U.S. patent application number 10/546994 was filed with the patent office on 2006-08-10 for process for production of sulfoxide derivatives or salts thereof in the amorphous state.
Invention is credited to Yukio Morita, Masahiko Tsujii.
Application Number | 20060178406 10/546994 |
Document ID | / |
Family ID | 33094891 |
Filed Date | 2006-08-10 |
United States Patent
Application |
20060178406 |
Kind Code |
A1 |
Tsujii; Masahiko ; et
al. |
August 10, 2006 |
Process for production of sulfoxide derivatives or salts thereof in
the amorphous state
Abstract
A process for producing sulfoxide derivatives or salts thereof
in the amorphous state, characterized by heat-drying solvated
crystals of a sulfoxide derivative or a salt thereof represented by
the general formula (I): wherein R.sub.1 represents a hydrogen
atom, a methoxy group, or a difluoromethoxy group; R.sub.2
represents a methyl group or a methoxy group; R.sub.3 represents a
3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy
group; R.sub.4 represents a hydrogen atom or a methoxy group; and B
represents a hydrogen atom, an alkali metal or 1/2 alkaline earth
metal. ##STR1##
Inventors: |
Tsujii; Masahiko; (Chiba,
JP) ; Morita; Yukio; (Kayaba, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
33094891 |
Appl. No.: |
10/546994 |
Filed: |
March 17, 2004 |
PCT Filed: |
March 17, 2004 |
PCT NO: |
PCT/JP04/03525 |
371 Date: |
August 26, 2005 |
Current U.S.
Class: |
514/338 ;
546/273.7 |
Current CPC
Class: |
A61P 1/04 20180101; C07D
401/12 20130101 |
Class at
Publication: |
514/338 ;
546/273.7 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 24, 2003 |
JP |
2003-081261 |
Claims
1. A method of preparing an amorphous substance of sulfoxide
derivative (I) or the salt thereof, which comprises heat-drying an
solvated crystal of sulfoxide derivative represented by the
following formula (I) or the salt thereof: ##STR6## wherein R.sub.1
represents a hydrogen atom, a methoxy group or a difluoromethoxy
group; R.sub.2 represents a methyl group or a methoxy group;
R.sub.3 represents a 3-methoxypropoxy group, a methoxy group or a
2,2,2-trifluoroethoxy group; R.sub.4 represents a hydrogen atom or
a methyl group; respectively, and B represents a hydrogen atom, an
alkaline metal or 1/2 alkaline earth metal.
2. The method according to claim 1, wherein the solvated crystal of
sulfoxide derivative (I) or the salt thereof is heat-dried under
reduced pressure.
3. The method according to claim 1, wherein the solvated crystal of
sulfoxide derivative (I) or the salt thereof is heat-dried with
moist gas.
4. The method according to claim 1, wherein the solvated crystal of
sulfoxide derivative (I) or the salt thereof is heat-dried in an
inert medium.
5. The method according to claim 1, wherein the sulfoxide
derivative is
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole,
2-[[4-(2,2,2-trifluoroethoxy)-3-methylpyridine-2-yl]methylsulfiny-
l]-1 H-benzimidazole,
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimi-
dazole or
5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1
H-benzimidazole.
6. A method of preparing an amorphous substance of
2-[[4-(3-methoxypropoxy)-3
-methylpyridine-2-yl]methylsulfinyl]-1H-benzimidazole sodium salt,
comprising heat-drying an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt or an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt under reduced pressure.
7. A method of preparing an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which comprises heat-drying an acetone complex
of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt under reduced pressure.
8. The method according to claim 1, wherein the heating temperature
ranges from 30 to 130.degree. C.
9. The method according to claim 1, wherein the heating temperature
ranges from 100 to 110.degree. C.
10. The method according to claim 1, wherein the amorphous
substance of sulfoxide derivative (I) or the salt thereof has 50
.mu.m or less of average particle diameter and 80 .mu.m or less of
90% cumulative diameter, measured by laser diffractometry.
11. The method according to claim 1, wherein the amorphous
substance of sulfoxide derivative (I) or the salt thereof has 30
.mu.m or less of average particle diameter and 50 .mu.m or less of
90% cumulative diameter, measured by laser diffractometry.
12. The method according to claim 1, wherein the amorphous
substance of sulfoxide derivative (I) or the salt thereof has from
1 to 75 .mu.m of particle diameter, from 5 to 30 .mu.m of average
particle diameter and from 10 to 50 .mu.m of 90% cumulative
diameter, measured by laser diffractometry.
13. The method according to claim 1, wherein the amorphous
substance of sulfoxide derivative (I) or the salt thereof has from
1 to 50 .mu.m of particle diameter, from 5 to 15 .mu.m of average
particle diameter and from 10 to 25 .mu.m of 90% cumulative
diameter, measured by laser diffractometry.
14. An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtainable by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benz-
imidazole sodium salt or an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt under reduced pressure.
15. An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtainable by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benz-
imidazole sodium salt under reduced pressure.
16. The amorphous substance according to claim 14, which has from 1
to 75 .mu.m of particle diameter, from 5 to 30 .mu.m of average
particle diameter and from 10 to 50 .mu.m of 90% cumulative
diameter, measured by laser diffractometry.
17. The amorphous substance according to claim 14, which has from 1
to 50 .mu.m of particle diameter, from 5 to 15 .mu.m of average
particle diameter and from 10 to 25 .mu.m of 90% cumulative
diameter, measured by laser diffractometry.
18. An acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to a method of effectively
preparing an amorphous substance of sulfoxide derivative or the
salt thereof, wherein the substance is useful as medical drugs such
as inhibitors of gastric acid secretion and anti-ulcer agents, and
said method comprises heat-drying a solvated crystal of sulfoxide
derivative or the salt thereof.
BACKGROUND OF THE INVENTION
[0002] In the prior method of preparing one of sulfoxide derivative
or the salt thereof,
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (general designation: Rabeprazole sodium salt)
represented by the formula (I) wherein R.sub.1 represents a
hydrogen atom, a methoxy group or a difluoromethoxy group; R.sub.2
represents a methyl group or a methoxy group; R.sub.3 represents a
3-methoxypropoxy group, a methoxy group or a 2,2,2-trifluoroethoxy
group; R.sub.4 represents a hydrogen atom or a methyl group;
respectively, and B represents a hydrogen atom, an alkaline metal
or 1/2 alkaline earth metal,
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-
-benzimidazole (general designation: Rabeprazole) had been
dissolved in aqueous sodium hydroxide solution and then
freeze-dried to obtain the amorphous substance thereof (see Patent
Publication 1), or an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt had been freeze-dried to obtain the amorphous
substance thereof (see Patent Publication 2). ##STR2##
[0003] The method of preparing an amorphous substance by freeze-dry
is general means for obtaining drugs, as a solid, mainly unstable
protein drugs and antibiotics.
[0004] However, such methods have serious problems in light of
preparing time, cost or environmental protection, for example, 1)
the production scale is restricted due to plant-capacity or
-ability and a large scale plant for freeze-dry exclusive use is
required in case of industrial scale production, and 2) additional
drying step of removing water is required after freeze-dry in case
of drugs which are unstable to water.
[0005] In addition, it has been known to be difficult to make the
particle diameter of the amorphous substance obtained by freeze-dry
the same size. In particular, in case of compounds such as
Rabeprazole, whose water-controlling is important due to their
deliquescence, there was a problem, that is, it is difficult to add
steps of grinding and screening. [0006] [Patent Publication 1]
[0007] U.S. Pat. No. 5,045,552 [0008] [Patent Publication 2] [0009]
U.S. Pat. No. 6,180,652
DISCLOSURE OF THE INVENTION
[0010] In light of the above-mentioned things, an object of the
present invention is to provide a method of effectively preparing
an amorphous substance of sulfoxide derivative (I) or the salt
thereof in industrial scale, said method overcoming the
above-mentioned problem caused in the freeze-dry method.
[0011] The inventors have assiduously conducted investigations in
light of the above-mentioned things. They have consequently found
that a colorless amorphous substance of sulfoxide derivative (I) or
the salt thereof is successively, stably obtained in industrial
scale by subjecting a solvated crystal of sulfoxide derivative (I)
or the salt thereof to heat-drying at high temperature which defies
the prior common sense, and that said drying method provides the
amorphous substance of sulfoxide derivative (I) or the salt
thereof, whose particle diameter is in a uniformly arranged
condition. This finding has led to the completion of the present
invention.
[0012] The present invention provides the following <1> to
<32>:
[0013] <1> A method of preparing an amorphous substance of
sulfoxide derivative (I) or the salt thereof, which comprises
heat-drying an solvated crystal of sulfoxide derivative represented
by the following formula (I) or the salt thereof: ##STR3## wherein
R.sub.1 represents a hydrogen atom, a methoxy group or a
difluoromethoxy group; R.sub.2 represents a methyl group or a
methoxy group; R.sub.3 represents a 3-methoxypropoxy group, a
methoxy group or a 2,2,2-trifluoroethoxy group; R.sub.4 represents
a hydrogen atom or a methyl group; respectively, and B represents a
hydrogen atom, an alkaline metal or 1/2 alkaline earth metal.
[0014] <2> The method according to the above item <1>,
wherein the solvated crystal of sulfoxide derivative (I) or the
salt thereof is heat-dried under reduced pressure.
[0015] <3> The method according to the above item <1>
or <2>, wherein the solvated crystal of sulfoxide derivative
(I) or the salt thereof is heat-dried with moist gas.
[0016] <4> The method according to the above item <1>,
wherein the solvated crystal of sulfoxide derivative (I) or the
salt thereof is heat-dried in an inert medium.
[0017] <5> The method according to any one of the above items
<1> to <4>, wherein the sulfoxide derivative is
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole,
2-[[4-(2,2,2-trifluoroethoxy)-3-methylpyridine-2-yl]methylsulfiny-
l]-1H-benzimidazole,
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimi-
dazole or
5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1H-
-benzimidazole.
[0018] <6> A method of preparing an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, comprising heat-drying an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt or an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-
[0019] 1H-benzimidazole sodium salt under reduced pressure.
[0020] <7> A method of preparing an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which comprises heat-drying an acetone complex
of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt under reduced pressure.
[0021] <8> The method according to any one of the above items
<1> to <7>, wherein the heating temperature ranges from
30 to 130.degree. C.
[0022] <9> The method according to any one of the above items
<1> to <7>, wherein the heating temperature ranges from
100 to 110.degree. C.
[0023] <10> The method according to any one of the above
items <1> to <9>, wherein the amorphous substance of
sulfoxide derivative (I) or the salt thereof has 50 .mu.m or less
of average particle diameter and 80 .mu.m or less of 90% cumulative
diameter, measured by laser diffractometry.
[0024] <11> The method according to any one of the above
items <1> to <9>, wherein the amorphous substance of
sulfoxide derivative (I) or the salt thereof has 30 .mu.m or less
of average particle diameter and 50 .mu.m or less of 90% cumulative
diameter, measured by laser diffractometry.
[0025] <12> The method according to any one of the above
items <1> to <9>, wherein the amorphous substance of
sulfoxide derivative (I) or the salt thereof has from 1 to 75 .mu.m
of particle diameter, from 5 to 30 .mu.m of average particle
diameter and from 10 to 50 .mu.m of 90% cumulative diameter,
measured by laser diffractometry.
[0026] <13> The method according to any one of the above
items <1> to <9>, wherein the amorphous substance of
sulfoxide derivative (I) or the salt thereof has from 1 to 50 .mu.m
of particle diameter, from 5 to 15 .mu.m of average particle
diameter and from 10 to 25 .mu.m of 90% cumulative diameter,
measured by laser diffractometry.
[0027] <14> The method according to any one of the above
items <1> to <9>, wherein the amorphous substance of
sulfoxide derivative (I) or the salt thereof has from 1 to 75 .mu.m
of particle diameter, measured by laser diffractometry.
[0028] <15> The method according to any one of the above
items <1> to <9> and <14>, wherein the amorphous
substance of sulfoxide derivative (I) or the salt thereof has from
1 to 50 .mu.m of particle diameter, measured by laser
diffractometry.
[0029] <16> The method according to any one of the above
items <1> to <9>, <14> and <15>, wherein
the amorphous substance of sulfoxide derivative (I) or the salt
thereof has from 5 to 30 .mu.m of average particle diameter,
measured by laser diffractometry.
[0030] <17> The method according to any one of the above
items <1> to <9> and <14> to <16>, wherein
the amorphous substance of sulfoxide derivative (I) or the salt
thereof has from 5 to 15 .mu.m of average particle diameter,
measured by laser diffractometry.
[0031] <18> The method according to any one of the above
items <1> to <9> and <14> to <17>, wherein
the amorphous substance of sulfoxide derivative (I) or the salt
thereof has from 10 to 50 .mu.m of 90% cumulative diameter,
measured by laser diffractometry.
[0032] <19> The method according to any one of the above
items <1> to <9> and <14> to <18>, wherein
the amorphous substance of sulfoxide derivative (I) or the salt
thereof has from 10 to 25 .mu.m of 90% cumulative diameter,
measured by laser diffractometry.
[0033] <20> An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtainable by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benz-
imidazole sodium salt or an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt under reduced pressure.
[0034] <21> An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtained by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt or an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt under reduced pressure.
[0035] <22> An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtainable by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benz-
imidazole sodium salt under reduced pressure.
[0036] <23> An amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, which is obtained by heat-drying an acetone
complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt under reduced pressure.
[0037] <24> The amorphous substance according to the above
items <20> to <23>, which has from 1 to 75 .mu.m of
particle diameter, from 5 to 30 .mu.m of average particle diameter
and from 10 to 50 .mu.m of 90% cumulative diameter, measured by
laser diffractometry.
[0038] <25> The amorphous substance according to the above
items <20>to <23>, which has from 1 to 50 .mu.m of
particle diameter, from 5 to 15 .mu.m of average particle diameter
and from 10 to 25 .mu.m of 90% cumulative diameter, measured by
laser diffractometry.
[0039] <26> The amorphous substance according to the above
items <20>to <23>, which has from 1 to 75 .mu.m of
particle diameter, measured by laser diffractometry.
[0040] <27> The amorphous substance according to the above
items <20> to <23> and <26>, which has from 1 to
50 .mu.m of particle diameter, measured by laser
diffractometry.
[0041] <28> The amorphous substance according to the above
items <20> to <23>, <26> and <27>, which
has from 5 to 30 .mu.m of average particle diameter, measured by
laser diffractometry.
[0042] <29> The amorphous substance according to the above
items <20> to <23> and <26> to <28>, which
has from 5 to 15 .mu.m of average particle diameter, measured by
laser diffractometry.
[0043] <30> The amorphous substance according to the above
items <20> to <23> and <26> to <29>, which
has from 10 to 50 .mu.m of 90% cumulative diameter, measured by
laser diffractometry.
[0044] <31> The amorphous substance according to the above
items <20> to <23> and <26> to <30>, which
has from 10 to 25 .mu.m of 90% cumulative diameter, measured by
laser diffractometry.
[0045] <32> An acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt.
BRIEF DESCRIPTION OF DRAWINGS
[0046] FIG. 1 is a graph showing powder X-ray diffraction pattern
as for an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt.
[0047] FIG. 2 is a graph showing powder X-ray diffraction pattern
as for the freeze-dried product (Reference Example 2).
[0048] FIG. 3 is a graph showing powder X-ray diffraction pattern
as for the heat-dried product (Example 1).
[0049] FIG. 4 is a graph showing particle size distribution as for
the freeze-dried product (Reference Example 2).
[0050] FIG. 5 is a graph showing particle size distribution as for
the heat-dried product (Example 3).
[0051] FIG. 6 is a graph showing the result of thermal analysis as
for the acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt.
[0052] FIG. 7 is a graph showing .sup.1H-NMR chart as for the
acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt.
[0053] FIG. 8 is a graph showing powder X-ray diffraction pattern
as for the acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt.
[0054] FIG. 9 is a graph showing powder X-ray diffraction pattern
as for the heat-dried product (Example 16).
BEST MODE FOR CARRYING OUT THE INVENTION
[0055] Hereinafter, the present invention will be described in
detail.
[0056] The term "alkaline metal" used herein concretely means, for
example, sodium, potassium, lithium and the like. The term
"alkaline earth metal" concretely means, for example, calcium,
magnesium and the like. Sodium or magnesium is preferable. Sodium
is more preferable.
[0057] Furthermore, in the case where "B" represents "1/2 alkaline
earth metal", the salt of sulfoxide derivative is represented by
the following formula (II): ##STR4## wherein each of R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 has the same meaning as defined above,
and B' represents an alkaline earth metal.
[0058] In particular, the sulfoxide derivative (I) or the salt
thereof may include, for example,
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole disclosed in U.S. Pat. No. 5,045,552 (general designation:
Rabeprazole);
2-[[4-(2,2,2-trifluoroethoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-b-
enzimidazole disclosed in U.S. Pat. No. 4,628,098 (general
designation: Lansoprazole),
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimi-
dazole disclosed in U.S. Pat. No. 4,255,431 (general designation:
Omeprazole) or
5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimid-
azole disclosed in U.S. Pat. No. 4,758,579 (general designation:
Pantoprazole) and the salts thereof. Each compound can be prepared
according to each method disclosed in each of the
specification.
[0059] The solvated crystal of sulfoxide derivative (I) or the salt
thereof may include, for example, the acetone complex
(acetone-solvate crystal), the acetonitrile complex
(acetonitrile-solvate crystal) or the ethyl acetate complex (ethyl
acetate-solvate crystal) of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole,
2-[[4-(2,2,2-trifluoroethoxy)-3-methylpyridine-2-yl]methylsulfinyl-
]-1H-benzimidazole,
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimi-
dazole or
5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1H-
-benzimidazole, and the acetone complex, the acetonitrile complex
or the ethyl acetate complex of the salt thereof.
[0060] The acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt and the acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt are preferable. The acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt is more preferable.
[0061] The solvated crystal of sulfoxide derivative (I) or the salt
thereof is basically obtained by, for example, contacting sulfoxide
derivative (I) or the salt thereof with a solvent or dissolving it
in a solvent, and then treating the resultant, for example,
crystallizing the resultant.
[0062] Furthermore, the acetone complex of sulfoxide derivative (I)
or the salt thereof is disclosed in U.S. Pat. No. 6,180,652, and,
in particular, is represented by the following formula. The complex
or the salt thereof can be prepared according to the method
disclosed in the specification: ##STR5## wherein R.sub.1 represents
a hydrogen atom, a methoxy group or a difluoromethoxy group;
R.sub.2 represents a methyl group or a methoxy group; R.sub.3
represents a 3-methoxypropoxy group, a methoxy group or a
2,2,2-trifluoroethoxy group; R.sub.4 represents a hydrogen atom or
a methyl group; respectively, m and n each independently represents
an integer of 1 to 4, and B represents a hydrogen atom, an alkaline
metal or 1/2 alkaline earth metal.
[0063] The acetonitrile complex of sulfoxide derivative (I) or the
salt thereof can be prepared by dissolving sulfoxide derivative (I)
or the salt thereof in acetonitrile, being left to stand, filtering
off the precipitated crystal and drying it.
[0064] The acetone complex or acetonitrile complex of sulfoxide
derivative (I) or the salt thereof can be used after filtering off
without drying in the method of preparing the amorphous
substance.
[0065] The term "amorphous substance" used herein means an
amorphous solid.
[0066] The term "moist gas" used herein means gases comprising
water and being inert to the sulfoxide derivative (I) or the salt
thereof, such as moist air or moist nitrogen. In addition, the
moisture content of the moist gas is in the range of from 15 to
60%, preferably from 30 to 40%, in case where the temperature of
the moist gas is in the range of from 20 to 35.degree. C.
[0067] The term "inert medium" used herein means gas or liquid
being inert to the sulfoxide derivative (I) or the salt thereof.
Specific example of the inert gas may include nitrogen gas, argon
gas, dried air and the like. The inert liquid may include, but is
not limited to, for example, aliphatic hydrocarbons such as
1-heptane and cyclohexene; aromatic hydrocarbons such as toluene;
ethers; and the like, as long as 1) the inert liquid does not
dissolve the sulfoxide derivative (I) or the salt thereof and 2)
the inert liquid has boiling point of about 60.degree. C. or
more.
[0068] Hereinafter, the method of preparing the amorphous substance
of sulfoxide derivative (I) or the salt thereof according to the
present invention, which comprises heat-drying an solvated crystal
of the sulfoxide derivative (I) or the salt thereof, will be
concretely described.
[0069] According to the present invention, the amorphous substance
of sulfoxide derivative (I) or the salt thereof can be basically
prepared by incorporating an solvated crystal of sulfoxide
derivative (I) or the salt thereof into a vibrating vacuum dryer
and heat-drying it while the heat medium is circulated. Preferably,
heat-drying is conducted under reduced pressure.
[0070] The heat-drying according to the present invention can be
conducted with moist gas. In particular, the heat-drying is
conducted by removing the solvent from the solvated crystal while
the moist gas flows little by little so as to contact with the
sulfoxide derivative (I) or the salt thereof at the same time of
depressurizing under the heat-vibrating condition. In the drying in
which the moisture gas is used, the solvent can be separated by
replacing the solvent in the powder with water to facilitate the
diffusion migration thereof and promote the evaporation thereof.
Accordingly, said drying has an advantage that the heating
temperature and depressurizing degree can be decreased by using the
moist gas.
[0071] The heat-drying according to the present invention can be
conducted in an inert medium. In the case where an inert gas is
used as the inert medium, the heat-drying is conducted by flowing
the inert gas little by little into the reaction container so as to
contact with the sulfoxide derivative (I) or the salt thereof at
the same time of heating. In the case where an inert liquid is used
as the inert medium, in particular, sulfoxide derivative (I) or the
salt thereof is suspended, dispersed in the inert liquid, and
heated under the condition with good heat conductance.
[0072] While the heating temperature is not limited, the
heat-drying can be usually conducted in the range of from 30 to
130.degree. C., preferably from 60 to 120.degree. C., more
preferably 100 to 110.degree. C. In addition, the heat-drying time
can be usually in the range of from 1 to 160 hour(s), preferably
from 3 to 30 hours, although the drying time depends on a drying
equipment, heating temperature, degree of depressurization, scale
and the like.
[0073] The measurement of particle size distribution by laser
diffractometry can be conducted, for example, by using "Microtrac
X100 " (made by Leeds And Northrup). In the case where the particle
size distribution of the amorphous substance of sulfoxide
derivative (I) or the salt thereof, which is prepared by conducting
the above-mentioned heat-drying, is measured by the laser
diffractometry, the amorphous substance of sulfoxide derivative (I)
or the salt thereof has 50 .mu.m or less, preferably 30 .mu.m or
less of average particle diameter, and 80 .mu.m or less, preferably
50 .mu.m or less of 90% cumulative diameter.
[0074] In addition, in the case where the particle size
distribution of the amorphous substance of sulfoxide derivative (I)
or the salt thereof, which is prepared by conducting the
above-mentioned heat-drying, is measured by the laser
diffractometry, the amorphous substance of sulfoxide derivative (I)
or the salt thereof has from 1 to 75 .mu.m of particle diameter,
from 5 to 30 .mu.m of average particle diameter and from 10 to 50
.mu.m of 90% cumulative diameter. Preferably, the amorphous
substance has from 1 to 50 .mu.m of particle diameter, from 5 to 15
.mu.m of average particle diameter and from 10 to 25 .mu.m of 90%
cumulative diameter. The step of making the particle diameter the
uniform size can be deleted by obtaining the particles each having
the above-mentioned ranges. In addition, since the specific surface
of the particles each having relatively small particle diameter can
be generally depressed, the particles each having an improved
water-resistance property can be obtained.
EXAMPLES
[0075] The present invention will be described by way of the
following examples which are intended to illustrate, but not limit
the present invention.
HPLC Condition for Purity Measurement
[0076] Stationary phase: YMC-Pack Pro C18 AS-303 (4.6 mm I. D.
.times.250 mm, 5 .mu.m); [0077] Mobile phase:
MeOH/H.sub.2O/AcONH.sub.4=550 mL/450 mL/2 g; [0078] Flow rate: 1.0
mL/min; [0079] Temperature: 35.degree. C.; and [0080] Detector: UV
290 nm. [0081] Condition for Measuring Powder X-Ray Diffraction
Pattern [0082] X-ray: Cu; [0083] Filter: no use; [0084] Voltage: 40
kV; [0085] Current: 20 mA; [0086] Counter monochromator: Curved
crystal monochromator; [0087] Diffusing slit: 1 deg; [0088]
Scattering slit: 1 deg; [0089] Light accepting slit: 0.15 mm;
[0090] Scan speed: 2 deg/min; and [0091] Scanning range: 5 to
40.
Reference Example 1
Preparation of an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt
[0092] The titled compound was prepared according to the method
described in U.S. Pat. No. 6,180,652 (Example 7).
Reference Example 2
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by freeze-dry
[0093] The titled compound was prepared according to the method
described in U.S. Pat. No. 5,045,552 (Example 33).
Example 1
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 110.degree. C./drying under reduced pressure
in 6 kg scale
[0094] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VH-25 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (6 kg: acetone content 26%: 12.35 mol) was
placed, and a vibrating vacuum-heating was conducted by circulating
a heat medium (80% ethylene glycol/water) heated at 110.degree. C.
After heating for 75 minutes, the jacket temperature of the dryer
reached at 104.degree. C. (the material temperature: 83.degree.
C.). After 5 hours (the jacket temperature: 109.degree. C., the
material temperature: 107.degree. C., the degree of vacuum: 0.2
pKa), the drying was stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (4.66 kg, acetone: 260 ppm, HPLC purity: 99.6%)
was obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 2
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 105.degree. C./drying under reduced pressure
in 6 kg scale
[0095] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VH-25 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (6 kg: acetone content 26%: 12.35 mol) was
placed, and a vibrating vacuum-heating was conducted by circulating
a heat medium (80% ethylene glycol/water) heated at 105.degree. C.
After heating for 2 hours, the jacket temperature of the dryer
reached at 103.degree. C. (the material temperature: 75.degree. C.,
the degree of vacuum: 0.2 pKa). After 7 hours, the drying was
stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-ben-
zimidazole sodium salt (4.57 kg, acetone: 280 ppm, HPLC purity:
99.6%) was obtained. The powder X-ray diffraction pattern of the
resulting amorphous substance was consistent with that of the
freeze-dried product.
Example 3
Preparation of an amorphous substance of
.sup.2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-be-
nzimidazole sodium salt by 100.degree. C./drying under reduced
pressure in 6 kg scale
[0096] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VH-25 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (6 kg: acetone content 26%: 12.35 mol) was
placed, and a vibrating vacuum-heating was conducted for 3 hours by
circulating a heat medium (80% ethylene glycol/water) heated at
60.degree. C. Then, a vibrating vacuum-heating was conducted by
circulating a heat medium (80% ethylene glycol/water) heated at
100.degree. C. After heating for 1 hour and 40 minutes, the jacket
temperature of the dryer reached at 88.degree. C. (the material
temperature: 69.degree. C., the degree of vacuum: 0.2 pKa). After
14 hours, the drying was stopped and then, the amorphous substance
of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt (4.54 kg, acetone: 290 ppm, HPLC purity: 99.6%)
was obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 4
Preparation of an amorphous substance of
2-[]4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 120.degree. C./drying under reduced pressure
in 50 g scale
[0097] To a 300 mL eggplant type flask, an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (50 g: acetone content 12%: 122 mmol) was
placed, and a heat-drying under reduced pressure was conducted for
2 hours by a vacuum pump and an evaporator while conducting an
intermittent rotation in oil bath heated at 60.degree. C. Then, a
heat-drying under reduced pressure (the degree of vacuum: 0.2 pKa)
was conducted by evaporator while conducting an intermittent
rotating in oil bath heated at 120.degree. C. After 1 hour, the
drying was stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (acetone: 80 ppm, HPLC purity: 99.6%) was
obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 5
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt by 115.degree. C./drying under reduced pressure
in 50 g scale
[0098] To a 300 mL eggplant type flask, an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (50 g: acetone content 12%: 122 mmol) was
placed, and a heat-drying under reduced pressure was conducted for
2 hours by a vacuum pump and an evaporator while conducting
intermittent rotation in oil bath heated at 60.degree. C. Then, a
heat-drying under reduced pressure (the degree of vacuum: 0.2 pKa)
was conducted by an evaporator while conducting an intermittent
rotation in oil bath heated at 115.degree. C. After heating for 2
hours, the drying was stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (acetone: 240 ppm, HPLC purity: 99.6%) was
obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 6
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 105.degree. C./drying under reduced pressure
in 50 g scale
[0099] To a 300 mL eggplant type flask, an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt (50 g: acetone content 10%: 125 mmol) was
placed, and a heat-drying under reduced pressure was conducted for
2 hours by a vacuum pump and an evaporator while conducting an
intermittent rotation in oil bath heated at 60.degree. C. Then, a
heat-drying under reduced pressure (the material temperature:
100.degree. C., the degree of vacuum: 0.2 pKa) was conducted by an
evaporator while conducting an intermittent rotation in oil bath
heated at 105.degree. C. After heating for 5 hours, the drying was
stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt (acetone: 190 ppm, HPLC purity: 99.6%) was
obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 7
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt by 82.degree. C./drying under reduced pressure
in 1 kg scale
[0100] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VU-15 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (1 kg: acetone content 10%: 2.5 mol) was placed,
and a vibrating vacuum-heating (the degree of vacuum: <0.2 pKa)
was conducted by circulating hot water heated at 82.degree. C.
After 137 hours, the drying was stopped and then, the amorphous
substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (acetone: 1870 ppm) was obtained.
Example 8
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 80.degree. C./drying under reduced pressure
in 15 g scale
[0101] To a tray-type vacuum dryer, an acetone complex of
.sup.2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-be-
nzimidazole sodium salt (15 g: acetone content 10%: 38 mmol) was
placed, and a drying under reduced pressure was conducted at
80.degree. C. (the degree of vacuum: <0.2 pKa). After heating
for 15 hours, the drying was stopped and then, the amorphous
substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (13 g, acetone: 130 ppm, HPLC purity: 99.6%) was
obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 9
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt by 105.degree. C./drying under reduced pressure
in 12 kg scale
[0102] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VH-25 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (11.5 kg: acetone content 17%: 25.0 mol) was
placed, and a vibrating vacuum-heating (the degree of vacuum: 0.2
pKa) was conducted by circulating a heat medium (80% ethylene
glycoVwater) heated at 105.degree. C. After 15 hours from the time
of reaching the jacket temperature at 100.degree. C. or more, the
drying was stopped and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (9.4 kg, acetone: 130 ppm, HPLC purity: 99.3%)
was obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
Example 10
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 60.degree. C./moist drying under reduced
pressure in 10 kg scale
[0103] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VU-15 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (10.2 kg: acetone content about 24%: 26.7 mol)
was placed, and a vibrating vacuum-heating was conducted by
circulating hot water for 1 hour at 30.degree. C. and then, for 1
hour at 40.degree. C. and then, for 30 minutes at 50.degree. C.
Then, hot water heated at 60.degree. C. was circulated, and
nitrogen gas flowed little by little to control the degree of
vacuum to 13 mmHg. Further, drying was conducted for 67 hours.
Then, while atmospheric air (room temperature: 22 to 27.degree. C.,
humidity: 16 to 60%, air flow rate: 10 to 13 m.sup.3/hr) flowed
little by little (13 mmHg), and further, drying was conducted at
60.degree. C. for 84 hours. After 152 hours, the drying was stopped
and then, the amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (acetone: 340 ppm) was obtained.
Example 11
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt by 60.degree. C./moist drying under reduced
pressure in 9 kg scale
[0104] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VU-15 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (9.1 kg: acetone content about 20%: 19.1 mol)
was placed. Hot water was circulated at 20.degree. C. for 2 hours,
then at 30.degree. C., and while atmospheric air (room temperature:
26 to 32.degree. C., humidity: 30 to 40%, air flow rate: 10 to 13
m.sup.3/hr) flowed little by little (650 mmHg), drying was
conducted for 67 hours. Further, leak was stopped and drying under
reduced pressure was conducted for 48 hours (for 24 hours at
30.degree. C., and for 24 hours at 50.degree. C.). The amorphous
substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt (2.1 kg, acetone: 600 ppm, HPLC purity: 99.8%)
was obtained.
Example 12
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt by 60.degree. C./moist drying under reduced
pressure in 3 kg scale
[0105] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VU-15 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (2.5 kg: acetone content about 24%: 6.6 mol) was
placed, hot water heated at 60.degree. C. was circulated, and while
atmospheric air (room temperature: 27 to 32.degree. C., humidity:
30 to 40%, air flow rate: 0.68 to 1.25 L/min) flowed little by
little (4 mmHg), drying was conducted for 92 hours. The amorphous
substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt (2.0 kg, acetone: 1600 ppm) was obtained.
Example 13
Preparation of an amorphous substance of
2-[]4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 30.degree. C./drying under reduced pressure
and moist condition in 3 kg scale
[0106] To a vibrating vacuum dryer (made by CHUO KAKOHKI Co., Ltd.,
VUA-20 type), an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (2.5 kg: acetone content about 15%: 5.5 mol) was
placed. Hot water heated at 30.degree. C. was circulated, moist
nitrogen flowed little by little to control the degree of vacuum to
13 mmHg, and drying was conducted for 21 hours (room temperature:
30.degree. C., humidity: 40%, moist nitrogen flow rate: 207
m.sup.3/hr). The amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (acetone: 510 ppm) was obtained.
Example 14
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 50.degree. C./moist drying with air supply in
10 g scale
[0107] In a box-type air supply-dryer, an acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (10 g: acetone content about 12%: 23 mmol) was
placed in petri dish. The temperature of the dryer was set at
50.degree. C., and air supply-drying was conducted for 48 hours
(humidity in the room: 50%). The amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt (9.0 g, acetone: 40 ppm, HPLC purity 99.8%) was
obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product.
[0108] FIG. 1 shows a powder X-ray diffraction pattern as for an
acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt; FIG. 2 shows a powder X-ray diffraction pattern
as for the freeze-dried product (Reference Example 2); and FIG. 3
shows a powder X-ray diffraction pattern as for the heat-dried
product (Example 1), respectively.
Example 15
Preparation of an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt
[0109] 10.0 g of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt was dissolved in 20 ml of acetonitrile and
then, was left to stand at 22.degree. C. for 18 hours. The
precipitated crystal was filtered off, washed with 30 ml of
acetonitrile, and dried under reduced pressure for 2 hours, to
obtain 9.1 g of a colorless acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-ben-
zimidazole sodium salt (acetonitrile: 8.4%). The powder X-ray
diffraction pattern as for the resulting acetone complex denotes
crystal structure. Furthermore, FIG. 7 shows a .sup.1H-NMR chart as
for the acetonitrile complex; FIG. 8 shows a powder X-ray
diffraction pattern as for the acetonitrile complex; and Table 1
shows diffraction angle and relative intensity in the powder X-ray
diffraction pattern as for the acetonitrile complex;
respectively.
[0110] .sup.1H-NMR(400 MHz, DMSO-d.sub.6)
[0111] .delta.: 1.97 (quintet, J=6 Hz, 2H) 2.17 (s, 3H) 3.24 (s,
3H) 3.48 (t, J=6 Hz, 2H) 4.09 (t, J=6 Hz, 2H) 4.39 (d, J=13 Hz, 1H)
4.76 (d, J=13 Hz, 1H) 6.85 (m, 2H) 6.92 (d, J=6 Hz, 1H) 7.44 (m,
2H) 8.27 (d, J=6 Hz, 1H). TABLE-US-00001 TABLE 1 Diffraction angle
Relative intensity (2.theta., .degree.) (I/I.sub.0) 6.74 89 7.76 51
8.08 74 9.98 22 10.36 32 10.48 29 14.74 35 14.80 37 15.80 43 15.90
45 16.76 97 17.98 100 18.30 55 18.60 29 19.46 23 19.80 35 19.86 38
21.16 57 22.48 27 23.08 41 23.44 43 23.84 45 24.24 50 26.28 31
26.62 25 27.86 27 28.20 25 28.96 25 29.12 25
Example 16
Preparation of an amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt by 105.degree. C./drying under reduced pressure
in 5 g scale
[0112] To a tray-type vacuum dryer, an acetonitrile complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
d azole sodium salt (10 g, acetone content: 8.4%, 38 mmol) was
placed, and dried under reduced pressure at 105.degree. C. by a
vacuum pump (the degree of vacuum: 0.2 pKa). After heating for 5
hours, the drying was stopped. The amorphous substance of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]-methylsulfinyl]-1H-benzim-
idazole sodium salt (4 g, acetonitrile: 4 ppm, HPLC purity: 99.7%)
was obtained. The powder X-ray diffraction pattern of the resulting
amorphous substance was consistent with that of the freeze-dried
product. Furthermore, FIG. 9 shows a powder X-ray diffraction
pattern as for the heat-dried product (Example 16).
Measurement of Particle Size Distribution:
[0113] As for each of amorphous substances of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt obtained by freeze-drying (Reference example 2),
heat-drying (Example 3), respectively, the particle size
distributions were measured by "Microtrac X100" (prepared by Leeds
And Northrup). FIG. 4 shows the result of the freeze-dried product,
and FIG. 5 shows the result of the heat-dried product.
[0114] While the particle size distribution of the freeze-dried
product was broad, that of the heat-dried product was sharp. Thus,
the heat-drying could provide an amorphous substance having high
uniformity.
Measurement of Specific Surface:
[0115] As for each of amorphous substances of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt obtained by freeze-drying (Reference example 2),
heat-drying (Example 3), respectively, the nitrogen-absorption
isotherms were measured at liquid nitrogen temperature (77 K) by a
high accuracy full automatic gas absorption equipment "BELSORP 36"
(prepared by Japan Bell) after vacuum degassing at 50.degree. C.
These isotherms were analyzed by BET method to obtain the specific
surface. The following Table 2 shows the specific surface and 90%
cumulative diameter calculated by measurement of the particle size
distribution, as for the freeze-dried product and the heat-dried
product. TABLE-US-00002 TABLE 2 Specific surface Relative 90%
cumulative m.sup.2/g comparison diameter (.mu.m) The freeze-dried
product 2.3 1.00 192.3 The heat-dried product 1.6 0.70 18.0
[0116] It was found that the particle diameter and the specific
surface of the heat-dried product were smaller than those of the
freeze-dried product. Accordingly, it is believed that the
heat-dried product has the water resistance superior to the
freeze-dried product.
Measurement of Thermal Analysis:
[0117] As for the acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt, the thermal analysis (TG-DTA) was conducted
under the following conditions:
[0118] Reference: Al.sub.2O.sub.3;
[0119] Scan speed: 2.degree. C./min;
[0120] Upper limit temperature: 120.degree. C.; and
[0121] Lower limit temperature: 20.degree. C.
[0122] FIG. 6 shows the result of the thermal analysis.
[0123] The measurement result shows that at the temperature of
65.7.degree. C. or more, the weight of the acetone complex of
2-[[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methylsulfinyl]-1H-benzimi-
dazole sodium salt starts to be decreased, and that at the
temperature of 76.7.degree. C. or more, the acetone starts to be
effectively decreased.
INDUSTRIAL APPLICABILITY
[0124] The heat-drying method according to the present invention
enables to stably obtain the amorphous substance of sulfoxide
derivative (I) or the salt thereof in industrial scale from the
solvated crystal of sulfoxide derivative (I) or the salt thereof
Further, the drying method according to the present invention can
make the particle size of the amorphous substance of sulfoxide
derivative (I) or the salt thereof the same or similar size.
Accordingly, the drying method according to the present invention,
by comparison of the prior freeze-dry method, reduces the steps at
the same time of greatly reducing the cost including time and
energy, furthermore is believed to be preferred in light of
environmental protection.
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