U.S. patent application number 10/240465 was filed with the patent office on 2003-08-14 for novel crystal form of pyrrolidylthiocarbapenem derivative.
Invention is credited to Kawakita, Toshio, Saitoh, Izumi, Takahira, Masayuki, Yoshioka, Yasuyuki.
Application Number | 20030153191 10/240465 |
Document ID | / |
Family ID | 18614158 |
Filed Date | 2003-08-14 |
United States Patent
Application |
20030153191 |
Kind Code |
A1 |
Saitoh, Izumi ; et
al. |
August 14, 2003 |
Novel crystal form of pyrrolidylthiocarbapenem derivative
Abstract
A novel crystal of a pyrrolidylthiocarbapenem derivative having
excellent stability is provided. According to the present
invention, a crystal of
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3
[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.-
0]hept-2-ene-2-carboxylic acid having a diffraction pattern in
powder X-ray diffraction preferably having main peaks at
diffraction angles (2.theta.)=13.04, 14.98, 15.88, 16.62, 20.62,
21.06, 22.18, 23.90, 26.08, 28.22 and 28.98 (degrees) is
provided.
Inventors: |
Saitoh, Izumi; (Hyogo,
JP) ; Takahira, Masayuki; (Hyogo, JP) ;
Kawakita, Toshio; (Hyogo, JP) ; Yoshioka,
Yasuyuki; (Hyogo, JP) |
Correspondence
Address: |
FISH & NEAVE
1251 AVENUE OF THE AMERICAS
50TH FLOOR
NEW YORK
NY
10020-1105
US
|
Family ID: |
18614158 |
Appl. No.: |
10/240465 |
Filed: |
September 30, 2002 |
PCT Filed: |
March 30, 2001 |
PCT NO: |
PCT/JP01/02834 |
Current U.S.
Class: |
540/350 |
Current CPC
Class: |
A61P 31/04 20180101;
A61P 31/00 20180101; C07D 477/20 20130101; C07B 2200/13
20130101 |
Class at
Publication: |
438/694 |
International
Class: |
H01L 021/311 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2000 |
JP |
2000-998683 |
Claims
1. A crystal of
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(-
3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]he-
pt-2-ene-2-carboxylic acid having a diffraction pattern in powder
X-ray diffraction having main peaks at diffraction angles
(2.theta.)=13.04, 14.98, 15.88, 16.62, 20.62, 21.06, 22.18, 23.90,
26.08, 28.22 and28.98 (degrees), or a hydrate thereof.
2. A medicament containing a crystal according to claim 1.
3. A medicament according to claim 2, wherein the medicament is an
injection.
4. A medicament according to claim 2, wherein the medicament is a
powder filling preparation.
5. A crystal of
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(-
3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.
0]hept-2-ene-2-carboxylic acid having a diffraction pattern in
powder X-ray diffraction having main peaks at diffraction angles
(2.theta.)=6.78, 6.96, 15.74, 17.92, 21.16, 23.56, and 25.80
(degrees), or a hydrate thereof.
6. A method for producing a crystal according to claim 5,
comprising the steps of: (A) dissolving in water
(+)-(4R,5S,6S)-6-[(1R)-l-hydroxyethyl]--
4-methyl-7-oxo-3[[(3S,S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-a-
zabicyclo[3.2.0]hept-2-ene-2-carboxylic acid or a hydrate thereof;
and (B) depositing the crystal from an aqueous solution obtained in
step (A).
7. A method for producing a crystal according to claim 1,
comprising the steps of: (A) dissolving in water
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]--
4-methyl-7-oxo-3[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1--
azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid or a hydrate thereof;
and (B') depositing the crystal from an aqueous solution obtained
in step (A), wherein a diffraction pattern of the deposited crystal
in powder X-ray diffraction has main peaks at diffraction angles
(2')=6.78, 6.96, 15.74, 17.92, 21.16, 23.56, and 25.80 (degrees);
and (C) drying the crystal obtained in step (B').
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel
pyrrolidylthiocarbapenem derivative crystal and a method for
producing the same.
BACKGROUND ART
[0002] The compound
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo--
3[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.-
0]hept-2-ene-2-carboxylic acid (hereinafter simply referred to as
S-4661) having a structure represented by the formula below is a
pyrrolidylthiocarbapenem derivative, which is a useful compound as
an antimicrobial drug. 1
[0003] Note that this compound is also designated as
"(4R,5S,6S)-3-[[(3S,5S)-5-(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-6-[-
(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0.]hept-2-ene-2-carbo-
xylic acid" or
"(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoyla-
minomethyl-1-pyrrolidin-3-yl]thio-1-methyl-1-carba-2-penem-3-carboxylic
acid".
[0004] S-4661 is described in Japanese Laid-Open Publication No.
5-294970. However, Japanese Laid-Open Publication No. 5-294970
describes only examples in which an amorphous form thereof was
isolated. The amorphous solid of S-4661 has insufficient stability
in storage, so that long-term storage under typical storage
conditions disadvantageously leads to discoloration and a reduction
in purity. Therefore, in order to develop S-4661 as a medicament,
particularly an injection, a crystalline preparation having higher
storage stability as compared to amorphous preparations is
desired.
[0005] For this reason, a variety of crystals of S-4661 have been
studied for improvements in storage stability, ease of handling,
and the like of S-4661. As a result, a variety of crystals of
S-4661 were confirmed.
[0006] For example, JP No. 2843444 discloses a type I crystal and a
type II crystal of S-4661. The peaks of the type I crystal and type
II crystal have characteristic diffraction angles (2.theta.) in
X-ray diffraction as follows:
[0007] Type I: 7.32, 14.72, 18.62, 20.42, 21.1, 22.18, 23.88, and
29.76 (degrees) and
[0008] Type II: 6.06, 12.2, 14.56, 17.0, 18.38, 20.68, 24.38,
24.60, 25.88, and 30.12 (degrees)
[0009] (conditions for measurement of X-ray diffraction: CuK.alpha.
ray, 1.54 Angstroms (monochromator), tube voltage 40 kV, tube
current 40 mA).
[0010] However, in the art, a still further improvement in the
stability of S-4661 has been desired.
Problems to be Solved by the Invention
[0011] The present invention solves the above-described
conventional problems. An object of the present invention is to
provide a novel crystal having excellent storage stability, good
ease of handling and the like, and a method for producing the
same.
[0012] Another object of the present invention is to provide a
novel crystal applicable to a powder filling preparation and a
method for producing the same.
DISCLOSURE OF THE INVENTION
Means for Solving the Problems
[0013] (1) According to the present invention, a crystal of
[0014]
(+)-(4R,5S,6S)-6-[(1R)-l-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5--
(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]1-
azabicyclo[3.2.0]hept-2-ene-- 2-carboxylic acid having a
diffraction pattern in powder X-ray diffraction having main peaks
at diffraction angles (2.theta.)=13.04, 14.98, 15.88, 16.62, 20.62,
21.06, 22.18, 23.90, 26.08, 28.22 and 28.98 (degrees), or a hydrate
thereof, is provided.
[0015] (2) According to the present invention, a medicament
containing the crystal of (1) is provided.
[0016] (3) In one embodiment, the medicament of (2) is an
injection.
[0017] (4) In one embodiment, the medicament of (2) is a powder
filling preparation.
[0018] (5) According to the present invention, a crystal of
[0019]
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5--
(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene--
2-carboxylic acid having a diffraction pattern in powder X-ray
diffraction having main peaks at diffraction angles
(2.theta.)=6.78, 6.96, 15.74, 17.92, 21.16, 23.56, and 25.80
(degrees), or a hydrate thereof, is also provided.
[0020] (6) In one aspect, a method according to the present
invention is a method for producing the crystal of (5), comprises
the steps of:
[0021] (A) dissolving in water
[0022]
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5--
(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene--
2-carboxylic acid; and
[0023] (B) depositing the crystal from an aqueous solution obtained
in step (A).
[0024] (7) In another aspect, a method according to the present
invention is a method for producing the crystal of (1), comprising
the steps of:
[0025] (A) dissolving in water
[0026]
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5--
(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene--
2-carboxylic acid;
[0027] (B') depositing the crystal from an aqueous solution
obtained in step (A), wherein a diffraction pattern of the
deposited crystal in powder X-ray diffraction has main peaks at
diffraction angles (2.theta.)=6.78, 6.96, 15.74, 17.92, 21.16,
23.56, and 25.80 (degrees); and
[0028] (C) drying the crystal obtained in step (B').
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 shows a result of powder X-ray diffraction
measurement for a type III crystal obtained in Example 1.
[0030] FIG. 2 shows a result of powder X-ray diffraction
measurement for a type IV crystal obtained in Example 2.
[0031] FIG. 3 shows a result of powder X-ray diffraction
measurement for a type IV crystal obtained in Example 4.
BEST MODE FOR CARRYING OUT THE INVENTION
Embodiments of the Invention
(Explanation of S-4661
[0032] The compound
[0033]
(+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3[[(3S,5S)-5--
(sulfamoylaminomethyl)pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene--
2-carboxylic acid (S-4661) is a pyrrolidylthiocarbapenem
derivative. S-4661is useful as an antimicrobial drug, and is orally
or parenterally administered. This compound has broad spectrum of
antibacterial activity and is effective against any gram-positive
and gram-negative bacteria.
[0034] A crystal of the above-described S-4661 may be an inner salt
crystal. The inner salt crystal of S-4661 is believed to have a
betaine structure represented by a formula below. 2
[0035] Such an inner salt crystal is more preferable since the
crystal is in a pure form which contains no counterions other than
the component of interest, unlike a Na salt or the like.
[0036] Results of powder X-ray diffraction measurement revealed
that two new different types of S-4661 crystal forms exist. These
two types of crystal form are hereinafter referred to as type III
and type IV, respectively. The type III crystal and the type IV
crystal are identified by their characteristic peaks obtained in
powder X-ray diffraction. These crystals may be hydrates.
Preferably, the type III crystal is a dihydrate and the type IV
crystal is a monohydrate.
[0037] Diffraction angles (2.theta.) of characteristic main peaks
of each crystal are indicated below.
[0038] Type III: diffraction angle (2.theta.)=6.78, 6.96, 15.74,
17.92, 21.16, 23.56, and 25.80 (degrees).
[0039] Type IV: diffraction angle (2.theta.)=13.04, 14.98, 15.88,
16.62, 20.62, 21.06, 22.18, 23.90, 26.08, 28.22 and 28.98
(degrees)
[0040] (conditions for measurement of X-ray diffraction: CuK.alpha.
ray, 1.54 Angstroms (monochromator), tube voltage 40 kV, tube
current 40 mA).
[0041] When the crystal of the present invention is measured by
X-ray diffraction, measurement error may occur in peaks to some
extent depending on a measurement apparatus or measurement
conditions. Specifically, for example, a measurement error of about
.+-.0.2 may occur in the value of 2.theta.. Even when a very
high-precision equipment is used, a measurement error of about
.+-.0.1 may occur. Therefore, measurement error should be
considered in identifying each crystal structure. Note that even
when measurement error in X-ray diffraction is considered, the
above-described characteristic peaks of the type I to type IV
crystals in X-ray diffraction are absolutely different from one
another. Therefore, X-ray diffractometry can be used to easily
confirm the difference between the crystals of the present
invention and other crystals.
[0042] Production of these crystals of S-4661 is a novel finding.
The stability of the type III and type IV crystals is higher than
that of the conventional type I and type II crystals. Therefore,
the type III and IV crystals are more preferable than the type I
and II crystals. Comparing the type III with the type IV, the
stability of the type IV crystal is higher than that of the type
III crystal. Therefore, the type IV crystal is more preferable than
the type III crystal.
Synthesis Method of S-4661
[0043] S-4661 can be synthesized by conventionally known methods.
For example, a method disclosed in Japanese Laid-Open Publication
No. 5-294970 is available. Specifically, for example,
4-hydroxypyrrolidin-2-c- arboxylic acid or a derivative thereof is
employed as a starting material. The steps comprises converting a
hydroxyl group at position 4 of the
4-hydroxypyrrolidin-2-carboxylic acid derivative to a mercapto
group; converting a carboxy group at position 2 to a hydroxymethyl
group; converting a hydroxyl group of the hydroxymethyl group
directly to sulfamide, or converting to an amino group and
thereafter further converting to sulfamoyl; and optionally removing
a protecting group Y1, can prepare the pyrrolidine derivative. The
order of the steps can be changed, as desired. Position 4 of a
pyrrolidine ring of the resultant pyrrolidine derivative may be
optionally deprotected to a SH group. Thereafter, the pyrrolidine
derivative is reacted with a carbapenem derivative to obtain a
pyrrolidyl carbapenem derivative.
Production Method of Crystals
[0044] The crystal of S-4661 of the present invention may be
obtained by a method of recrystallization or the like.
[0045] In one embodiment, the type III crystal of the present
invention is obtained by recrystallization from water.
[0046] In one embodiment, the type IV crystal of the present
invention is obtained by drying the type III crystal.
Production Method of Type III Crystal
[0047] The type III crystal of S-4661 can be obtained by, for
example, crystallizing S-4661 synthesized by the above-described
method from solution. Specifically, for example, S-4661is
crystallizedfroman organic solvent (e.g., alcohol, acetone,
acetonitrile, and tetrahydrofuran), water, or a mixture thereof.
Preferably, water alone is used as a solvent. Crystals are
preferably deposited from substantially pure water containing no
inorganic ions or the like. Examples of alcohol which may be used
herein include methanol, ethanol, isopropanol, and isobutanol. When
a mixed solvent of an organic solvent and water is used, the
mixture ratio of water/organic solvent is preferably 1:0.5 to 1:100
(v/v).
[0048] In order to obtain the type III crystal, S-4661 is dissolved
in preferably water, or the above-described mixed solvent of water
and an organic solvent to prepare S-4661 solution. The
concentration of the S-4661 solution is preferably about 5 to 40%
by weight. In order to deposit a crystal of S-4661 from the
solution, any crystallizing operation, such as cooling and/or
stirring, or the like can be performed. Preferably, the solution is
stirred while being cooled at about 0 to 10.degree. C. to obtain a
crystal of S-4661.
[0049] The type III crystal may be obtained as a single crystal by
controlling crystallization conditions. For example, the type III
crystal can be obtained by crystallizing S-4661 from water or a
water/ethanol system. Preferably, the type III crystal is
crystallized from water.
[0050] Here, when a seed crystal is not employed, a crystal of
types other than type III may be deposited. For example, the type I
crystal or the type II crystal may be deposited. Therefore, it is
preferable to employ a seed crystal in order to selectively and
efficiently deposit the type III crystal.
[0051] After crystallization from solution, the crystal is
optionally dried. As such a drying method, conventionally known
drying methods may be employed. For example, a drying method under
reduced pressure using an aspirator or the like can be used.
Specific drying conditions are, for example, as follows. The
temperature is preferably 10.degree. C. to 50.degree. C., more
preferably 15.degree. C. to 40.degree. C., and more preferably room
temperature. The pressure is, for example, preferably 10 to 300
mmHg, more preferably 0 to 100 mmHg, more preferably 0 to 50 mmHg,
and even more preferably 10 to 40 mmHg. The drying time is, for
example, preferably 1 minute to 1 hour, more preferably 2 to 30
minutes, and even more preferably 5 to 20 minutes.
[0052] The moisture content of the type III crystal is not
necessarily constant, but depends on the drying conditions and
storage conditions. Preferably, the type III crystal is a
dehydrate. The amount of organic solvent remaining in the crystal
is not constant, varying depending on the crystallization method,
drying conditions, and the like.
[0053] As with other crystals, the type III crystal may be
preferably used as a material for pharmaceutical preparations.
Moreover, as described below, the type III crystal can be used as
an intermediate to easily produce the type IV crystal. Therefore,
the type III crystal is very useful as an intermediate for
production of the type IV crystal.
Production Method of Type IV Crystal
[0054] The type IV crystal can be easily obtained preferably by
drying the above-described type III crystal. As the drying method,
conventionally known drying methods may be adopted. Preferably,
drying is conducted by application of heat and reduced pressure.
Specifically, for example, the temperature is preferably 20.degree.
C. to 100.degree. C., more preferably 30.degree. C. to 70.degree.
C., and even more preferably 40.degree. C. to 60.degree. C.
Further, the pressure is preferably, for example, 0 to 100 mmHg,
more preferably 0 to 30 mmHg, even more preferably 0 to 20 mmHg,
and particularly preferably 0 to 10 mmHg. The drying time is
preferably, for example, 1 to 20 hours, more preferably 2 to 15
hours, and even more preferably 5 to 10 hours.
[0055] The moisture content of the type IV crystal is not
necessarily constant, but depends on drying conditions and storage
conditions. However, preferably, the type IV crystal is a
monohydrate. The amount of organic solvent remaining in the crystal
varies depending on the crystallization method, drying conditions,
and the like, i.e., it is not constant. Note that the type IV
crystal is preferably isolated as a monohydrate by drying a
dihydrate type III crystal.
[0056] Thus, according to the present invention, a crystal of
S-4661 having excellent crystal storage stability and a high
industrial utility value is obtained.
Medicaments Containing the Crystals of the Present Invention
[0057] The crystals of the present invention can be employed as
preparations for any medicament applications in which
pyrrolidylthiocarbapenem derivatives have been conventionally used.
Particularly, the crystals of the present invention are useful as
antimicrobial drugs.
[0058] The preparation of the present invention may contain either
of the above-described two crystals (i.e., the type III crystal and
the type IV crystal) alone or a mixture thereof. When the
preparation of the present invention contains the mixture of the
two crystals, the crystals may be contained at an arbitrary mixture
ratio. The type IV crystal is superior to the type III crystal in
terms of storage stability. Therefore, the type IV crystal is more
preferably used.
[0059] When a composition containing a crystal of the present
invention is administered as an antimicrobial drug, a route of the
administration is oral or parenteral. Examples of the dosage form
include injections (ampoules, vials, solutions, suspensions, and
the like for intravenous, intramuscular, drip, and hypodermic
injections), external agents, topically administered agents (ear
drops, nose drops, eye drops, ointments, emulsion, spray agents,
suppositories, and the like), and orally administered agents.
Particularly, the injection can be prepared using a powder filling
preparation or a lyophilized preparation containing the crystal of
the present invention.
[0060] The above-described preparations may contain an appropriate
excipient, an auxiliary agent, a stabilizer, a wetting agent, an
emulsifier, and other additives, depending on the dosage form.
These have to be substances which can be pharmaceutically and
pharmacologically utilized and have no influence on
pyrrolidylthiocarbapenem derivatives. For example, the oral
preparations may contain lactose, stearic acid, magnesium stearate,
clay, sucrose, cornstarch, talc, gelatin, agar, pectin, peanut oil,
olive oil, cacao butter, ethylene glycol, tartaric acid, citric
acid, fumaric acid, and the like. The parenteral preparations may
contain a solvent (alcohol, buffer, methyl oleate, water, and the
like), a buffer solution, a dispersing agent, an auxiliary
dissolving agent, a stabilizer (methyl p-hydroxybenzoate or ethyl
p-hydroxybenzoate, sorbic acid, and the like), an absorbefacient (a
mono- or dioctanate of glycerin), an antioxidant, a perfume, an
analgesic, a dispersing agent, an adverse effect inhibitor, an
action potentiator (an agent for regulating absorption and
elimination, an inhibitor for enzyme decomposition, a
.beta.-lactamase inhibitor, other antimicrobial drugs), and the
like.
[0061] The dose of the crystal of pyrrolidylthiocarbapenem
derivative of the present invention varies depending on the age of
a patient, the type and state of the disease, the type of compound
used, and the like. In general, the daily dose falls within the
range between 1 mg/patient (external application) and about 4000
mg/patient (intravenous injection). More than or equal to such an
amount may be administered, if necessary. For treatment of
infectious diseases, the crystal of the present invention is
administered, for example, several times per day where a dose is 1
mg (external application), and 2 to 4 times per day where a dose is
1000 mg (intravenous injection).
[0062] When the crystal of pyrrolidylthiocarbapenem derivative of
the present invention is used as an antimicrobial drug, target
bacteria are any bacteria which are tackled by conventional
pyrrolidylthiocarbapenem derivatives. It exhibits strong
antimicrobial activity against both gram-positive bacteria and
gram-negative bacteria.
EXAMPLES
Example 1
Production Method of Type III Crystal
[0063] Crude S-4661 (20.0 g) was added to ion-exchanged water (360
ml) and dissolved by heating to about 50 to 55.degree. C., followed
by filtration of the solution through a filtering instrument coated
with activated carbon (600 mg) while maintaining a temperature of
at least 50.degree. C. After the filtrate was cooled to 15 to
20.degree. C., a seed crystal of the type III crystal (20 mg) was
put into the solution and stirred for about 120 minutes to deposit
a crystal. Further, the crystal was cooled to 0 to 5.degree. C. and
aged for 2 hours. Isopropyl alcohol (200 ml) was poured into the
solution over about 1 hour. Thereafter, the crystal was further
deposited and aged at 0 to 5.degree. C. for 2 hours and further
overnight at the same temperature. The crystal was then filtered
out. The resultant crystal was washed with 80% isopropyl alcohol
water (40 ml), followed by drying under reduced pressure (20 to 30
mmHg) with an aspirator using tap water at room temperature for
about 10 minutes to obtain the type III S-4661 crystal (18.1
g)(recovery rate: 90.5%).
[0064] A result of powder X-ray diffraction measurement for the
resultant crystal is shown in FIG. 1. For the resultant crystal,
the diffraction pattern of powder X-ray diffraction had main peaks
at diffraction angles (2.theta.)=6.78, 6.96, 15.74, 17.92, 21.16,
23.56, and 25.80 (degrees). Further, relatively low peaks were
present at diffraction angles (2.theta.)=11.56, 11.74, 13.38,
14.90, 16.88, 18.92, 19.82, 22.18, 23.02, 24.96, 25.32, 26.52,
27.66, 28.40, 29.70, 31.26, 33.00, 34.40, 39.46 and 39.70
(degrees).
[0065] Elemental analysis: for
C.sub.15H.sub.24N.sub.4O.sub.6S.sub.2.2H.su- b.2O Theoretical
values: C39.46, H6.18, N12.27, S14.05 Analytical values: C39.53,
H6.14, N12.40, S14.06 Moisture content Theoretical value
(dihydrate): 7.89% Karl Fischer moisture meter (KF) measured value:
7.74% Melting point: 173.degree. C. (decomposition).
Example 2
Production Method of Type IV Crystal
[0066] The type III crystal (5.0 g) obtained in the above-described
Example 1 was spread on a glass petri dish, and allowed to stand at
50.degree. C. under reduced pressure (0 to 5 mmHg) for about 7
hours for drying. Thus, type IV crystal (4.8 g) was obtained
(recovery rate: 96.0%). A result of powder X-ray diffraction
measurement of the result ant crystal is shown in FIG. 2. The
diffraction pattern of the resultant crystal in powder X-ray
diffraction had main peaks at diffraction angles (2.theta.)=13.04,
14.98, 15.88, 16.62, 20.62, 21.06, 22.18, 23.90, 26.08, 28.22 and
28.98 (degrees). Further, relatively low peaks were present at
diffraction angles(2.theta.)=23.42, 24.20, 24.46, 27.54, 31.70,
34.14, 34.36, 34.92, 39.82 and 45.24 (degrees).
[0067] Elemental analysis: for
C.sub.15H.sub.24N.sub.4O.sub.6S.sub.2.H.sub- .2O Theoretical
values: C41.08, H5.98, N12.78, S14.62 Analytical values: C41.01,
H5.92, N12.83, S14.56 Moisture content Theoretical value
(monohydrate): 4.11% Karl Fischer moisture meter (KF) measured
value: 4.28% Melting point: 173.degree. C. (decomposition).
Example 3
Reproducibility of Production of Type III Crystal
[0068] A repeat experiment was conducted in order to confirm the
reproducibility of the above-described Example 1.
[0069] The diffraction pattern of a resultant type III crystal in
powder X-ray diffraction had main peaks at diffraction angles
(2.theta.)=6.62, 13.04, 15.44, 16.58, 17.64, 20.88, 23.26, 25.02
and 25.52 (degrees).
Example 4
Reproducibility of Production of Type IV Crystal
[0070] A repeat experiment was conducted in order to confirm the
reproducibility of the above-described Example 2.
[0071] The type III crystal obtained in the above-described Example
3 was used to prepare type IV crystal in accordance with the method
of the above-described Example 2. A result of a resultant crystal
in powder X-ray diffraction measurement is shown in FIG. 3.
[0072] The diffraction pattern of the resultant type IV crystal in
powder X-ray diffraction had main peaks at diffraction angles
(2.theta.)=12.90, 15.74, 16.48, 23.78, and 25.92 (degrees).
[0073] Elemental analysis: for
C.sub.15H.sub.24N.sub.4O.sub.6S.sub.2.H.sub- .2O Theoretical value:
C41.08, H5.98, N12.78, S14.62 Analytical value: C41.93, H6.03,
N13.02, S14.52 Moisture content Theoretical value (monohydrate):
4.11% Karl Fischer moisture meter (KF) measured value: 4.3%
Assessment of Stability
[0074] The storage stability of the thus-obtained crystal of the
present invention was assessed. As a result, it was found that the
type III crystal of the present invention has excellent storage
stability as compared to conventional type I or II crystals, and
the type IV crystal of the present invention has more excellent
storage stability.
[0075] Hereinafter, a result of evaluation of comparing the
stability of the crystals of the present invention with that of a
conventional crystal (type II crystal) is specifically shown.
[0076] The stability of type II crystal of S4661 (conventional
crystal) was compared with that of the type IV crystal obtained in
the above-described Example 4.
[0077] Firstly, the testing method will be described.
[0078] Storage conditions were 40.degree. C. and 75% RH. The
periods of time for storage were 1 week, 2 weeks and 1 month.
During these storage periods, samples were stored in opened petri
dishes.
[0079] After storage in this manner, the moisture and potency of
each sample were measured.
[0080] The moisture was measured according to REQUIREMENT FOR
ANTIBIOTIC PRODUCTS OF JAPAN General Tests MOISTURE DETERMINATION
II Water determination. Note that Karl Fischer formamide methanol
mixture II was used as the solvent.
[0081] A potency test was conducted by the following method. About
0.025 g of each of the type IV crystal obtained in Example 4 and
type II crystal and a standard product of S-4661 was precisely
measured. Each sample was dissolved in water to precisely 100 mL.
10 mL of each solution was precisely measured, to which 5 ml of
internal standard solution was added. As the internal standard
solution, aqueous acetaminophen solution (concentration 1/20000: 1
g of acetaminophen in 20000 ml of the solution) was used.
Thereafter, water was added to each solution to 50 mL. Solutions
prepared from the type IV or II crystals were used as sample
solutions. A solution prepared from a standard product of S-4661
was used as a standard solution. 10 .mu.L of each of the sample
solutions and the standard solution were subjected to liquid
chromatography under the following conditions. For the sample
solution, the ratio Q.sub.T of the peak area of S-4661 to the peak
area of the internal standard substance was obtained. For the
standard solution, the ratio Q.sub.s of the peak area of S-4661 to
the peak area of the internal standard substance was obtained.
[0082] Conditions for operation
[0083] Detector: ultraviolet absorptiometer (measurement
wavelength: 240 nm)
[0084] Column: a stainless steel tube having an inner diameter of
about 4.6 mm and a length of about 15 cm was filled with 5 .mu.m of
octadecylsilylated silica gel for liquid chromatography (L-column
ODS).
[0085] Column temperature: a constant temperature of around
25.degree. C.
[0086] Mobile phase: 2 mmol/L phosphate buffer pH 5.8 acetonitrile
mixture (191:9)
[0087] Flow rate: Flow rate was adjusted so that the retention time
of S-4661 was about 8 to 9 minutes (about 1 mL/min).
[0088] Selection of column: 10 .mu.L of standard solution was used
and the operation was conducted under the above-described
conditions. A column, which elutes S-4661 and the internal standard
substance in this order and has a resolution between S-4661 and the
internal standard substance of at least 3, was used.
[0089] Potencies were calculated by the following expression. 1
Potency per 1 mg of the type IV or II crystal ( g / mg ) = Q T Q S
.times. Weight ( mg ) of Standard product of S - 4661 ( titer )
Weight ( mg ) equivalent to dehydrated product of crystal .times.
1000
[0090] The obtained test results are shown below.
1 Result of Moisture Measurement Unit (%) Storage period Type II
Type IV Initial time 4.56 4.62 1 week 9.51 4.79 2 weeks 10.36 4.89
1 month 10.31 4.99 3
[0091] In the case of the type II crystal, it can be understood
that the moisture increased over time, and the moisture became
constant after about two weeks (about 10%). On the other hand, in
the case of the type IV crystal, the initial amount of moisture was
maintained for a long period of time. Therefore, it was confirmed
that whereas the type II crystal absorbs moisture, the type IV
crystal absorbs substantially no moisture.
2 Result of Potency Measurement Unit (.mu.g/mg) Storage period Type
II Type IV Initial time 983.2 993.3 1 week 956.2 990.8 2 weeks
923.0 992.4 1 month 826.4 981.5 4
[0092] In the case of the type II crystal, it was confirmed that
the potency decreased over time. In the case of the type IV
crystal, no significant change was detected.
[0093] As can be seen from the moisture measurement result, the
type II crystal has moisture absorption ability. Therefore, a
procedure of weighing the type II crystal has to be performed in a
dry chamber. Other procedures have to be conducted under constant
humidity. On the other hand, the type IV crystal is not observed to
absorb moisture in an environment of 40.degree. C. and 75% RH and
therefore above-described procedures can be omitted. Other test
results revealed that the type IV crystal was more stable than the
type II crystal.
Assessment of Preparations
[0094] Preparations employing the crystal of the present invention
are assessed as follows. 250 mg of type IV crystal is dissolved in
100 mL of physiological saline to prepare an injection. If the
efficacy of the injection is assessed, it is confirmed that the
type IV crystal has efficacy similar to that of the conventional
type I and II crystals.
Industrial Applicability
Effects of the Invention
[0095] According to the present invention, novel crystals having
excellent storage stability and a production method thereof are
provided. Further, according to the present invention, novel
crystals which can be used in powder filling preparations and the
like and a production method thereof are provided.
* * * * *