, 747, 704. [0036] Example 9 155.8 g of donepezil wet body (dry donepezil amount: 120 g, water content: 13.5%) obtained by the similar method to that in Example 7 (1) was dissolved in a mixture solution of 720 ml of ethanol and 10 ml of water with heating at 500C and then the solution was cooled to 400C. 6.0 g of Type-F seed crystals were added thereto and then the mixture was gradually cooled to 8°C. 47 hours after the addition of the seed crystals, the abtained crystals were collected by filtration and dried to give 103.5 g of Type-F white crystals.
Claims
1. A polymorphic crystal (F) of donepezil represented by the following chemical formula:
and characterized by having peaks at the following diffraction angles expressed as 2θ in a powder X-ray diffraction pattern.
Diffraction angle (2 θ , ° ) Intensity ( I / I 0)
7.859 10.0
9.023 4.6
10.615 2.1
11.982 4.3
13.108 1.9
15.625 40.6
16.186 4.8
16.899 2.3
17.633 12.3
18.237 39.0
18.98 100.0
19.852 4.2
20.707 64.3
21.061 7.7
22.005 91.6
22.525 8.5
22.917 14.4
23.463 6.1
23.790 3.1
23.951 2.8
24.517 3.3
24.789 4.4
24.959 4.1
25.499 2.3
26.298 4.8
26.824 6.8
27.720 26.9
2. A polymorphic crystal (F) of donepezil characterized by having peaks at chemical shifts: 132.3, 104.4, and 41.8 ppm in a 13C solid NMR spectrum.
3. A polymorphic crystal (F) of donepezil characterized by having peaks at wavenumbers: 3008, 2918, 1688, 1591, 1498, 747, and 704 cm'1 in an infrared absorption spectrum in potassium bromide.
4. A process for producing a polymorphic crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (A) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
5. A process for producing a polymorphic crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (B) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
6. A process for producing a polymorphic crystal (F) of donepezil, which comprises: suspending a polymorphic crystal (C) of donepezil in a solvent, stirring, and filtering off a polymorphic crystal (F) of donepezil from the obtained suspension.
7. A process for producing a polymorphic crystal (F) of donepezil, which comprises: adding seed crystals of polymorphic crystal (F) to a donepezil solution, and filtering off a precipitated polymorphic crystal (F) of donepezil.
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| JP2011522719A JP5562337B2 (en) | 2008-12-17 | 2009-12-15 | Donepezil polymorph crystal and process for producing the same |
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| US13827708P | 2008-12-17 | 2008-12-17 | |
| JP2008320551 | 2008-12-17 | ||
| JP2008-320551 | 2008-12-17 | ||
| US61/138,277 | 2008-12-17 |
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| WO2010071216A1 true WO2010071216A1 (en) | 2010-06-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/JP2009/071198 WO2010071216A1 (en) | 2008-12-17 | 2009-12-15 | Polymorphic crystal of donepezil and process for producing the same |
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| WO (1) | WO2010071216A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9757338B2 (en) | 2010-03-01 | 2017-09-12 | Dexcel Pharma Technologies Ltd. | Sustained-release donepezil formulation |
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| TWI660965B (en) * | 2014-01-15 | 2019-06-01 | 美商基利科學股份有限公司 | Solid forms of tenofovir |
| JP6785822B2 (en) | 2018-06-11 | 2020-11-18 | 光山 冬樹 | Alzheimer's disease drug |
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|---|---|---|---|---|
| JPS6479151A (en) | 1987-06-22 | 1989-03-24 | Eisai Co Ltd | Cyclic amine derivative |
| WO1999029668A1 (en) | 1997-12-05 | 1999-06-17 | Eisai Co., Ltd. | Donepezil polycrystals and process for producing the same |
| WO2005089511A2 (en) | 2004-03-19 | 2005-09-29 | Transform Pharmaceuticals, Inc. | Novel pharmaceutical forms, and methods of making and using the same |
| EP1669349A1 (en) | 2004-12-08 | 2006-06-14 | Chemagis Ltd. | New crystalline forms of donepezil base |
| WO2008050351A1 (en) | 2006-10-25 | 2008-05-02 | Jubilant Organosys Limited | NOVEL POLYMORPHIC FORMS OF l-BENZYL-4-[(5,6-DIMETHOXY-l-INDANONE)-2-YL]METHYL PIPERIDINE [DONEPEZIL] AND PROCESS FOR PREPARING THE SAME |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6453576A (en) * | 1987-08-25 | 1989-03-01 | Ricoh Kk | Semiconductor device |
| EP1019374B1 (en) * | 1996-06-07 | 2003-01-02 | Eisai Co., Ltd. | Polymorphs of donepezil hydrochloride and process for production |
| IL154711A0 (en) * | 2000-09-25 | 2003-10-31 | Eisai Co Ltd | Methods of producing polymorphic crystals of donepezil hydrochloride |
| US7560560B2 (en) * | 2003-04-16 | 2009-07-14 | Hetero Drugs Limited | Crystalline forms of donepezil hydrochloride |
-
2009
- 2009-12-15 WO PCT/JP2009/071198 patent/WO2010071216A1/en active Application Filing
- 2009-12-15 JP JP2011522719A patent/JP5562337B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6479151A (en) | 1987-06-22 | 1989-03-24 | Eisai Co Ltd | Cyclic amine derivative |
| WO1999029668A1 (en) | 1997-12-05 | 1999-06-17 | Eisai Co., Ltd. | Donepezil polycrystals and process for producing the same |
| EP1048653A1 (en) * | 1997-12-05 | 2000-11-02 | Eisai Co., Ltd. | Donepezil polycrystals and process for producing the same |
| WO2005089511A2 (en) | 2004-03-19 | 2005-09-29 | Transform Pharmaceuticals, Inc. | Novel pharmaceutical forms, and methods of making and using the same |
| EP1669349A1 (en) | 2004-12-08 | 2006-06-14 | Chemagis Ltd. | New crystalline forms of donepezil base |
| EP1935884A2 (en) * | 2004-12-08 | 2008-06-25 | Chemagis Ltd. | New crystalline forms of donepezil base |
| WO2008050351A1 (en) | 2006-10-25 | 2008-05-02 | Jubilant Organosys Limited | NOVEL POLYMORPHIC FORMS OF l-BENZYL-4-[(5,6-DIMETHOXY-l-INDANONE)-2-YL]METHYL PIPERIDINE [DONEPEZIL] AND PROCESS FOR PREPARING THE SAME |
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| CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9757338B2 (en) | 2010-03-01 | 2017-09-12 | Dexcel Pharma Technologies Ltd. | Sustained-release donepezil formulation |
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| Publication number | Publication date |
|---|---|
| JP5562337B2 (en) | 2014-07-30 |
| JP2012512133A (en) | 2012-05-31 |
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