U.S. patent application number 11/899918 was filed with the patent office on 2008-12-11 for process for the crystallization of (r) - or (s) - lansoprazole.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. Invention is credited to Hideo Hashimoto, Tadashi Urai.
Application Number | 20080306118 11/899918 |
Document ID | / |
Family ID | 18838123 |
Filed Date | 2008-12-11 |
United States Patent
Application |
20080306118 |
Kind Code |
A1 |
Hashimoto; Hideo ; et
al. |
December 11, 2008 |
Process for the crystallization of (R) - or (S) - Lansoprazole
Abstract
The present invention relates to a production method of a
crystal of (R)-lansoprazole or (S)-lansoprazole, which includes
crystallization at a temperature of about 0.degree. C. to about
35.degree. C. from a C.sub.1-4 alkyl acetate solution containing
(R)-lansoprazole or (S)-lansoprazole at a concentration of about
0.1 g/mL to about 0.5 g/mL and the like. According to the
production method of the present invention, a crystal of
(R)-lansoprazole or (S)-lansoprazole superior in preservation
stability can be produced efficiently on an industrial large
scale.
Inventors: |
Hashimoto; Hideo; (Kobe-shi,
JP) ; Urai; Tadashi; (Kawanishi-shi, JP) |
Correspondence
Address: |
HAMRE, SCHUMANN, MUELLER & LARSON, P.C.
P.O. BOX 2902
MINNEAPOLIS
MN
55402-0902
US
|
Assignee: |
Takeda Pharmaceutical Company
Limited
Osaka
JP
|
Family ID: |
18838123 |
Appl. No.: |
11/899918 |
Filed: |
September 7, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10432798 |
May 27, 2003 |
7285668 |
|
|
PCT/JP01/10462 |
Nov 30, 2001 |
|
|
|
11899918 |
|
|
|
|
Current U.S.
Class: |
514/338 ;
546/273.7 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
31/04 20180101; A61P 35/00 20180101; A61P 7/04 20180101; C07D
401/12 20130101; A61P 1/04 20180101; A61P 1/02 20180101; A61K
9/5026 20130101; A61K 9/5078 20130101; A61K 31/44 20130101 |
Class at
Publication: |
514/338 ;
546/273.7 |
International
Class: |
A61K 31/435 20060101
A61K031/435; C07D 401/12 20060101 C07D401/12; A61P 1/02 20060101
A61P001/02; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 1, 2000 |
JP |
367757/2000 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. A crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole produced according to the method which comprises
crystallizing at a temperature of about 0.degree. C. to about
35.degree. C. from a C.sub.1-4 alkyl acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL and a method which comprises crystallizing at a temperature of
about 0.degree. C. to about 35.degree. C. from a C.sub.1-4 alkyl
acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL, and adding dropwise to the C.sub.1-4 alkyl acetate solution,
at the same temperature, C.sub.5-8 hydrocarbon in an amount of not
more than 7 times the amount of the C.sub.1-4 alkyl acetate
solution.
10. A crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole produced according to the method which comprises
crystallizing at a temperature of about 0.degree. C. to about
35.degree. C. from a C.sub.1-4 alkyl acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL and a method which comprises crystallizing at a temperature of
about 0.degree. C. to about 35.degree. C. from a C.sub.1-4 alkyl
acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL, and adding dropwise to the C.sub.1-4 alkyl acetate solution,
at the same temperature, C.sub.5-8 hydrocarbon in an amount of not
more than 7 times the amount of the C.sub.1-4 alkyl acetate
solution.
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. A method of preventing or treating digestive ulcer, gastritis,
reflux esophagitis, NUD (Non Ulcer Dyspepsia), gastric cancer,
gastric MALT lymphoma, upper gastrointestinal hemorrhage, ulcer
caused by a nonsteroidal anti-inflammatory agent, hyperacidity and
ulcer due to postoperative stress, or a disease due to Helicobacter
pylori, which comprises administering the crystal of claim 9.
16. (canceled)
17. (canceled)
Description
[0001] This application is a division of application Ser. No.
10/732,798 filed on May 27, 2003, which is a National Stage of
PCT/JP01/10462, which applications are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to production methods of an
optically active sulfoxide compound having an antiulcer activity, a
crystal of an optically active sulfoxide compound having remarkably
improved stability, and the like.
BACKGROUND ART
[0003] As a method for producing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole [hereinafter sometimes to be referred to as
(R)-lansoprazole] or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole [hereinafter sometimes to be referred to as
(S)-lansoprazole] having an antiulcer activity, for example,
JP-A-11-508590 (WO 97/02261) describes a method for optically
purifying a compound product adjusted to contain an enriched
enantiomer and crystallization method by removing the solvent,
which comprises treating a compound containing either
(+)-enantiomer or (-)-enantiomer in a greater amount, namely, a
compound enriched in one enantiomer, with a solvent, selectively
precipitating a racemic compound from the solvent utilizing the
crystallinity of the racemate, filtering off the precipitated
racemic compound and removing the solvent to give a single
enantiomer of the compound having an increased optical purity,
which corresponds to lansoprazole and the like.
[0004] JP-A-10-504290 (WO 96/02535) describes a production method
of an optically active sulfoxide compound, which comprises
subjecting a thio compound to an oxidation reaction, and
crystallization (Example 11) of omeprazole, which comprises
concentrating an acetonitrile solution and the like.
[0005] Lansoprazole is now on the market worldwide as a
pharmaceutical product having a superior antiulcer activity. The
crystal of lansoprazole is a racemate and is superior in
preservation stability.
[0006] A crystal of optically active (R)-lansoprazole and
(S)-lansoprazole obtained according to the above-mentioned
conventional method does not necessarily satisfy the preservation
stability, with the undeniable possibility of decreased purity,
increased amounts of analogous materials, coloring and the like
during preservation.
[0007] Therefore, there is a demand for a production method of the
crystal of (R)-lansoprazole or (S)-lansoprazole sufficiently
superior in the preservation stability.
DISCLOSURE OF INVENTION
[0008] As a result of various studies of the production methods of
crystals of (R)-lansoprazole and (S)-lansoprazole, the present
inventors have unexpectedly found for the first time that
crystallization of (R)-lansoprazole and (S)-lansoprazole under
specific conditions produces an extremely stable crystal and that
this method is sufficiently satisfactory on an industrial scale,
and completed the present invention.
[0009] Accordingly, the present invention provides the
following:
[1] a method for producing a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole, which comprises crystallizing at a temperature of
about 0.degree. C. to about 35.degree. C. from a C.sub.1-4 alkyl
acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL; [2] a method for producing a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole, which comprises crystallizing at a temperature of
about 0.degree. C. to about 35.degree. C. from a C.sub.1-4 alkyl
acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL, and adding dropwise to the C.sub.1-4 alkyl acetate solution,
at the same temperature, C.sub.5-8 hydrocarbon in an amount of not
more than 7 times the amount of the C.sub.1-4 alkyl acetate
solution; [3] the method of the above-mentioned [1] or [2], wherein
the crystallization temperature is about 20.degree. C. to about
30.degree. C.; [4] the method of the above-mentioned [1] or [2]
wherein the crystallization is conducted for about 30 minutes to
about 4 hours; [5] the method of the above-mentioned [1] or [2],
wherein the C.sub.1-4 alkyl acetate is ethyl acetate or propyl
acetate; [6] the method of the above-mentioned [2], wherein the
C.sub.5-8 hydrocarbon is added in an amount of not more than 5
times the amount of the C.sub.1-4 alkyl acetate solution; [7] the
method of the above-mentioned [2], wherein the C.sub.5-8
hydrocarbon is heptane or hexane; [8] the method of the
above-mentioned [2], wherein the C.sub.5-8 hydrocarbon is added
dropwise over about 15 minutes to about 4 hours; [9] a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole produced according to the method of the
above-mentioned [1] or [2]; [10] a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole produced according to the method of the
above-mentioned [1] or [2]; [11] a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole having a melting start temperature of not lower
than about 131.degree. C.; [12] the crystal of the above-mentioned
[11], wherein the melting start temperature is about 135.degree.
C.; [13] a pharmaceutical composition containing the crystal of the
above-mentioned [9] or [11]; [14] the pharmaceutical composition of
the above-mentioned [13], which is for the prophylaxis or treatment
of digestive ulcer, gastritis, reflux esophagitis, NUD (Non Ulcer
Dyspepsia), gastric cancer, gastric MALT lymphoma, upper
gastrointestinal hemorrhage, ulcer caused by a nonsteroidal
anti-inflammatory agent, hyperacidity and ulcer due to
postoperative stress, or a disease due to Helicobacter pylori; [15]
a method of preventing or treating digestive ulcer, gastritis,
reflux esophagitis, NUD (Non Ulcer Dyspepsia), gastric cancer,
gastric MALT lymphoma, upper gastrointestinal hemorrhage, ulcer
caused by a nonsteroidal anti-inflammatory agent, hyperacidity and
ulcer due to postoperative stress, or a disease due to Helicobacter
pylori, which comprises administering the crystal of the
above-mentioned [9] or [11] to human; [16] use of the crystal of
the above-mentioned [9] or [11] for the production of a
pharmaceutical composition for the prophylaxis or treatment of
digestive ulcer, gastritis, reflux esophagitis, NUD (Non Ulcer
Dyspepsia), gastric cancer, gastric MALT lymphoma, upper
gastrointestinal hemorrhage, ulcer caused by a nonsteroidal
anti-inflammatory agent, hyperacidity and ulcer due to
postoperative stress, or a disease due to Helicobacter pylori; [17]
a method for stabilizing a crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole, which comprises crystallizing at a temperature of
about 0.degree. C. to about 35.degree. C. from a C.sub.1-4 alkyl
acetate solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole or
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole at a concentration of about 0.1 g/mL to about 0.5
g/mL; and the like.
BRIEF DESCRIPTION OF DRAWINGS
[0010] FIG. 1 shows the appearance of a crystal (Example 1) having
a melting start temperature of about 134.degree. C. and a crystal
(Reference Example 6) having a melting start temperature of about
130.degree. C., before stability test (initial) and after stability
test at 40.degree. C. for 2 weeks, 50.degree. C. for 2 weeks and
60.degree. C. for 2 weeks.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The "(R)-lansoprazole" or "(S)-lansoprazole" used as a
starting material in the crystal production method of the present
invention can be produced according to a method known per se, such
as the method described in JP-A-10-504290 (WO 96/02535) or a method
analogous thereto, or the method described in the following
production method 1 or 2.
(1) Production Method 1
[0012]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-
-benzimidazole and an excess amount (about 1.5-10 molar
equivalents) of an oxidant (e.g., peroxide such as hydrogen
peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, etc.) are
reacted in the presence of a catalyst for asymmetric induction
(e.g., optically active diol, complex of titanium(IV) alkoxide and
water, etc.), an organic solvent [e.g., alcohols such as methanol,
ethanol, propanol, isopropanol etc.; aromatic hydrocarbons such as
benzene, toluene, xylene etc.; ethers such as diethyl ether,
diisopropyl ether, butyl methyl ether, dioxane, tetrahydrofuran
etc.; esters such as ethyl acetate, methyl acetate etc.; ketones
such as acetone, methyl isobutyl ketone etc.; halogenated
hydrocarbons such as chloroform, dichloromethane, ethylene
dichloride, carbon tetrachloride etc.; amides such as
N,N-dimethylformamide etc.; sulfoxides such as dimethylsulfoxide
etc.; acetic acid and the like] and a base [such as an inorganic
base (e.g., alkali metal carbonates (potassium carbonate, sodium
carbonate etc.), alkali metal hydroxides (sodium hydroxide,
potassium hydroxide etc.), alkali metal hydrides (sodium hydride,
potassium hydride etc.) etc.); an organic base such as alkali metal
alkoxides (sodium methoxide, sodium ethoxide, etc.), alkali metal
carboxylates (sodium acetate, etc.), amines (piperidine,
piperazine, pyrrolidine, morpholine, triethylamine, tripropylamine,
tributylamine, trioctylamine, diisopropylethylamine,
dimethylphenylamine, etc.), pyridines (pyridine,
dimethylaminopyridine, etc.) and the like; a basic amino acid
(e.g., arginine, lysin, ornithine etc.) and the like], at about
-20.degree. C. to 20.degree. C. for about 0.1 to 50 hours.
[0013] The obtained compound can be isolated by a separation and
purification method known per se, such as concentration, solvent
extraction, crystallization, redissolution, chromatography or a
combination thereof.
(2) Production Method 2
[0014]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl-
]-1H-benzimidazole is subjected to optical resolution to give an
isomer.
[0015] The method of optical resolution includes a method known per
se, for example, a fractional recrystallization method, a chiral
column method, a diastereomer method, and so forth.
[0016] The "fractional recrystallization method" includes a method
in which a salt is formed between a racemate and an optically
active compound [e.g., (+)-mandelic acid, (-)-mandelic acid,
(+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine,
(-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.],
which salt is separated by fractional recrystallization etc., and,
if desired, subjected to a neutralization process, to give a free
optical isomer.
[0017] The "chiral column method" includes a method in which a
racemate or a salt thereof is applied to a column for separation of
optical isomer (chiral column). In the case of liquid
chromatography, for example, optical isomers are separated by
adding a racemate to a chiral column such as ENANTIO-OVM (produced
by Tosoh Corporation) or the DAICEL CHIRAL series (produced by
Daicel Corporation), and developing the racemate in water, a buffer
(e.g., phosphate buffer), an organic solvent (e.g., hexane,
ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid,
diethylamine, triethylamine, etc.), or a solvent mixture thereof.
In the case of gas chromatography, for example, a chiral column,
such as CP-Chirasil-DeX CB (produced by GL Science), is used to
separate optical isomers.
[0018] The "diastereomer method" includes a method in which a
racemate and an optically active reagent are reacted (preferably,
an optically active reagent is reacted with the 1-position of the
benzimidazole group) to give a diastereomer mixture, which is then
subjected to ordinary separation methods (e.g., fractional
recrystallization, chromatography, etc.) to obtain either
diastereomer, which is subjected to a chemical reaction (e.g., acid
hydrolysis, base hydrolysis, hydrogenolysis, etc.) to cut off the
optically active reagent moiety, whereby the desired optical isomer
is obtained. Said "optically active reagent" includes, for example,
optically active organic acids such as MTPA
[.alpha.-methoxy-.alpha.-(trifluoromethyl)phenylacetic acid] and
(-)-menthoxyacetic acid; and optically active alkoxymethyl halides
such as
(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane
and the like.
[0019] The above-mentioned
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole can be produced according to the method described in
JP-A-61-50978, U.S. Pat. No. 4,628,098, JP-A-10-195068, WO 98/21201
and the like or a method analogous thereto.
[0020]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl-
]-1H-benzimidazole is produced by the method described in
JP-A-61-50978, U.S. Pat. No. 4,628,098 etc. or a method analogous
thereto.
[0021] The (R)-lansoprazole or (S)-lansoprazole produced by the
above-mentioned method may be a solid (crystal, amorphous) or an
oily substance and may not be isolated or purified.
[0022] The crystal of (R)-lansoprazole or (S)-lansoprazole may or
may not be a hydrate.
[0023] The "hydrate" includes 0.5 hydrate to 5.0 hydrate. Among
others, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5
hydrate are preferred. More preferred is 0.5 hydrate, 1.0 hydrate
and 1.5 hydrate.
[0024] When the (R)-lansoprazole or (S)-lansoprazole obtained
according to the above-mentioned method as, for example, a crystal
(hereinafter sometimes to be referred to as crystal (I)) and then
subjected to the crystal production method of the present
invention, the method of crystallization of crystal (I) includes
methods known per se, for example, crystallization from a solution,
crystallization from vapor, and crystallization from a molten
form.
[0025] The method of the "crystallization from a solution" include,
for example, a concentration method, a slow cooling method, a
reaction method (diffusion method, electrolysis method), a
hydrothermal growth method, a fusing agent method, and so forth.
The solvents to be used include, for example, aromatic hydrocarbons
(e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons
(e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons
(e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g., diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitrites
(e.g., acetonitrile, etc.), ketones (e.g., acetone, etc.),
sulfoxides (e.g., dimethylsulfoxide, etc.), acid amides (e.g.,
N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.),
alcohols (e.g., methanol, ethanol, isopropyl alcohol. etc.), water,
and so forth. These solvents may be used singly or in a mixture of
two or more kinds at appropriate ratios (e.g., 1:1 to 1:100).
[0026] The method of the "crystallization from vapor" includes, for
example, a gasification method (sealed tube method, gas stream
method), a gas phase reaction method, a chemical transportation
method, and so forth.
[0027] The method of the "crystallization from a molten form"
includes, for example, a normal freezing method (pulling-up method,
temperature gradient method, Bridgman method), a zone melting
method (zone leveling method, float zone method), a special growth
method (VLS method, liquid phase epitaxis method), and so
forth.
[0028] Examples of the crystal of (R)-lansoprazole or
(S)-lansoprazole to be used as a starting material in the crystal
production method of the present invention include the
following:
(1) a crystal showing an X-ray powder diffraction analysis pattern
having characteristic peaks at interplanar spacings (d) of 5.88,
4.70, 4.35, 3.66 and 3.48 Angstrom in an X-ray powder diffraction
of wet crystal; (2) a crystal showing an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom in an X-ray
powder diffraction of wet crystal; (3) a mixture of the crystals of
the aforementioned (1) and (2); and (4) a crystal showing an X-ray
powder diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09,
3.94, 3.89, 3.69, 3.41 and 3.11 Angstrom.
[0029] The enantiomeric excess of (R)-lansoprazole or
(S)-lansoprazole to be applied to the crystal production method of
the present invention is, for example, not less than about 80% ee,
preferably not less than about 90% ee.
[0030] More preferable (R)-lansoprazole does not contain
(S)-lansoprazole substantially. By "does not contain substantially"
is meant (R)-lansoprazole containing (S)-lansoprazole in 0-3%,
preferably 0-1%. More preferably, (S)-lansoprazole does not contain
(R)-lansoprazole substantially. By "does not contain substantially"
here is meant (S)-lansoprazole containing (R)-lansoprazole in 0-3%,
preferably 0-1%.
[0031] It is preferable that (R)-lansoprazole or (S)-lansoprazole
obtained by the above-mentioned production method be subjected to
the step to be mentioned below for improving the optical
purity.
[0032] For an increased optical purity of the (R)-lansoprazole or
(S)-lansoprazole obtained by the above-mentioned production method,
for example, the method described in JP-A-11-508590 (WO 97/02261)
or a method analogous thereto, or the following method [1] or [2]
is employed.
[1] A crystal of (R)-lansoprazole is selectively crystallized from
a solution containing (R)-lansoprazole in a greater amount than
(S)-lansoprazole and the precipitated crystal is separated to give
a crystal of (R)-lansoprazole substantially free of
(S)-lansoprazole. [2]. A crystal of (S)-lansoprazole is selectively
crystallized from a solution containing (S)-lansoprazole in a
greater amount than (R)-lansoprazole and the precipitated crystal
is separated to give a crystal of (S)-lansoprazole substantially
free of (R)-lansoprazole.
[0033] It is also possible to separate the precipitated crystal
after the above-mentioned [1] or [2] and subject the crystal to
recrystallization once or more.
[0034] The methods for "selective crystallization" include, for
example, a method of stirring a solution, a method of adding a seed
crystal to a solution, a method of changing the temperature of a
solution, a method of changing the solvent composition of a
solution, a method of decreasing the liquid amount of a solution,
or a method consisting of two or more of these methods in
combination and the like.
[0035] The "method of stirring a solution" includes, for example,
stirring a solution containing one of (R)-lansoprazole and
(S)-lansoprazole in a greater amount than the other at about
-80.degree. C. to 120.degree. C., preferably at about -20.degree.
C. to 60.degree. C., for about 0.01 to 100 hours, preferably for
about 0.1 to 10 hours.
[0036] The "method of adding a seed crystal to a solution" include,
for example, adding (1) a crystal showing an X-ray powder
diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 5.88, 4.70, 4.35, 3.66 and 3.48
Angstrom; (2) a crystal showing an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom; (3) a mixture
of the crystals of the aforementioned (1) and (2) or (4) in a
solution, a solid that transforms to the aforementioned (1)-(3)
(e.g., a crystal showing an X-ray powder diffraction analysis
pattern having characteristic peaks at interplanar spacings (d) of
11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and
3.11 Angstrom; a crystal showing an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 8.86, 8.01, 6.58; 5.91, 5.63, 5.02 and 4.48
Angstrom; a crystal showing an X-ray powder diffraction analysis
pattern having characteristic peaks at interplanar spacings (d) of
8.37, 4.07, 5.65, 5.59, 5.21, 4.81 and 4.21 Angstrom; a crystal
showing an X-ray powder diffraction analysis pattern having
characteristic peaks at interplanar spacings (d) of 11.68, 6.78,
5.85, 5.73, 4.43, 4.09, 3.94, 3.90, 3.69, 3.41 and 3.11 Angstrom,
etc.) to a solution containing one of (R)-lansoprazole and
(S)-lansoprazole in a greater amount than the other as a seed
crystal.
[0037] The "method of changing the temperature of a solution"
includes, for example, changing the temperature of a solution
containing one of (R)-lansoprazole and (S)-lansoprazole in a
greater amount than the other, preferably by cooling (e.g., lower
the liquid temperature by 5-100.degree. C.).
[0038] The "method of changing the solvent composition of a
solution" includes, for example, adding water, a low polar organic
solvent (e.g., esters, ethers, aromatic hydrocarbons, hydrocarbons,
halogenated hydrocarbons or a mixture of two or more of these etc.)
or a mixture of two or more of these to a solution containing one
of (R)-lansoprazole and (S)-lansoprazole in a greater amount than
the other.
[0039] The "method of decreasing the liquid amount of a solution"
includes, for example, distilling away or evaporating the solvent
from a solution containing one of (R)-lansoprazole and
(S)-lansoprazole in a greater amount than the other and, the
like.
[0040] Of these, preferred are:
(i) a method of stirring a solution, (ii) a method comprising a
method of stirring a solution and a method of adding a seed crystal
to a solution, (iii) a method comprising a method of stirring a
solution and a method of changing the temperature of a solution,
(iv) a method comprising a method of stirring a solution and a
method of changing the solvent composition of a solution, (v) a
method comprising a method of stirring a solution and a method of
decreasing the liquid amount of a solution, (vi) a method
comprising a method of stirring a solution, a method of changing
the temperature of a solution and a method of adding a seed crystal
to a solution, (vii) a method comprising a method of stirring a
solution, a method of changing the solvent composition of a
solution and a method of adding a seed crystal to a solution,
(viii) a method comprising a method of stirring a solution, a
method of decreasing the liquid amount of a solution and a method
of adding a seed crystal to a solution, (ix) a method comprising a
method of stirring a solution, a method of changing the temperature
of a solution and a method of changing the solvent composition of a
solution, (x) a method comprising a method of stirring a solution,
a method of changing the temperature of a solution, a method of
changing the solvent composition of a solution and a method of
adding a seed crystal to a solution, (xi) a method comprising a
method of stirring a solution, a method of changing the temperature
of a solution and a method of decreasing the liquid amount of a
solution, and (xii) a method comprising a method of stirring a
solution, a method of changing the temperature of a solution, a
method of decreasing the liquid amount of a solution and a method
of adding a seed crystal to a solution.
[0041] The precipitated crystal can be separated by, for example,
filtration, centrifugation and the like.
[0042] The thus-obtained crystal may be used as it is, or dried,
where necessary, or may be subjected to a recrystallization step,
where necessary.
[0043] The "drying" includes, for example, vacuum drying,
through-flow drying, drying by heating, air drying and the
like.
[0044] When, for example, (R)-lansoprazole or (S)-lansoprazole
obtained by asymmetric synthesis is used, it is applied to the
method of the above-mentioned [1] or [2], or where necessary,
recrystallization once or more times to reduce the amount of
analogous materials (e.g.,
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole and/or
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfonyl]-1H-b-
enzimidazole, etc.) in the precipitated crystals.
[0045] To be specific, the obtained crystal or a dry crystal
thereof is dissolved in a solvent (e.g., water, esters, ketones,
phenols, alcohols, ethers, aromatic hydrocarbons, amides,
sulfoxides, hydrocarbons, nitrites, halogenated hydrocarbons,
pyridines or a mixture of two or more of these), applied to a
dehydration step where necessary, and crystallized.
[0046] The "dehydrating" is performed by a conventional dehydration
method, such as a concentration method, a method using a
dehydrating agent [e.g., anhydrous magnesium sulfate, anhydrous
sodium sulfate, molecular sieve (trade name)] and the like.
[0047] Examples of the "crystallization" method include the
aforementioned crystallization method.
[0048] The crystal obtained after the above-mentioned
recrystallization is exemplified by:
(1) a crystal showing an X-ray powder diffraction analysis pattern
having characteristic peaks at interplanar spacings (d) of 5.88,
4.70, 4.35, 3.66 and 3.48 Angstrom in an X-ray powder diffraction
of wet crystal, (2) a crystal showing an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom in an X-ray
powder diffraction of wet crystal, (3) a mixture of the crystals of
the aforementioned (1) and (2), and (4) a crystal showing an X-ray
powder diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09,
3.94, 3.89, 3.69, 3.41 and 3.11 Angstrom.
[0049] The amount of the analogous materials in the crystal is less
than 1 wt %, preferably less than 0.4 wt %.
[0050] The crystal precipitated in the recrystallization step can
be separated by, for example, filtration, centrifugation and the
like.
[0051] The thus-obtained crystal may be used as it is, or dried,
where necessary, or may be subjected to a second recrystallization
step, where necessary.
[0052] The "drying" is done by a method similar to the
above-mentioned "drying".
[0053] To be specific, the obtained crystal is dissolved in a
solvent (e.g., water, esters, ketones, phenols, alcohols, ethers,
aromatic hydrocarbons, amides, sulfoxides, hydrocarbons, nitrites,
halogenated hydrocarbons, pyridines or a mixture of two or more of
these etc.), applied to a dehydration step where necessary,
crystallized, separated and dried.
[0054] The "dehydrating" is performed by a method such as the
above-mentioned "dehydration method".
[0055] Examples of the "crystallization" method include the
aforementioned crystallization method.
[0056] The crystal obtained in the above-mentioned second
recrystallization step is exemplified by a crystal of (R)- or
(S)-lansoprazole, which shows an X-ray powder diffraction analysis
pattern having characteristic peaks at interplanar spacings (d) of
11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and
3.11 Angstrom.
[0057] The crystal obtained in the second recrystallization step
may be separated by, for example, filtration, centrifugation and
the like.
[0058] The separated crystal can be dried by, for example, vacuum
drying, through-flow drying, drying by heating, air drying and the
like.
[0059] The "esters" include, for example, methyl acetate, ethyl
acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl
acetate, ethyl formate and the like.
[0060] The "ketones" include, for example, acetone, methyl ethyl
ketone, methyl isopropyl ketone, methyl butyl ketone, methyl
isobutyl ketone and the like.
[0061] The "phenols" include, for example, anisole and the
like.
[0062] The "alcohols" include, for example, methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,
pentanol, 3-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol,
ethylene glycol and the like.
[0063] The "ethers" include, for example, t-butyl methyl ether,
diethyl ether, 1,1-diethoxypropane, 1,1-dimethoxypropane,
2,2-dimethoxypropane, isopropyl ether, tetrahydrofuran,
methyltetrahydrofuran and the like.
[0064] The "aromatic hydrocarbons" include, for example,
chlorobenzene, toluene, xylene, cumene and the like.
[0065] The "amides" include, for example, formamide,
N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone
and the like.
[0066] The "sulfoxides" include, for example, dimethylsulfoxide and
the like.
[0067] The "hydrocarbons" include, for example, propane, hexane,
pentane, octane, isooctane and the like.
[0068] The "nitriles" include, for example, acetonitrile and the
like.
[0069] The "halogenated hydrocarbons" include, for example,
chloroform, dichloromethane, dichloroethene, trichloroethene and
the like.
[0070] The "pyridines" include, for example, pyridine and the
like.
[0071] The crystal obtained by crystallization by the
above-mentioned method and dry crystal thereof do not substantially
contain the other enantiomer.
[0072] (R)-Lansoprazole or (S)-lansoprazole obtained by the
above-mentioned various methods is applied to the crystal
production method of the present invention.
[0073] The crystal production method of the present invention is
described in detail in the following.
(1) Step for crystallization at a temperature of about 0.degree. C.
to about 35.degree. C. from C.sub.1-4 alkyl acetate solution
containing (R)-lansoprazole or (S)-lansoprazole at a concentration
of about 0.1 g/mL to about 0.5 g/mL
[0074] First, (R)-lansoprazole or (S)-lansoprazole is made to be
present in C.sub.1-4 alkyl acetate at a concentration of about 0.1
g/mL to about 0.5 g/mL (preferably about 0.1 g/mL to about 0.35
g/mL, more preferably about 0.2 g/mL to about 0.3 g/mL,
particularly preferably about 0.25 g/mL to about 0.28 g/mL).
[0075] For example, an excess C.sub.1-4 alkyl acetate is added to
(R)-lansoprazole or (S)-lansoprazole, and the mixture is heated
where necessary at about 30.degree. C. to 60.degree. C. to dissolve
same and concentrated under reduced pressure to achieve a given
concentration (about 0.1 g/mL to about 0.5 g/mL).
[0076] As used herein, the concentration is measured according to
an area comparison method with a standard product solution using
high performance liquid chromatography. The measurement method is
explained in detail in the following.
Measurement Conditions
[0077] Column: Shiseido CAPCELL PAK C18 SG120 5 .mu.m 4.6.times.250
mm
[0078] Column Temp.: 25.degree. C.
[0079] Mobile phase: H.sub.2O:CH.sub.3CN:Et.sub.3N=50:50:1
(adjusted to pH 7.0 with phosphoric acid)
[0080] Flow rate: 1.0 mL/min.
[0081] Inject. Vol.: 10 .mu.l
[0082] Wavelength: 285 nm
Sample Preparation
[0083] Standard solution: standard product (about 75 mg) is
precisely weighed and mobile phase is added to make the amount 100
mL.
[0084] Sample solution: mobile phase is added to ethyl acetate
solution (1 mL) to make the amount 100 mL.
Concentration Measurement Method
[0085] Standard solution (10 .mu.l) and sample solution (10 .mu.l)
are tested by liquid chromatography under the aforementioned HPLC
conditions and peak area A.sub.S of (R)-lansoprazole or
(S)-lansoprazole in the Standard solution, and the peak area
A.sub.T Of (R)-lansoprazole or (S)-lansoprazole in the sample
solution are measured by automatic integration, based on which the
concentration of (R)-lansoprazole or (S)-lansoprazole is calculated
from the following formula:
(A.sub.T/A.sub.S).times.(W.sub.S/1000)
[0086] W.sub.S: standard product sample amount (mg)
[0087] The concentration can be made to fall within the optimal
range for the selected solvent, wherein the state of saturation or
per-saturation (R)-lansoprazole or (S)-lansoprazole is preferable
for crystallization.
[0088] The C.sub.1-4 alkyl acetate includes methyl acetate, ethyl
acetate, propyl acetate, butyl acetate and the like, of which
preferably used are ethyl acetate and propyl acetate.
[0089] The crystallization is performed by standing or stirring a
C.sub.1-4 alkyl acetate solution containing the above-mentioned
(R)-lansoprazole or (S)-lansoprazole according to a method known
per se at a crystallization temperature of about 0.degree. C. to
about 35.degree. C.
[0090] The lower limit of crystallization temperature is preferably
about 10.degree. C., more preferably about 15.degree. C., most
preferably about 20.degree. C. The upper limit of crystallization
temperature is preferably about 30.degree. C. Particularly,
crystallization temperature is preferably about 20.degree. C. to
about 30.degree. C.
[0091] The crystallization time is about 30 minutes to about 10
hours, preferably about 30 minutes to about 4 hours, particularly
preferably about 1 hour to about 2 hours.
[0092] In this step, a seed crystal may be added to the solution.
Examples of the seed crystal include one that may be added to the
solution before or during dropwise addition of C.sub.5-8
hydrocarbon to be mentioned below.
[0093] This step is carried out in an atmosphere or under an inert
gas atmosphere, or in an inert gas stream. As the "inert gas", one
usable for dropwise addition of C.sub.5-8 hydrocarbon to be
mentioned below is employed.
[0094] The crystal obtained by this step can be separated by a
method such as filtration, centrifugation and the like.
[0095] The separated crystal may be washed, where necessary, with a
(1:0-1:10) mixture of C.sub.1-4 alkyl acetate-C.sub.5-8
hydrocarbon, and the like. The C.sub.1-4 alkyl acetate here is
exemplified by those mentioned above, and the C.sub.5-8 hydrocarbon
is exemplified by those mentioned below. The separated crystal can
be dried by, for example, vacuum drying, through-flow drying,
drying by heating, air drying and the like.
[0096] The crystal obtained by this step is superior in
preservation stability and can be used as the pharmaceutical
product to be mentioned below. By the following step (2), the
objective crystal superior in preservation stability can be
obtained in a high yield.
(2) Step for adding dropwise C.sub.5-8 hydrocarbon in an amount of
not more than 7 times the amount of the C.sub.1-4 alkyl acetate
solution at the same temperature after step (1)
[0097] By applying this step to the crystal obtained by the
above-mentioned step (1) after separation or without separation,
the crystal can be obtained in greater amounts.
[0098] This step is preferably applied after precipitation of the
crystal in the above-mentioned step (1). It is preferably applied
after precipitation of a crystal in at least about 20 wt %, more
preferably about 30 wt % to about 90 wt %, particularly preferably
about 50 wt % to about 90 wt %, of (R)-lansoprazole or
(S)-lansoprazole added as a starting material.
[0099] The crystallization temperature in this step is the same as
in step (1).
[0100] Examples of C.sub.5-8 hydrocarbon include straight chain or
branched C.sub.5-8 aliphatic hydrocarbon, such as pentane,
isopentane, neopentane, hexane, isohexane, 3-methylpentane,
neohexane, 2,3-dimethylbutane, heptane, 2-methylhexane,
3-methylhexane, 3-ethylpentane, 2,2-dimethylpentane,
2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane,
2,2,3-trimethylbutane, octane, isooctane and the like, and
C.sub.7-8 aromatic hydrocarbon, such as toluene, xylene and the
like. Preferably, heptane and straight chain C.sub.5-8 aliphatic
hydrocarbon such as hexane and the like, are used.
[0101] The amount of dropwise addition of C.sub.5-8 hydrocarbon is
not more than 7 times, preferably not more than 5 times, more
preferably 1 to 3 times, the amount of the C.sub.1-4 alkyl acetate
solution containing (R)-lansoprazole or (S)-lansoprazole in step
(1).
[0102] The dropwise addition includes sequential dropwise addition
of almost the same amount over, for example, about 15 minutes to
about 4 hours (preferably about 1 hour to about 2 hours) while
standing or stirring the solution.
[0103] The temperature during dropwise addition is preferably
adjusted to the above-mentioned crystallization temperature.
[0104] In this step, a seed crystal may be added to the solution
before or during the dropwise addition of C.sub.5-8
hydrocarbon.
[0105] The seed crystal includes, for example,
(1) a crystal showing an X-ray powder diffraction analysis pattern
having characteristic peaks at interplanar spacings (d) of 5.88,
4.70, 4.35; 3.66 and 3.48 Angstrom, (2) a crystal showing an X-ray
powder diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom
X-ray powder diffraction, (3) a crystal showing an X-ray powder
diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09,
3.94, 3.89, 3.69, 3.41 and 3.11 Angstrom, (4) a crystal showing an
X-ray powder diffraction analysis pattern having characteristic
peaks at interplanar spacings (d) of 8.86, 8.01, 6.58, 5.91, 5.63,
5.02 and 4.48 Angstrom, (5) a crystal showing an X-ray powder
diffraction analysis pattern having characteristic peaks at
interplanar spacings (d) of 8.37, 4.07, 5.65, 5.59, 5.21, 4.81 and
4.21 Angstrom, (6) a crystal showing an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.78, 5.85, 5.73, 4.43, 4.09, 3.94, 3.90,
3.69, 3.41 and 3.11 Angstrom, (7) a mixture of two or more crystals
from the aforementioned (1)-(6) and (8) a solid that transforms
into the aforementioned (1)-(6) in a solution.
[0106] After the dropwise addition, the mixture may be stood or
stirred on demand for about 1 hour to about 3 hours.
[0107] This step is applied in an atmosphere or under an inert gas
atmosphere, or in an inert gas stream. The "inert gas" includes,
for example, nitrogen, helium, neon, argon and the like.
[0108] The crystal obtained by this step can be separated by
filtration, centrifugation and the like.
[0109] The separated crystal may be washed, where necessary, with a
C.sub.1-4 alkyl acetate-C.sub.5-8 hydrocarbon (1:0-1:10) mixture
and the like. As used herein, the C.sub.1-4 alkyl acetate and
C.sub.5-8 hydrocarbon are exemplified by those mentioned above. The
separated crystal can be dried by, for example, vacuum drying,
through-flow drying, drying by heating, air drying and the
like.
[0110] The obtained crystal can be analyzed generally by crystal
analysis by X-ray diffraction. The orientation of the crystal can
be determined by a mechanical method, optical method and the
like.
[0111] The crystal obtained by the above-mentioned production
method (step (1) alone, or step (2) after step (1)) has the
following melting start temperature by DSC measurement (temperature
rise rate 0.5.degree. C./min). As used herein, the "melting start
temperature" refers to the temperature at which crystals start to
melt when heated under, for example, the DSC measurement conditions
to be mentioned below. The crystal has the melting start
temperature of not less than about 131.degree. C., preferably about
131.degree. C. to about 137.degree. C., more preferably about
132.degree. C. to about 135.degree. C., most preferably about
133.degree. C. to about 135.degree. C., particularly preferably
about 135.degree. C. For example, the melting start temperature of
the crystal obtained in the above-mentioned step (1) can be about
135.degree. C. In addition, the melting start temperature of the
crystal obtained by step (2) after applying the above-mentioned
step (1) can be about 132.degree. C. to about 135.degree. C.
[0112] The melting start temperature of the crystal obtained by a
conventional method is less than about 131.degree. C. For example,
the melting start temperature of the crystal obtained by the method
of Reference Example 3 mentioned below was about 125.degree. C. to
about 130.degree. C.
[0113] The crystal having a melting start temperature of not less
than about 131.degree. C., which is obtained by the production
method of the present invention, has extremely superior
preservation stability as compared to the crystal having a melting
start temperature of less than about 131.degree. C., which is
obtained by a prior art method. In the stability test (40.degree.
C.--one month residual ratio, 60.degree. C.--one month residual
ratio) to be mentioned below, for example, the crystal obtained by
the production method of the present invention showed a residual
ratio of not less than 99%, but the ratio of the crystal obtained
by a conventional method was less than 94%. Moreover, the crystal
obtained by a conventional method showed noticeable coloring during
preservation.
[0114] The crystal having a melting start temperature of not less
than about 131.degree. C., which is obtained by the production
method of the present invention, has such superior preservation
stability and can be used advantageously as a pharmaceutical
product, as compared to the crystal having a melting start
temperature of less than about 131.degree. C., which is obtained by
a prior art method.
[0115] The crystal of (R)-lansoprazole or (S)-lansoprazole obtained
by the crystal production method of the present invention is useful
as a pharmaceutical product because it shows excellent antiulcer
activity, gastric acid secretion-inhibiting action,
mucosa-protecting action, anti-Helicobacter pylori action, etc.,
and because it is of low toxicity. The dry crystal of
(R)-lansoprazole or (S)-lansoprazole is stabler than a precipitated
crystal (wet crystal) of (R)-lansoprazole or (S)-lansoprazole, and
when it is used as a pharmaceutical product, a dry crystal of
(R)-lansoprazole or (S)-lansoprazole is preferably used.
[0116] The crystal or dry crystal obtained by the method of the
present invention is useful for mammals (e.g., humans, monkeys,
sheep, bovines, horses, dogs, cats, rabbits, rats, mice, etc.) in
the treatment and prevention of digestive ulcer (e.g., gastric
ulcer, duodenal ulcer, stomach ulcer, Zollinger-Ellison syndrome,
etc.), gastritis, reflux esophagitis, NUD (non-ulcer dyspepsia),
gastric cancer (inclusive of gastric cancer caused by promotion of
interleukin-1.beta. production due to genetic polymorphism of
interleukin-1) and gastric MALT lymphoma; Helicobacter pylori
eradication; suppression of upper gastrointestinal hemorrhage due
to digestive ulcer, acute stress ulcer and hemorrhagic gastritis;
suppression of upper gastrointestinal hemorrhage due to invasive
stress (stress from major surgery necessitating intensive
management after surgery, and from cerebral vascular disorder, head
trauma, multiple organ failure and extensive burn necessitating
intensive treatment); treatment and prevention of ulcer caused by a
nonsteroidal anti-inflammatory agent; treatment and prevention of
hyperacidity and ulcer due to postoperative stress; pre-anesthetic
administration and the like. For eradication of Helicobacter
pylori, the crystal or dry crystal obtained by the method of the
present invention and antibiotic penicillins (e.g., amoxicillin
etc.) and antibiotic erythromycins (e.g., clarithromycin, etc.) are
preferably used.
[0117] For the above-mentioned various pharmaceutical uses, the
crystal of (R)-lansoprazole is preferably used.
[0118] The crystal of the present invention can be safely
administered orally or non-orally (e.g., topical, rectal and
intravenous administration, etc.), as such or in the form of
pharmaceutical compositions formulated with a pharmacologically
acceptable carrier, e.g., tablets (including sugar-coated tablets
and film-coated tablets), powders, granules, capsules (including
soft capsules), orally disintegrating tablets, liquids, injectable
preparations, suppositories, sustained-release preparations and
patches, in accordance with a commonly known method.
[0119] The content of the crystal of the present invention in the
pharmaceutical composition of the present invention is about 0.01
to 100 wt % relative to the entire composition. Varying depending
on subject of administration, route of administration, target
disease etc., its dose is normally about 0.5 to 1,500 mg/day,
preferably about 5 to 150 mg/day, based on the active ingredient,
when, for example, it is orally administered as an antiulcer agent
to an adult human (60 kg). The crystal of the present invention may
be administered once daily or in 2 to 3 divided portions per
day.
[0120] Pharmacologically acceptable carriers that may be used to
produce the pharmaceutical composition of the present invention
include various organic or inorganic carrier substances in common
use as pharmaceutical materials, including excipients, lubricants,
binders, disintegrants, water-soluble polymers and basic inorganic
salts for solid preparations; and solvents, dissolution aids,
suspending agents, isotonicity agents, buffers and soothing agents
for liquid preparations. Other ordinary pharmaceutical additives
such as preservatives, antioxidants, coloring agents, sweetening
agents, souring agents, bubbling agents and flavorings may also be
used as necessary.
[0121] Such "excipients" include, for example, lactose, sucrose,
D-mannitol, starch, cornstarch, crystalline cellulose, light
silicic anhydride, titanium oxide and the like.
[0122] Such "lubricants" include, for example, magnesium stearate,
sucrose fatty acid esters, polyethylene glycol, talc, stearic acid
and the like.
[0123] Such "binders" include, for example, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, crystalline cellulose,
.alpha.-starch, polyvinylpyrrolidone, gum arabic powder, gelatin,
pullulan, low-substituted hydroxypropyl cellulose and the like.
[0124] Such "disintegrants" include (1) crosslinked povidone, (2)
what is called super-disintegrants such as crosslinked carmellose
sodium (FMC-Asahi Chemical) and carmellose calcium (Gotoku
Yakuhin), (3) carboxymethyl starch sodium (e.g., product of
Matsutani Chemical), (4) low-substituted hydroxypropyl cellulose
(e.g., product of Shin-Etsu Chemical), (5) cornstarch, and so
forth. Said "crosslinked povidone" may be any crosslinked polymer
having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer,
including, what is called, polyvinylpyrrolidone (PVPP) and
1-vinyl-2-pyrrolidinone homopolymer, and is exemplified by Colidon
CL (produced by BASF), Polyplasdon XL (produced by ISP),
Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced
by ISP) and the like. Such "water-soluble polymers" include, for
example, ethanol-soluble water-soluble polymers [e.g., cellulose
derivatives such as hydroxypropyl cellulose (hereinafter also
referred to as HPC), polyvinylpyrrolidone etc.], ethanol-insoluble
water-soluble polymers [e.g., cellulose derivatives such as
hydroxypropylmethyl cellulose (hereinafter also referred to as
HPMC), methyl cellulose and carboxymethyl cellulose sodium, sodium
polyacrylate, polyvinyl alcohol, sodium alginate, guar gum etc.]
and the like.
[0125] Such "basic inorganic salts" include, for example, basic
inorganic salts of sodium, potassium, magnesium and/or calcium.
Preferred are basic inorganic salts of magnesium and/or calcium.
More preferred are basic inorganic salts of magnesium. Such basic
inorganic salts of sodium include, for example, sodium carbonate,
sodium hydrogen carbonate, disodium hydrogenphosphate, etc. Such
basic inorganic salts of potassium include, for example, potassium
carbonate, potassium hydrogen carbonate, etc. Such basic inorganic
salts of magnesium include, for example, heavy magnesium carbonate,
magnesium carbonate, magnesium oxide, magnesium hydroxide,
magnesium metasilicate aluminate, magnesium silicate, magnesium
aluminate, synthetic hydrotalcite
[Mg.sub.6Al.sub.2(OH).sub.16.CO.sub.3.4H.sub.2O], alumina hydroxide
magnesium, and so forth. Among others, preferred is heavy magnesium
carbonate, magnesium carbonate, magnesium oxide, magnesium
hydroxide, etc. Such basic inorganic salts of calcium include, for
example, precipitated calcium carbonate, calcium hydroxide and the
like.
[0126] Such "solvents" include, for example, water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive
oil and the like.
[0127] Such "dissolution aids" include, for example, polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0128] Such "suspending agents" include, for example, surfactants
such as stearyltriethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride,
benzethonium chloride and monostearic glycerol; and hydrophilic
polymers such as polyvinyl alcohol, polyvinylpyrrolidone,
carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl
cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
[0129] Such "isotonicity agents" include, for example, glucose,
D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.
[0130] Such "buffers" include, for example, buffer solutions of
phosphates, acetates, carbonates, citrates and the like.
[0131] Such "soothing agents" include, for example, benzyl alcohol
and the like.
[0132] Such "preservatives" include, for example, p-oxybenzoic acid
esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid, sorbic acid and the like.
[0133] Such "antioxidants" include, for example, sulfites, ascorbic
acid, .alpha.-tocopherol and the like.
[0134] Such "coloring agents" include, for example, foodcolors such
as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color
Blue No. 2; and food lake colors, Bengal and the like.
[0135] Such "sweetening agents" include, for example, saccharin
sodium, dipotassium glycyrrhetinate, aspartame, stevia, thaumatin
and the like.
[0136] Such "souring agents" include, for example, citric acid
(citric anhydride), tartaric acid, malic acid and the like.
[0137] Such "bubbling agents" include, for example, sodium
bicarbonate and the like.
[0138] Such "flavorings" may be synthetic substances or naturally
occurring substances, and include, for example, lemon, lime,
orange, menthol, strawberry and the like.
[0139] The crystal of the present invention may be prepared as a
preparation for oral administration in accordance with a commonly
known method, by, for example, compression-shaping it in the
presence of an excipient, a disintegrant, a binder, a lubricant or
the like, and subsequently coating it as necessary by a commonly
known method for the purpose of taste masking, enteric dissolution
or sustained release. For an enteric preparation, an intermediate
layer may be provided by a commonly known method between the
enteric layer and the drug-containing layer for the purpose of
separation of the two layers.
[0140] For preparing the crystal of the present invention as an
orally disintegrating tablet, available method include, for
example, a method in which a core containing crystalline cellulose
and lactose is coated with the crystal of the present invention and
a basic inorganic salt, and is further coated with a coating layer
containing a water-soluble polymer, to give a composition, which is
coated with an enteric coating layer containing polyethylene
glycol, further coated with an enteric coating layer containing
triethyl citrate, still further coated with an enteric coating
layer containing polyethylene glycol, and still yet further coated
with mannitol, to give fine granules, which are mixed with
additives and shaped. The above-mentioned "enteric coating layer"
includes, for example, aqueous enteric polymer substrates such as
cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose
phthalate, hydroxymethyl cellulose acetate succinate, methacrylic
acid copolymers [e.g., Eudragit L30D-55 (trade name; produced by
Rohm), Colicoat MAE30DP (trade name; produced by BASF), Polykid
PA30 (trade name; produced by San-yo Chemical) etc.],
carboxymethylethyl cellulose and shellac; sustained-release
substrates such as methacrylic acid polymers [e.g., Eudragit NE30D
(trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade
name), etc.]; water-soluble polymers; plasticizers such as triethyl
citrate, polyethylene glycol, acetylated monoglycerides, triacetine
and castor oil; and mixtures of one or more thereof. The
above-mentioned "additive" includes, for example, water-soluble
sugar alcohols (e.g., sorbitol, mannitol, multitol, reduced starch
saccharides, xylitol, reduced paratinose, erythritol. etc.),
crystalline cellulose [e.g. Ceolas KG 801, Avicel PH 101, Avicel PH
102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline
cellulose carmellose sodium) etc.], low-substituted hydroxypropyl
cellulose [e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical)
and mixtures thereof etc.] etc.; binders, souring agents, bubbling
agents, sweetening agents, flavorings, lubricants, coloring agents,
stabilizers, excipients, disintegrants etc. are also used.
[0141] The crystal of the present invention may be used in
combination with 1 to 3 other active ingredients.
[0142] Such "other active ingredients" include, for example,
anti-Helicobacter pylori activity substances, imidazole compounds,
bismuth salts, quinolone compounds, and so forth. Of these
substances, preferred are anti-Helicobacter pylori action
substances, imidazole compounds etc. Such "anti-Helicobacter pylori
action substances" include, for example, antibiotic penicillins
(e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinam,
etc.), antibiotic cefems (e.g., cefixime, cefaclor, etc.),
antibiotic macrolides (e.g., erythromycin. clarithromycin, etc.),
antibiotic tetracyclines (e.g., tetracycline, minocycline,
streptomycin. etc.), antibiotic aminoglycosides (e.g., gentamicin,
amikacin, etc.), imipenem, and so forth. Of these substances,
preferred are antibiotic penicillins, antibiotic macrolides etc.
Especially preferred is a triple therapy of an antibiotic
penicillins, an antibiotic macrolide and the crystal of
(R)-lansoprazole or (S)-lansoprazole. Such "imidazole compounds"
include, for example, metronidazole, miconazole, etc. Such "bismuth
salts" include, for example, bismuth acetate, bismuth citrate, etc.
Such "quinolone compounds" include, for example, ofloxacin,
ciploxacin, etc.
[0143] Such "other active ingredients" and the crystal of the
present invention may also be used in combination as a mixture
prepared as a single pharmaceutical composition [e.g., tablets.
powders, granules, capsules (including soft capsules), liquids,
injectable preparations, suppositories, sustained-release
preparations, etc.], in accordance with a commonly known method.
and may also be prepared as separate preparations and administered
to the same subject simultaneously or at a time interval.
[0144] While the present invention is explained in detail in the
following by referring to Reference Examples and Examples, the
present invention is not limited by these Examples.
[0145] The X-ray powder diffraction was measured using X-ray
Diffractometer RINT Ultima+ (Rigaku).
[0146] The melting start temperature was measured using DSC
(differential scanning calorimeter SEIKO DSC220C) under the
following measurement conditions.
[0147] DSC measurement conditions;
[0148] temperature range: room temperature to 220.degree. C.
[0149] temperature rise rate: 0.5.degree. C./min.
[0150] sample container: aluminum pan (without cover)
[0151] atmosphere: nitrogen gas (100 mL/min)
[0152] Enantiomeric excess (% ee) was measured by high performance
liquid chromatography using an optically active column for the
following conditions (A).
[0153] The amounts of sulfide and sulfone present were measured by
high performance liquid chromatography using an optically active
column for the following conditions (A) or high performance liquid
chromatography under the conditions (B).
High Performance Liquid Chromatography Conditions (A);
[0154] Column: CHIRALCEL OD (4.6.times.250 mm; DAICEL CHEMICAL
INDUSTRIES, LTD.)
[0155] Mobile phase: hexane/ethanol=90/10
[0156] Flow rate: 1.0 mL/min
[0157] Detection: UV 285 nm
High Performance Liquid Chromatography Conditions (B);
[0158] Column: CAPCELL PAK C18 SG120 5 .mu.m 4.6.times.250 mm
(Shiseido Co., Ltd.)
[0159] Mobile Phase: acetonitrile:water:triethylamine mixture
(50:50:1) adjusted to pH 7.0 with phosphoric acid
[0160] Flow rate: 1.0 mL/min
[0161] Detection: UV 285 nm
REFERENCE EXAMPLE 1
Production of solution containing
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole by asymmetric oxidation
[0162]
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-
-benzimidazole monohydrate (6 kg, 16.2 mol) was dried in vacuo at
80.degree. C. for 21 hours to give
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole (5.73 kg, water content 0.0364%).
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole (5.00 kg, 14.1 mol, containing water 1.82 g), toluene (25
L), water (13.18 g, 0.732 mol, as total water content 0.833 mol)
and (+)-diethyl tartrate (531 mL, 3.10 mol) were mixed under a
nitrogen gas stream. Titanium(IV) isopropoxide (414 mL, 1.40 mol)
was added at 50-60.degree. C. under a nitrogen gas stream, and the
mixture was stirred at the same temperature for 30 min.
Diisopropylethylamine (815 mL, 4.68 mol) was added under a nitrogen
gas stream at 15-25.degree. C., and cumene hydroperoxide (7.65 L,
content 82%, 42.7 mol) was added at -10.degree. C. to 5.degree. C.
and the mixture was stirred at -8.degree. C. to 2.degree. C. for 3
hours to allow reaction.
[0163] The analysis results of the reaction mixture by high
performance liquid chromatography (conditions (A)) are as
follows.
[0164] The enantiomeric excess of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the reaction mixture was 96.9% ee.
[0165] As a result of the analysis of the reaction mixture by high
performance liquid chromatography (conditions (B)), analogous
materials in the reaction mixture were found to be sulfide 1.0% and
sulfone 1.7% alone.
REFERENCE EXAMPLE 2
Purification method of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole
[0166] (1) To the reaction mixture obtained in the above-mentioned
Reference Example 1 was added 30% aqueous sodium thiosulfate
solution (13.5 kg) under a nitrogen gas stream, and the remaining
cumene hydroperoxide was decomposed. The mixture was concentrated
under reduced pressure until the liquid amount became about 25 L.
Heptane-t-butyl methyl ether (heptane:t-butyl methyl ether=1:1, 20
L) was added dropwise while maintaining the mixture at 0-10.degree.
C. and heptane (70 L) was added dropwise. The precipitated crystals
were separated, and washed with cooled t-butyl methyl ether-toluene
(t-butyl methyl ether:toluene=4:1, 5 L).
[0167] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the crystal was found to be 98.3% ee.
[0168] As a result of the analysis of the reaction mixture by high
performance liquid chromatography (conditions (B)), analogous
materials in the reaction mixture were found to be sulfide 0.45%
and sulfone 1.8% alone.
(2) A suspension of the wet crystal obtained in the above-mentioned
(1) in acetone (20 L) was added dropwise to a mixture of acetone
(7.5 L) and water (37.5 L), and water (52.5 L) was added. The
precipitated crystals were separated and washed with cooled
acetone-water (acetone:water=1:3, 5 L) and water (6.5 L).
[0169] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the crystal was found to be 100% ee.
[0170] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), analogous
materials in the crystal were found to be sulfide 0.19% and sulfone
0.08% alone.
(3) The wet crystal obtained in the above-mentioned (2) was
suspended in ethyl acetate (50 L) and magnesium sulfate (2.5 kg)
was added. Magnesium sulfate was separated and the residue was
washed with ethyl acetate (3.5 L). After addition of triethylamine
(250 mL), the mixture was concentrated under reduced pressure until
the liquid amount became about 10 L. To the concentrate were added
methanol (2.5 L), about 12.5% aqueous ammonia (25.5 L, about
50.degree. C.) and t-butyl methyl ether (24.5 L, about 50.degree.
C.) for partitioning. About 12.5% aqueous ammonia (12 L, about
50.degree. C.) was added to the organic layer and the mixture was
partitioned (this step was repeated once). The aqueous layers were
combined, ethyl acetate (24.5 L) was added, and acetic acid was
added dropwise at not more than 20.degree. C. to adjust the pH to
about 8. After partitioning, the aqueous layer was extracted with
ethyl acetate (24.5 L). The organic layers were combined and washed
with about 20% brine (24.5 L). After addition of triethylamine (250
mL), the organic layer was concentrated under reduced pressure.
Acetone (5.55 L) was added to the concentrate and the mixture was
concentrated under reduced pressure. The concentrate was dissolved
in acetone (10 L) and the solution was added dropwise to a mixture
of acetone (5 L) and water (25 L). Water (20 L) was added dropwise
to the obtained mixture. The precipitated crystal was separated and
successively washed with cooled acetone-water (1:3, 4 L) and water
(13 L).
[0171] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the crystal was found to be 100% ee.
[0172] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), analogous
materials in the crystal were found to be sulfide 0.018% and
sulfone 0.016% alone.
REFERENCE EXAMPLE 3
Purification method of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole
[0173] The wet crystal obtained by the method of the
above-mentioned Reference Example 2 was dissolved in ethyl acetate
(43 L). The separated aqueous layer was partitioned and the
obtained organic layer was concentrated under reduced pressure
until the liquid amount became about 19 L. Ethyl acetate (48 L) was
added to the concentrate, and the mixture was concentrated under
reduced pressure until the liquid amount became about 19 L. Ethyl
acetate (48 L) and activated carbon (360 g) were added to the
concentrate and the mixture was stirred and the activated carbon
was filtered off. The filtrate was concentrated under reduced
pressure until the liquid amount became about 19 L. Heptane (150 L)
was added dropwise to the concentrate at about 40.degree. C. The
mixture was stirred at the same temperature for about 30 minutes
and the crystal was separated and washed with ethyl acetate-heptane
(1:8, 8 L, about 40.degree. C.) and dried to give the title
compound (4.5 kg).
[0174] The analysis results of the crystal by X-ray powder
diffraction are as follows.
[0175] The crystal showed an X-ray powder diffraction analysis
pattern having characteristic peaks at interplanar spacings (d) of
11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and
3.11 Angstrom.
[0176] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), analogous
materials in the crystal were found to be sulfone 0.02% alone, and
other analogous materials such as sulfide and the like were not
found. The enantiomeric excess of (R)-lansoprazole in the crystal
was 100% ee.
[0177] The melting start temperature of the crystal was
127.5.degree. C.
REFERENCE EXAMPLE 4
Production of (S)-lansoprazole
[0178] (1)
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio-
]-1H-benzimidazole (50.0 g, 0.14 mol, containing water 20 mg),
toluene (250 mL), water (130 mg, 0.0072 mol, total water content
0.0083 mol) and (-)-diethyl tartrate (5.31 mL, 0.031 mol) were
mixed under a nitrogen atmosphere. Titanium(IV) isopropoxide (4.14
mL, 0.014 mol) was added to the mixture at 50.degree. C. and the
mixture was stirred at 50-55.degree. C. for 1 hour under a nitrogen
atmosphere. Diisopropylethylamine (8.13 mL, 0.047 mol) was added to
the obtained mixture under a nitrogen atmosphere and cooling, and
cumene hydroperoxide (76.50 mL, content 82%, 0.42 mol) was added at
-10.degree. C. to 0.degree. C. The mixture was stirred at
-5.degree. C. to 5.degree. C. for 3.5 hours to give a reaction
mixture.
[0179] As a result of the analysis of the reaction mixture by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of (S)-lansoprazole in the reaction mixture was
96.5% ee.
[0180] As a result of the analysis of the reaction mixture by high
performance liquid chromatography (conditions (B)), analogous
materials in the reaction mixture were found to be sulfone 1.90%
and sulfide 1.50% alone.
(2) To the reaction mixture obtained in the above-mentioned (1) was
added 30% aqueous sodium thiosulfate solution (180 mL) under a
nitrogen gas stream, and the remaining cumene hydroperoxide was
decomposed. The mixture was partitioned, and water (50 mL), heptane
(150 mL), t-butyl methyl ether (200 mL) and heptane (300 mL) were
successively added to the obtained organic layer to allow
crystallization. The crystal was separated and washed with t-butyl
methyl ether-toluene (t-butyl methyl ether:toluene=4:1, 45 mL) to
give (S)-lansoprazole having interplanar spacings (d) in the
following X-ray powder diffraction, as a wet crystal.
[0181] As a result of the analysis of the crystal by X-ray powder
diffraction, the wet crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 5.88, 4.70, 4.35, 3.66 and 3.48 Angstrom.
[0182] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of the crystal was 100% ee.
[0183] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), the analogous
material in the crystal was sulfone 0.72% and other analogous
materials such as sulfide and the like were not found. (3) A
suspension of the wet crystal obtained in the above-mentioned (2)
in acetone (220 mL) was added dropwise to a mixture of acetone (75
mL) and water (370 mL), and then water (520 mL) was added. The
precipitated crystal was separated and washed with acetone-water
(acetone:water=1:3, 44 mL) and water (130 mL) to give a wet crystal
of (S)-lansoprazole having interplanar spacings (d) in the
following X-ray powder diffraction.
[0184] As a result of the analysis of the wet crystal by X-ray
powder diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 8.33, 6.63, 5.86 and 4.82 Angstrom.
[0185] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of the crystal was 100% ee.
[0186] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), analogous
materials such as sulfone, sulfide and the like were not found.
REFERENCE EXAMPLE 5
Production of (S)-lansoprazole
[0187] The wet crystal (containing the title compound 35.37 g,
content of analogous materials: 0%, enantiomeric excess: 100% ee)
obtained according to Reference Example 4 was dissolved in ethyl
acetate (340 mL). The aqueous layer was separated by partitioning
and the obtained organic layer was concentrated under reduced
pressure until the liquid amount became about 100 mL. Ethyl acetate
(400 mL) and activated carbon (3 g) were added to the concentrate
and the mixture was stirred. The activated carbon was removed by
filtration. The filtrate was concentrated under reduced pressure
until the liquid amount became about 100 mL. Heptane (1000 mL) was
added dropwise to the concentrate at about 40.degree. C. The
mixture was stirred at the same temperature for about 30 minutes,
and the crystal was separated and washed with ethyl acetate-heptane
(1:8, 63 mL, about 40.degree. C.). The crystal was dried to give
the title compound (35.08 g, yield: 99.2%).
[0188] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom.
[0189] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), analogous
materials such as sulfone, sulfide and the like were not found in
the crystal. The enantiomeric excess of (S)-lansoprazole in the
crystal was 100% ee.
[0190] The melting start temperature of the crystal was
127.0.degree. C.
REFERENCE EXAMPLE 6
[0191] The crystal (1.5 g, 4.06 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (30 mL) and
concentrated to 6 mL under reduced pressure at an outer temperature
of about 25.degree. C. Heptane (24 mL) was added dropwise at about
-5.degree. C. for about 30 minutes. After stirring for about 2.5
hours, the precipitated crystal was separated and dried to give the
title compound (1.46 g, yield: 97.3%).
[0192] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom.
[0193] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), analogous
materials such as sulfone, sulfide and the like were not found in
the crystal. The enantiomeric excess of (R)-lansoprazole in the
crystal was 100% ee.
[0194] The melting start temperature of the crystal was
130.0.degree. C.
REFERENCE EXAMPLE 7
[0195] The crystal (1.5 g, 4.06 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (30 mL) and
concentrated to 20 mL under reduced pressure at an outer
temperature of about 25.degree. C. Heptane (90 mL) was added
dropwise at about 25.degree. C. for about 30 minutes. After
stirring for about 2.5 hours, the precipitated crystal was
separated and dried to give the title compound (1.40 g, yield:
93.3%).
[0196] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom.
[0197] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), analogous
materials such as sulfone, sulfide and the like were not found in
the crystal. The enantiomeric excess of (R)-lansoprazole in the
crystal was 100% ee.
[0198] The melting start temperature of the crystal was
128.5.degree. C.
EXAMPLE 1
Production method of high melting point crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole
[0199] The wet crystal obtained according to the method of the
above-mentioned Reference Example 2 was dissolved in ethyl acetate
(50 L). The mixture was partitioned and the organic layer was
concentrated under reduced pressure until the liquid amount became
about 25 L. Ethyl acetate (30 L) was added to the concentrate, and
the mixture was concentrated under reduced pressure until the
liquid amount became about 15 L. Ethyl acetate (30 L) and activated
carbon (150 g) were added to the concentrate. The activated carbon
was removed and the mixture was washed with ethyl acetate (1.5 L).
The filtrate was concentrated under reduced pressure until the
concentration of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole became about 0.28 g/mL (12.5 L). The mixture was
stirred under a nitrogen gas stream, at about 25.degree. C. for
about 2 hours, and after confirmation of crystal precipitation,
heptane (25 L) was dropwise added over about 1.5 hours, and the
mixture was stirred for about 1.5 hours. The precipitated crystal
was separated, washed with ethyl acetate-heptane (ethyl
acetate:heptane=1:5, 6 L) and dried to give the title compound
(3.66 kg, yield: 70% based on
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole).
[0200] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom.
[0201] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the crystal was 100% ee.
[0202] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), the analogous
material was sulfone 0.01% alone, and sulfide and the like were not
found. The melting start temperature of the crystal was
134.0.degree. C.
EXAMPLE 2
[0203] The crystal (3 g, 8.12 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (12 mL) at about
50.degree. C. and the solution was stirred at about 25.degree. C.
for about 6 hours. The precipitated crystal was separated, washed
with ethyl acetate-heptane (ethyl acetate:heptane=1:5, 3 mL) and
dried to give the title compound (1.55 g, yield: 52%).
[0204] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom. As a result of the analysis of the
crystal by high performance liquid chromatography (conditions (A)),
analogous materials such as sulfone, sulfide and the like were not
found. The enantiomeric excess of (R)-lansoprazole in the crystal
was 100% ee.
[0205] The melting start temperature of the crystal was
135.0.degree. C.
EXAMPLE 3
[0206] The crystal (1.5 g, 4.06 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in n-propyl acetate (30 mL) and
concentrated to 6 mL under reduced pressure at an outer temperature
of about 25.degree. C. After stirring for about 2.5 hours, the
precipitated crystal was separated and dried to give the title
compound (0.94 g, yield: 63%).
[0207] The melting start temperature of the crystal was
134.5.degree. C.
EXAMPLE 4
[0208] The crystal (3.0 g, 8.12 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (12 mL) at about
50.degree. C. The mixture was stirred at about 25.degree. C. for
about 2.5 hours, and after confirmation of crystal precipitation,
heptane (60 mL) was dropwise added over about 15 minutes. The
precipitated crystal was separated, washed with ethyl
acetate-heptane (ethyl acetate:heptane=1:5, 3 mL) and dried to give
the title compound (2.84 g, yield: 95%).
[0209] The melting start temperature of the crystal was
133.5.degree. C.
EXAMPLE 5
[0210] The crystal (3.0 g, 8.12 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (12 mL) at about
50.degree. C. The mixture was stirred at about 25.degree. C. for
about 2 hours, and after confirmation of crystal precipitation,
hexane (24 mL) was dropwise added over about 20 minutes. The
precipitated crystal was separated, washed with ethyl
acetate-hexane (ethyl acetate:hexane=1:5, 3 mL) and dried to give
the title compound.
[0211] The melting start temperature of the crystal was
133.5.degree. C.
EXAMPLE 6
[0212] The crystal (2.0 g, 5.41 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in n-propyl acetate (30 mL) at about
30.degree. C. The mixture was concentrated to 8 mL under reduced
pressure at an outer temperature of about 25.degree. C. After
stirring for about 1.5 hours, crystal precipitation was confirmed,
and heptane (16 mL) was dropwise added over about 20 minutes. The
precipitated crystal was separated, washed twice with n-propyl
acetate-heptane (n-propyl acetate:heptane=1:5, 6 mL) and dried to
give the title compound (1.86 g, yield: 93%).
[0213] The melting start temperature of the crystal was
134.0.degree. C.
EXAMPLE 7
[0214] The crystal (2.0 g, 5.41 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in i-propyl acetate (40 mL) at about
35.degree. C. The mixture was concentrated to 8 mL under reduced
pressure at an outer temperature of about 35.degree. C. After
stirring for about 1.5 hours, crystal precipitation was confirmed,
and heptane (16 mL) was dropwise added over about 20 minutes. The
precipitated crystal was separated, washed twice with i-propyl
acetate-heptane (i-propyl acetate:heptane=1:5, 6 mL) and dried to
give the title compound (1.89 g, yield: 95%).
[0215] The melting start temperature of the crystal was
133.0.degree. C.
EXAMPLE 8
[0216] The crystal (2.0 g, 5.41 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in n-butyl acetate (40 mL) at about
35.degree. C. The mixture was concentrated to 8 mL under reduced
pressure at an outer temperature of about 35.degree. C. After
stirring for about 1 hour, crystal precipitation was confirmed, and
heptane (16 mL) was dropwise added over about 20 minutes. The
precipitated crystal was separated, washed twice with n-butyl
acetate-heptane (n-butyl acetate:heptane=1:5, 6 mL) and dried to
give the title compound (1.87 g, yield: 93%).
[0217] The melting start temperature of the crystal was
133.0.degree. C.
EXAMPLE 9
[0218] The crystal (2.0 g, 5.41 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in methyl acetate (15 mL). The
mixture was concentrated to 8 mL under reduced pressure at an outer
temperature of about 25.degree. C. After stirring for about 1.5
hours, crystal precipitation was confirmed, and heptane (16 mL) was
dropwise added over about 20 minutes. The precipitated crystal was
separated, washed twice with methyl acetate-heptane (methyl
acetate:heptane=1:5, 6 mL) and dried to give the title compound
(1.71 g, yield: 86%).
[0219] The melting start temperature of the crystal was
134.0.degree. C.
EXAMPLE 10
[0220] The wet crystal obtained according to the method of the
above-mentioned Reference Example 4 was dissolved in ethyl acetate
(50 L). The mixture was partitioned and the organic layer was
concentrated under reduced pressure until the liquid amount became
about 27 L. Ethyl acetate (30 L) was added to the concentrate, and
the mixture was concentrated under reduced pressure until the
liquid amount became about 16 L. Ethyl acetate (30 L) and activated
carbon (150 g) were added to the concentrate. The activated carbon
was removed and the mixture was washed with ethyl acetate (1.5 L).
The filtrate was concentrated under reduced pressure until the
concentration of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole became about 0.27 g/mL (12.5 L). After stirring at
about 25.degree. C. for about 2 hours under a nitrogen gas stream,
crystal precipitation was confirmed, and heptane (25 L) was
dropwise added over about 1.5 hours. The mixture was stirred for
about 1.5 hours. The precipitated crystal was separated, washed
with ethyl acetate-heptane (ethyl acetate:heptane=1:5, 6 L) and
dried to give the title compound (3.76 kg, yield: 72% based on
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzi-
midazole).
[0221] As a result of the analysis of the crystal by X-ray powder
diffraction, the crystal showed an X-ray powder diffraction
analysis pattern having characteristic peaks at interplanar
spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89,
3.69, 3.41 and 3.11 Angstrom.
[0222] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (A)), the
enantiomeric excess of
(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole in the crystal was 100% ee.
[0223] As a result of the analysis of the crystal by high
performance liquid chromatography (conditions (B)), analogous
materials in the crystal, such as sulfone, sulfide and the like
were not found.
[0224] The melting start temperature of the crystal was
133.5.degree. C.
EXAMPLE 11
[0225] The crystal (1.5 g, 4.06 mmol) of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole was dissolved in ethyl acetate (30 mL). The
mixture was concentrated to 6 mL under reduced pressure at an outer
temperature of about 25.degree. C. The mixture was stirred for
about 2 hours at the same temperature, and precipitation of the
crystal was confirmed. Heptane (24 mL) was dropwise added over
about 30 minutes. The mixture was stirred for about 2.5 hours, and
the precipitated crystal was separated and dried to give the title
compound (1.46 g, yield: 97.3%).
[0226] The melting start temperature of the crystal was
133.5.degree. C.
EXPERIMENTAL EXAMPLE
Stability Test (Relationship Between Melting Start Temperature and
Stability)
[0227] Various (R)-lansoprazole crystals obtained in the
above-mentioned Reference Examples and Examples were subjected to a
stability test at 60.degree. C. for one month. The partial results
are shown in Table 1 below.
TABLE-US-00001 TABLE 1 melting start 60.degree. C. one month
production method temperature residual ratio present invention (1)
135.0.degree. C. 100% (Example 2) present invention (2)
134.0.degree. C. 99.7% (Example 1) present invention (3)
134.0.degree. C. 99.2% (Example 6) conventional method (A)
130.0.degree. C. 93.8% (Reference Example 6) conventional method
(B) 127.5.degree. C. 89.8% (Reference Example 3)
[0228] The crystal obtained by the method of the present invention
shows a residual ratio of not less than 99% in a 60.degree. C. one
month stability test. The crystal obtained by a conventional method
shows a residual ratio decreased to about 90-94%.
[0229] The crystal of (R)-lansoprazole was subjected to a
40.degree. C. one month stability test. The partial results are
shown in the following Table 2.
TABLE-US-00002 TABLE 2 production method present invention
conventional method (Example 11) (Reference Example 7) melting
start 133.5.degree. C. 128.5.degree. C. temperature initial
appearance almost white almost white content 99.5% 99.6% analogous
material 0.2% 0.1% content 40.degree. C. one month appearance
almost white brown content 99.7% 93.8% analogous material 0.2% 4.6%
content
[0230] By the method of the present invention, decomposition was
not found in the 40.degree. C. one month stability test, but the
appearance was degraded, the content decreased and the analogous
material content increased by the conventional method.
[0231] In FIG. 1, the appearance of a crystal (Example 1) having a
melting start temperature of about 134.degree. C. and a crystal
(Reference Example 6) having a melting start temperature of about
130.degree. C. before stability test and after stability tests
(40.degree. C. 2 weeks, 50.degree. C. 2 weeks and 60.degree. C. 2
weeks) is shown. The crystal having a melting start temperature of
about 134.degree. C. did not show changes in the appearance but the
crystal having a melting start temperature of about 130.degree. C.
showed appreciably degraded appearance.
[0232] From the foregoing results, it is apparent that there exists
a clear relationship between melting start temperature and
stability in the case of the crystals of (R)-lansoprazole and
(S)-lansoprazole, and that the crystal having a melting start
temperature of not lower than about 131.degree. C. is stable but
the crystal having a melting start temperature of less than about
131.degree. C. is unstable.
FORMULATION EXAMPLE 1
Production of Capsule
[0233] Capsules (15 mg) were obtained according to the charge
amount-1 in the following Table 3 and the following method (in
Table 4, amounts per capsule are shown). (1) The crystal of
(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]--
1H-benzimidazole (hereinafter to be referred to as compound A)
obtained in Example 1 and the ingredients (3) to (6) were
thoroughly mixed to give a dusting powder. In a centrifugal
fluidized coating granulator was charged (2) Nonpareil and the
above-mentioned dusting powder was coated while spraying an aqueous
solution of (7) hydroxypropyl cellulose in purified water. The
spherical granules were dried in vacuo at 40.degree. C. for 16-20
hours and passed through a sieve (600 .mu.m, 1180 .mu.m) to give
base granules. The base granules were placed in a roll flow type
coating machine and coated with a suspension of (8) methacrylic
acid copolymer LD-(12) polysorbate 80 in purified water. The coated
granules were passed through a sieve (710 .mu.m, 1400 .mu.m) and
dried in vacuo at 40.degree. C. for 16-20 hours to give enteric
coated granules. To the enteric coated granules were added (13)
talc and (14) light silicic anhydride and mixed granules were
produced in a tumbler mixer. The mixed granules were filled in (17)
HPMC Capsule No. 2 by a capsule filling machine to give 15 mg
capsules.
[0234] By controlling the amount to be filled of the
above-mentioned mixed granules, 20 mg and 10 mg capsules were
produced.
TABLE-US-00003 TABLE 3 Charge amount-1 ingredients 15 mg capsule
[base granule] (1) compound A 450.0 g (2) sucrose.starch spherical
1650.0 granule (Nonpareil) (3) magnesium carbonate 336.0 (4)
purified sucrose 897.0 (5) cornstarch 546.0 (6) low-substituted
hydroxypropyl 600.0 cellulose (7) hydroxypropyl cellulose 21.0
purified water 1029.0 subtotal 4500.0 g [enteric coated granule]
base granule 3600.0 g (8) methacrylic acid copolymer LD 535.2
(Eudragit L30D-55.sup.TR) (9) talc 160.8 (10) macrogol 6000 52.8
(11) titanium oxide 52.8 (12) polysorbate 80 24.0 purified water
2054.4 subtotal 4425.6 g [mixed granule] enteric coated granule
3688.0 g (13) talc 6.0 (14) light silicic anhydride 2.0 subtotal
3696.0 g [capsule] mixed granule 924.0 g (15) HPMC Capsule No. 2
5000.0 cap.
TABLE-US-00004 TABLE 4 Formulation per capsule ingredients 15 mg
capsule [base granule] (1) compound A 15.00 mg (2) sucrose.starch
spherical 55.00 granule (Nonpareil) (3) magnesium carbonate 11.20
(4) purified sucrose 29.90 (5) cornstarch 18.20 (6) low-substituted
hydroxypropyl 20.00 cellulose (7) hydroxypropyl cellulose 0.70
subtotal 150.00 mg [enteric coated granule] base granule 150.00 mg
(8) methacrylic acid copolymer LD 22.30 (Eudragit L30D-55.sup.TR)
(9) talc 6.70 (10) macrogol 6000 2.20 (11) titanium oxide 2.20 (12)
polysorbate 80 1.00 subtotal 184.40 mg [mixed granule] enteric
coated granule 184.40 mg (13) talc 0.30 (14) light silicic
anhydride 0.10 subtotal 184.80 mg [capsule] mixed granule 184.80 mg
(15) HPMC Capsule No. 2 62.00 subtotal 246.80 mg
FORMULATION EXAMPLE 2
Production of Capsule
[0235] Capsules (15 mg) were obtained according to the charge
amount-2 in the following Table 5 and the following method (in
Table 6, amounts per capsule are shown). (1) Compound A and the
ingredients (3) to (6) were thoroughly mixed to give a main drug
dusting powder. The ingredients (7) to (9) were thoroughly mixed to
give a cover coating agent. In a centrifugal fluidized coating
granulator was charged (2) Nonpareil and the above-mentioned main
drug dusting powder and the cover coating agent were successively
coated while spraying an aqueous solution of (10) hydroxypropyl
cellulose in purified water. The spherical granules were dried in
vacuo at 40.degree. C. for 16-20 hours and passed through a sieve
(600 .mu.m, 1180 .mu.m) to give base granules. The base granules
were placed in a roll flow type coating machine and coated with a
suspension of (11) methacrylic acid copolymer LD-(15) polysorbate
80 in purified water. The coated granules were passed through a
sieve (710 .mu.m, 1400 .mu.m) and dried in vacuo at 40.degree. C.
for 16-20 hours to give enteric-coated granules. To the enteric
coated granules were added (16) talc and (17) light silicic
anhydride and mixed granules were produced in a tumbler mixer. The
mixed granules were filled in (18) HPMC Capsule No. 2 by a capsule
filling machine to give 15 mg capsules.
TABLE-US-00005 TABLE 5 Charge amount-2 ingredients [base granule]
(1) compound A 450.0 g (2) sucrose.starch spherical 1650.0 granule
(Nonpareil) (3) magnesium carbonate 336.0 (4) purified sucrose
597.0 (5) cornstarch 300.0 (6) low-substituted hydroxypropyl 354.0
cellulose (7) purified sucrose 300.0 (8) cornstarch 246.0 (9)
low-substituted hydroxypropyl 246.0 cellulose (10) hydroxypropyl
cellulose 21.0 purified water 1029.0 subtotal 4500.0 g [enteric
coated granule] base granule 3600.0 g (11) methacrylic acid
copolymer LD 535.2 (Eudragit L30D-55.sup.TR) (12) talc 160.8 (13)
macrogol 6000 52.8 (14) titanium oxide 52.8 (15) polysorbate 80
24.0 purified water 2054.4 subtotal 4425.6 g [mixed granule]
enteric coated granule 3688.0 g (16) talc 6.0 (17) light silicic
anhydride 2.0 subtotal 3696.0 g [capsule] mixed granule 924.0 g
(18) HPMC Capsule No. 2 5000.0 cap.
TABLE-US-00006 TABLE 6 Formulation per capsule ingredients 15 mg
capsule [base granule] (1) compound A 15.0 mg (2) sucrose.starch
spherical 55.0 granule (Nonpareil) (3) magnesium carbonate 11.2 (4)
purified sucrose 19.9 (5) cornstarch 10.0 (6) low-substituted
hydroxypropyl 11.8 cellulose (7) purified sucrose 10.0 (8)
cornstarch 8.2 (9) low-substituted hydroxypropyl 8.2 cellulose (10)
hydroxypropyl cellulose 0.7 subtotal 150.0 mg [enteric coated
granule] base granule 150.0 mg (11) methacrylic acid copolymer LD
22.3 (Eudragit L30D-55.sup.TR) (12) talc 6.7 (13) macrogol 6000 2.2
(14) titanium oxide 2.2 (15) polysorbate 80 1.0 subtotal 184.4 mg
[mixed granule] enteric coated granule 184.4 mg (16) talc 0.3 (17)
light silicic anhydride 0.1 subtotal 184.8 mg [capsule] mixed
granule 184.8 mg (18) HPMC Capsule No. 2 62.0 subtotal 246.8 mg
INDUSTRIAL APPLICABILITY
[0236] According to the production method of the present invention,
a crystal of (R)-lansoprazole or (S)-lansoprazole superior in
preservation stability can be produced efficiently on an industrial
large scale.
[0237] This application is based on patent application No.
2000-367757 filed in Japan, the contents of which are hereby
incorporated by reference.
* * * * *