U.S. patent application number 14/358709 was filed with the patent office on 2015-06-25 for use of surface free energy for differential evaluation of crystal, crystal evaluated on basis of surface free energy as index, and pharmaceutical composition prepared by containing the crystal.
The applicant listed for this patent is NIHON NOHYAKU CO., LTD., POLA PHARMA INC.. Invention is credited to Hideo Kaneda, Takaaki Masuda.
Application Number | 20150177210 14/358709 |
Document ID | / |
Family ID | 48471073 |
Filed Date | 2015-06-25 |
United States Patent
Application |
20150177210 |
Kind Code |
A1 |
Masuda; Takaaki ; et
al. |
June 25, 2015 |
USE OF SURFACE FREE ENERGY FOR DIFFERENTIAL EVALUATION OF CRYSTAL,
CRYSTAL EVALUATED ON BASIS OF SURFACE FREE ENERGY AS INDEX, AND
PHARMACEUTICAL COMPOSITION PREPARED BY CONTAINING THE CRYSTAL
Abstract
An object is to provide means for suppressing the formation of
any isomer of luliconazole on account of any influence of, for
example, the humidity and the light and improving the stability.
Disclosed is a method for differential evaluating a crystal of
luliconazole, comprising differential evaluating the crystal by
using, as indexes, surface free energy of the crystal of
luliconazole and a ratio of a polar component of the surface free
energy, wherein the crystal is evaluated to be stable on condition
that the surface free energy is smaller and the ratio of the polar
component is lower.
Inventors: |
Masuda; Takaaki; (Kanagawa,
JP) ; Kaneda; Hideo; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
POLA PHARMA INC.
NIHON NOHYAKU CO., LTD. |
Tokyo
Tokyo |
|
JP
JP |
|
|
Family ID: |
48471073 |
Appl. No.: |
14/358709 |
Filed: |
April 30, 2013 |
PCT Filed: |
April 30, 2013 |
PCT NO: |
PCT/JP2013/063094 |
371 Date: |
May 15, 2014 |
Current U.S.
Class: |
73/866 |
Current CPC
Class: |
C07B 2200/13 20130101;
A61P 31/10 20180101; C07D 409/06 20130101; G01N 33/15 20130101 |
International
Class: |
G01N 33/15 20060101
G01N033/15; C07D 409/06 20060101 C07D409/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 14, 2012 |
JP |
2012-203028 |
Claims
1. A method for differential evaluation a crystal of luliconazole,
comprising: evaluating the crystal by using, as indexes, surface
free energy of the crystal of luliconazole and a ratio of a polar
component of the surface free energy, wherein the crystal is
evaluated as that formation rate of the z isomer is low and the
crystal is suitable for a pharmaceutical preparation on condition
that the surface free energy is not more than 28 mJ/m.sup.2 and the
ratio of the polar component of the surface free energy is not more
than 35%.
2. (canceled)
3. (canceled)
4. The method according to claim 1, wherein the crystal is
evaluated to be suitable for a solid pharmaceutical
preparation.
5.-11. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to a crystal of luliconazole
having a useful crystal habit as an active pharmaceutical
ingredient for a pharmaceutical composition, and pharmaceutical
compositions which contain the crystal as the active pharmaceutical
ingredient.
BACKGROUND ART
[0002] Luliconazole is an antifungal agent which is excellent in
the action on fungi. At present, luliconazole is widely used as a
pharmaceutical or medicine for tinea pedis and tinea corporis, and
it is going to be applied to tinea unguium as well. Further,
luliconazole has an extremely high suppressing effect on
Aspergillus. Therefore, it is also expected to be applied to
profound mycosis (fungal disease) in a form of a pharmaceutical
preparation (medicament preparation) for inhalation or the like for
pneumonia and a vaginal agent for vaginitis. In relation to the
pharmaceutical preparation of luliconazole, it is known as problems
which should be solved that luliconazole is converted to
stereoisomers, such as the SE isomer and the Z isomer, and that the
crystallization of luliconazole is caused immediately after the
application (see, for example, Patent Documents 1 to 6). In
particular, as for the isomerization, the present inventors have
confirmed that the stereoisomerization to the SE isomer or the Z
isomer is influenced by the components of the pharmaceutical
preparation, pH, the temperature, the humidity, and the light.
Especially, the humidity and pH greatly affect the formation of the
Z isomer. Therefore, it is necessary to provide any countermeasure
thereagainst in relation to the pharmaceutical preparation which is
to be used in a situation relevant thereto. For example, in the
case of the tablet, the tablet must be stored for a long period of
time under a wet or moist condition at low pH, for example, in
gastric juice. In the case of the vaginal agent, the agent must be
stored at a high humidity and low pH as well. It is doubtless that
the inhalation should be used under a high humidity condition. It
is clear that the formation of the Z isomer should be suppressed as
far as possible during the period of time of the action. However,
in the present circumstances, any effective measure should be
inevitably found out by means of trial and error. On the other
hand, it is known for the crystal or the like that the surface free
energy is the factor which exerts any influence, for example, on
the surface wetting characteristic (wettability) of the crystal or
the like (see, for example, Patent Documents 7 to 10). However, it
is not known at all that the surface free energy is changed
depending on the condition of completion of an active
pharmaceutical ingredient (crystal), and the change serves as an
index for the stability or the like.
[0003] That is, it has been demanded to develop any means to
improve the stability, for example, against the humidity, pH, and
the temperature in relation to a crystal in a solid state or a
pharmaceutical composition in a solid state prepared by using the
crystal as described above.
##STR00001##
PRECEDING TECHNICAL DOCUMENTS
Patent Documents
[0004] Patent Document 1: WO2007/102241; [0005] Patent Document 2:
WO2007/102242; [0006] Patent Document 3: WO2007/102243; [0007]
Patent Document 4: WO2009/031642; [0008] Patent Document 5:
WO2009/031643; [0009] Patent Document 6: WO2009/031644; [0010]
Patent Document 7: JP2005-223345A; [0011] Patent Document 8:
JP2007-24735A; [0012] Patent Document 9: JP2004-341328A; [0013]
Patent Document 10: JP2007-147550A.
SUMMARY OF THE INVENTION
Technical Problem
[0014] The present invention has been made in the circumstances as
described above, an object of which is to provide means for
suppressing the formation of any isomer of luliconazole on account
of any influence of, for example, the humidity and the light and
improving the stability.
Solution to Problem
[0015] Taking the foregoing circumstances into consideration, the
present inventors have repeatedly performed diligent researches and
efforts in order to seek for any means for suppressing the
formation of any isomer of luliconazole on account of any influence
of, for example, the humidity and the light. As a result, it has
been found out that the surface free energy differs depending on
the form of crystal, and the crystal, which has small surface free
energy and which has a low ratio of a polar component of the
surface free energy, is hardly affected, for example, by the
humidity and the light, and thus the invention has been completed.
That is, the present invention is as follows.
[0016] <1> A method for differential evaluation of a crystal
of luliconazole, comprising:
[0017] evaluating the crystal by using, as indexes, surface free
energy of the crystal of luliconazole and a ratio of a polar
component of the surface free energy, wherein the crystal is
evaluated to be stable on condition that the surface free energy is
smaller and the ratio of the polar component is lower.
[0018] <2> The method as defined in <1>, wherein the
surface free energy is not more than 28 mJ/m.sup.2.
[0019] <3> The method as defined in <1> or <2>,
wherein the ratio of the polar component of the surface free energy
is not more than 35%.
[0020] <4> The method as defined in any one of <1> to
<3>, wherein it is evaluated whether or not the crystal is
suitable for a solid pharmaceutical preparation.
[0021] <5> A crystal which is evaluated to be highly stable
in accordance with the method as defined in any one of <1> to
<4>.
[0022] <6> A crystal of luliconazole which fulfills the
following conditions 1 to 4:
[0023] (1) a ratio of a polar component of surface free energy of
the crystal is not more than 31%;
[0024] (2) a dispersion component of the surface free energy of the
crystal is not less than 18 mJ/m.sup.2;
[0025] (3) the polar component of the surface free energy of the
crystal is not more than 8.2 mJ/m.sup.2; and
[0026] (4) the surface free energy of the crystal is not more than
27.4 mJ/m.sup.2.
[0027] <7> A pharmaceutical composition comprising
luliconazole which contains the crystal as defined in <5> or
<6>.
[0028] <8> The pharmaceutical composition comprising
luliconazole as defined in <7>, wherein the pharmaceutical
composition is a solid pharmaceutical preparation.
[0029] <9> The pharmaceutical composition comprising
luliconazole as defined in <7> or <8>, wherein the
pharmaceutical composition contains a pharmaceutical preparation
component which is appropriate to stabilize the crystal.
[0030] <10> A production method for producing a
pharmaceutical composition comprising luliconazole, comprising a
step of blending the crystal which is evaluated to be highly stable
in accordance with the differential evaluating method as defined in
any one of <1> to <4>.
[0031] <11> A pharmaceutical composition comprising
luliconazole which is produced by the production method as defined
in <10>.
Advantageous Effects of Invention
[0032] According to the present invention, it is possible to
provide means for suppressing the formation of any isomer of
luliconazole on account of any influence of, for example, the
humidity and the light. That is, it is possible to provide means
for improving the stability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 shows results of powder X-ray diffraction
measurement.
[0034] FIG. 2 shows results of DSC (differential scanning
calorimetry).
[0035] FIG. 3 shows the concept of the surface tension.
[0036] FIG. 4 shows a diagram of an apparatus for measuring the
contact angle .theta. in Example 1.
DESCRIPTION OF EMBODIMENTS
[0037] Abbreviations used in this specification are explained:
[0038] .gamma.s: surface free energy;
[0039] .gamma.s.sup.d: dispersion component of surface free
energy;
[0040] .gamma.s.sup.p: polar component of surface free energy;
[0041] .gamma.s.sup.p/.gamma.s: ratio of polar component of surface
free energy.
<1> the Differential Evaluating Method of the Present
Invention
[0042] The differential evaluating method of the present invention
resides in a method for differential evaluating the stability of
the crystal of luliconazole, characterized in that the surface free
energy of the luliconazole crystal is measured to evaluate whether
the stability is low or high on the basis of the magnitude of the
surface free energy and the ratio of the polar component of the
surface free energy. As for the stability in the differential
evaluation as described above, the change of the contents of the
isomer and the analog of luliconazole, in particular, the increment
(increase in amount) of the content thereof is used as the index.
The isomer of luliconazole is preferably exemplified by the SE
isomer and the Z isomer as described above. Further, the present
inventors have noticed the amide form which appears depending on
the type of the solvent selected in relation to the luliconazole
pharmaceutical preparation and which is an analog different from
the SE isomer and the Z isomer. The amide form is not preferred as
well in view of the decrease in the activity, and hence it serves
as the index of the stability in the differential evaluation as
described above.
##STR00002##
[0043] Luliconazole, which is the objective of the differential
evaluating method of the present invention, is an active
pharmaceutical ingredient composed of crystal. According to the
single crystal (monocrystal) X-ray diffraction analysis, the
structure of the crystal resides in the crystal system, the space
group, the lattice constant, and the R factor which substantially
have the following values. At present, any form other than that of
the following crystal system is not found in relation to
luliconazole, and it is estimated that no polymorph exists.
[0044] Crystal system: Monoclinic; space group: P2.sub.1; lattice
constant: a=9.0171(9) .ANG., b=8.167(1) .ANG., c=10.878(1) .ANG.,
.beta.=95.917(9).degree.; R factor: R=0.046, Rw=0.047.
[0045] The present inventors have noticed that the stability,
especially the time-dependent changes of the Z isomer, the SE
isomer, and the amide form differ depending on the production
method in relation to the single crystal system of luliconazole as
described above. Diligent investigations have been made about from
what the difference in the stability depending on the production
method originates. Surprisingly, it has been found out that the
surface free energy of the crystal differs depending on any
delicate or fine difference in the production method and/or the
condition. The present invention has been made on the basis of the
knowledge as described above.
[0046] The measurement of the surface free energy of the crystal
may be performed in accordance with an ordinary method. For
example, the contact angle with respect to the crystal is measured
by means of the liquid penetration (permeation) rate measurement
(machine type of apparatus: Processor Tensiometer K12,
manufacturer: KRUSS GmbH) by using several solvents for which the
surface free energy, the dispersion component of the surface free
energy, and the polar component of the surface free energy are
already known, and thus it is possible to perform the calculation
therefrom by applying the model of Owens, Wendt, Rabel, and
Kaelble. Preferred solvents for measurement in this method can be
appropriately exemplified, for example, by n-hexane,
tetrachloroethane, benzene, nitrobenzene, 1-nitropropane, and
water. As for the method as described above, it is possible to make
reference, for example, to a method described in Japanese Patent
Application Laid-open No. 2010-183064.
[0047] That is, according to Examples described later on, a
relationship of linear regression of y=0.017x+0.03 with a
correction coefficient of 0.9 exists between the ratio (%) of the
polar component of the surface free energy of the crystal of
luliconazole and the formation rate of the Z isomer under a
humidified condition. Further, the evident difference in the rate
of occurrence (formation) of the Z isomer exists between 44% and
31% in relation to the ratio of the polar component of the surface
free energy. It has been shown that the ratio of the polar
component is preferably not more than 35% and more preferably not
more than 31%.
[0048] Further, a relationship of linear regression of
y=-0.009x+0.25 with a correction coefficient of 0.9 also exists
between the dispersion component of the surface free energy and the
formation rate of the Z isomer. The evident difference in the
formation rate of the Z isomer exists between 18.4 mJ/m.sup.2 and
16.1 mJ/m.sup.2 in relation to the dispersion component of the
surface free energy. The value is preferably not less than 17
mJ/m.sup.2 and more preferably not less than 18 mJ/m.sup.2.
[0049] A relationship of linear regression of y=0.006x+0.03 with a
correction coefficient of 0.9 also exists between the polar
component and the formation rate of the Z isomer. The evident
difference in the formation rate of the Z isomer exists between 8.2
mJ/m.sup.2 and 12.7 mJ/m.sup.2 of the value. The value is
preferably not more than 8.5 mJ/m.sup.2 and more preferably not
more than 8.2 mJ/m.sup.2.
[0050] A relationship of linear regression of y=0.012x-0.255 with a
correction coefficient of 0.9 exists between the surface free
energy and the formation rate of the Z isomer. As for the value,
the evident difference in the formation rate of the Z isomer exists
between 27.4 mJ/m.sup.2 and 28.8 mJ/m.sup.2 of the value. The value
is preferably not more than 28 mJ/m.sup.2 and more preferably not
more than 27.4 mJ/m.sup.2.
[0051] That is, in relation to the surface free energy of the
crystal, any one of the surface free energy itself, the dispersion
component of the surface free energy, the polar component of the
surface free energy, and the ratio of the polar component of the
surface free energy can be used as the index for differential
evaluation. It is preferable that the evaluation is performed while
taking all of them into consideration.
[0052] That is, the preferred conditions are the following (1) to
(4) in relation to the stability of the crystal, especially in
relation to the stability of the crystal in order to provide the
solid pharmaceutical preparation. When all of the conditions are
fulfilled, the crystal is evaluated as being especially
preferable.
[0053] (1) a ratio of a polar component of surface free energy of
the crystal is not more than 31%;
[0054] (2) a dispersion component of the surface free energy of the
crystal is not less than 18 mJ/m.sup.2;
[0055] (3) the polar component of the surface free energy of the
crystal is not more than 8.2 mJ/m.sup.2; and
[0056] (4) the surface free energy of the crystal is not more than
27.4 mJ/m.sup.2.
[0057] It is possible to estimate and confirm that the crystal of
luliconazole, which has the property of the surface free energy as
described above, is selected as a result of the execution of the
differential evaluating method of the present invention.
[0058] The condition of the surface free energy in the crystal as
described above greatly differs depending on, for example, the way
of formation of the crystal, even in the case of the same solvent
for the recrystallization. Therefore, it is preferable that the
measurement is performed for every crystal to judge or distinguish
whether the crystal is adequate or inadequate for the use as the
active pharmaceutical ingredient for the pharmaceutical or
medicine. The difference evidently exists between the
recrystallization solvents. However, the other factors play
considerable roles as well.
[0059] That is, a preferred production method for producing the
pharmaceutical composition of the present invention is exemplified
such that the production is performed by blending the crystal which
is evaluated to be highly stable, where the crystal is evaluated in
accordance with the differential evaluating method of the present
invention.
<2> Crystal of the Present Invention
[0060] The crystal of the present invention resides in a crystal of
luliconazole, which is characterized in that the crystal is
evaluated to be highly stable in accordance with the differential
evaluating method of the present invention described above. Those
which are preferably usable as the crystal of the present invention
satisfy any one of the following conditions. Those which fulfill
all of the following conditions are especially preferable in the
present invention.
[0061] (1) a ratio of a polar component of surface free energy of
the crystal is not more than 31%;
[0062] (2) a dispersion component of the surface free energy of the
crystal is not less than 18 mJ/m.sup.2;
[0063] (3) the polar component of the surface free energy of the
crystal is not more than 8.2 mJ/m.sup.2; and
[0064] (4) the surface free energy of the crystal is not more than
27.4 mJ/m.sup.2.
[0065] The crystal of the present invention, which fulfills the
conditions as described above, exhibits such characteristics that
the formation rate of the Z isomer as the isomer is low and the
stability is high even in the case of a high humidity when the
crystal is stored in a solid state. Therefore, the crystal of the
present invention is preferred as an active pharmaceutical
ingredient of a pharmaceutical preparation which is in a solid
state and which is exposed to a high humidity. The pharmaceutical
preparation, which is in a solid state and which is exposed to a
high humidity, is preferably exemplified, for example, by oral
administration pharmaceutical preparations including, for example,
tablets, powders, capsules, and granules, inhalation pharmaceutical
preparations, vaginal tablet pharmaceutical preparations, and
vaginal suppository pharmaceutical preparations.
<3> Pharmaceutical Composition of the Present Invention
[0066] The pharmaceutical composition of the present invention is
characterized in that the pharmaceutical composition contains the
crystal of the present invention described above. When the
pharmaceutical composition of the present invention is a solid
pharmaceutical preparation, the content of the crystal of the
present invention is preferably 5 to 95% by mass, more preferably
10 to 90% by mass, and much more preferably 20 to 80% by mass. It
is preferable that the pharmaceutical composition of the present
invention is a solid pharmaceutical preparation in view of the
characteristic thereof for the following reason. That is, even in
the case of a liquid pharmaceutical preparation, the crystal can be
maintained stably during a storage period until the production,
which is preferred. However, in the case of the solid
pharmaceutical preparation, the stability as the pharmaceutical
preparation is improved as well.
[0067] The pharmaceutical composition of the present invention can
contain any arbitrary component usable for ordinary medicines
(pharmaceutical preparations) other than the crystal of the present
invention described above. The arbitrary component as described
above is preferably exemplified, for example, by excipient, binding
agent, disintegrating agent, dispersing agent,
taste/odor-correcting agent, extending agent, coating agent,
plasticizer, and lubricant. The pharmaceutical composition of the
present invention can be produced by treating the essential
components and the arbitrary components as described above in
accordance with an ordinary method. For example, in the case of the
pharmaceutical composition having a form of granule, granules may
be formed with a fluidized (powder) bed by using, for example, the
crystal of the present invention, an excipient, a
taste/odor-correcting agent, and a binding agent, followed by being
sieved, graded (subjected to grading), and packaged. In the case of
the tablet, graded granules may be subjected to tablet making
(compression).
[0068] A pharmaceutical preparation component, which is preferred
to stabilize the crystal, may be contained in the pharmaceutical
composition of the present invention in view of the further
improvement of the stabilization.
[0069] The pharmaceutical composition of the present invention is
preferably used to treat or cure the disease caused by any fungus
or prevent the deterioration of the disease by utilizing the
characteristic of luliconazole. The disease caused by any fungus
can be exemplified by profound mycosis (fungal disease) such as
pneumonia and vaginitis Caused by the fungus, tinea pedis such as
athlete's foot, tinea corporis such as candidiasis and tinea
versicolor, and trichophytosis of hard keratin portion such as
tinea unguium. The following dosage regimen is preferably available
for the pharmaceutical composition of the present invention. That
is, as for the administration route, it is possible to preferably
exemplify, for example, oral administration, vaginal
administration, inspiration or inhalation administration via
trachea, and administration by injection. As for the dosage, it is
preferable to use 10 to 10000 mg per day. The dosage differs in
some cases depending on the administration route. It is possible to
make reference to the amount of use of luliconazole usually used
for the disease caused by any fungus.
[0070] The pharmaceutical composition of the present invention
obtained as described above has such characteristics that the
formation rate of the Z isomer is low and the pharmaceutical
composition is stable even when the pharmaceutical composition is
exposed to a high humidity.
EXAMPLES
[0071] The present invention will be explained in further detail
below as exemplified by Examples. However, the present invention is
not limited to Examples described below.
Example 1
[0072] Luliconazole was recrystallized under various conditions to
obtain crystals in different states. The powder X-ray diffraction
measurement was performed for these crystals (machine type of
apparatus: XRD-DSCII, manufacturer: Rigaku Corporation, Condition:
X-ray source: CuK.alpha., measurement temperature: room
temperature, tube voltage: 40 kV, tube current: 40 mA, 2.theta.: 5
to 35.degree., step angle: 0.05.degree.). As a result, the
positions of the diffraction angle 2.theta. of the diffraction
peaks were identical in relation to all of them (see FIG. 1).
Further, the peak was also single in DSC (machine type of
apparatus: DSC7, manufacturer: PerkinElmer), and the melting point
was observed in the vicinity of 149.degree. C. (see FIG. 2, crystal
recrystallized with water-containing ethanol (25%), crystal
recrystallized with water-containing ethanol (50%), crystal
recrystallized with water-containing ethanol (75%), and crystal
recrystallized with ethyl acetate/n-hexane are shown from the top).
According to these results, it is acknowledged that the crystal
forms thereof are the same and any solvation does not exist as
well.
[0073] In relation to the surface free energy, the contact angle
.theta. is calculated in accordance with the Washburn's equation
from the penetration (permeation) rate of liquid into powder
obtained by the liquid penetration (permeation) rate measurement
(machine type of apparatus: Processor Tensiometer K12,
manufacturer: KRUSS GmbH). As for the surface free energy, the
concept of Young's equation shown in FIG. 3 exists. The penetration
(permeation) rate of the liquid in the chamber into the powder is
measured by using a chamber tube shown in FIG. 4. From this result,
the contact angle can be calculated utilizing Young's equation.
Washburn's equation is represented by the following equation 1.
v = l 2 t = .gamma. L r cos .theta. 2 .eta. ( Washburn ' s equation
) Equation 1 ##EQU00001##
[0074] If this equation is converted into the weight of the solvent
permeated into the powder per unit time, the following equation 2
is presented.
v = w 2 t = .gamma. L c .rho. 2 cos .theta. .eta. Equation 2
##EQU00002##
[0075] The contact angle .theta. is determined by measuring the
penetration (permeation) rate by using a solvent for which the
surface tension (.gamma..sub.L), the density (.rho.), and the
viscosity (.eta.) of the liquid are known. The polar component and
the dispersion component of the surface free energy are calculated
in accordance with the Owens-Wendt-Rabel-Kaelble method by using
.theta. thus determined. That is, assuming that the surface free
energy is composed of the non-polar dispersion component
.gamma..sup.d and the polar component .gamma..sup.p, the following
equations are presented.
.gamma..sub.S=.gamma..sub.S.sup.d+.gamma..sub.S.sup.p
.gamma..sub.L=.gamma..sub.L.sup.d+.gamma..sub.L.sup.p
.gamma..sub.SL=.gamma..sub.S+.gamma..sub.L=2 {square root over
(.gamma..sub.S.sup.d.gamma..sub.L.sup.d)}-2 {square root over
(.gamma..sub.S.sup.p.gamma..sub.L.sup.p)} Equation 3
[0076] If Young's equation, which holds among the surface tension
of the liquid, the surface tension of the solid, and the
solid-liquid interfacial tension, is substituted with the above,
the following equation is obtained.
1 + cos .theta. 2 .gamma. L .gamma. L d = .gamma. S p .gamma. L p
.gamma. L p + .gamma. s d Equation 4 ##EQU00003##
[0077] The contact angle .theta. is determined, and plotted by
using several types of solvents having known .gamma..sub.L,
.gamma..sub.L.sup.d, .gamma..sub.L.sup.p, and thus it is possible
to determine .gamma..sub.S.sup.p from the slope and
.gamma..sub.S.sup.d from the intercept. n-Hexane,
tetrachloromethane, benzene, 1-nitropropane, and water were used as
the known solvents. The values of .gamma..sub.L,
.gamma..sub.L.sup.d, .gamma..sub.L.sup.p thereof are shown in Table
1 below.
TABLE-US-00001 TABLE 1 Surface free energy (mJ/m.sup.2) No. Name of
solvent .sub..gamma.L.sup.d .sub..gamma.L.sup.P .sub..gamma.L 1
n-Hexane 18.4 0.0 18.4 2 Tetrachloromethane 26.7 0.3 27.0 3 Benzene
26.7 1.7 28.4 4 1-Nitropropane 25.5 3.9 29.4 5 Water 26.0 46.8
72.8
[0078] By utilizing the above, the surface free energy, the
dispersion component of the surface free energy, the polar
component of the surface free energy, and the ratio (%) of the
polar component with respect to the surface free energy were
calculated for samples (specimens) manufactured by the following
methods.
Production Example 1
[0079] Luliconazole was dissolved in ethanol while being heated, to
which water in an amount of 1/3 of that of ethanol was gradually
added, followed by being gently cooled to obtain Crystal 1
(ethanol/water (75:25) not pulverized).
Production Example 2
[0080] Crystal 1 was ground or pulverized with an agate mortar for
3 minutes to obtain Crystal 2 (ethanol/water (75:25) pulverized for
3 minutes).
Production Example 3
[0081] Luliconazole was dissolved in ethanol while being heated, to
which water in the same amount as that of ethanol was quickly
added, followed by being quickly cooled to obtain Crystal 3
(ethanol/water (50:50)).
Production Example 4
[0082] Luliconazole was dissolved in ethyl acetate while being
heated, to which n-hexane in the same amount as that of ethyl
acetate was quickly added, followed by being quickly cooled to
obtain Crystal 4 (ethyl acetate/n-hexane).
[0083] The surface free energy, the dispersion component of the
surface free energy, the polar component of the surface free
energy, and the ratio (%) of the polar component with respect to
the surface free energy, which are calculated for Crystals 1 to 4,
are shown in Table 2.
TABLE-US-00002 TABLE 2 Surface free energy (mJ/m.sup.2) No. Name of
sample .gamma.s.sup.d .gamma.s.sup.P .gamma.s
.gamma.s.sup.P/.gamma.s 1 Ethanol/water (75:25) 16.1 12.7 28.8 44
not pulverized 2 Ethanol/water (75:25) 19.5 7.9 27.4 29 pulverized
for 3 minutes 3 Ethanol/water (50:50) 18.4 8.2 26.6 31 4 Ethyl
acetate/n-hexane 20.3 5.2 25.5 20
[0084] The storage testing under severely stressed condition was
performed for Crystals 1 to 4. That is, each of the samples was
suspended in water (infiltration condition or humidified
condition), which was exposed to light at 6000 lx at 80.degree. C.
for 6 hours, followed by being collected by filtration and dried.
After that, the ratio of the Z isomer of luliconazole with respect
to the charging amount of luliconazole was measured and calculated.
The measurement was performed by means of HPLC. The HPLC condition
was as follows.
(HPLC Condition)
[0085] Column: CHIRALCEL OD-RH 4.6.times.150 mm, column
temperature: 35.degree. C., mobile phase: mixture solution of
methanol/1.8% aqueous solution of potassium hexafluorophosphate
(83:17, v/v), flow rate: 0.56 mL/min., detection: 295 nm.
[0086] Results are shown in Table 3.
TABLE-US-00003 TABLE 3 Amount of formation of Z isomer (%) under
condition of suspension in water and No. Name of sample
.gamma.s.sup.P/.gamma.s (%) exposure to light 1 Ethanol/water
(75:25) 44 0.11 not pulverized 2 Ethanol/water (75:25) 29 0.08
pulverized for 3 minutes 3 Ethanol/water (50:50) 31 0.07 4 Ethyl
acetate/n-hexane 20 0.07
[0087] The following facts are affirmed when the data is
statistically processed.
[0088] 1) A relationship of linear regression of y=0.017x+0.03 with
a correction coefficient of 0.9 exists between the ratio (%) of the
polar component and the formation rate of the Z isomer under a
humidified condition in relation to the surface free energy. This
fact means that the higher the ratio of the polar component is, the
larger the amount of formation of the Z isomer is.
[0089] 2) A relationship of linear regression of y=-0.009x+0.25
with a correction coefficient of 0.9 exists between the dispersion
component and the formation rate of the Z isomer. This fact means
that the larger the dispersion component of the surface free energy
is, the more decreased the amount of formation of the Z isomer
is.
[0090] 3) A relationship of linear regression of y=0.006x+0.03 with
a correction coefficient of 0.9 exists between the polar component
and the formation rate of the Z isomer. This fact means that the
larger the polar component of the surface free energy is, the more
increased the amount of formation of the Z isomer is as well.
[0091] 4) A relationship of linear regression of y=0.012x-0.255
with a correction coefficient of 0.9 exists between the surface
free energy and the formation rate of the Z isomer. This fact means
that the larger the surface free energy is, the more increased the
amount of formation of the Z isomer is as well.
Example 2
[0092] Tablet 1 and Tablet 3 were prepared by using Crystal 1
(Production Example 1) and Crystal 3 (Production Example 3) of
Example 1. That is, the tablets were prepared by mixing formulation
components and then performing tablet making (compression) for 200
mg of the mixture at a tablet making (compression) pressure of 5
t/g in accordance with a direct tablet making (compression)
method.
TABLE-US-00004 TABLE 4 Component % by mass Granulated lactose 50
Luliconazole crystal 50
[0093] Tablet 1 and Tablet 3 were stored for 24 hours under a
condition corresponding to a humidity of 100% while being exposed
to light (6000 lx) at 80.degree. C. to carry out the storage
testing under severely stressed testing. After carrying out the
stressed testing, the amount of formation of the Z isomer and the
amount of formation of the SE isomer of each of the tablets were
quantitatively measured by HPLC. Results are shown in Table 5. Any
numerical value indicates % by mass with respect to the charged
crystal. Accordingly, the same tendency as that of the crystal was
found in relation to the Z isomer. Such a tendency was found that
the amount of formation of the Z isomer was more increased in
relation to the tablet containing the crystal in which the surface
free energy or the polar component of the surface free energy was
large. On the other hand, a tendency which was not observed and was
different from that of the crystal was found in relation to the SE
isomer. It was revealed that the formation was more increased for
the tablet containing the crystal in which the surface free energy
was large or the polar component of the surface free energy was
large.
[0094] As for the SE isomer, the storage testing under severely
stressed testing was performed for the crystal in the same manner
as the Z isomer. As a result, any difference was not observed in
relation to the amount of formation depending on the difference in
the crystal. That is, the tendency of the SE isomer was not
observed for the crystal itself. It is suggested that the stability
may be possibly more suppressed in the case of those relevant to
the pharmaceutical preparation as compared with the crystal itself.
This also means, vice versa, that it is important for the solid
pharmaceutical preparation to maintain a more stable form in
relation to the crystal.
TABLE-US-00005 TABLE 5 Sample Z isomer SE isomer Tablet 1 0.08 0.09
Tablet 3 0.04 0.04
INDUSTRIAL APPLICABILITY
[0095] The present invention can be applied to the
pharmaceutical.
* * * * *