U.S. patent application number 11/259509 was filed with the patent office on 2006-02-23 for carbapenem compound crystals and injection preparations.
This patent application is currently assigned to EISAI CO., LTD.. Invention is credited to Kazuhide Ashizawa, Hiroyuki Chiba, Hiroyuki Ishizuka, Akio Kayano, Astsushi Koiwa, Ikuo Kushida, Taiju Nakamura, Hiroyuki Saito, Masahiro Sakurai, Shin Sakurai, Yasuyuki Suzuki, Masahiko Tsujii, Eiichi Yamamoto, Takako Yoshiba.
Application Number | 20060040916 11/259509 |
Document ID | / |
Family ID | 26484468 |
Filed Date | 2006-02-23 |
United States Patent
Application |
20060040916 |
Kind Code |
A1 |
Chiba; Hiroyuki ; et
al. |
February 23, 2006 |
Carbapenem compound crystals and injection preparations
Abstract
The present invention provides carbapenem hydrochloride
trihydrate crystals, which are chemically stable, easily purified
and useful as antimicrobial agents, a process for producing them,
and a powdery charged preparation for injection containing them.
That is, it provides carbapenem hydrochloride trihydrate crystals
having a powdery X-ray diffraction pattern containing lattice
distances (d) of 9.0, 4.1 and 2.8 .ANG., a process for producing
them, and a powdery charged preparation for injection containing
them.
Inventors: |
Chiba; Hiroyuki; (Ibaraki,
JP) ; Tsujii; Masahiko; (Chiba, JP) ; Koiwa;
Astsushi; (Ibaraki, JP) ; Sakurai; Shin;
(Chiba, JP) ; Kayano; Akio; (Ibaraki, JP) ;
Ishizuka; Hiroyuki; (Ibaraki, JP) ; Saito;
Hiroyuki; (Ibaraki, JP) ; Nakamura; Taiju;
(Ibaraki, JP) ; Kushida; Ikuo; (Ibaraki, JP)
; Suzuki; Yasuyuki; (Ibaraki, JP) ; Yoshiba;
Takako; (Ibaraki, JP) ; Ashizawa; Kazuhide;
(Ibaraki, JP) ; Sakurai; Masahiro; (Ibaraki,
JP) ; Yamamoto; Eiichi; (Ibaraki, JP) |
Correspondence
Address: |
FLYNN THIEL BOUTELL & TANIS, P.C.
2026 RAMBLING ROAD
KALAMAZOO
MI
49008-1631
US
|
Assignee: |
EISAI CO., LTD.
|
Family ID: |
26484468 |
Appl. No.: |
11/259509 |
Filed: |
October 26, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09979679 |
Nov 16, 2001 |
|
|
|
PCT/JP00/03642 |
Jun 5, 2000 |
|
|
|
11259509 |
Oct 26, 2005 |
|
|
|
Current U.S.
Class: |
514/210.12 ;
540/350 |
Current CPC
Class: |
A61K 31/407 20130101;
A61P 31/04 20180101; C07D 477/20 20130101 |
Class at
Publication: |
514/210.12 ;
540/350 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61K 31/407 20060101 A61K031/407 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 3, 1999 |
JP |
11-156810 |
May 25, 2000 |
JP |
2000-153891 |
Claims
1.
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrr-
olidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-car-
boxylic acid monohydrochloride trihydrate crystals having a powdery
X-ray diffraction pattern containing lattice distances (d) of 9.0,
4.1 and 2.8 .ANG., represented by the following formula (1-1):
##STR8##
2. The crystals according to claim 1, which are trihydrate having a
powdery X-ray diffraction pattern containing lattice distances (d)
of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6
.ANG..
3. A process for producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals, which comprises
dissolving
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid or a salt thereof in a solvent system consisting of water
and isopropanol; and then crystallizing from the solution.
4. The process according to claim 3, wherein 50 to 90% (v/v)
aqueous isopropanol solution is used as the crystallization
solvent.
5. The process according to claim 3, wherein crystallization is
conducted at a temperature of 0 to 20.degree. C.
6. The process according to claim 5, wherein crystallization is
conducted at a temperature of 10.degree. C.
7. The process according to claim 3, wherein a solution of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid at a concentration of 7 to 10% (w/w) in solvent is used
in crystallization.
8. The process for producing according to claim 3, wherein the
trihydrate crystals are crystals having a powdery X-ray diffraction
pattern containing lattice distances (d) of 9.0, 4.1 and 2.8
.ANG..
9. The process for producing according to claim 3, wherein the
trihydrate crystals are crystals having a powdery X-ray diffraction
pattern containing lattice distances-(d) of 9.0, 5.4, 5.2, 5.0,
4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 .ANG..
10. A process for producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals, which comprises
dissolving
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2'-[(2S,4S)-2-[(3R)-pyrrol-
idine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbo-
xylic acid monohydrochloride monohydrate crystals in 50 to 90%
(v/v) aqueous isopropanol solution; and crystallizing at a
temperature of 0 to 20.degree. C.
11. The process according to claim 10, wherein the trihydrate
crystals are crystals having a powdery X-ray diffraction pattern
containing lattice distances (d) of 9.0, 4.1 and 2.8 .ANG..
12. The process for producing according to claim 10, wherein the
trihydrate crystals are crystals having a powdery X-ray diffraction
pattern containing lattice distances (d) of 9.0, 5.4, 5.2, 5.0,
4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 .ANG..
Description
[0001] This is a continuation of Ser. No. 09/979,679, filed Nov.
16, 2001, which was the national stage of International Application
No. PCT/JP00/03642, filed Jun. 5, 2000, which International
Application was not published in English.
TECHNICAL FIELD
[0002] The present invention relates to a salt of a carbapenem
compound or hydrate crystals of the salt, a process for producing
it, and a powdery charged preparation for injection. The carbapenem
compound is useful as an antimicrobial agent and an antibiotic.
PRIOR ART
[0003] The carbapenem compound or a salt thereof is known to have a
strong and wide antimicrobial spectrum ranging from Gram negative
to positive bacteria, but there is a problem with stability thereof
in the human body and with safety in the human body owing to its
toxicity.
[0004] However, JP-A 8-73462 discloses that the carbapenem
compound, that is,
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyr-
rolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-ca-
rboxylic acid or a salt thereof is a compound having a strong
antimicrobial activity and useful as a pharmaceutical preparation
having high safety to the human body.
[0005] Further, its hydrochloride is one desirable salt form
superior in solubility as a medicine having a strong antimicrobial
activity.
[0006] Generally for converting a chemical into an injection, it is
dissolved, emulsified or dispersed in a liquid such as water to
form a liquid injection, or converted into a powdery preparation
for injection, which just before use, is dissolved, emulsified or
dispersed in a liquid.
[0007] However, this carbapenem compound or its hydrochloride is
unstable in solution, and the degradation thereof is promoted under
heating conditions, so it is hardly formed into a liquid
injection.
[0008] Further, when the carbapenem compound or its hydrochloride
is formed into a freeze-dried preparation frequently used as a
powdery injection preparation to be dissolved just before use, the
degradation thereof is promoted under heating conditions in the
case where e.g. mannitol is used as the major filler in the
freeze-dried preparation. Accordingly, it is hardly formed into a
freeze-dried preparation.
[0009] Further, the carbapenem compound or a salt thereof which was
formed by freeze-drying into a powdery charged preparation is
amorphous and chemically unstable.
[0010] Further, because the carbapenem compound or a salt thereof
could not easily be crystallized by techniques at that time, it was
finally purified by reverse phase silica gel column chromatography
to give an amorphous product. In such column purification, however,
a large amount of solvent is used to increase production costs and
to make industrial large-scale treatment difficult, and further
there are many problems such as possible pyrolysis in concentration
of fractions, residual solvent, waste liquor, and environmental
pollution resulting from solvent evaporation. In addition, this
amorphous substance is instable in solution, so the degradation
thereof is promoted under heating conditions, thus making
pharmaceutical manufacturing problematic.
Definition of Terms
[0011]
(+)-(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)--
pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-
-carboxylic acid, or
(+)-(4R,5S,6S)-6-[(R)-1-hydroxyethyl]-3-[(2S,4S)-2-[(R)-1-hydroxy-1-[(R)--
pyrrolidine-3-yl]methyl]pyrrolidine-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[-
3.2.0]hept-2-ene-2-carboxylic acid according to nomenclature by
IUPAC, is called the carbapenem compound. Salts thereof such as
hydrochloride, hydrate crystals of the salts, starting salts for
synthesizing them, and other starting compounds having a carbapenem
skeleton are called carbapenem derivatives. Examples thereof
include
(+)-(4R,5S,6S)-6-[(R)-1-hydroxyethyl]-3-[(2S,4S)-2-[(R)-1-hydroxy-1-[(R)--
pyrrolidine-3-yl]methyl]pyrrolidine-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[-
3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride monohydrate
and
(+)-(4R,5S,6S)-6-[(R)-1-hydroxyethyl]-3-[(2S,4S)-2-[(R)-1-hydroxy-1-[(R)--
pyrrolidine-3-yl]methyl]pyrrolidine-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[-
3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride
trihydrate.
DISCLOSURE OF INVENTION
[0012] As a result of further extensive study for solving the
problem described above, the present inventors found that among
salts of the carbapenem compound, there are monohydrate crystals
and trihydrate crystals which are chemically stable crystals and
industrially useful compounds easily separated from impurities, and
the present invention was thereby completed.
[0013] The present invention relates to
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals having a powdery
X-ray diffraction pattern containing lattice distances (d) of 9.0,
4.1 and 2.8 .ANG., represented by formula (1-1): ##STR1## or
monohydrate crystals having a powdery X-ray diffraction pattern
containing lattice distances (d) of 5.2, 4.3 and 4.0 .ANG.,
represented by formula (1-2): ##STR2##
[0014] Preferably, the trihydrate crystals have a powdery X-ray
diffraction pattern containing lattice distances (d) of 9.0, 5.4,
5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 .ANG..
[0015] The present invention also provides a process for producing
the above hydrate crystals. That is, the present invention relates
to a process for producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals, which comprises
dissolving
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid (referred to hereinafter as the carbapenem compound) or a
derivative thereof in a solvent system consisting of water and at
least one crystallization solvent selected from the group
consisting of dimethyl ether, diethylene glycol monomethyl ether,
triethylene glycol monomethyl ether, diethylene glycol monoethyl
ether, 1-acetoxy-2-methyl ethane, 3-methoxybutanol,
1-ethoxy-2-propanol, 1-methoxy-2-propanol, 2-ethoxyethanol,
2-isopropoxyethanol, 3-methoxy-3-methyl-1-butanol, tetrahydrofuran,
n-propanol, t-butanol, 2-butoxyethanol, ethanol, isopropanol and
acetonitrile, and subsequent crystallization from the solution.
[0016] In a preferable embodiment, a system consisting of
isopropanol and water is used as the crystallization solvent. 50 to
90% (v/v) aqueous isopropanol solution is used as the
crystallization solvent. The crystallization is conducted at a
temperature of 0 to 20.degree. C. The crystallization is preferably
conducted at a temperature of 10.degree. C. A solution of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid at a concentration of 7 to 10% (w/w) in solvent is used
in crystallization. Crystals of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate are seeded in
crystallization in an amount of about 3 to 5% (wt. %) based on the
quantified amount of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid.
[0017] The resulting trihydrate crystals preferably have a powdery
X-ray diffraction pattern containing lattice distances (d) of 9.0,
4.1 and 2.8 .ANG.. The crystals further preferably have a powdery
X-ray diffraction pattern containing lattice distances (d) of 9.0,
5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 .ANG..
[0018] The trihydrate crystals can also be obtained in another
process. That is, the present invention provides a process for
producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals, which comprises
dissolving
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate crystals in 50 to 90% (v/v)
aqueous isopropanol solution and subjecting the solution to
crystallization at a temperature of 0 to 20.degree. C.
[0019] The present invention also encompasses the above-described
monohydrate crystals. Further, the crystals have a powdery X-ray
diffraction pattern containing lattice distances (d) of 9.4, 6.2,
5.4, 5.2, 4.8, 4.7, 4.4, 4.3, 4.0, 3.8, 3.6, 3.4 and 3.3 .ANG..
[0020] The monohydrate crystals can be obtained in the following
manner. That is, the present invention provides a process for
producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate crystals, which comprises
dissolving
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid or a derivative thereof in a crystallization solvent in a
methanol/water system, a dimethyl sulfoxide/water system, a
dimethylformamide/water system, a 2-methoxyethanol/water system or
a dimethylacetamide/water system and then crystallizing the
compound.
[0021] In a preferable embodiment, the process for producing the
monohydrate crystals makes use of a system consisting of methanol
and water as the crystallization solvent. 50 to 90% (v/v) aqueous
methanol solution is used as the crystallization solvent. A
solution of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid at a concentration of 5 to 10% (w/w) in solvent is used
in crystallization. The resulting monohydrate crystals are crystals
having a powdery X-ray diffraction pattern containing lattice
distances (d) of 5.2, 4.3 and 4.0 .ANG.. The crystals further
preferably have a powdery X-ray diffraction pattern containing
lattice distances (d) of 9.4, 6.2, 5.4, 5.2, 4.8, 4.7, 4.4, 4.3,
4.0, 3.8, 3.6, 3.4 and 3.3 .ANG..
[0022] The monohydrate crystals can also be produced in another
process. That is, the present invention provides a process for
producing
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate crystals, wherein 50 to 90%
(v/v) aqueous isopropanol solution is used as the crystallization
solvent, and
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate crystals are added as
nucleating crystals in an amount of at least 20% (wt. %) based on
the quantified amount of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3-
R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-e-
m-3-carboxylic acid. In a preferable embodiment, the
crystallization is conducted at a temperature of 20 to 50.degree.
C. The crystallization is most preferably conducted at a
temperature of 22.degree. C.
[0023] In crystallization in production of the trihydrate crystals
and monohydrate crystals, the carbapenem compound (free form,
carboxylic acid form) or its derivative is dissolved as the
starting material in solvent etc. The derivative is a salt, a
hydrate or a salt hydrate. The salt includes e.g. ordinarily used
salts such as hydrochloride, sulfate, acetate, phthalate, phosphate
and oxalate. When the salt is other than hydrochloride, a
hydrochloride-forming agent such as calcium chloride may be used.
Use can also be made of a derivative of the carbapenem compound
whose substituent group has been replaced by another substituent
group and which has the intended carbapenem skeleton in the step of
crystallization.
[0024] In the crystallization step, salt formation and
crystallization can also be carried out successively. The salt may
be subjected to crystallization. Further, the monohydrate crystals
can be formed into trihydrate crystals or the trihydrate crystals
can be formed into monohydrate crystals.
[0025] Further, the present invention provides a powdery charged
preparation for injection, which comprises
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid (referred to hereinafter as carbapenem compound)
represented by the following formula 2: ##STR3## a salt thereof,
crystals of the salt, a hydrate of the salt, or hydrate crystals of
the salt (referred to hereinafter as carbapenem derivatives)
charged and capped in a vial.
[0026] Preferably, the air in the vial is partially or wholly
removed and/or replaced by nitrogen or argon. The medicine is
preferably in the form of hydrochloride trihydrate crystals having
a powdery X-ray diffraction pattern containing lattice distances
(d) of 9.0, 4.1 and 2.8 .ANG.. The medicine may be hydrochloride
monohydrate crystals having a powdery X-ray diffraction pattern
containing lattice distances (d) of 5.2, 4.3 and 4.0 .ANG..
[0027] Further, the present invention provides a method of
administering the above preparation, wherein the preparation is
dissolved just before use in an injection liquid such as water and
administered by injection into a patient immediately while the
medicine is stable.
DETAILED DESCRIPTION OF THE INVENTION
[0028] First, the trihydrate and monohydrate crystals and the
process for producing these crystals are described.
[0029] That is, the present invention relates to carbapenem
monohydrochloride trihydrate crystals having a powdery X-ray
diffraction pattern containing lattice distances (d) of 9.0, 4.1
and 2.8 .ANG., carbapenem monohydrochloride trihydrate crystals
having a powdery X-ray diffraction pattern containing lattice
distances (d) of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1,
2.8 and 2.6 .ANG., a process for producing the above-mentioned
monohydrochloride trihydrate crystals, which comprises using, as a
crystallization solvent, a system consisting of water and a mixed
solvent of one or more members selected from the group consisting
of dimethyl ether, diethylene glycol monomethyl ether, triethylene
glycol monomethyl ether, diethylene glycol monoethyl ether,
1-acetoxy-2-methyl ethane, 3-methoxybutanol, 1-ethoxy-2-propanol,
1-methoxy-2-propanol, 2-ethoxyethanol, 2-isopropoxyethanol,
3-methoxy-3-methyl-1-butanol, tetrahydrofuran, n-propanol,
t-butanol, 2-butoxyethanol, ethanol, isopropanol and acetonitrile,
the process for producing the above monohydrochloride trihydrate
crystals, wherein a system consisting of isopropanol and water is
used as the crystallization solvent, the process for producing the
above monohydrochloride trihydrate crystals, wherein 50 to 90%
(v/v) aqueous isopropanol solution is used as the crystallization
solvent, the process for producing the above monohydrochloride
trihydrate crystals, wherein crystallization is conducted at a
temperature of 0 to 20.degree. C., the process for producing the
above monohydrochloride trihydrate crystals, wherein
crystallization is conducted at a temperature of 10.degree. C., the
process for producing the above monohydrochloride trihydrate
crystals, wherein a solution of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid at a concentration of 7 to 10% (w/w) in solvent is used
in crystallization, the process for producing the above
monohydrochloride trihydrate crystals, wherein crystals of
carbapenem monohydrochloride trihydrate are seeded in
crystallization in an amount of about 3 to 5% (wt-%) based on the
quantified amount of the carbapenem compound, the process for
producing the above monohydrochloride trihydrate crystals, wherein
the crystals have a powdery X-ray diffraction pattern containing
lattice distances (d) of 9.0, 4.1 and 2.8 .ANG..
[0030] Further, the present invention relates to a process for
producing a monohydrochloride monohydrate crystals of carbapenem
compound, which comprises using, as a crystallization solvent, a
methanol/water system, a dimethyl sulfoxide/water system, a
dimethylformamide/water system, a 2-methoxyethanol/water system or
a dimethylacetamide/water system, the process for producing the
above monohydrochloride monohydrate crystals, wherein a system
consisting of water and isopropanol is used as the crystallization
solvent, the process for producing the above monohydrochloride
monohydrate crystals, wherein 50 to 90% (v/v) aqueous methanol
solution is used as the crystallization solvent, the process for
producing the above monohydrochloride monohydrate crystals, wherein
a solution of the carbapenem compound at a concentration of 5 to
10% (w/w) in solvent is used in crystallization, the process for
producing the above monohydrochloride monohydrate crystals, wherein
50 to 90% (v/v) aqueous isopropanol solution is used as the
crystallization solvent, and the monohydrochloride monohydrate
crystals are added as nucleating crystals in an amount of at least
20% (wt. %) based on the quantified amount of the carbapenem
compound, the process for producing the above monohydrochloride
monohydrate crystals, wherein crystallization is conducted at a
temperature of 20 to 50.degree. C., the process for producing the
above monohydrochloride monohydrate crystals, wherein
crystallization is conducted at a temperature of 22.degree. C.
[0031] Further, it relates to a process for producing the above
monohydrochloride trihydrate crystals, which comprises dissolving
the above monohydrochloride monohydrate crystals in 50 to 90% (v/v)
aqueous isopropanol solution and subjecting the solution to
crystallization at a temperature of 0 to 20.degree. C.
[0032] In any of the processes described above, the
monohydrochloride trihydrate crystals can be crystals having a
powdery X-ray diffraction pattern containing lattice distances (d)
of 9.0, 4.1 and 2.8 .ANG..
[0033] Hereinafter, the present invention, as well as terms etc.
used in this specification, is described in detail.
[0034] The compound of the present invention, that is,
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals, is represented by
the following formula: ##STR4##
[0035] The lattice distance (d) of the carbapenem monohydrochloride
trihydrate crystals can be calculated from 20 value in the scanning
axis of each diffraction peak obtained in powdery X-ray diffraction
evaluation. That is, the lattice distance (d) of the crystals can
be determined from the Bragg equation (1/d=2 sin .theta./.lamda.,
where .lamda.=1.5418 .ANG.) on the basis of the .theta. value of
each of major diffraction peaks.
[0036] Evaluation by powdery X-ray diffraction was conducted under
the following measurement conditions using an instrument (INT-2500
Ultrax 18) manufactured by Rigaku Co., Ltd. [0037] X-ray used: Cu K
alpha ray [0038] Counter: Scintillation counter [0039] Goniometer:
Vertical goniometer (RINT2000) [0040] Applied voltage: 40 kV [0041]
Applied current: 200 mA [0042] Scan speed: 2.degree./min [0043]
Scanning axis: 2.theta. [0044] Scanning range: 2.theta.=5 to
30.degree. [0045] Divergent slit: 1.degree. [0046] Scattering slit:
1.degree. [0047] Light receiving slit: 0.15 mm
[0048] The
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals according to the
present invention have a powdery X-ray diffraction pattern
containing lattice distances (d) of preferably 9.0, 4.1 and 2.8
.ANG., more preferably 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4,
3.1, 2.8 and 2.6 .ANG..
[0049] In the present invention, the carbapenem compound or its
salt as an antibiotic to be first dissolved for crystallization can
be produced in a usual manner or in a known organic chemical
synthesis method. It can also be produced by methods described in
e.g. JP-A 8-73462 and JP-A 11-35556.
[0050] The antibiotic hydrochloride hydrate crystals according to
the present invention can be produced by the above known method in
the following general scheme. ##STR5## wherein PNB means a
p-nitrobenzyl group.
[0051] Hereinafter, the conditions for crystallization are
described in detail.
[0052] The carbapenem monohydrochloride trihydrate crystals
according to the present invention can be produced under the
following conditions.
[0053] The solvent used for crystallization of the trihydrate
crystals is preferably a system consisting of water and a mixed
solvent of one or more members selected from the group consisting
of dimethyl ether, diethylene glycol monomethyl ether, triethylene
glycol monomethyl ether, diethylene glycol monoethyl ether,
1-acetoxy-2-methyl ethane, 3-methoxybutanol, 1-ethoxy-2-propanol,
1-methoxy-2-propanol, 2-ethoxyethanol, 2-isopropoxyethanol,
3-methoxy-3-methyl-1-butanol, tetrahydrofuran, n-propanol,
t-butanol, 2-butoxyethanol, ethanol, isopropanol and acetonitrile,
more preferably a system consisting of water and a mixed solvent of
one or more members selected from the group consisting of
diethylene glycol monomethyl ether, diethylene glycol monoethyl
ether, 1-ethoxy-2-propanol, 2-ethoxyethanol, 2-isopropoxyethanol,
tetrahydrofuran, n-propanol, t-butanol, isopropanol and
acetonitrile, more preferably a system consisting of water and a
mixed solvent of one or more members selected from the group
consisting of diethylene glycol monoethyl ether, 2-ethoxyethanol,
tetrahydrofuran, t-butanol, isopropanol and acetonitrile, more
preferably a system consisting of water and a mixed solvent of one
or more members selected from the group consisting of diethylene
glycol monoethyl ether and isopropanol, and most preferably an
isopropanol/water system.
[0054] The mixing ratio of one or more organic solvents described
above or the mixing ratio thereof to water is not particularly
limited. The solubility of the antibiotic is increased as water is
increased, and use can be made of an organic solvent at a
concentration (v/v) of 1 to 95%, preferably 10 to 90%, further
preferably 40 to 90%, more preferably 50 to 90%, and most
preferably 55 to 85% in water. When an aqueous isopropanol solution
is used as a crystallization solvent, e.g. 50 to 90% (v/v) aqueous
isopropanol solution can be used.
[0055] The crystallization temperature is not particularly limited,
but in consideration of the stability of the antibiotic, the
temperature is preferably 20.degree. C. or less, more preferably 0
to 20.degree. C. and most preferably 10.degree. C.
[0056] The concentration of the carbapenem compound in the
mother-liquor solvent for precipitating crystals is not
particularly limited either. The concentration is preferably 7 to
10% (w/w).
[0057] For crystallization, crystals of carbapenem
monohydrochloride trihydrate can also be seeded, and the amount to
be seeded is not particularly limited, but is preferably about 3 to
5% (wt. %), more preferably 3%, based on the quantified amount of
the carbapenem compound.
[0058] The carbapenem monohydrochloride monohydrate crystals can be
produced under the following conditions.
[0059] As the crystallization solvent for the monohydrate crystals,
use can be made of a methanol/water system, a dimethyl
sulfoxide/water system, a dimethylformamide/water system, a
2-methoxyethanol/water system or a dimethylacetamide/water system,
preferably a methanol/water system, a dimethyl sulfoxide/water
system, a dimethylformamide/water system, and most preferably a
methanol/water system.
[0060] The mixing ratio thereof is not particularly limited. The
solubility of the antibiotic is increased as water is increased,
and use can be made of an organic solvent at a concentration (v/v)
of 1 to 95%, preferably 10 to 90%, further preferably 40 to 90%,
more preferably 50 to 90%, and most preferably 55 to 85% in water.
The crystallization temperature is not particularly limited
either.
[0061] For crystallization of the monohydrate crystals, 50 to 90%
(v/v) aqueous isopropanol solution is used as the crystallization
solvent to which carbapenem monohydrochloride monohydrate crystals
can be seeded in an amount of at least 20% (wt. %) based on the
quantified amount of the carbapenem compound. The ratio of
isopropanol to water and the amount of crystals to be seeded can be
suitably regulated, but the amounts described above are more
preferable. The crystallization temperature is more preferably a
temperature of 20 to 50.degree. C. The temperature is more
preferably 22.degree. C.
[0062] The monohydrate crystals obtained as described above can be
converted into trihydrate crystals for example by dissolving the
monohydrate crystals in 50 to 90% (v/v) aqueous isopropanol
solution followed by re-crystallization at a temperature of 0 to
20.degree. C.
[0063] The carbapenem monohydrochloride trihydrate crystals
according to the present invention are advantageous in that they
are stable, can be kept easily for maintaining the qualities of the
pharmaceutical preparation, can keep the qualities for a long
period and can be easily purified by readily removing impurities in
manufacturing. In particular, the trihydrate can be easily purified
by removing impurities hardly separated from the monohydrate, and
is thus industrially very useful.
[0064] Now, the monohydrate crystals are described.
[0065] The present invention relates to carbapenem
monohydrochloride monohydrate crystals having a powdery X-ray
diffraction pattern containing lattice distances (d) of 5.2, 4.3
and 4.0 .ANG., represented by the following structural formula 1:
##STR6##
[0066] Further, the present invention relates to carbapenem
hydrochloride monohydrate crystals having an X-ray diffraction
pattern containing lattice distances (d) of 9.4, 6.2, 5.4, 5.2,
4.8, 4.7, 4.4, 4.3, 4.0, 3.8, 3.6, 3.4 and 3.3 .ANG., represented
by formula 1. The crystals are those characterized by having
diffraction intensity in the lattice distances (d) of 19.4, 6.2,
5.4, 5.2, 4.8, 4.7, 4.4, 4.3, 4.0, 3.8, 3.6, 3.4 and 3.3 .ANG.,
particularly by having strong diffraction intensity in the three
lattice distances (d) of 5.2, 4.3 and 4.0 .ANG..
[0067] The carbapenem hydrochloride monohydrate crystals are stable
under heated and humidified conditions.
[0068] The carbapenem hydrochloride monohydrate crystals can also
be obtained by crystallization from a mixed solvent of water and
ethanol or isopropyl alcohol, followed by drying the resulting
crystals. The hydrochloride monohydrate crystals can also be
produced by crystallization from a mixed solvent of water and a
poor solvent such as ethanol or isopropyl alcohol, followed by
drying the resulting crystals until their water content is reduced
to 3 to 8% (w/w), preferably 4 to 6% (w/w). The carbapenem
hydrochloride or its monohydrate may be first dissolved in water
and then crystallized by adding a poor solvent, or may from the
start be dissolved in a mixed solvent of water and a poor solvent
and then crystallized. In the case of dissolution in water and
crystallization by adding a poor solvent, the solution temperature
is kept desirably at 0 to 15.degree. C., and for example the
compound is dissolved under cooling on ice. Examples of the poor
solvent include, but are not limited to, ethanol and
isopropanol.
[0069] The mixing ratio of water/ethanol or isopropyl alcohol in
the solvent used for precipitating the crystals of the present
invention is 1 part by weight of water/0.1 to 100 parts by weight,
preferably 5 to 20 parts by weight of ethanol or isopropanol.
Examples of drying after crystallization include, but are not
limited to, vacuum drying, drying in a nitrogen stream, drying in a
dry air stream, and air-drying.
[0070] In the present invention,
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid, a salt thereof, another salt or another derivative to be
first dissolved in the solvent for crystallization can be produced
in a known method. For example, it can be produced by a method
disclosed in JP-A 8-73462.
[0071] Further, the present invention relates to a powdery charged
preparation for injection, which comprises
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate crystals having an X-ray
diffraction pattern containing lattice distances (d) of 5.2, 4.3
and 4.0 .ANG., or lattice distances (d) of 9.4, 6.2, 5.4, 5.2, 4.8,
4.7, 4.4, 4.3, 4.0, 3.8, 3.6, 3.4 and 3.3 .ANG., or
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride trihydrate crystals having an X-ray
diffraction pattern containing lattice distances (d) of 9.0, 4.1
.ANG., or lattice distances of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8,
3.6, 3.4, 3.1, 2.8 and 2.6 .ANG. charged and capped in a vial. That
is, the hydrochloride monohydrate and trihydrate crystals according
to the present invention are stable under heated and humidified
conditions so that the crystals can be charged and capped in a vial
to provide a stable powdery charged preparation.
[0072] The lattice distance (d) of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate crystals can be calculated from
20 value in the scanning axis of each diffraction peak obtained in
powdery X-ray diffraction evaluation. That is, the lattice distance
(d) of the crystals can be determined from the Bragg equation
(1/d=2 sin .theta./.lamda., where .lamda.=1.5418 .ANG.) on the
basis of the .theta. value of each of major diffraction peaks.
[0073] Further, the present invention relates to a powdery charged
preparation for injection, which was subjected to degasification of
a part or the whole of the air in a vial and/or replacement thereof
by nitrogen or argon.
[0074] The
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate and trihydrate crystals
according to the present invention are superior in stability.
However, due to a change in manufacturing conditions and a
difference in production lot, the coloration of the outward
appearance on the surface of the crystals may be recognized with
time under heated conditions and/or humidified conditions. In this
case, one feature of the present invention is that the coloration
of the powdery charged preparation for injection can be prevented
by 1) degassing a part or the whole of the air in a vial to remove
a part or the whole of residual oxygen in the vial, 2) replacing a
part or the whole of the air in a vial by nitrogen or argon, or 3)
degassing a part or the whole of the air in a vial thereby removing
a part or the whole of residual oxygen followed by replacement by
nitrogen or argon.
[0075] Degasification of the air in the vial is conducted by e.g.
an air suction device, a vacuum suction device etc., but is not
particularly limited. When a part or the whole of the air in the
vial is degasified to remove a part or the whole of residual
oxygen, the pressure in the vial is desirably 100 hPa (hectopascal)
or less, more desirably 10 hPa (hectopascal) or less. The oxygen
concentration in the air in the vial is desirably 5% or less, more
desirably 0.5% or less.
[0076] The powdery charged preparation for injection, comprising
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate and trihydrate crystals
according to the present invention is advantageous in that the
preparation is superior in stability, can be easily stored, and can
maintain predetermined qualities for a long period from the
viewpoint of maintenance of the qualities of the pharmaceutical
preparation.
[0077] When the powdery charged preparation for injection according
to the present invention is administered into human beings or
animals, a series of production steps are conducted preferably
under aseptic conditions.
[0078] By way of example, an outline of a process for producing the
powdery charged preparation for injection according to the present
invention is shown in FIG. 8. That is,
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride is weighed, dissolved in e.g. a mixed
solvent of water and isopropyl alcohol, filtered aseptically with a
filter, and crystallized from e.g. a mixed solvent of water and a
poor solvent such as isopropyl alcohol. The resulting crystals are
collected by filtration on a crystal filter, washed and dried, and
the crystals are introduced in powdery form into vials previously
washed and sterilized. Then, rubber stoppers are placed on the
vials, and after the air in the vials is replaced by nitrogen, the
vials are tightly capped with the rubber stoppers and finally bound
with vial caps.
[0079] Further, the present invention relates to a powdery charged
preparation for injection, which comprises
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]-pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbo-
xylic acid represented by structural formula 2, a salt thereof, or
hydrate crystals thereof charged and capped in a vial. The salt may
be any acidic salts and includes, but is not limited to,
hydrochloride, sulfate, acetate, phthalate and phosphate.
[0080] In the powdery charged preparation for injection using these
crystals, a part or the whole of the air in the vial may be
degasified so that a part or the whole of residual oxygen is
removed or may be further replaced by nitrogen or argon.
[0081] The
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate and trihydrate crystals
according to the present invention can be used in various
preparations to produce chemically stable preparations. That is,
the crystals can be formed not only into the powdery charged
preparation but also into stable lyophilized preparations
(injections, oral agents) and stable oral preparations (tablets,
granules, capsules etc.), which were crystallized in the step of
freeze-drying.
[0082] Hereinafter, the present invention is described in more
detail by reference to the Examples, which however are not intended
to limit the present invention.
[0083] According to the present invention, there can be provided
novel carbapenem hydrochloride hydrate crystals from which
impurities can be easily separated. Examples of the effects thereof
are described below.
[0084] According to the present invention, there can be provided a
stable injection preparation of novel carbapenem hydrochloride.
Examples of the effects thereof are described below.
BRIEF DESCRIPTION OF DRAWINGS
[0085] FIG. 1 shows a powdery X-ray diffraction pattern of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl)-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride trihydrate crystals.
[0086] FIG. 2 shows a powdery X-ray diffraction pattern of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid hydrochloride monohydrate crystals.
[0087] FIG. 3 shows the solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate (.box-solid.) and
trihydrate (.quadrature.) in aqueous MeOH at 40.degree. C.
[0088] FIG. 4 shows the solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate (.box-solid.) and
trihydrate (.quadrature.) in aqueous MeOH at 20.degree. C.
[0089] FIG. 5 shows the solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate (.box-solid.) and
trihydrate (.quadrature.) in aqueous MeOH at 10.degree. C.
[0090] FIG. 6 shows the solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate (.box-solid.) and
trihydrate (.quadrature.) in aqueous MeOH at 4.degree. C.
[0091] FIG. 7 shows the solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate (.box-solid.) and
trihydrate (.quadrature.) in 62.5% (v/v) aqueous MeOH at each
temperature.
[0092] FIG. 8 shows an outline of the process for producing a
powdery charged preparation for injection comprising (+)-(1R,
5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-y-
l-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic
acid hydrochloride monohydrate and trihydrate.
EXAMPLES
[0093] Hereinafter, the present invention is described in more
detail by reference to the Examples, which however are not intended
to limit the present invention.
[0094] In Examples, hydrochloride hydrate crystals were produced in
the following scheme as one example. ##STR7## wherein PNB means the
same group as defined above, and IPA means isopropyl alcohol.
Example 1-1
(+)-(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolid-
ine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxy-
lic acid monohydrochloride trihydrate
[0095] Reductive de-protection of p-nitrobenzyl
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-
-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylat-
e monoxalate (29.0 g; free form, 23.11 g, 42.3 mmol) was carried
out in 2 steps as follows.
[0096] p-Nitrobenzyl
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-
-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylat-
e monoxalate (14.5 g), 20% palladium hydroxide-carbon (3.08 g, 50%
wet material) and H.sub.2O (333.5 mL) were introduced into a 500 mL
four-necked flask equipped with a pH stat and a stirrer, and then
suspended and stirred under cooling on a water bath (10.degree.
C.). After replacement by nitrogen was conducted 3 times, the
mixture was vigorously stirred for 2.5 hours in a hydrogen
atmosphere (hydrogen was supplied from a balloon at normal
pressure), during which the pH of the reaction solution was kept at
5.5 by adding 1 N aqueous sodium hydroxide solution dropwise by a
pump connected to the pH stat. When consumption of 1 N aqueous
sodium hydroxide was stopped (total 24.5 mL), supply of hydrogen
was stopped, and Celite (14.5 g) was introduced to it under
stirring and stirred for 7 minutes. This suspension was combined
with a Celite suspension obtained by carrying out the same reaction
as above, and filtered under reduced pressure on a Buchner funnel
having Celite (87 g) thereon, and the resulting cake was washed
with H.sub.2O (188 mL) to give an aqueous solution of the title
compound (892.9 g). By quantification in HPLC, the resulting
aqueous solution contained 13.2 g the title compound in free from
(yield, 75.8%).
[0097] The resulting aqueous solution was clarified by filtration
(with a filter paper GA100; filtrate weight, 996.8 g), and a part
(147.7 g) of the filtrate was treated with charcoal (0.66 g, Taiko
FCS Co., Ltd.) for 10 minutes, and then the charcoal was filtered
off (the title compound in free form; 1.881 g). An aqueous calcium
chloride solution (5.76 g, 7.5% w/w) was added to the solution
under ice-cooling and stirring, and charcoal in an amount (0.495 g)
of 10% relative to the free compound was added thereto. After an
additional aqueous calcium chloride solution (3.10 g, 7.0% w/w) was
added thereto, the mixture was filtered through a Buchner funnel
having 0.9 g Celite thereon to give a filtrate (17-4.8 g; the title
compound in free form, 1.82 g). This aqueous solution was
concentrated into 24 g concentrate, and water was added thereto to
give 36 g solution. This solution was cooled to 10.degree. C., and
IPA (50 mL) was added thereto under stirring, and the mixture was
seeded with crystals (0.08 g) of the title compound. After 15
minutes, precipitation of crystals was confirmed, and after aging
for 1 hour, IPA (94 mL) was added dropwise thereto. After aging for
1 hour, the crystals were collected by filtration under suction,
washed with 80% (v/v) aqueous IPA solution (20 mL) and then with
acetone (10 mL), and dried under suction for 30 minutes in a
nitrogen stream, to give 1.95 g of the title compound (free form,
1.61 g; yield, 85.5%).
[0098] The novel carbapenem hydrochloride crystals were evaluated
by powdery X-ray diffraction (INT-2500 Ultrax 18, manufactured by
Rigaku Co., Ltd.). FIG. 1 shows its powdery X-ray diffraction
pattern.
[0099] Further, .theta. (.degree.), lattice distance (d) and
intensity (cps) of the major three characteristic peaks are shown
in Table 1, and .theta. (.degree.), lattice distance (d), intensity
(cps) and relative intensity of the major peaks are shown in Table
2. The relative intensity of each peak was determined by the
equation (relative intensity=intensity of each peak/intensity of
maximum peak (d=4.0)). TABLE-US-00001 TABLE 1 2.theta. (.degree.)
lattice distance (d) (.ANG.) intensity (cps) 9.8 9.0 7470 21.6 4.1
12113 32.0 2.8 3067
[0100] TABLE-US-00002 TABLE 2 2.theta. (.degree.) lattice distance
(d) (.ANG.) intensity (cps) relative intensity * 9.8 9.0 7470 62
16.4 5.4 9960 82 17.1 5.2 2682 22 17.8 5.0 3308 27 21.6 4.1 12113
100 22.2 4.0 2417 20 23.4 3.8 4617 38 24.7 3.6 5705 47 26.2 3.4
5857 48 28.7 3.1 3538 29 32.0 2.8 3067 25 34.6 2.6 2357 19
Example 1-2
(+)-(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolid-
ine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxy-
lic acid monohydrochloride trihydrate (conversion of monohydrate to
trihydrate)
[0101] 1500 g aqueous solution of 174.4 g (free form, 150 g) of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrol-
idine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbo-
xylic acid monohydrochloride monohydrate was introduced into a 10 L
four-necked flask, and 1766 g of 2-propanol was added dropwise over
1 hour to this solution under stirring and cooling at 10.degree. C.
After it was confirmed that precipitation of crystals was
initiated, the sample was aged for 1 hour, and 2944 g of 2-propanol
(i.e. 81.6% (v/v) aqueous IPA in a 4-fold excess amount relative to
the aqueous solution) was added dropwise thereto over 1 hour. After
aging for 1 hour, the precipitated crystals were collected by
filtration and washed with 750 mL of 80% (v/v) aqueous 2-propanol
and then with 750 mL 2-propanol, and air-dried (1 hour) on a filter
in a nitrogen stream under reduced pressure, to give 175.7 g
desired trihydrate crystals (crystal yield, 96%). The powdery X-ray
diffraction pattern of the resulting crystals with 11.6% water
content agreed with that of trihydrate (FIG. 1). HPLC purity was
99.3%.
Example 1-3
(+)-(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolid-
ine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxy-
lic acid monohydrochloride monohydrate
[0102] Out of the solution (996.8 g) clarified by filtration with a
glass filter (GA100) in Example 1-1, 849.1 g solution (free form:
10.79 g) was adjusted to pH 8.5 with 1 N aqueous sodium hydroxide,
and the solution (871.4 g) was purified by applying it onto a resin
(SP850) column (5 cm.PHI..times.50 cm, flow rate of 50 mL/min,
previously equilibrated with 0.05 M phosphate buffer). The column
was charged with 20% aqueous methanol solution containing 0.05 M
phosphate buffer, water and 1.0 equivalent of hydrochloric acid and
then with 20% (v/v) aqueous methanol solution, and the resulting
major fractions were stored overnight at 10.degree. C. or less
(yield, 81%). Out of the resulting solution (1985 g, containing
8.74 g free compound), 1621.1 g solution was concentrated into
125.2 g concentrate (containing 7.08 g free compound). Out of this
concentrate, 93.9 g concentrate was discolored by adding 531 mg
charcoal, and water was added to the filtrate to adjust the
concentration of the free compound to 5% (weight of the solution:
102.67 g). This solution was further divided into 33.9 g (A) and
67.8 g (B).
[0103] While solution (A) was stirred at 22.degree. C., 26.6 g of
2-propanol was added dropwise thereto over 1 hour, and monohydrate
crystals, 0.4 g (corresponding to 20% (wt. %) relative to the
quantified amount of the free compound
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,
4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-ca-
rbapen-2-em-3-carboxylic acid) were added thereto as nucleating
crystals. After precipitation of crystals was confirmed, the
suspension was aged for 1 hour, and then a mixture of 53.2 g of
2-propanol and solution (B) was added dropwise thereto at
22.degree. C. over 1 hour. After aging for 30 minutes, 239 g of
2-propanol was added dropwise thereto over 1 hour and the mixture
was aged at 10.degree. C. overnight. The precipitated crystals were
collected by filtration and washed with 30 mL 80% (v/v) aqueous
2-propanol solution, 30 mL 2-propanol and 30 mL acetone in this
order. The crystals were air-dried for 1 hour in a nitrogen stream,
to give 5.71 g of the desired monohydrate crystals (yield, 92%).
HPLC purity was 99.8%. The powdery X-ray diffraction pattern agreed
with that of the monohydrate in FIG. 2 in Example 2-1 described
later.
Example 1-4
(+)-(1R,5S,6S)-6-[(R)-1-Hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolid-
ine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxy-
lic acid monohydrochloride monohydrate
[0104] 2.00 g
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate was dissolved at 20.degree.
C. in a mixed solvent of 8.0 ml distilled water and 6.0 ml
methanol, then the insoluble matters were filtered off and 30 ml
methanol was added dropwise thereto at 20.degree. C. over 7 minutes
under stirring. One hour after the dropwise addition was finished,
the resulting crystals were collected by filtration. The crystals
were washed with 5 ml methanol and air-dried for 1 hour in a
nitrogen stream, to give 1.70 g of the desired monohydrate crystals
(yield 85%). The powdery X-ray diffraction pattern is as shown in
FIG. 2.
Example 1-5
Examination of the Solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate and trihydrate in various
aqueous organic solutions
[0105] The solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate and trihydrate in various
aqueous organic solvents at a concentration of 62.5% (v/v) in water
at 20.degree. C. was determined by HPLC in the following
manner.
[0106] 200 mg monohydrate crystals (or trihydrate crystals) were
placed in a 30-ml two-necked flask, and 6.4 ml of 62.5% (v/v)
organic solvent in water was added thereto and stirred with a
stirrer at 20.degree. C. for 30 minutes, and the solubility thereof
was examined by quantification in HPLC. The results are shown in
Table 3. TABLE-US-00003 TABLE 3 solvent (mg/ml) (mg/ml) dimethyl
ether 1.93 1.44 diethylene glycol monomethyl ether 3.93 2.41
triethylene glycol monomethyl ether 2.86 2.47 diethylene glycol
monoethyl ether 6.56 2.68 1-acetoxy-2-methyl ethane 4.18 2.85
3-methoxybutanol 4.39 3.24 1-ethoxy-2-propanol 5.06 3.32
1-methoxy-2-propanol 4.12 3.37 2-ethoxyethanol 6.74 4.36
2-isopropoxyethanol 6.03 4.36 dimethyl acetamide 4.06 4.53 IPA
(isopropyl alcohol) 6.31 4.74 3-methoxy-3-methyl-1-butanol 5.93
4.86 tetrahydrofuran 7.22 5.29 2-methoxyethanol 5.37 6.39 dimethyl
formamide 5.03 7.31 n-propanol 12.33 10.46 t-butanol 8.65 6.06
dimethyl sulfoxide 7.50 11.84 2-butoxyethanol 13.29 11.85
acetonitrile 15.75 12.99 ethanol 6.60 6.32 methanol 10.22 14.38
[0107] From these results, the crystallization solvent for the
monohydrate crystals is preferably a methanol/water system, a
dimethyl sulfoxide/water system, a dimethylformamide/water system,
a 2-methoxyethanol/water system or a dimethylacetamide/water
system, and the crystallization solvent for the trihydrate crystals
is preferably a system consisting of water and a mixed solvent of
one or more members selected from the group consisting of dimethyl
ether, diethylene glycol monomethyl ether, triethylene glycol
monomethyl ether, diethylene glycol monoethyl ether,
1-acetoxy-2-methyl ethane, 3-methoxybutanol, 1-ethoxy-2-propanol,
1-methoxy-2-propanol, 2-ethoxyethanol, 2-isopropoxyethanol,
3-methoxy-3-methyl-1-butanol, tetrahydrofuran, n-propanol,
t-butanol, 2-butoxyethanol, ethanol, isopropanol and
acetonitrile.
Example 1-6
Examination of the Solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate and trihydrate in aqueous
MeOH
[0108] The solubility of
(+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrroli-
dine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carbox-
ylic acid monohydrochloride monohydrate and trihydrate in aqueous
MeOH was examined in aqueous MeOH at a concentration (v/v) ranging
from 54 to 84% at a temperature ranging from 4 to 40.degree. C. in
the same manner as in Examples 1 to 5.
[0109] The results are shown in FIG. 3 (at 40.degree. C.), FIG. 4
(at 20.degree. C.), FIG. 5 (at 10.degree. C.), FIG. 6 (at 4.degree.
C.) and FIG. 7 (at 62.5% (v/v) aqueous MeOH). The solubility of the
monohydrate is expressed as ".box-solid." while the solubility of
the trihydrate is expressed as ".quadrature.". It can be seen that
the monohydrate and trihydrate can be separately produced in such
wide range.
Example 1-7
Aseptic Crystallization of a Trihydrate Preparation
[0110] Water for injection was added to 2000 g titer equivalent
amount of novel non-aseptic carbapenem hydrochloride derivative to
give 20 kg dispersion. This dispersion was stirred and dissolved
under ice-cooling to prepare a charge solution. Thereafter, the
solution was aseptically filtered through a 0.2 .mu.m membrane
filter (MCGL20S03, 0.2 .mu.m, Millipore) and fed to a
crystallization tank (equipped with a jacket). Then, the
crystallization tank was stirred by bubbling with nitrogen at 0 to
.about.15.degree. C., and 25 L isopropyl alcohol was aseptically
added thereto. After crystallization, 55 L isopropyl alcohol was
added aseptically added thereto over 1 hour or so. After aging for
a predetermined time, the precipitated crystals were collected
aseptically by filtration. The crystals were washed with isopropyl
alcohol and acetone, and dried in a nitrogen stream with regulated
humidity (20 to 40 RH %) for 10 hours or more, to give novel
aseptic carbapenem hydrochloride trihydrate crystals.
Example 1-8
[0111] The crystals obtained in Example 1-7 were divided and
charged in an aseptic environment into sterilized glass vials (25
mg/vial, 50 mg/vial, 100 mg/vial, 150 mg/vial, 180 mg/vial, 200
mg/vial), then sealed with sterilized rubber stoppers and bound
with aluminum caps to give powdery charged preparations for
injection comprising the novel carbapenem hydrochloride
crystals.
Example 1-9
[0112] The crystals obtained in Example 1-7 were divided and
charged in an aseptic environment into sterilized glass vials (25
mg/vial, 50 mg/vial, 100 mg/vial, 0.150 mg/vial, 180 mg/vial, 200
mg/vial) by a weigh automatic micro-powder-filling machine (Ikeda
Kikai Co., Ltd.), then sealed with sterilized rubber stoppers and
bound with aluminum caps to give powdery charged preparations for
injection comprising the crystalline powder of the carbapenem
derivative.
Example 2-1
[0113] Monohydrate crystals were obtained in the same manner as in
Example 1-3. The crystals were evaluated by powdery X-ray
diffraction (INT-2500 Ultrax 18, manufactured by Rigaku Co.,
Ltd.).
[0114] The diffraction pattern thereof is as shown in FIG. 2.
[0115] Further, .theta. (.degree.), lattice distance (d) and
intensity (cps) of the major three characteristic peaks are shown
in Table 4, and .theta. (.degree.), lattice distance (d), intensity
(cps) and relative intensity of the major peaks are shown in Table
5. The relative intensity of each peak was determined by the
equation (relative intensity=intensity of each peak/intensity of
maximum peak (d=4.0)). TABLE-US-00004 TABLE 4 2.theta. (.degree.)
lattice distance (d) (.ANG.) intensity (cps) 17.1 5.2 6496 20.2 4.3
10342 22.3 4.0 17317
[0116] TABLE-US-00005 TABLE 5 2.theta. (.degree.) lattice distance
(d) (.ANG.) intensity (cps) relative intensity * 9.4 9.4 2717 86.5
14.2 6.2 3708 118.0 16.3 5.4 5512 175.4 17.1 5.2 6496 206.7 18.7
4.8 4162 132.5 18.9 4.7 4179 133.0 20.0 4.4 3500 111.4 20.5 4.3
10342 329.2 22.3 4.0 17317 551.1 23.5 3.8 3142 100.0 24.8 3.6 2904
92.4 26.1 3.4 4529 144.1 27.3 3.3 3042 96.8
Example 2-2
[0117] The crystals obtained in Example 2-1 were divided and
charged in an aseptic environment into sterilized glass vials (25
mg/vial, 50 mg/vial, 100 mg/vial, 150 mg/vial, 180 mg/vial, 200
mg/vial), then sealed with sterilized rubber stoppers and bound
with aluminum caps to give powdery charged preparations for
injection comprising the novel carbapenem hydrochloride
crystals.
Example 2-3
[0118] The crystals obtained in Example 2-1 were divided and
charged in an aseptic environment into sterilized glass vials (25
mg/vial, 50 mg/vial, 100 mg/vial, 150 mg/vial, 180 mg/vial, 200
mg/vial) by a weigh automatic micro-powder-filling machine (Ikeda
Kikai Co., Ltd.) and then semi-capped with sterilized rubber
stoppers, and after the air in the vials was replaced by nitrogen,
the vials were sealed with the rubber stoppers and bound with
aluminum caps, to give powdery charged preparations for injection
comprising the crystalline powder of the carbapenem derivative.
Example 2-4
[0119] 900 g of the raw medicine, that is, the novel non-aseptic
carbapenem hydrochloride was weighed and dissolved in 8500 g
distilled water for injection (WFI) under ice-cooling to prepare a
charge solution, and then aseptically filtered through a 0.2 .mu.m
membrane filter (MCGL10S03, 0.2 .mu.m, Millipore). Then, 40 L ethyl
alcohol was added to the filtrate in a crystallization tank
(equipped with a jacket) under aseptic conditions, and crystals
were precipitated at 5.degree. C. under stirring with a magnetic
stirrer under bubbling with nitrogen. Then, the novel carbapenem
trihydrate crystals were collected by a crystal filter and dried
with dry air until their ethyl alcohol content was reduced to 1% or
less. Thereafter, the crystals were divided and charged into vial
vessels (50 mg/vial, 100 mg/vial) in an aseptic environment, sealed
with sterilized rubber stoppers and bound with aluminum caps, to
give powdery charged preparations for injection comprising the
novel carbapenem hydrochloride crystals.
EXPERIMENTAL EXAMPLES
1) Stabilization Effect by the Powdery Charged Preparation for
Injection
[0120] 250 mg carbapenem hydrochloride was dissolved in 10 mL
distilled water for injection to prepare an aqueous injection. The
pH value of this aqueous injection was 5.04.
[0121] As the injection to be dissolved just before use, a
freeze-dried preparation was prepared in the following manner. 3.5
g carbapenem hydrochloride, 456 mg sodium chloride and 2.815 g
lactose were dissolved in 250 mL distilled water for injection.
This solution was introduced into 2 mL glass vials (0.25 ml/vial),
which were then semi-capped with rubber stoppers and freeze dried
for 1 day. After it was confirmed that the samples were dried, the
vials were fully capped and bound with aluminum caps.
[0122] As the powdery charged preparation of the amorphous raw
medicine, a carbapenem hydrochloride compound prepared in the
method described in JP-A 8-73462 was used.
[0123] As the crystalline powdery charged preparation of
monohydrate crystals, the preparation (25 mg/vial) obtained in
Example 2-2 was used. Further, as the crystalline powdery charged
preparation of trihydrate crystals, the preparation (25 mg/vial)
obtained in Example 1-8 was used.
[0124] These 5 preparations for injection were examined as follows:
The aqueous injection was stored at 25.degree. C. for 24 hours, and
the freeze-dried preparation and the powdery charged preparations
were stored at 40.degree. C. under 75% relative humidity
(40.degree. C.-75% RH) for 1 month, and these preparations were
examined for the content of the novel carbapenem hydrochloride by
high performance liquid chromatography. The content of the residual
carbapenem compound in each preparation relative to the content
(=100%) in the counterpart preparation stored in the cold place is
shown in Table 6. TABLE-US-00006 TABLE 6 Stability test content of
residual carbapenem crystalline Storage compound preparation form
state conditions (%) aqueous injection -- 25.degree. C. 87.2 for 24
hours freeze-dried preparation amorphous 40.degree. C.-75% RH 95.3
for 1 month powdery charged amorphous 40.degree. C.-75% RH 73.5
preparation for 1 month powdery charged crystal form 40.degree.
C.-75% RH 100.3 preparation for 1 month (monohydrate) powdery
charged crystal form 40.degree. C.-75% RH 100.2 preparation
(trihydrate) for 1 month
[0125] As is evident from the result of content stability in Table
6, the powdery charged preparation of the novel carbapenem
hydrochloride crystals according to the present invention is a very
stable preparation for injection as compared with the amorphous
powdery charged preparation for injection and other preparations
for injection (aqueous injection and lyophilized product).
2) Effect of Degasification of the Air in a Vial and/or Replacement
Thereof by Nitrogen
[0126] As the monohydrate crystals, the powdery charged preparation
of the novel carbapenem hydrochloride crystals (25 mg/vial)
obtained in the method in Example 2-3 (replacement by nitrogen),
the powdery charged preparation (25 mg/vial) subjected to
replacement by oxygen in place of replacement by nitrogen in
Example 2-3, and the powdery charged preparation (25 mg/vial) not
subjected to replacement in Example 2-2 were stored at 60.degree.
C. for 5 days (N=3) and then measured for their color difference
(.DELTA.E), water content, powdery X-ray diffraction pattern,
content of residual carbapenem, and HPLC impurities. As the
trihydrate crystals, the powdery charged preparation of the novel
carbapenem hydrochloride crystals (25 mg/vial) obtained the method
(replacement by nitrogen) in Example 1-9 and the powdery charged
preparation (25 mg/vial) not subjected to replacement in Example
1-8 were stored at 40.degree. C. for 1 month and then measured for
their color difference (.DELTA.E), water content and content of
residual carbapenem. The color difference was evaluated by a color
difference meter (ZE-200, Nippondenso Co., Ltd.); the water content
by a Karl-Fisher moisture meter (CA-05, Mitsubishi Kagaku Kogyo);
the powdery X-ray diffraction under the method and conditions in
Example 1-1 or 2-1; and the content of residual carbapenem and HPLC
impurities by high performance liquid chromatography (Shimadzu
Corporation). The color difference (.DELTA.E) is a parameter
indicative of a change in the color of the outward appearance of
crystals, and its higher value indicates a greater coloration
change than at an initial stage (just after production). The
results of the monohydrate and trihydrate are shown in Tables 7 and
8, respectively. TABLE-US-00007 TABLE 7 initial stage water HPLC
content impurity (%) (%) 5.99 1.03 content of oxygen color water
powdery X-ray residual carbapenem gas for content difference
content diffraction compound HPLC impurity replacement (%)
(.DELTA.E) (%) pattern (%) mean (%) (%) mean (%) nitrogen 0.99 4.23
5.80 no change 98.8 98.40 0.63 0.63 0.59 4.57 5.78 no change 98.1
0.63 0.61 5.23 5.77 no change 9.2 0.64 oxygen 85.3 12.7 5.78 no
change 97.5 97.80 0.63 0.64 85.6 12.14 5.77 no change 98.1 0.64
86.8 11.46 5.75 no change 97.8 0.64 20.6 10.48 5.87 no change 98.6
98.40 0.62 0.63 control (air) 20.6 11.21 5.87 no change 98.6 0.64
20.6 10.41 5.93 no chanae 98.1 0.64
[0127] TABLE-US-00008 TABLE 8 Stability in storage at 40.degree. C.
for 1 month content of residual gas for color difference water
content carbapenem compound replacement (.DELTA.E) (%) (%) nitrogen
0.00 11.3 100.2 control (air) 2.78 12.0 101.0
[0128] Regardless of which treatment was conducted, the powdery
charged preparations charged with the novel carbapenem
hydrochloride crystals were stable without any change in the water
content, powdery X-ray diffraction pattern, content of residual
carbapenem, and HPLC impurities. However, the color difference
(.DELTA.E) of the surface of the crystals subjected to replacement
by nitrogen was reduced as compared with that of the crystals
subjected by replacement by oxygen or not subjected to any
replacement treatment. That is, a thermal change in the color on
the surface of the crystals could be prevented by replacement by
nitrogen.
[0129] It is evident that the stability of the powdery charged
preparations for injection, particularly of their outward
appearance, against heat (temperature) is improved by replacing a
part or the whole of the air in the vial by nitrogen.
[0130] The novel carbapenem hydrochloride crystals were weighed in
25 mL wide-mouthed glass bottles (30 mg/bottle), and in the bottles
without caps, the monohydrate was stored for 1 week at 40.degree.
C. at a relative humidity of 0%, 19.2%, 53% and 75%, and the
trihydrate was stored for 2 weeks at 2.5.degree. C. at a relative
humidity of 11%, 33%, 51%, 75% and 93%. Then, the crystals were
measured for their color difference (.DELTA.E), water content,
powdery X-ray diffraction pattern, and content of residual
carbapenem. The monohydrate was also examined in the presence or
absence of an oxygen absorbent (trade name: Ageless, produced by
Mitsubishi Gas Chemical Co., Ltd.) during storage at each relative
humidity. The oxygen absorbent makes oxygen-free conditions under
which the preparation is placed. The results of the monohydrate and
trihydrate are shown in Tables 9 and 10, respectively.
TABLE-US-00009 TABLE 9 initial stage water HPLC content impurity
(%) (%) 5.49 0.93 powdery content of relative color water X-ray
residual humidity oxygen difference content diffraction carbapenem
(%) absorbent (.DELTA.E) (%) pattern compound (%) 0 absence 1.87
5.08 no change 101.1 19.2 absence 5.01 6.18 no change 99.9 53
absence 6.28 6.17 no change 100.6 75 absence 35.98 6.60 no change
99.8 0 presence 2.95 5.31 no change 100.3 19.2 presence 3.97 5.72
no change 100.5 53 presence 5.85 6.29 no change 102.0 75 presence
4.56 6.43 no chanae 100.8
[0131] TABLE-US-00010 TABLE 10 hygroscopicity (25.degree. C., 2
weeks) trihydrate crystals monohydrate crystals relative water
powdery X-ray water powdery X-ray humidity content diffraction
content diffraction (%) (%) pattern (%) pattern 11 11.0 no change
5.0 no change 33 11.1 no change 5.6 no change 51 11.1 no change 5.9
no change 75 11.1 no change 6.2 no change 93 11.4 no change 8.4 no
change
[0132] The powdery charged preparations charged with the novel
carbapenem hydrochloride crystals indicated a slightly increasing
water content as the relative humidity was increased at 40.degree.
C. or 25.degree. C., but there was no significant change in the
content of residual carbapenem and the powdery X-ray diffraction
pattern. Regardless of whether the oxygen absorbent was present or
not, there was no difference in the water content, the content of
residual carbapenem, and the powder X-ray diffraction pattern.
However, the color difference (.DELTA.E) was smaller in the
presence of the oxygen absorbent than in the absence thereof under
the same temperature condition. That is, the coloration change on
the surface of the crystals by humidity could be prevented by
deoxidation treatment.
[0133] It is evident that the stability of the powdery charged
preparations for injection, particularly the stability of their
outward appearance, against humidity is evidently improved by
degasification of a part or the whole of the air in the vial and
subsequent deoxidation treatment.
[0134] As the monohydrate, the powdery charged preparation for
injection of the novel carbapenem hydrochloride crystals (25
mg/vial) obtained in Example 2-2, the powdery charged preparation
for injection (25 mg/vial) obtained in Example 2-3 (replacement of
the air in the vial by nitrogen), and as the trihydrate, the
powdery charged preparation for injection of the novel carbapenem
hydrochloride crystals obtained in Example 1-8 and the powdery
charged preparation for injection obtained in Example 1-9
(replacement of the air in the vial by nitrogen) were stored for 1
week, 1 month, or 3 months in the cold place (5.degree. C.), at
25.degree. C., 60% relative humidity (25.degree. C./60% RH), at
40.degree. C., 75% relative humidity (40.degree. C./75% RH), or at
60.degree. C., and the change in the outward appearance of the
crystals (coloration change) was visually evaluated. The results of
the monohydrate and trihydrate are shown in Tables 11 and 12,
respectively. TABLE-US-00011 TABLE 11 storage storage term
condition vial no. 1 week 1 month 3 months Charged into vials
replaced therein by nitrogen 5.degree. C. 1 - - - 2 - - - 3 - - - 4
- - - 25.degree. C./60% RH 1 - - - 2 - - - 3 - - - 4 - - -
40.degree. C./75% RH 1 - - .+-. 2 - - .+-. 3 - - .+-. 4 - - .+-.
60.degree. C. 1 .+-. .+-. 2 .+-. .+-. 3 .+-. .+-. 4 .+-. .+-.
Charged into usual vials 5.degree. C. 1 - - - 2 - - - 3 - - - 4 - -
- 25.degree. C./60% RH 1 .+-. .+-. + 2 .+-. .+-. + 3 .+-. .+-. + 4
.+-. .+-. + 40.degree. C./75% RH 1 + + ++ 2 + + ++ 3 + + ++ 4 + +
++ 60.degree. C. 1 ++ ++ 2 ++ ++ 3 ++ ++ 4 ++ ++
[0135] TABLE-US-00012 TABLE 12 storage term: 1 month storage
charged into vials replaced charged into condition vial no. therein
by nitrogen usual vials 5.degree. C. 1 - - 2 - - 3 - - 4 - -
25.degree. C./60% RH 1 - .+-. 2 - .+-. 3 - .+-. 4 - .+-. 40.degree.
C./75% RH 1 - + 2 - + 3 - + 4 - + 60.degree. C. 1 .+-. ++ 2 .+-. ++
3 .+-. ++ 4 .+-. ++
[0136] In the cold (5.degree. C.), there was no change in the
outward appearance regardless of whether nitrogen replacement was
conducted or not, but it was recognized that under heating
conditions (60.degree. C.) or humidified conditions (25.degree.
C./60% RH, 40.degree. C./75% RH), the coloration change was reduced
by replacement of the air in the vial by nitrogen.
[0137] It is evident that the stability of the powdery charged
preparation for injection against heat (temperature) and the
stability of the outward appearance against humidity are improved
by replacement of a part or the whole of the air in the vial by
nitrogen and subsequent deoxidation treatment.
[0138] As the monohydrate, the powdery charged preparations for
injection of the novel carbapenem crystals (25 mg/vial) obtained by
degasification of the air in the vial at 100, 10, 1, 0.1 and 0.01
hPa (hectopascal) respectively and subsequent replacement by
nitrogen according to the method in Example 2-3 (replacement by
nitrogen) were stored at 60.degree. C. for 1 or 4 weeks (N=6) and
then measured for their color difference (.DELTA.E). The oxygen
concentrations in the preparations in vials degasified at 100, 10,
1, 0.1, 0.01 hPa (hectopascal) were measured by an oxygen analyzer
(RO-101, Iizima Kogyo). As the trihydrate, the powdery charged
preparations of the novel carbapenem hydrochloride crystals (25
mg/vial) obtained in the method in Example 1-9 (replacement by
nitrogen) were degasified in the same manner, stored at 80.degree.
C. for 1 week (N=6) and then measured for their color difference
(.DELTA.E). As the control, the powdery charged preparation of the
novel carbapenem hydrochloride crystals (25 mg/vial) subjected to
neither degasification nor replacement by nitrogen was used. The
results of the monohydrate and trihydrate are shown in Tables 13
and 14, respectively. TABLE-US-00013 TABLE 13 color pressure oxygen
concentration (%) difference (.DELTA.E) (hPa) mean .+-. S.D. 1 week
4 weeks 100 3.01 .+-. 1.12 2.85 8.02 10 0.29 .+-. 0.08 2.40 5.69 1
0.24 .+-. 0.04 2.62 4.51 0.1 0.21 .+-. 0.01 2.28 4.98 0.01 0.24
.+-. 0.03 3.11 4.91 control 7.37 14.94 (n = 6)
[0139] TABLE-US-00014 TABLE 14 pressure color difference (.DELTA.E)
(hPa) 80.degree. C./1 week 100 4.90 10 3.92 1 3.62 control 10.06 (n
= 6)
[0140] After storage at 60.degree. C. for 1 or 4 weeks or at
80.degree. C. for 1 week, any of the powder charged preparations in
the degassed vials indicated a smaller color difference (.DELTA.E)
on the surface of the crystals than that of the control
preparation. Particularly by degassing the air in the vial at 10
hPa (hectopascal) or less, that is, at an oxygen concentration of
0.5% or less in the vial, a thermal change in the color on the
surface of the crystals could be significantly prevented.
[0141] It is evident that the stability of the outward appearance
of the powdery charged preparations for injection against heat
(temperature) is improved by reducing the oxygen concentration in
the air in the vial to 0.5% or less followed by replacement by
nitrogen.
* * * * *