U.S. patent application number 10/380780 was filed with the patent office on 2004-02-19 for process for producing multiform crystal of donepezil hydrochloride.
Invention is credited to Imai, Akio, Shimotani, Akihiko.
Application Number | 20040034057 10/380780 |
Document ID | / |
Family ID | 26600625 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040034057 |
Kind Code |
A1 |
Imai, Akio ; et al. |
February 19, 2004 |
Process for producing multiform crystal of donepezil
hydrochloride
Abstract
The present invention provides a simple method of producing
polymorphic crystal (III), which has high safety to environment and
the bodies of operators; is gentle to environment; and can produce
at low costs; and has a high refining effect. It is a method of
producing polymorphic crystal (III) of donepezil hydrochloride
(chemical name:
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine.multidot.mono-
hydrochloride) represented by the following structural formula
(formula (I)), which comprises dissolving donepezil (chemical name:
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) in
ethanol; and adding hydrochloric acid or hydrogen chloride thereto,
followed by stirring.
Inventors: |
Imai, Akio; (Ibaraki,
JP) ; Shimotani, Akihiko; (Ibaraki, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
26600625 |
Appl. No.: |
10/380780 |
Filed: |
March 18, 2003 |
PCT Filed: |
September 17, 2001 |
PCT NO: |
PCT/JP01/08057 |
Current U.S.
Class: |
514/315 ;
546/184 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 9/10 20180101; A61P 25/00 20180101; C07D 211/32 20130101; A61P
43/00 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/315 ;
546/184 |
International
Class: |
A61K 031/445; C07D
211/82 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 2000 |
JP |
2000-289956 |
Oct 23, 2000 |
JP |
2000-322184 |
Claims
1. A method of producing polymorphic crystal (III) of donepezil
hydrochloride (chemical name:
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-
methylpiperidine.multidot.monohydrochloride) represented by the
following structural formula (formula (I)), which comprises
dissolving donepezil (chemical name:
1-benzyl-4-[(5,6-dimethoxy-l-indanon)-2-yl]methylpiperidi- ne) in
ethanol; adding hydrochloric acid or hydrogen chloride thereto; and
stirring. 3
2. A method of producing polymorphic crystal (III) of donepezil
hydrochloride, which comprises dissolving donepezil in ethanol;
adding hydrochloric acid or hydrogen chloride thereto; stirring;
and then collecting by filtration and drying the crystals.
3. The method of producing polymorphic crystal (III) of donepezil
hydrochloride according to claim 1 or 2, wherein the polymorphic
crystal (III) of donepezil hydrochloride is a polymorphic crystal
having peaks at the following diffraction angles (2.theta.) in its
powder X-ray diffraction patterns;
6 TABLE 1 Diffraction angle (2 .theta..degree.) Intensity (I/Io)
6.56 30 9.94 8 13.00 17 15.00 47 15.26 14 15.74 6 16.48 35 17.42 4
18.10 21 18.50 56 19.50 17 20.10 32 20.94 21 21.66 100 22.32 25
22.92 17 23.92 19 24.68 17 26.00 44 27.20 23 28.02 29 28.22 40
28.60 13
and absorption at the following wave numbers in its infrared
absorption spectrum in potassium bromide: 559, 641, 648, 702, 749,
765, 786, 807, 851, 872, 927, 949, 966, 975, 982, 1007, 1034, 1071,
1080, 1111, 1119, 1131, 1177, 1190, 1205, 1217, 1230, 1250, 1265,
1292, 1313, 1367, 1389, 1420, 1438, 1453, 1461, 1470, 1500, 1589,
1605, 1697, 2407, 2419, 2461, 2624, 2641, 2651, 2667, 2837, 2848,
2873, 2924, 2954, 2961, 2993, 3007, 3377 and 3433 cm.sup.-1, or a
polymorphic crystal having peaks at the following diffraction
angles (2.theta.) in its powder X-ray diffraction patterns;
7 TABLE 2 Diffraction angle (2 .theta..degree.) Intensity (I/Io)
6.48 21 9.84 7 12.96 19 14.94 45 15.20 13 16.44 31 18.04 20 18.46
55 19.44 17 20.02 30 20.86 20 21.02 13 21.58 100 22.22 23 22.90 15
23.92 13 24.64 15 25.92 40 26.18 17 27.14 21 28.14 37 28.56 11
29.94 12
and absorption at the following wave numbers in its infrared
absorption spectrum in potassium bromide: 558.3, 641.1, 702.4,
748.5, 765.0, 786.1, 807.3, 850.8, 872.0, 926.8, 974.9, 1034.1,
1071.5, 1111.6, 1190.1, 1216.6, 1265.4, 1291.9, 1312.9, 1364.4,
1420.2, 1438.1, 1458.8, 1499.1, 1522.2, 1542.6, 1560.1,1570.2,
1589.1, 1638.8, 1647.8, 1654.3,1697.3, 1718.1, 1734.5, 1751.4,
1773.7, 1793.5, 1845.8, 2345.3, 2461.6, 2924.2 and 3447.9
cm.sup.-1.
4. The method of producing polymorphic crystal (III) of donepezil
hydrochloride according to claim 1 or 2, wherein the amount of
ethanol is 3 to 20 parts by weight to one part by weight of
donepezil.
5. The method of producing polymorphic crystal (III) of donepezil
hydrochloride according to claim 1 or 2, which comprises, after
adding hydrochloric acid or hydrogen chloride thereto, stirring
while keeping the internal temperature at 10 to 40.degree. C.
6. The method of producing polymorphic crystal (III) of donepezil
hydrochloride according to claim 5, which comprises, after adding
hydrochloric acid or hydrogen chloride thereto, stirring while
keeping the internal temperature at 10 to 40.degree. C.; and, after
one hour passes after crystals starts precipitating, cooling to the
internal temperature of 0.degree. C. or more and less than
10.degree. C.
7. The method of producing polymorphic crystal (III) of donepezil
hydrochloride according to claim 1 or 2, wherein after hydrochloric
acid or hydrogen chloride is added thereto, seed crystals of
polymorphic crystal (III) of donepezil hydrochloride is added
thereto in an amount of 0.01 to 10% by weight to the weight of
donepezil.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a method of industrially
producing a highly stable polymorphic crystal (III) of donepezil
hydrochloride (chemical name:
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidi-
ne.multidot.monohydrochloride) which is disclosed in JP-A 10-53576
(WO-A 97-46527) and has a superior effect as medicines.
PRIOR ART
[0002] Donepezil hydrochloride has an acetylcholinesterase
inhibitory action and is useful as an agent for treating,
preventing or improving various senile dementia especially
Alzheimer-type senile dementia, cerebrovascular disorder associated
with cerebral apoplexy (cerebral hemorrhage and cerebral
infarction), cerebral arteriosclerosis, head injury etc.,
attention-deficit, logopathy, hypobulia, attention deficit
hyperactivity disorders, emotional disorders, memorization
disorders, paranoid hallucinatory states, abnormal behavior etc.
associated with sequelae of encephalitis, cerebral paralysis etc.,
etc.
[0003] This agent is mostly administered for a long period of time
in the forms of oral solid formulations such as tablets, capsules
and granules, percutaneous absorption formulations such as
ointments, tapes and suppositories, and injections. The storage
stability of the agent in the course of distribution and in
hospitals and homes is therefore important. Particularly, in the
case of oral solid formulations prepared by mixing original drug
put in a powder state with various additives, the selection of
polymorphic crystal of the original drug having superior physical
properties including stability is important.
[0004] In JP-A 10-53576, five types of polymorphic crystal ((I),
(II), (III), (IV) and (V)) having high stability and the physical
properties thereof are disclosed. It is shown that, particularly,
the polymorphic crystal (III) has the following superior
characteristics to the other crystal forms: (1) it has a lower
water content and does not absorb moisture until relative humidity
reaches 96.6% (25.degree. C., two weeks) and (2) an increase in the
amount of HPLC impurities is not observed when it is stored at
80.degree. C. for two weeks. Also, as a method of producing the
polymorphic crystal (III) of donepezil hydrochloride, a method in
which using donepezil, hydrochlorination and crystallization are
carried out either simultaneously or successively (the following
methods 1) to 9)) and a method in which an amorphous or various
polymorphic crystals of donepezil hydrochloride is used to carry
out crystallization of the polymorphic crystal (III) (the following
methods 10) to 18)) are disclosed.
[0005] Production method in which hydrochlorination and
crystallization of the polymorphic crystal (III) are carried out
either simultaneously or successively by using donepezil (JP-A
10-53576)
[0006] 1) Donepezil is dissolved in acetone, to which is added
hydrochloric acid or hydrogen chloride.
[0007] 2) Donepezil is dissolved in ethyl acetate, to which is
added hydrochloric acid or hydrogen chloride.
[0008] 3) Donepezil is dissolved in ethanol, to which is added
hydrochloric acid or hydrogen chloride, and then is added one
solvent selected from diethyl ether, isopropyl ether or
n-hexane.
[0009] 4) Donepezil is dissolved in methanol, to which is added
hydrochloric acid or hydrogen chloride, and then is added
acetone.
[0010] 5) Donepezil is dissolved in ethanol, to which is added
hydrochloric acid or hydrogen chloride, and then is added t-butyl
methyl ether.
[0011] 6) Donepezil is dissolved in acetonitrile, acetone, hydrate
acetone, tetrahydrofuran or N,N-dimethylformamide, to which is
added hydrochloric acid or hydrogen chloride.
[0012] 7) Donepezil is dissolved in ethyl acetate, to which is
added hydrochloric acid or hydrogen chloride, and then is added
t-butyl methyl ether.
[0013] 8) Donepezil is dissolved in dimethylsulfoxide, to which is
added hydrochloric acid or hydrogen chloride, and then is added
t-butyl methyl ether.
[0014] 9) Donepezil is dissolved in toluene, to which is added
hydrochloric acid or hydrogen chloride.
[0015] Production method in which crystallization of the
polymorphic crystal (III) is carried out using amorphous or various
polymeric crystals of donepezil hydrochloride (JP-A 10-53576)
[0016] 10) Donepezil hydrochloride is dissolved in ethanol, to
which is added diethyl ether.
[0017] 11) Donepezil hydrochloride is dissolved in methylene
chloride, to which is added n-hexane.
[0018] 12) The polymorphic crystal (I) or (II) of donepezil
hydrochloride is heated.
[0019] 13) Donepezil hydrochloride is recrystallized from methanol
at 10.degree. C. or more.
[0020] 14) Donepezil hydrochloride is dissolved in methanol, to
which is added t-butyl methyl ether or acetonitrile.
[0021] 15) Donepezil hydrochloride is dissolved in ethanol, to
which is added t-butyl methyl ether or acetonitrile, followed by
stirring at 10.degree. C. or more.
[0022] 16) Donepezil hydrochloride is dissolved in
N,N-dimethylformamide or dimethylsulfoxide, to which is then added
t-butyl methyl ether.
[0023] 17) Donepezil hydrochloride is recrystallized from isopropyl
alcohol.
[0024] 18) The polymorphic crystal (I), (II), (IV) or (V) of
donepezil hydrochloride or amorphous donepezil hydrochloride is
stirred in a solvent such as methanol, ethanol, ethyl acetate or
acetone, and converted.
[0025] However, the methods 1) to 9) in which using donepezil,
hydrochlorination and crystallization of the polymolphic crystal
(III) are carried out either simultaneously or successively in a
solvent use, as a solvent, 1) acetone, 2) ethyl acetate, 3) one
solvent selected from diethyl ether, isopropyl ether and n-hexane,
4) acetone, 5) t-butyl methyl ether, 6) acetonitrile, acetone,
hydrate acetone, tetrahydrofuran or N,N-dimethylformamide, 7) ethyl
acetate and t-butyl methyl ether, 8) dimethylsulfoxide and t-butyl
methyl ether, and 9) toluene, respectively. These methods therefore
have the problems concerning flammability based on high volatility
of organic solvents, safety to environment and the health of
operators and solvents remaining in the produced donepezil
hydrochloride crystal and the like.
[0026] Also, the methods 10) to 18) (excluding the method (12)) in
which using amorphous donepezil hydrochloride or various
polymorphic crystals of donepezil hydrochloride, the
crystallization of the polymorphic crystal (III) is carried out
also use, as a solvent, 10) diethyl ether, 11) methylene chloride
and n-hexane, 13) methanol, 14) methanol and t-butyl methyl ether
or acetonitrile, 15) t-butyl methyl ether or acetonitrile, 16)
N,N-dimethylformamide or dimethylsulfoxide and t-butyl methyl
ether, 17) isopropyl alcohol and 18) methanol, ethyl acetate or
acetone and the like. These methods therefore have the same
problems as above.
[0027] It is to be noted that the production method 12) in which
"the polymorphic crystals (I) or (II) of donepezil hydrochloride is
heated" poses many problems as an industrial production method
because decomposition is accelerated in a heating step and it is
therefore difficult to secure chemical stability.
[0028] Also, in 18), a method in which the polymorphic crystal (I),
(II), (IV) or (V) of donepezil hydrochloride or amorphous donepezil
hydrochloride is stirred in ethanol which is a highly safe solvent
is also disclosed. However, no simple method for preparing the
polymorphic crystal (III) of donepezil hydrochloride directly from
donepezil has been developed yet.
[0029] A simple method of producing the polymorphic crystal (III)
which method has high safety to environment and the bodies of
operators, is gentle to environment, can produce at low costs and
is excellent in refining effect has been desired much as the method
of the production of the polymorphic crystal (III).
[0030] Particularly, "a method of producing the polymorphic crystal
(III) which can produce the polymorphic crystal (III) of donepezil
hydrochloride directly from donepezil" has been sought, which is a
method of producing the polymorphic crystal (III) fulfilling these
requirements and is a simpler process.
DISCLOSURE OF THE INVENTION
[0031] In the above situation, the inventors of the present
invention have made earnest studies and as a result, found that the
intended object can be attained by the structure shown below, and
they completed the present invention.
[0032] The present invention is a method of producing polymorphic
crystal (III) of donepezil hydrochloride (chemical name:
1-benzyl-4-[(5,6-dimetho-
xy-1-indanon)-2-yl]methylpiperidine.multidot.monohydrochloride)
represented by the following structural formula (formula (I)),
which comprises dissolving donepezil (chemical name:
1-benzyl-4-[(5,6-dimethoxy- -1-indanon)-2-yl]methylpiperidine) in
ethanol; adding hydrochloric acid or hydrogen chloride thereto; and
stirring. The synthetic flow according to the present invention is
shown in the (formula 2). Ethanol used to dissolve donepezil may be
either pure ethanol or denatured ethanol. 1
[0033] In JP-A 10-53576, the presence of polymorphic crystals (I),
(II), (III), (IV) and (V) is disclosed. It is clarified that each
has its intrinsic powder X-ray diffraction pattern, infrared
absorption spectrum and melting point, and is largely different in
physical properties. Especially, it is also shown that the
polymorphic crystal (III) has more marked characteristics than
other crystal types: specifically it has smaller hygroscopicity and
higher heat stability.
[0034] That is, it provides the method of producing polymorphic
crystal (III) of donepezil hydrochloride according to claim 1 or 2,
wherein the polymorphic crystal (III) of donepezil hydrochloride is
a crystal having peaks at the following diffraction angles
expressed as 2.theta. in its powder X-ray diffraction patterns:
1 TABLE 3 Diffraction angle (2 .theta..degree.) Intensity (I/Io)
6.56 30 9.94 8 13.00 17 15.00 47 15.26 14 15.74 6 16.48 35 17.42 4
18.10 21 18.50 56 19.50 17 20.10 32 20.94 21 21.66 100 22.32 25
22.92 17 23.92 19 24.68 17 26.00 44 27.20 23 28.02 29 28.22 40
28.60 13
[0035] and absorption at the following wave numbers in its infrared
absorption spectrum in potassium bromide: 559, 641, 648, 702, 749,
765, 786, 807, 851, 872, 927, 949, 966, 975, 982, 1007, 1034, 1071,
1080, 1111, 1119, 1131, 1177, 1190, 1205, 1217, 1230, 1250, 1265,
1292, 1313, 1367, 1389, 1420, 1438, 1453, 1461, 1470, 1500, 1589,
1605, 1697, 2407, 2419, 2461, 2624, 2641, 2651, 2667, 2837, 2848,
2873, 2924, 2954, 2961, 2993, 3007, 3377 and 3433 cm.sup.-1, or a
polymorphic crystal having peaks at the following diffraction
angles expressed as 2.theta. in its powder X-ray diffraction
patterns:
2 TABLE 4 Diffraction angle (2 .theta..degree.) Intensity (I/Io)
6.48 21 9.84 7 12.96 19 14.94 45 15.20 13 16.44 31 18.04 20 18.46
55 19.44 17 20.02 30 20.86 20 21.02 13 21.58 100 22.22 23 22.90 15
23.92 13 24.64 15 25.92 40 26.18 17 27.14 21 28.14 37 28.56 11
29.94 12
[0036] and absorption at the following wave numbers in its infrared
absorption spectrum in potassium bromide: 558.3, 641.1, 702.4,
748.5, 765.0, 786.1, 807.3, 850.8, 872.0, 926.8, 974.9, 1034.1,
1071.5, 1111.6, 1190.1, 1216.6, 1265.4, 1291.9,1312.9, 1364.4,
1420.2, 1438.1,1458.8, 1499.1, 1522.2, 1542.6, 1560.1, 1570.2,
1589.1, 1638.8,1647.8, 1654.3, 1697.3, 1718.1, 1734.5, 1751.4,
1773.7, 1793.5,1845.8, 2345.3,2461.6, 2924.2 and 3447.9 cm.sup.-1.
The melting point of the polymorphic crystal (III) is 229 to
231.degree. C. (decomposed).
[0037] Further, the present invention is a method of producing
polymorphic crystal (III) of donepezil hydrochloride, which
comprises dissolving donepezil in ethanol; adding hydrochloric acid
or hydrogen chloride thereto; stirring; and then collecting by
filtration and drying the crystals.
[0038] In the present invention, the amount of ethanol used as the
crystallizing solvent is not particularly limited, however, the
amount is preferably 3 to 20 parts by weight, more preferably 3 to
15 parts by weight and still more preferably 3 to 10 parts by
weight to one part by weight of donepezil.
[0039] Although no particular limitation is imposed on the internal
temperature (crystallization temperature) of the solvent when
stirring after donepezil is dissolved in ethanol and hydrochloric
acid or hydrogen chloride is added, the temperature is generally 10
to 40.degree. C., preferably 15 to 35.degree. C. and more
preferably 20 to 30.degree. C. It is desirable to stir with keeping
that internal temperature. This makes it possible to produce
polymorphic crystal (III) of donepezil hydrochloride which is
reduced in the amount of the residual solvent (ethanol), and has a
small particle diameter and a small 90% volume cumulative diameter
in the particle size distribution in a high yield.
[0040] The particle size distribution of the polymorphic crystal
(III) of donepezil hydrochloride produced in the present invention
is affected also by stirring speed and stirring time besides the
crystallization temperature, and varies with time during
crystallization. Specifically, in the crystallizing step, crystals
having a double-peak type particle size distribution first
precipitates. When the stirring is continued, the coagulate falls
to small pieces and the resulting crystals has a small diameter,
showing a particle size distribution with a single peak. It is
therefore desirable to increase stirring speed and/or to set a
baffle plate in a reactor to carry out stirring, to thereby
accelerate the collapse of the coagulate.
[0041] It is generally preferable that the stirring speed be 10 to
1000 m/min in terms of line speed, though it differs depending on
the size of the reactor (apparatus).
[0042] When donepezil is dissolved in ethanol, hydrochloric acid or
hydrogen chloride is added thereto and the mixture is stirred, the
precipitation of polymorphic crystal of donepezil hydrochloride
starts immediately. In order to obtain the polymorphic crystal
(III) of donepezil hydrochloride in a high yield, it is necessary
to take a plenty time for allowing the system to stand with
stirring after the precipitation of crystals starts. It is
desirable to continue stirring for at least one hour after the
precipitation of crystal starts.
[0043] Also, a process may be adopted in which after hydrochloric
acid or hydrogen chloride is added, the system is stirred under
keeping the internal temperature at 10 to 40.degree. C., and then
cooled to 0.degree. C. or more and less than 10.degree. C. on and
after one hour passes after the precipitation of crystal starts.
This cooling operation ensures that the polymorphic crystal (III)
can be obtained in a high yield.
[0044] Moreover, in the present invention, polymorphic crystal
(III) of donepezil hydrochloride may be added as seed crystals to
the system and stirred, after donepezile is dissolved in ethanol
and hydrochloric acid or hydrogen chloride is added thereto. The
amount of the polymorphic crystal (III) of donepezil hydrochloride
to be added as the seed crystals is usually 0.01 to 10% by weight,
preferably 0.01 to 5% by weight and particularly preferably 0.1 to
1% by weight to one part by weight of donepezil.
[0045] The residual solvent in the polymorphic crystal (III)
obtained by the method of producing polymorphic crystal (III) of
donepezil hydrochloride according to the present invention and the
waste solvent generated in the production steps are only ethanol
having almost no safety problem, and also the amount of these
solvents is very small. Therefore, it is superior in safety to a
patient who takes the product and to operators, and also in safety
to working environment. Also, it has the effect of improving
qualities from a viewpoint of the residual solvents.
[0046] In addition, the production method according to the present
invention has the effect of refining donepezil and therefore
polymorphic crystal (III) of donepezil hydrochloride with high
purity can be produced.
[0047] In the present invention, the polymorphic crystal (III) of
donepezil hydrochloride may be produced using, for example, the
following method.
[0048] 1 kg of donepezil is dissolved by stirring in 6.4 kg of
ethanol under heating, followed by adding 302 g of concentrated
hydrochloric acid thereto. Then, it is continued stirring while
keeping the internal temperature at about 10 to 40.degree. C. After
the precipitation started, the mixture is stirred at the internal
temperature of about 10 to 40.degree. C. for 18 hours and then
cooled to the internal temperature of 9.degree. C. The crystals are
collected by filtration and dried about 5 hours after the cooling
is started, to produce polymorphic crystal (III) of donepezil
hydrochloride.
EXAMPLES
[0049] The present invention will be further explained in more
detail by way of the following Examples, which, however, are not
intended to be limiting of the present invention.
Example 1
[0050] 50 g of donepezil was dissolved by stirring in 315 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C. Then, it was cooled and continued stirring while keeping the
internal temperature at 30.degree. C. Crystals started
precipitating about 30 minutes after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 15.degree.
C. for 18 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 4 hours after the cooling was started, to give 52.32 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
95.5%).
Example 2
[0051] 50 g of donepezil was dissolved by stirring in 240 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C. Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 1 hour after the concentrated hydrochloric acid
was poured into the mixture. After the precipitation started, the
mixture was stirred at the internal temperature of 25.degree. C.
for 17 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 3 hours after the cooling was started, to give 52.25 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
95.3%).
Example 3
[0052] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C. After concentrated hydrochloric acid was poured, 100 mg of seed
crystals were added. The mixture was cooled and continued stirring
while keeping the internal temperature at about 20.degree. C.
Crystals started precipitating immediately after the seed crystals
were added. After the precipitation started, the mixture was
stirred at the internal temperature of 20.degree. C. for 18 hours
and then cooled to the internal temperature of 9.degree. C. The
crystals were collected by filtration and dried about 3 hours after
the cooling was started, to give 52.90 g of polymorphic crystal
(III) of donepezil hydrochloride (yield: 96.5%).
Example 4
[0053] 50 g of donepezil was dissolved by stirring in 280 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 28.degree.
C. Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 40 minutes after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 25.degree.
C. for 18 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 4 hours after the cooling was started, to give 52.81 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
96.4%).
Example 5
[0054] 30 g of donepezil was dissolved by stirring in 360 g of
ethanol under heating, followed by adding 9 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C.
[0055] Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 2 hours after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 25.degree.
C. for 17 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 4 hours after the cooling was started, to give 30.85 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
93.8%).
Example 6
[0056] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C.
[0057] Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 30 minutes after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 25.degree.
C. for 18 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 48 hours after the cooling was started, to give 52.47 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
95.7%).
Example 7
[0058] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C.
[0059] Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 1 hour after the concentrated hydrochloric acid
was poured into the mixture. After the precipitation started, the
mixture was stirred at the internal temperature of 25.degree. C.
for 22 hours. Then, the crystals were collected by filtration and
dried, to give 51.28 g of polymorphic crystal (III) of donepezil
hydrochloride (yield: 93.6%).
Example 8
[0060] 50 g of donepezil was dissolved by stirring in 320 g (400
ml) of ethanol under heating, followed by adding 15.1 g of
concentrated hydrochloric acid thereto at the internal temperature
of 30.degree. C. Then, it was cooled and continued stirring while
keeping the internal temperature at about 20.degree. C. Crystals
started precipitating about 30 minutes after the concentrated
hydrochloric acid was poured into the mixture. After the
precipitation started, the mixture was stirred at the internal
temperature of 20.degree. C. for 18 hours and then cooled to the
internal temperature of 9.degree. C. The crystals were collected by
filtration and dried about 5 hours and a half after the cooling was
started, to give 52.3 g of polymorphic crystal (III) of donepezil
hydrochloride (yield: 95.4%).
Example 9
[0061] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 30.degree.
C.
[0062] Then, it was cooled and continued stirring while keeping the
internal temperature at about 25.degree. C. Crystals started
precipitating about 30 minutes after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 25.degree.
C. for 18 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 4 hours after the cooling was started, to give 52.5 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
95.8%).
Example 10
[0063] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 32.degree.
C.
[0064] Then, it was cooled and continued stirring while keeping the
internal temperature at about 30.degree. C. Crystals started
precipitating about 30 minutes after the concentrated hydrochloric
acid was poured into the mixture. After the precipitation started,
the mixture was stirred at the internal temperature of 30.degree.
C. for 17 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 5 hours after the cooling was started, to give 52.74 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
96.2%).
Example 11
[0065] 50 g of donepezil was dissolved by stirring in 320 g of
ethanol under heating, followed by adding 15.1 g of concentrated
hydrochloric acid thereto at the internal temperature of 35.degree.
C.
[0066] It was continued stirring while keeping the internal
temperature at about 35.degree. C. Crystals started precipitating
about 1 hour and a half after the concentrated hydrochloric acid
was poured into the mixture. After the precipitation started, the
mixture was stirred at the internal temperature of 35.degree. C.
for 19 hours and then cooled to the internal temperature of
9.degree. C. The crystals were collected by filtration and dried
about 4 hours after the cooling was started, to give 52.37 g of
polymorphic crystal (III) of donepezil hydrochloride (yield:
95.6%).
Example 12
[0067] Using a 200 L reactor can (equipped with a retreated
impellor and a baffle plate) provided with a glass lining, 12.9 kg
of donepezil was dissolved in 103 L of denatured ethanol by heating
under stirring (linear velocity: 144 m/min). When the internal
temperature reached 30.degree. C., 3.91 kg of concentrated
hydrochloric acid was added thereto. After concentrated
hydrochloric acid was added, 25 g of seed crystals were added.
Then, the internal temperature of the mixture was adjusted at about
25.degree. C. 16 hours after the precipitation started, it was
cooled to the internal temperature of 9.degree. C. The crystals
were collected by filtration and dried about 4 hours after the
cooling was started, to give 13.19 kg of polymorphic crystal (III)
of donepezil hydrochloride (yield: 93%).
[0068] The present invention is a simpler method of producing
polymorphic crystal (III) of donepezil hydrochloride, which can
produce the polymorphic crystal (III) directly from donepezil.
Particularly, the method has high safety to environment and the
bodies of operators; is gentle to environment; and can produce
polymorphic crystal (III) of donepezil hydrochloride having a high
refining effect at low costs.
[0069] Examples of the effect thereof will be shown below.
Experimental Example
[0070] (1) Safety of the Production Method According to the Present
Invention and Effect of Improving Qualities
[0071] With regard to the polymorphic crystal (III) of donepezil
hydrochloride obtained in Example 9, the type and amount of
residual solvents were evaluated by gas chromatography. Also, the
amount of the waste solvent generated in the "step of producing
polymorphic crystal (III) of donepezil hydrochloride from
donepezil" in Example 9 was measured. As a control test,
polymorphic crystal (III) of donepezil hydrochloride was produced
by the method (Control Example 1) shown below according to the
method described in the publication (Example 97) of JP-A 10-53576,
and the same evaluation test was conducted.
[0072] The results are shown in Table 5.
Control Example 1
[0073] 500 ml of ethanol was added to 50 g of donepezil to dissolve
donepezil by heating at 40.degree. C. After cooling to room
temperature, 15.05 g of concentrated hydrochloric acid was added
thereto at the internal temperature of 20.degree. C. After stirring
for 9 minutes, 750 ml of isopropyl ether was added thereto at the
internal temperature of 20.degree. C. and the resulting mixture was
continued stirring at room temperature for 120 minutes. Then, the
precipitated crystals were collected by filtration and dried, to
give polymorphic crystal (III) of donepezil hydrochloride.
3TABLE 5 Example 9 Control Example 1 The amount of the 1) Ethanol
200 ppm 200 ppm residual solvent 2) Isopropyl ether -- 100 ppm The
amount of the 1) Ethanol 400 ml 500 ml waste solvent 2) Isopropyl
ether -- 750 ml Total 400 ml 1250 ml
[0074] The residual solvent in the polymorphic crystal (III) of
donepezil hydrochloride obtained in Example 9 was only ethanol free
from any safety problem, and also the amount of the solvent was as
very small as 200 ppm (0.02%). On the other hand, the residual
solvents in the polymorphic crystal (III) of donepezil
hydrochloride obtained in Control Example 1 were 200 ppm (0.02%) of
ethanol and 100 ppm (0.01%) of isopropyl ether. Isopropyl ether is
classified among the "solvents for which no adequate toxicological
data was found" in the ICH guide line presented in 1990's at
International Conference Harmonization (ICH) concerning the medical
supplies pharmaceutical regulation harmonization in Japan, USA and
Europe. It is therefore undesirable that isopropyl ether is
administered as a residual solvent together with a chemical to the
interior of the body of patients. In the "production method in
which hydrochlorination and the crystallization of the polymolphic
crystal (III) are carried out either simultaneously or successively
using donepezil" other than Control Example 1 which was disclosed
in JP-A 10-53576, acetone, ethyl acetate, diethyl ether, n-hexane,
t-butyl methyl ether, acetonitrile, tetrahydrofuran,
N,N-dimethylformamide, dimethylsulfoxide and toluene are also used
besides ethanol. It is clear that like isopropyl ether of Control
Example 1, these solvents will be detected as the residual
solvents.
[0075] The amount of the waste solvents generated in the "step of
producing polymorphic crystal (III) of donepezil crystal (III) from
donepezil" in Example 9 was 400 ml of ethanol, whereas in Control
Test (Control Example 1), the amount of the waste solvents was as
large as 1250 ml (500 ml of ethanol and 750 ml of isopropyl ether).
Isopropyl ether is highly volatile and is therefore unsuitable to
working environments including the health control of operators
during production steps. Also, there is a fear as to safety, for
example, explosion. Also, in the "production method in which
hydrochlorination and the crystallization of the polymolphic
crystal (III) are carried out either simultaneously or successively
using donepezil" other than Control Example 1 which was disclosed
in JP-A 10-53576, a large amount of waste solvents are generated
corresponding to acetone, ethyl acetate, diethyl ether, n-hexane,
t-butyl methyl ether, acetonitrile, tetrahydrofuran,
N,N-dimethylformamide, dimethylsulfoxide and toluene to be used
similarly to the case of isopropyl ether.
[0076] In the method of producing polymorphic crystal (III) of
donepezil hydrochloride according to the present invention, the
residual solvents in the polymorphic crystal (III) obtained by the
production method and the waste solvent generated in the course of
the production are only a very small amount of ethanol. It is clear
that as compared with prior art method, the method of the present
invention is more improved in the safety of patients who takes the
agent and operators and in the safety of working environments and
also has the effect of improving qualities (reducing residual
solvents).
[0077] (2) Refining Effect of the Production Method According to
the Present Invention
[0078] An evaluation was conducted using high performance liquid
chromatography as to the amount of donepezil hydrochloride and the
amount of impurities in polymorphic crystal (III) of donepezil
hydrochloride produced in the same manner as in Example 8 except
that a mixture obtained by adding 0.3% (0.015 g) of
1-benzyl-4-[(5,6-dimethoxy-1-indanon- )-2-ylidenyl]methylpiperidine
represented by the following formula (formula 3) to 5 g (which was
{fraction (1/10)} the amount of donepezil used in Example 8) of
donepezil was used in place of 50 g of donepezil used in Example 8,
and each amount of ethanol and concentrated hydrochloric acid was
decreased to {fraction (1/10)} that used in Example 8.
Incidentally,
1-benzyl-4-[(5,6-dimethoxy-indanon)-2-ylidenyl]methylpip- eridine
is an impurity which is generally produced when synthesizing
donepezil.
[0079] Also, for a control test, polymorphic crystal (III) of
donepezil hydrochloride was produced in the same manner as in
Control Example 1 except that a mixture obtained by adding 0.3%
(0.015 g) of the impurity represented by the (formula 3) to 5 g
(which was {fraction (1/10)} the amount of donepezil used in
Control Example 1) of donepedil was used in place of 50 g of
donepezil in Control Example 1 and each amount of ethanol and
concentrated hydrochloric acid was decreased to {fraction (1/10)}
that used in Control Example 1. The same evaluation as above was
conducted. The purity of the donepezil (5 g each) used in both
examples was 99.55%.
[0080] The results are shown in Table 6.
4TABLE 6 2 Example 8 Control Example 1 Donepezil hydrochloride
content 99.86% 99.66% Impurity content 0.07% 0.25%
[0081] In the polymorphic crystal (III) of donepezil hydrochloride
obtained in Example 8 to which the impurity (0.3%) was added, the
content of the impurity was found to be decreased to 0.07%. On the
other hand, in the polymorphic crystal (III) obtained in Control
Example 1 to which the impurity was added, the content of the
impurity was 0.25%. The contents of donepezil hydrochloride
corresponded to the contents of the impurity and were respectively
99.86% and 99.66% showing that the crystals in both cases were
found to differ in impurity content.
[0082] According to the method of producing the polymorphic crystal
(III) of donepezil hydrochloride according to the present
invention, the purity of the polymorphic crystal (III) of donepezil
hydrochloride is higher than that in a prior art method, and it is
therefore clear that the method of the present invention has the
effect of refining donepezil.
[0083] (3) Effect of Crystallization Temperature on the Production
Method According to the Present Invention
[0084] The internal temperature (crystallization temperature) of
the solvent during stirring after concentrated hydrochloric acid
was added in the production method according to the present
invention was varied, to evaluate the effects on the amount of the
residual solvent (ethanol) in the polymorphic crystal (III) of
donepezil hydrochloride, 90% volume cumulative diameter in the
particle size distribution and yield. Specifically, polymorphic
crystal (III) of donepezil hydrochloride was produced according to
the following production method.
[0085] "50 g of donepezil was dissolved by stirring in 320 g (400
ml) of ethanol under heating, followed by adding 15.1 g of
concentrated hydrochloric acid thereto at the internal temperature
of 30.degree. C. Then, it was cooled and continued stirring while
keeping the internal temperature at 15.degree. C., 20.degree. C.,
25.degree. C., 30.degree. C. or 35.degree. C. Also after the
precipitation started, the mixture was stirred for 18 hours while
keeping the each internal temperature and then cooled to 9.degree.
C. Then, the crystals were collected by filtration and dried under
reduced pressure for 22 hours, to give polymorphic crystal (III) of
donepezil hydrochloride."
[0086] The amount of the residual solvent (ethanol) and the 90%
volume cumulative diameter in the particle size distribution were
evaluated using a gas chromatography apparatus and a laser
diffraction particle size distribution measuring device,
respectively.
[0087] The results are shown in Table 7.
5TABLE 7 the bulk temperature of the amount the 90% volume the
solvent during of the cumulative diameter stirring (cyrstallization
residual solvent in the particle yeild temperature) (ethanol) size
distribution (%) 15.degree. C. 455 ppm 6.9 um 95.5% 20.degree. C.
441 ppm 11.9 um 95.4% 25.degree. C. 244 ppm 14.3 um 95.8%
30.degree. C. 163 ppm 18.2 um 96.2% 35.degree. C. 74 ppm 21.7 um
95.6%
[0088] When the internal temperature of the solvent during stirring
after concentrated hydrochloric acid was added was in a range from
15.degree. C. to 35.degree. C., the amount of the residual solvent
was small (500 ppm or less) and the 90% volume cumulative diameter
in the particle size distribution was 30 .mu.m or less, and good
qualities were therefore exhibited. However, with a rise in the
internal temperature of the solvent, the amount of the residual
solvent (ethanol) decreased and an increase in the 90% volume
cumulative diameter in the particle size distribution was
observed.
[0089] The particle size distribution of crystals is among the
important factors determining the dissolving rate of the original
drug and absorbing rate in vivo when the agent is administered.
Generally, the smaller the particle size is, the better the
dissolution rate of the original drug and the absorbing rate in
vivo become. The internal temperature (crystallization temperature)
of the solvent during stirring is particularly preferably
20.degree. C. to 30.degree. C. from viewpoint of the balance
between the amount of the residual solvent (ethanol) and the
particle size distribution.
[0090] It is clear that the method of producing polymorphic crystal
(III) of donepezil hydrochloride according to the present invention
has the effect of producing polymorphic crystal (III) of donepezil
hydrochloride which is reduced in the amount of residual solvents
(ethanol) and has a small 90% volume cumulative diameter in the
particle size distribution in a high yield, by keeping the internal
temperature (crystallization temperature) of the solvent during
stirring at 15.degree. C. to 35.degree. C. and more preferably at
20.degree. C. to 30.degree. C.
* * * * *