U.S. patent application number 15/762895 was filed with the patent office on 2019-07-18 for crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof.
This patent application is currently assigned to Zhejiang Hisun Pharmaceutical Co., Ltd.. The applicant listed for this patent is Zhejiang Hisun Pharmaceutical Co., Ltd.. Invention is credited to Hongying LUO, Zhenjuan SHI, Zhiqing YANG, Liang ZHANG, Xiangyang ZHANG, Min ZHAO.
Application Number | 20190218210 15/762895 |
Document ID | / |
Family ID | 58385580 |
Filed Date | 2019-07-18 |
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United States Patent
Application |
20190218210 |
Kind Code |
A9 |
YANG; Zhiqing ; et
al. |
July 18, 2019 |
CRYSTAL FORM OF PYRROLOQUINOLINE QUINONE SODIUM SALT AND
PREPARATION METHOD AND USE THEREOF
Abstract
Provided are crystal forms I, II, III and IV of a
pyrroloquinoline quinone sodium salt and a preparation method
thereof. Also provided are a pharmaceutical composition, a cosmetic
composition, a functional food or a nutritional agent containing
the above-mentioned crystal forms. The crystal forms have excellent
properties in terms of solubility, crystal stability,
hygroscopicity and the like.
Inventors: |
YANG; Zhiqing; (Taizhou
City, CN) ; ZHANG; Liang; (Taizhou City, CN) ;
ZHANG; Xiangyang; (Taizhou City, CN) ; SHI;
Zhenjuan; (Taizhou City, CN) ; ZHAO; Min;
(Taizhou City, CN) ; LUO; Hongying; (Taizhou City,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zhejiang Hisun Pharmaceutical Co., Ltd. |
Taizhou City, Zhejiang |
|
CN |
|
|
Assignee: |
Zhejiang Hisun Pharmaceutical Co.,
Ltd.
Taizhou City, Zhejiang
CN
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20180273526 A1 |
September 27, 2018 |
|
|
Family ID: |
58385580 |
Appl. No.: |
15/762895 |
Filed: |
September 14, 2016 |
PCT Filed: |
September 14, 2016 |
PCT NO: |
PCT/CN2016/099013 PCKC 00 |
371 Date: |
March 23, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
A61K 2800/10 20130101; A61Q 19/00 20130101; A61K 8/4926 20130101;
A61P 9/10 20180101; C07D 471/04 20130101; A61P 29/00 20180101; A23L
33/10 20160801; A61P 3/02 20180101; A61K 31/4745 20130101; A61P
31/00 20180101; A61P 25/28 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 2015 |
CN |
201510621701.1 |
Claims
1. A crystal form I of pyrroloquinoline quinone disodium salt,
wherein Cu target is used, and the X-ray powder diffraction pattern
of the crystal form I has characteristic peaks at the following
2.theta. diffraction angles: 8.0.+-.0.2.degree.,
10.9.+-.0.2.degree., 11.2.+-.0.2.degree., 15.1.+-.0.2.degree.,
15.8.+-.0.2.degree., 22.4.+-.0.2.degree., 25.5.+-.0.2.degree. and
27.7.+-.0.2.degree..
2. The crystal form I of pyrroloquinoline quinone disodium salt
according to claim 1, Cu target is used, wherein the X-ray powder
diffraction pattern of the crystal form I also has characteristic
peaks at the following 2.theta. diffraction angles:
16.9.+-.0.2.degree., 18.2.+-.0.2.degree., 20.6.+-.0.2.degree.,
21.5.+-.0.2.degree., 23.7.+-.0.2.degree., 26.0.+-.0.2.degree.,
27.3.+-.0.2.degree., 28.1.+-.0.2.degree., 28.5.+-.0.2.degree. and
29.8.+-.0.2.degree..
3. A method for preparing the crystal form I of pyrroloquinoline
quinone disodium salt according to claim 1, said method comprises
the following steps: (1) using pyrroloquinoline quinone as solute,
pure water or ethanol/water as solvent; (2) adjusting the pH to
1-2; (3) crystallizing; (4) continue to adjust the pH to 3-4; (5)
filtering to give the crystal form I of pyrroloquinoline quinone
disodium salt.
4. The method according to claim 3, wherein with g/ml as the unit,
the weight-to-volume ratio of pyrroloquinoline quinone to the mixed
solvent is preferably from 1:10 to 1:400, more preferably from 1:50
to 1:200 when water or ethanol/water is used as solvent, the
temperature of the solvent is controlled at 15.degree. C-60.degree.
C, preferably 25.degree. C-50.degree. C.
5. A crystal form II of pyrroloquinoline quinone disodium salt,
wherein Cu target is used, and the X-ray powder diffraction pattern
of the crystal form II has characteristic peaks at the following
2.theta. diffraction angles: 7.8.+-.0.2.degree.,
10.8.+-.0.2.degree., 11.1.+-.0.2.degree., 22.2.+-.0.2.degree. and
27.5.+-.0.2.degree..
6. The crystal form II of pyrroloquinoline quinone disodium salt
according to claim 5, wherein Cu target is used, the X-ray powder
diffraction pattern of the crystal form II also has characteristic
peaks at the following 2.theta. diffraction angles:
8.9.+-.0.2.degree., 15.6.+-.0.2.degree., 18.0.+-.0.2.degree.,
23.5.+-.0.2.degree. and 28.2.+-.0.2.degree..
7. A method for preparing the crystal form II of pyrroloquinoline
quinone disodium salt according to claim 5, comprising drying the
crystal form I of pyrroloquinoline quinone disodium salt according
to claim 1 or 2 at 30.degree. C-60.degree. C under vacuum condition
to obtain crystal form II.
8. A crystal form III of pyrroloquinoline quinone disodium salt,
wherein Cu target is used, and the X-ray powder diffraction pattern
of the crystal form III has characteristic peaks at the following
2.theta. diffraction angles: 7.4.+-.0.2.degree.,
8.6.+-.0.2.degree., 14.0.+-.0.2.degree., 14.6.+-.0.2.degree.,
19.9.+-.0.2.degree., 21.4.+-.0.2.degree., 26.0.+-.0.2.degree.,
27.3.+-.0.2.degree. and 28.5.+-.0.2.degree..
9. A method for preparing the crystal form III of pyrroloquinoline
quinone disodium salt according to claim 8, said method comprises
the following steps: (1) adding pyrroloquinoline quinone to a mixed
solvent of ethanol/water; (2) stirring, dissolving with the
temperature increased; (3) reducing the temperature, adjusting the
pH to 3-4; (4) crystallizing; (5) filtering to give the crystal
form III of pyrroloquinoline quinone disodium salt.
10. The method according to claim 8, wherein with g/ml as the unit,
the weight-to-volume ratio of pyrroloquinoline quinone to the mixed
solvent is from 1:200 to 1:400 when ethanol/water is used as
solvent, wherein the volume ratio of ethanol to water is 1:1-3:1,
the temperature of crystallization is controlled at 0.degree.
C-20.degree. C, preferably 5.degree. C-15.degree. C.
11-14. (canceled)
15. A pharmaceutical composition, a cosmetic composition, or a
functional food or nutritional agent comprising the crystal form I
of pyrroloquinoline quinone disodium salt according to claim 1.
16. A pharmaceutical composition, a cosmetic composition or a
functional food or nutritional agent comprising the crystal form II
of pyrroloquinoline quinone disodium salt according to claim 5.
17. A pharmaceutical composition, a cosmetic composition, or a
functional food or nutritional agent comprising the crystal form
III of pyrroloquinoline quinone disodium salt according to claim
8.
18. (canceled)
19. A method of preparing medicines, functional foods and cosmetics
by using the crystal form I of pyrroloquinoline quinone disodium
salt according to claim 1.
20. A method of preparing medicines, functional foods and cosmetics
by using the crystal form II of pyrroloquinoline quinone disodium
salt according to claim 5.
21. A method of preparing medicines, functional foods and cosmetics
by using the crystal form III of pyrroloquinoline quinone disodium
salt according to claim 8.
Description
TECHNICAL FIELD
[0001] The present invention relates to new crystal forms of
pyrroloquinoline quinone sodium salt and preparation methods
thereof, and the use of the new crystal forms in the fields of
medicines, functional foods and cosmetics.
TECHNICAL BACKGROUND
[0002] Pyrroloquinoline quinone, the chemical name is
4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic
acid, also known as methaxatin; it has the following structural
formula:
##STR00001##
[0003] Pyrroloquinoline quinone is a small molecule compound found
in microorganisms, it is widely distributed in various tissues and
organs of the human body and is called the fourteenth vitamin. It
is widely used in the fields of medicines, functional foods and
cosmetics. For example, pyrroloquinoline quinone can fully improve
the body's immune function, in the field of medicines,
pyrroloquinoline quinone can be used to prevent and cure liver
damage, reduce damage of free radicals to the human body,
conditioning a variety of nervous system diseases, promote the
absorption of amino acids, promote the synthesis of growth factors,
prevent and cure Alzheimer's disease, promote the synthesis of
glutathione, and pyrroloquinoline quinone has a strong anti-cancer
function. In addition, pyrroloquinoline quinone can be used as a
health food with anti-aging effects in the field of foods, in the
field of cosmetics, pyrroloquinoline quinone is an anti-allergic
and skin-beautifying substance.
[0004] For polymorphic compounds, different crystal forms may have
different physical and chemical properties; including melting
point, chemical stability, apparent solubility, dissolution rate,
optical and mechanical properties, etc. These physicochemical
properties directly determine the effect of a specific crystal form
in the fields of medicines, functional foods, cosmetics and the
like. For example, the crystal form of the pyrroloquinoline quinone
sodium salt obtained by the prior art method is unstable and has a
high hygroscopicity and a large extent of variation of humidity
within the temperature range of storage at normal temperature, and
the solid state is not ideal and is not suitable for processing
(filtering, drying, tabletting), thus adversely affecting the
application and storage of the pyrroloquinoline quinone sodium
salt. In the prior art, some modifications are made to the crystal
form of pyrroloquinoline quinone sodium salt, for example, in the
patent CN201080031945, the invention overcomes the defects of low
crystallinity and high content of residual solvent reported in some
literatures, but the prepared crystal form also has hygroscopicity,
the crystal form A in CN201210452297.6 has improved hygroscopicity,
the hygroscopicity is less than 3%, preferably less than 0.6% at
65%-85% RH, but such hygroscopicity still cannot satisfy the need
of the preparation process that has high requirement on
hygroscopicity of crystal forms.
[0005] Therefore, although some crystal forms of pyrroloquinoline
quinone have been disclosed in the prior art (in addition to the
two literatures that are mentioned above, the prior art includes
but is not limited to the following literatures, JP 2005-530786 A,
JP 2011-246442 A, JP 2007-269769 A, WO2011/007633, JPH07113024(B2),
CN201280028888.9), there is still a need to develop a new crystal
form that has better properties than the known crystal forms, and
has broad application prospects. Compared with the prior art, the
crystal form provided by the present invention has lower
hygroscopicity and the hygroscopixity is less than 0.3%, preferably
no hygroscopixity at 75% RH.
[0006] The present invention aims at providing a crystal form with
high crystallinity, high product purity and low content of residual
solvent, which is easy to be filtered, dried and stored, as well as
providing an environment-friendly and pollution-free process.
SUMMARY OF THE INVENTION
[0007] In a first aspect, the present invention aims to provide new
crystal forms of pyrroloquinoline quinone sodium salt that have
excellent chemical and physical stabilities and have excellent
properties in terms of solubility, crystal form stability,
hygroscopicity and processing (filtering, drying, tabletting)
adaptability. In a second aspect, the present invention aims to
provide the preparation methods of the new crystal forms of
pyrroloquinoline quinone sodium salt, and in the third aspect, the
present invention aims to provide pharmaceutical compositions,
cosmetic compositions, functional foods or nutritional agents that
comprise these new crystal forms and use of the crystal forms in
the fields of medicines, functional foods and cosmetics.
[0008] In the first aspect, the present invention provides a new
crystal form I of pyrroloquinoline quinone disodium salt, the
crystal form I has characteristic peaks at the following 2.theta.
diffraction angles in the X-ray powder diffraction (XRPD) pattern:
8.0.+-.0.2.degree., 10.9.+-.0.2.degree., 11.2.+-.0.2.degree.,
15.1.+-.0.2.degree., 15.8.+-.0.2.degree., 22.4.+-.0.2.degree.,
25.5.+-.0.2.degree., 27.7.+-.0.2.degree..
[0009] Further, in another embodiment of the present invention, the
crystal form I of pyrroloquinoline quinone disodium salt of the
present invention also has characteristic peaks at the following
2.theta. diffraction angles: 16.9.+-.0.2.degree.,
18.2.+-.0.2.degree., 20.6.+-.0.2.degree., 21.5.+-.0.2.degree.,
23.7.+-.0.2.degree., 26.0.+-.0.2.degree., 27.3.+-.0.2.degree.,
28.1.+-.0.2.degree., 28.5.+-.0.2.degree., 29.8.+-.0.2.degree..
[0010] In one embodiment of the present invention, the X-ray powder
diffraction pattern of the crystal form I of pyrroloquinoline
quinone disodium salt of the present invention has data of 2.theta.
angles, d-values, relative intensities of the characteristic peaks
as shown in Table 1 below:
TABLE-US-00001 TABLE 1 Peak No. 2.theta.(.degree.) d(.ANG.)
Relative intensity(%) 1 8.0 11.1 100 2 10.9 8.1 22.1 3 11.2 7.9 9.4
4 15.1 5.9 4.0 5 15.8 5.6 14.1 6 16.9 5.2 1.7 7 18.2 4.9 8.1 8 20.6
4.3 2.2 9 21.5 4.1 5.1 10 22.4 4.0 16.8 11 23.7 3.7 7.2 12 25.5 3.5
14.6 13 26.0 3.4 7.5 14 27.3 3.3 5.7 15 27.7 3.2 47.9 16 28.1 3.2
10.2 17 28.5 3.1 11.9 18 29.8 3.0 4.2
[0011] Unrestrictedly, the crystal form I of pyrroloquinoline
quinone disodium salt of the present invention has an X-ray powder
diffraction pattern as shown in FIG. 1.
[0012] The crystal form I of pyrroloquinoline quinone disodium salt
of the present invention can be characterized by an infrared
absorption spectrum measured by using a KBr pellet, the infrared
absorption spectrum has characteristic peaks at about 3502.68
cm.sup.-1, 3075.00 cm.sup.-1, 1745.31 cm.sup.-1, 1720.24 cm.sup.-1,
1662.49 cm.sup.-1, 1607.36 cm.sup.-1, 1542.24 cm.sup.-1, 1505.77
cm.sup.-1, 1372.28 cm.sup.-1, 1300.29 cm.sup.-1, 1280.01 cm.sup.-1,
1260.47 cm.sup.-1, 1220.80 cm.sup.-1, 1202.86 cm.sup.-1, 1176.23
cm.sup.-1, 971.91 cm.sup.-1, 940.36 cm.sup.-1, 886.67 cm.sup.-1,
812.19 cm.sup.-1, 792.93 cm.sup.-1, 770.80 cm.sup.-1, 747.86
cm.sup.-1, 702.98 cm.sup.-1, 610.52 cm, 538.17 cm.sup.-1, 430.94
cm.sup.-1.
[0013] Further, in another embodiment of the present invention, the
infrared absorption spectrum of the crystal form I of
pyrroloquinoline quinone disodium salt of the present invention
also has characteristic peaks at about 1431.23 cm.sup.-1, 1398.99
cm.sup.-1, 1144.92 cm.sup.1, 1082.92 cm.sup.-1.
[0014] Unrestrictedly, the crystal form I of pyrroloquinoline
quinone disodium salt of the present invention has an infrared
absorption spectrum as shown in FIG. 2.
[0015] Unrestrictedly, the crystal form I of pyrroloquinoline
quinone disodium salt of the present invention has a differential
scanning calorimetry (DSC) thermogram as shown in FIG. 3.
[0016] Unrestrictedly, the crystal form I of pyrroloquinoline
quinone disodium salt of the present invention has a
thermogravimetric analysis (TGA) thermogram as shown in FIG. 4.
[0017] In the first aspect, the present invention provides a new
crystal form II of pyrroloquinoline quinone disodium salt, the
crystal form II has characteristic peaks at the following 2.theta.
diffraction angles in the X-ray powder diffraction (XRPD) pattern:
7.8.+-.0.2.degree., 10.8.+-.0.2.degree., 11.1.+-.0.2.degree.,
22.2.+-.0.2.degree., 27.5.+-.0.2.degree..
[0018] Further, in another embodiment of the present invention, the
crystal form II of pyrroloquinoline quinone disodium salt of the
present invention also has characteristic peaks at the following
2.theta. diffraction angles: 8.9.+-.0.2.degree.,
15.6.+-.0.2.degree., 18.0.+-.0.2.degree., 23.5.+-.0.2.degree.,
28.2.+-.0.2.degree..
[0019] In one embodiment of the present invention, the X-ray powder
diffraction pattern of the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has data of 2.theta.
angles, d-values, relative intensities as shown in Table 2
below:
TABLE-US-00002 TABLE 2 Peak No. 2.theta.(.degree.) d(.ANG.)
Relative intensity(%) 1 7.8 11.3 100 2 8.9 9.9 17.5 3 10.1 8.8 5.8
4 10.8 8.2 52.9 5 11.1 8.0 32.6 6 15.0 5.9 7.6 7 15.6 5.7 13.1 8
18.0 4.9 17.6 9 20.7 4.3 7.2 10 21.6 4.1 10.3 11 22.2 4.0 26.3 12
23.5 3.8 16.4 13 24.4 3.6 6.1 14 25.3 3.5 14.2 15 26.0 3.4 11.8 16
26.6 3.3 9.8 17 27.5 3.2 88.8 18 28.2 3.2 33.4
[0020] Unrestrictedly, the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has an X-ray powder
diffraction pattern as shown in FIG. 5.
[0021] The crystal form II of pyrroloquinoline quinone disodium
salt of the present invention can be characterized by an infrared
absorption spectrum measured by using a KBr pellet, the infrared
absorption spectrum has characteristic peaks at about 1719.04
cm.sup.-1, 1667.65 cm.sup.-1, 1610.08 cm.sup.-1, 1541.60 cm.sup.-1,
1503.07 cm.sup.-1, 1279.55 cm.sup.-1, 1222.19 cm.sup.-1, 1142.30
cm.sup.-1, 1079.27 cm.sup.-1, 963.60 cm.sup.-1, 938.81 cm.sup.1,
792.11 cm.sup.-1, 771.05 cm.sup.-1, 702.30 cm.sup.-1, 609.59
cm.sup.-1, 535.29 cm.sup.-1, 429.20 cm.sup.-1, 411.27
cm.sup.-1.
[0022] Further, in another embodiment of the present invention, the
crystal form II of the pyrroloquinoline quinone disodium salt of
the present invention also has characteristic peaks at about
3499.74 cm.sup.-1, 3122.28 cm.sup.-1, 3074.36 cm.sup.-1, 2560.88
cm.sup.-1, 2360.30 cm.sup.-1, 1744.02 cm.sup.-1, 1397.72 cm.sup.-1,
888.38 cm.sup.-1.
[0023] Unrestrictedly, the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has an infrared
absorption spectrum as shown in FIG. 6.
[0024] Unrestrictedly, the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has a DSC thermogram
as shown in FIG. 7.
[0025] Unrestrictedly, the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has a TGA thermogram
as shown in FIG. 8.
[0026] In the first aspect, the present invention provides a new
crystal form III of pyrroloquinoline quinone disodium salt, the
crystal form III has characteristic peaks at the following 2.theta.
diffraction angles in the X-ray powder diffraction (XRPD) pattern:
7.4.+-.0.2.degree., 8.6.+-.0.2.degree., 14.0.+-.0.2.degree.,
14.6.+-.0.2.degree., 19.9.+-.0.2.degree., 21.4.+-.0.2.degree.,
26.0.+-.0.2.degree., 27.3.+-.0.2.degree., 28.5.+-.0.2.degree..
[0027] The X-ray powder diffraction pattern of the crystal form III
of pyrroloquinoline quinone disodium salt of the present invention
has data of 2.theta. angles, d-values, relative intensities as
shown in Table 3 below:
TABLE-US-00003 TABLE 3 Peak No. 2.theta.(.degree.) d(.ANG.)
Relative intensity (%) 1 7.4 12.0 67.4 2 8.6 10.3 100 3 14.0 6.3
20.9 4 14.6 6.1 14.1 5 15.8 5.6 3.9 6 17.1 5.2 3.2 7 18.9 4.7 2.1 8
19.9 4.4 27.5 9 21.4 4.2 7.4 10 22.7 3.9 8.7 11 24.2 3.7 3.6 12
24.6 3.6 2.9 13 26.0 3.4 8.2 14 27.3 3.3 50.7 15 28.5 3.1 14.7
[0028] Unrestrictedly, the crystal form III of pyrroloquinoline
quinone disodium salt of the present invention has an X-ray powder
diffraction pattern as shown in FIG. 9.
[0029] The crystal form III of pyrroloquinoline quinone disodium
salt of the present invention can be characterized by an infrared
absorption spectrum measured by using a KBr pellet, the infrared
absorption spectrum has characteristic peaks at about 3446.06
cm.sup.-1, 1721.16 cm.sup.-1, 1680.19 cm.sup.-1, 1613.68 cm.sup.-1,
1541.14 cm.sup.-1, 1496.91 cm.sup.-1, 1349.99 cm.sup.-1, 1243.04
cm.sup.-1, 940.32 cm.sup.-1, 722.10 cm.sup.-1, 562.47 cm.sup.-1,
424.89 cm.sup.-1.
[0030] Further, in another embodiment of the present invention, the
crystal form III of the pyrroloquinoline quinone disodium salt of
the present invention also has characteristic peaks at about
1077.39 cm.sup.-1, 801.05 cm.sup.-1, 749.60 cm.sup.-1.
[0031] Unrestrictedly, the crystal form II of pyrroloquinoline
quinone disodium salt of the present invention has an infrared
absorption spectrum as shown in FIG. 10.
[0032] Unrestrictedly, the crystal form III of pyrroloquinoline
quinone disodium salt of the present invention has a DSC thermogram
as shown in FIG. 11.
[0033] Unrestrictedly, the crystal form III of pyrroloquinoline
quinone disodium salt of the present invention has a TGA thermogram
as shown in FIG. 12.
[0034] In the first aspect, the present invention provides a new
crystal form IV of pyrroloquinoline quinone monosodium salt, the
crystal form IV has characteristic peaks at the following 2.theta.
diffraction angles in the X-ray powder diffraction (XRPD) pattern:
7.8.+-.0.2.degree., 10.8.+-.0.2.degree., 15.1.+-.0.2.degree.,
15.7.+-.0.2.degree., 16.9.+-.0.2.degree., 18.2.+-.0.2.degree.,
20.6.+-.0.2.degree., 27.7.+-.0.2.degree., 28.4.+-.0.2.degree..
[0035] Further, in another embodiment of the present invention, the
crystal form IV of pyrroloquinoline quinone monosodium salt of the
present invention also has characteristic peaks at the following
2.theta. diffraction angles: 18.0.+-.0.2.degree.,
22.3.+-.0.2.degree., 23.6.+-.0.2.degree., 25.4.+-.0.2.degree.,
25.8=0.2.degree..
[0036] In one embodiment of the present invention, the X-ray powder
diffraction pattern of the crystal form IV of pyrroloquinoline
quinone monosodium salt of the present invention has data of
2.theta. angles, d-values, relative intensities as shown in Table 4
below:
TABLE-US-00004 TABLE 4 Peak No. 2.theta.(.degree.) d(.ANG.)
Relative intensity(%) 1 7.8 11.3 42.7 2 10.8 8.2 40.2 3 12.6 7.0
2.3 4 13.2 6.7 3.2 5 15.1 5.9 8.0 6 15.7 5.6 9.9 7 16.9 5.3 5.5 8
18.0 4.9 10.8 9 18.2 4.9 18.1 10 20.6 4.3 6.8 11 21.6 4.1 11.0 12
22.3 4.0 15.4 13 23.6 3.8 10.2 14 24.4 3.6 6.0 15 25.4 3.5 22.7 16
25.8 3.5 13.0 17 27.7 3.2 100 18 28.4 3.1 34.0
[0037] Unrestrictedly, the crystal form IV of pyrroloquinoline
quinone monosodium salt of the present invention has an X-ray
powder diffraction pattern as shown in FIG. 13.
[0038] The crystal form IV of pyrroloquinoline quinone monosodium
salt of the present invention can be characterized by an infrared
absorption spectrum measured by using a KBr pellet, the infrared
absorption spectrum has characteristic peaks at about 3503.09
cm.sup.-1, 3074.74 cm.sup.-1, 1744.71 cm.sup.-1, 1720.37 cm.sup.-1,
1664.30 cm.sup.-1, 1606.88 cm.sup.-1, 1544.10 cm.sup.-1, 1505.39
cm.sup.-1, 1398.65 cm, 1301.22 cm.sup.-1, 1280.13 cm.sup.-1,
1259.72 cm.sup.-1, 1202.57 cm.sup.-1, 1176.96 cm.sup.-1, 1144.49
cm.sup.-1, 1082.30 cm.sup.-1, 970.03 cm.sup.-1, 939.56 cm.sup.-1,
793.39 cm.sup.-1, 770.25 cm.sup.-1, 748.91 cm.sup.-1, 717.95
cm.sup.-1, 608.86 cm.sup.-1, 536.98 cm.sup.-1, 430.96
cm.sup.-1.
[0039] Unrestrictedly, the crystal form IV of pyrroloquinoline
quinone monosodium salt of the present invention has an infrared
absorption spectrum as shown in FIG. 14.
[0040] Unrestrictedly, the crystal form IV of pyrroloquinoline
quinone monosodium salt of the present invention has a DSC
thermogram as shown in FIG. 15.
[0041] Unrestrictedly, the crystal form IV of pyrroloquinoline
quinone monosodium salt of the present invention has a TGA
thermogram as shown in FIG. 16.
[0042] In the second aspect, the present invention provides a
preparation method of said crystal form I of pyrroloquinoline
quinone disodium salt, said method comprises:
[0043] (1) using pyrroloquinoline quinone as solute, pure water or
ethanol/water as solvent;
[0044] (2) adjusting the pH to 1-2;
[0045] (3) crystallizing with stirring;
[0046] (4) continue to adjust the pH to 3-4;
[0047] (5) filtering to give the crystal form I of pyrroloquinoline
quinone disodium salt.
[0048] The weight-to-volume ratio (g/ml) of pyrroloquinoline
quinone to the mixed solvent is preferably from 1:10 to 1:400, more
preferably from 1:50 to 1:200 when water or ethanol/water is used
as solvent, wherein, the state of the liquid for crystallization
described in (1) can be clear or pyrroloquinoline quinone can be
suspended in the liquid; the temperature of the liquid is
controlled at 15.degree. C.-60.degree. C., preferably 25.degree.
C.-50.degree. C.
[0049] In the second aspect, the present invention also provides a
preparation method of said crystal form II of pyrroloquinoline
quinone disodium salt, said method comprises: drying the crystal
form I of pyrroloquinoline quinone disodium salt at 30.degree.
C.-60.degree. C. under vacuum condition to obtain crystal form
II.
[0050] In the second aspect, the present invention also provides a
preparation method of said crystal form III of pyrroloquinoline
quinone disodium salt, said method comprises:
[0051] (1) adding pyrroloquinoline quinone to a mixed solvent of
ethanol/water;
[0052] (2) stirring, dissolving with the temperature increased;
[0053] (3) filtering, reducing the temperature, adjusting the pH to
3-4;
[0054] (4) crystallizing;
[0055] (5) filtering to give the crystal form III of
pyrroloquinoline quinone disodium salt.
[0056] The weight-to-volume ratio (g/ml) of pyrroloquinoline
quinone to the mixed solvent is preferably from 1:200 to 1:400 when
ethanol/water is used as solvent, wherein the volume ratio of
ethanol to water is 1:1-3:1, the temperature of crystallization is
controlled at 0.degree. C.-20.degree. C., preferably 5.degree.
C.-15.degree. C.
[0057] In the second aspect, the present invention also provides a
preparation method of said crystal form IV of pyrroloquinoline
quinone monosodium salt, said method comprises:
[0058] (1) using pyrroloquinoline quinone as solute, pure water or
ethanol/water as solvent;
[0059] (2) adjusting the pH to 1-2;
[0060] (3) crystallizing with stirring;
[0061] (4) filtering to give the crystal form IV of
pyrroloquinoline quinone monosodium salt.
[0062] Wherein, the state of the liquid for crystallization
described in (1) can be clear or pyrroloquinoline quinone can be
suspended in the liquid; the temperature of the liquid is
controlled at 15.degree. C.-60.degree. C., preferably 25.degree.
C.-50.degree. C.
[0063] In the above method, the unit of the weight-volume ratio of
the pyrroloquinoline quinone to the corresponding solvent can be
g/ml, Kg/L and the like, depending on the specific operation
scale.
[0064] In the third aspect, the present invention provides
pharmaceutical compositions, cosmetic compositions, functional
foods or nutritional agents comprising the new crystal forms of the
present invention and use of the new crystal forms in the fields of
medicines, functional foods and cosmetics.
[0065] The raw material, pyrroloquinoline quinone used in the
methods of the present invention can be commercially available or
can be prepared according to known methods. There are no special
limitations of the solvents used in the present invention, common
solvents that are commercially available can be used.
[0066] Unless otherwise specified, the "stirring" in the method of
the present invention can be carried out by conventional methods in
the art, for example, stirring method includes magnetic stirring
and mechanical stirring.
[0067] The X-ray powder diffractometer (XRPD) and the test
conditions involved in the present invention are: X-ray powder
diffractometer model Rigaku D/max-2200Cu target; operation method,
scanning speed 4.degree./min, scanning step width 0.01'.
[0068] The infrared spectrophotometer and the test conditions
involved in the present invention are: infrared spectrophotometer
model: BRWKER JECTOR 22; operation method: using KBr pellet method,
scanning range 400-4000 cm.sup.-1.
[0069] The test conditions for differential scanning calorimetry
(DSC) involved in the present invention are: differential scanning
calorimeter model: NETZSCH DSC200F3 Jaia; operation method: heating
rate 10.degree. C./min, temperature range: 30-250.degree. C.
[0070] The test conditions for thermogravimetric analysis (TGA)
involved in the present invention are: thermogravimetric analyzer
model: PerkinElmer TGA400; operation method: heating rate
10.degree. C./min, temperature range: 30-300.degree. C.
[0071] The test conditions for microscope are: microscope model:
OLYMPUS CX31; operation method: eyepiece 10.times., objective lens
10.times..
[0072] The test conditions for liquid chromatography involved in
the present invention are: chromatographic column: Ultimate LP-C18
(Welch Materials), 4.6.times.250 mm, 5 .mu.m; phase A: 5 mM
monopotassium phosphate, the pH is adjusted to 2.2 with phosphoric
acid; phase B: pure acetonitrile; detection wavelength: 251 nm;
flow rate: 1.0 ml/min; injection volume: 10 .mu.l; column
temperature: 30.degree. C., the conditions for liquid
chromatographyare shown in Table 5:
TABLE-US-00005 TABLE 5 t (min) A(%) B(%) 0.0 min 93 7% 2.0 min 93
7% 15.0 min 85 15% 30.0 min 75 25% 31.0 min 70 30% 40.0 min 70 30%
40.1 min 93 7% 59.0 min 93 7%
[0073] It should be emphasized that the meaning or the intended
protection scope of the numerical values or numerical endpoints
involved in the technical solutions of the present invention are
not limited to the numbers themselves, and those skilled in the art
should understand that they include those allowable ranges of
errors that have been widely accepted in the art, such as
experimental errors, measurement errors, statistical errors and
random errors etc., and the ranges of these errors are all included
in the scope of the present invention.
[0074] In addition, the present invention also provides pictures of
the crystal habits of pyrroloquinoline quinone sodium salt under
the microscope. As shown in FIG. 17, wherein the crystal habit of
the crystal form I of pyrroloquinoline quinone disodium salt is
rhombohedral, the crystal form II is prepared by drying crystal
form I and the crystal habit does not change, the crystal habit of
crystal form IV is consistent with that of crystal form I. From the
pictures, it can be seen that the crystal habit of crystal form I
is regular, and the crystal form I has good solid fluidity, is easy
to be filtered and dried. In addition, the crystals obtained by
crystallization have high purity, poor hygroscopicity, and good
stability and are easy to be stored.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] FIG. 1 is an X-ray powder diffraction pattern of crystal
form I of pyrroloquinoline quinone disodium salt obtained in
Example 1.
[0076] FIG. 2 is an infrared absorption spectrum of crystal form I
of pyrroloquinoline quinone disodium salt obtained in Example
1.
[0077] FIG. 3 is a DSC thermogram of crystal form I of
pyrroloquinoline quinone disodium salt obtained in Example 1.
[0078] FIG. 4 is a TGA thermogram of crystal form I of
pyrroloquinoline quinone disodium salt obtained in Example 1.
[0079] FIG. 5 is an X-ray powder diffraction pattern of crystal
form II of pyrroloquinoline quinone disodium salt obtained in
Example 9.
[0080] FIG. 6 is an infrared absorption spectrum of crystal form II
of pyrroloquinoline quinone disodium salt obtained in Example
9.
[0081] FIG. 7 is a DSC thermogram of crystal form II of
pyrroloquinoline quinone disodium salt obtained in Example 9.
[0082] FIG. 8 is a TGA thermogram of crystal form II of
pyrroloquinoline quinone disodium salt obtained in Example 9.
[0083] FIG. 9 is an X-ray powder diffraction pattern of crystal
form III of pyrroloquinoline quinone disodium salt obtained in
Example 11.
[0084] FIG. 10 is an infrared absorption spectrum of crystal form
III of pyrroloquinoline quinone disodium salt obtained in Example
11.
[0085] FIG. 11 is a DSC thermogram of crystal form III of
pyrroloquinoline quinone disodium salt obtained in Example 11.
[0086] FIG. 12 is a TGA thermogram of crystal form III of
pyrroloquinoline quinone disodium salt obtained in Example 11.
[0087] FIG. 13 is an X-ray powder diffraction pattern of crystal
form IV of pyrroloquinoline quinone monosodium salt obtained in
Example 14.
[0088] FIG. 14 is an infrared absorption spectrum of crystal form
IV of pyrroloquinoline quinone monosodium salt obtained in Example
14.
[0089] FIG. 15 is a DSC thermogram of crystal form IV of
pyrroloquinoline quinone monosodium salt obtained in Example
14.
[0090] FIG. 16 is a TGA thermogram of crystal form IV of
pyrroloquinoline quinone monosodium salt obtained in Example
14.
[0091] FIG. 17 shows pictures of crystal habits of pyrroloquinoline
quinone sodium salts.
EMBODIMENTS
[0092] The following examples further illustrate the present
invention, however, they do not constitute a limitation on the
scope of the present invention.
[0093] The crude pyrroloquinoline quinone used in the present
invention is pyrroloquinoline quinone trisodium salt, which can be
prepared by using conventional methods in the art: for example, the
crude pyrroloquinoline quinone can be prepared by the methods in
the patent document CN101228963B or the document J. Am. Chem. Soc.,
1981, 103, 5599-5600.
[0094] Preparation of pyrroloquinoline quinone trisodium salt
solution in Example 1 and Example 14: a pyrroloquinoline quinone
fermentation broth was prepared by the method of the Japanese
Patent No. 2751183, the pH of the fermentation broth was adjusted
to 9-10, followed by column treatment (the sample was added to a
silica gel column, silica gel 200-300 mesh, alcohol-soluble
impurities were eluted with ethanol, and then the material was
eluted with water, the purified sample solution was collected), the
resulting solution was pyrroloquinoline quinone trisodium salt
solution.
EXAMPLES
Example 1
[0095] The pyrroloquinoline quinone trisodium salt solution 100 g
(HPLC purity >98%, concentration 0.7%) was heated up to
40.degree. C., stirring was continued for 30 min, the pH was
adjusted to 1.0-2.0; filtered to give a clear filtrate, the
temperature of the filtrate was decreased to 25.degree. C. with a
rate of 10.degree. C./h and the filtrate was crystallized under
stirring at 25.degree. C. for 12 h, the pH was adjusted to 3.0-4.0;
stirred, filtered, dried at 25.degree. C. under vacuum to give 0.45
g crystals, purity was 99.1% by HPLC, X-ray powder diffraction
pattern showed a new crystal form.
[0096] The X-ray powder diffraction pattern, the infrared
absorption spectrum, DSC thermogram and TGA thermogram of the
crystal form are detailed in FIGS. 1-4, the crystal form is named
as crystal form I of pyrroloquinoline quinone disodium salt in the
present invention.
Example 2
[0097] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was increased to
60.degree. C., stirring was continued for 30 min, dissolved;
filtered, the pH was adjusted to 1.0-2.0; filtered to give a clear
filtrate, the temperature of the filtrate was decreased to
25.degree. C. with a rate of 10.degree. C./h and the filtrate was
crystallized under stirring at 25.degree. C. for 48 h, the pH was
adjusted to 3.0-4.0; stirred, filtered, dried at 25.degree. C.
under vacuum to give 0.62 g crystals, purity was 98.8% by HPLC,
X-ray powder diffraction pattern showed crystal form I.
Example 3
[0098] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was increased to
40.degree. C., stirring was continued for 30 min, dissolved;
filtered, the temperature was decreased to 15.degree. C., the pH
was adjusted to 1.0-2.0; the temperature was increased to
45.degree. C. and the filtrate was crystallized under stirring at
45.degree. C. for 12 h, the pH was adjusted to 3.0-4.0; stirred,
filtered, dried at 25.degree. C. under vacuum to give 0.61 g
crystals, purity was 99.2% by HPLC, X-ray powder diffraction
pattern showed crystal form I.
Example 4
[0099] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was decreased to
15.degree. C., the pH was adjusted to 1.0-2.0; the solution was
stirred for 12 h, the pH was adjusted to 3.0-4.0; stirred,
filtered, dried at 30.degree. C. under vacuum to give 0.61 g
crystals, purity was 99.0% by HPLC, X-ray powder diffraction
pattern showed crystal form I.
Example 5
[0100] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in a mixed solvent of water (100 mL) and ethanol (100
mL), the temperature was increased to 50.degree. C., stirring was
continued for 30 min, dissolved; filtered, the temperature was
decreased to 15.degree. C., the pH was adjusted to 1.0-2.0; the
temperature was increased to 45.degree. C. and the filtrate was
crystallized under stirring at 45.degree. C. for 12 h, the pH was
adjusted to 3.0-4.0; stirred, filtered, dried at 25.degree. C.
under vacuum to give 0.80 g crystals, purity was 99.2% by HPLC,
X-ray powder diffraction pattern showed crystal form I.
Example 6
[0101] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in a mixed solvent of water (100 mL) and ethanol (300
mL), the temperature was increased to 30.degree. C., the pH was
adjusted to 1.0-2.0; stirred for 12, the pH was adjusted to
3.0-4.0; stirred, filtered, dried at 45.degree. C. under vacuum to
give 0.85 g crystals, purity was 99.1% by HPLC, X-ray powder
diffraction pattern showed crystal form I.
Example 7
[0102] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in a mixed solvent of water (100 mL) and ethanol (10
mL), the temperature was decreased to 15.degree. C., the pH was
adjusted to 1.0-2.0; stirred for 12, the pH was adjusted to
3.0-4.0; stirred, filtered, dried at 35.degree. C. under vacuum to
give 0.75 g crystals, purity was 98.7% by HPLC, X-ray powder
diffraction pattern showed crystal form I.
Example 8
[0103] The crude pyrroloquinoline quinone 1 Kg (HPLC purity
>98%) was dissolved in a mixed solvent of water (100 L) and
ethanol (100 L), the temperature was increased to 50.degree. C.,
stirring was continued for 30 min, dissolved; filtered, the
temperature was decreased to 15.degree. C., the pH was adjusted to
1.0-2.0; the temperature was increased to 45.degree. C. and the
filtrate was crystallized under stirring at 45.degree. C. for 12 h,
the pH was adjusted to 3.0-4.0; stirred, filtered, dried at
25.degree. C. under vacuum to give 800 g crystals, purity was 99.1%
by HPLC, X-ray powder diffraction pattern showed crystal form
I.
[0104] The X-ray powder diffraction patterns of the products
obtained in Examples 2 to 8 are the same as that in Example 1 and
will not be repeatedly shown here.
Example 9
[0105] The crystal form I of pyrroloquinoline quinone disodium salt
of Example 1 was dried at 60.degree. C. for 8 hours to obtain a new
crystal form. The X-ray powder diffraction pattern, the infrared
absorption spectrum, DSC thermogram and TGA thermogram of the
crystal form are detailed in FIGS. 5-9, the crystal form is named
as crystal form II of pyrroloquinoline quinone disodium salt in the
present invention.
Example 10
[0106] The crystal form I of pyrroloquinoline quinone disodium salt
of Example 2 was dried at 30.degree. C. for 8 hours to obtain the
crystal form II of pyrroloquinoline quinone disodium salt.
[0107] The X-ray powder diffraction pattern of the product obtained
in Example 10 is the same as that in Example 9 and will not be
repeatedly shown here.
Example 11
[0108] The crude pyrroloquinoline quinone 100 g (HPLC purity
>98%) was dissolved in a mixed solvent of water (10 L) and
ethanol (10 L), the temperature was increased to 50.degree. C.,
stirring was continued for 30 min, dissolved; filtered, the
temperature was decreased to 10.degree. C., the pH was adjusted to
3.0-4.0; stirred, filtered, dried at 25.degree. C. under vacuum to
give 900 g crystals, purity was 98.7% by HPLC, X-ray powder
diffraction pattern showed a new crystal form. The X-ray powder
diffraction pattern, the infrared absorption spectrum, DSC
thermogram and TGA thermogram of the crystal form are detailed in
FIGS. 9-12, the crystal form is named as crystal form III of
pyrroloquinoline quinone disodium salt in the present
invention.
Example 12
[0109] The crude pyrroloquinoline quinone 100 g (HPLC purity
>98%) was dissolved in a mixed solvent of water (10 L) and
ethanol (30 L), the temperature was increased to 50.degree. C.,
stirring was continued for 30 min, dissolved; filtered, the
temperature was decreased to 20.degree. C., the pH was adjusted to
3.0-4.0; stirred, filtered, dried at 25.degree. C. under vacuum to
give 920 g crystals, purity was 98.7% by HPLC, X-ray powder
diffraction pattern showed crystal form III.
Example 13
[0110] The crude pyrroloquinoline quinone 100 g (HPLC purity
>98%) was dissolved in a mixed solvent of water (10 L) and
ethanol (20 L), the temperature was increased to 50.degree. C.,
stirring was continued for 30 min, dissolved; filtered, the
temperature was decreased to 0.degree. C., the pH was adjusted to
3.0-4.0; stirred, filtered, dried at 25.degree. C. under vacuum to
give 930 g crystals, purity was 98.7% by HPLC, X-ray powder
diffraction pattern showed crystal form III.
Example 14
[0111] The pyrroloquinoline quinone trisodium salt solution 100 g
(HPLC purity >98%, concentration 0.7%) was heated up to
40.degree. C., stirring was continued for 30 min, the pH was
adjusted to 1.0-2.0; filtered to give a clear filtrate, the
temperature of the filtrate was decreased to 25.degree. C. with the
rate of 10.degree. C./h, and the filtrate was crystallized under
stirring at 25.degree. C. for 12 h, filtered, dried at 25.degree.
C. under vacuum to give 0.9 g crystals, purity was 99.4% by HPLC,
X-ray powder diffraction pattern showed a new crystal form.
[0112] The X-ray powder diffraction pattern, the infrared
absorption spectrum, DSC thermogram and TGA thermogram of the
crystal form are detailed in FIGS. 13-16, the crystal form is named
as crystal form IV of pyrroloquinoline quinone monosodium salt in
the present invention.
Example 15
[0113] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was increased to
60.degree. C., stirring was continued for 30 min, dissolved;
filtered, the pH was adjusted to 1.0-2.0; filtered to give a clear
filtrate, the temperature of the filtrate was decreased to
25.degree. C. with the rate of 10.degree. C./h, and the filtrate
was crystallized under stirring at 25.degree. C. for 48 h,
filtered, dried at 25.degree. C. under vacuum to give 0.72 g
crystals, purity was 99.1% by HPLC, X-ray powder diffraction
pattern showed crystal form IV.
Example 16
[0114] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was increased to
40.degree. C., stirring was continued for 30 min, dissolved;
filtered, the temperature was decreased to 15.degree. C., the pH
was adjusted to 1.0-2.0; stirred for 12 h, filtered, dried at
25.degree. C. under vacuum to give 0.71 g crystals, purity was
99.2% by HPLC, X-ray powder diffraction pattern showed crystal form
IV.
Example 17
[0115] The crude pyrroloquinoline quinone 1 g (HPLC purity >98%)
was dissolved in 100 mL of water, the temperature was decreased to
15.degree. C., the pH was adjusted to 1.0-2.0; stirred for 12 h,
filtered, dried at 30.degree. C. under vacuum to give 0.88 g
crystals, purity was 99.0% by HPLC, X-ray powder diffraction
pattern showed crystal form IV.
[0116] The X-ray powder diffraction patterns of the products
obtained in Examples 15 to 17 are the same as that in Example 14
and will not be repeatedly shown here.
Example 18
[0117] Hygroscopicity test. Test Conditions: watch glasses were
placed in the environment at the temperature of 25.degree. C. and
the humidity of 75% for 24 h, then for each of the following
samples, 1 g was weighed, and the weighted samples were quickly
placed in the environment at the temperature of 25.degree. C. and
the humidity of 75% for 24 h to absorb moisture sufficiently. The
results are as follows:
TABLE-US-00006 Weight before Weight after Rate of absorbing
absorbing moisture Crystal form moisture moisture absorption
Crystal form I 1.0050 g 1.0050 g 0% Crystal form II 1.0062 g 1.0092
g 0.30% Crystal form III 1.0034 g 1.0034 g 0% Crystal form IV
1.0025 g 1.0025 g 0% Crystal form of the 1.0031 g 1.0117 g 0.85%
disodium salt in CN201080031945
[0118] From the above experimental data, it can be seen that the
crystal form I, the crystal form III and the crystal form IV are
not hygroscopic and have good stabilities, followed by the crystal
form II, and the crystal form in CN201080031945 has the strongest
hygroscopicity. Therefore, the new crystal forms developed by the
present invention are not easy to exchange material with the
environment and can maintain good stabilities.
[0119] In addition, from the pictures of crystal habits in FIG. 17,
it can be seen that the crystal form I, the crystal form II and the
crystal form IV of the present invention are rhombohedral, the
crystal form III is needle-like, the crystal form I, the crystal
form II, the crystal form III and the crystal form IV have regular
crystal habits, they are easy to be filtered and washed, can
effectively reduce the amount of residual solution in the solid,
effectively improve the purity of the products, reduce solvent
residues, they are conducive to drying and have small specific
surface area per unit volume and low surface energy, and the
contact surfaces of the crystals with the environment are small,
which are conducive to material stabilities. In addition, the
crystal form I and the crystal form II of the present invention can
be prepared without using organic solvents, thereby effectively
avoiding the solvent residues in the samples, reducing the
production cost and reducing the solvent recovery cost, and the
process is more environment-friendly.
[0120] In summary, through an extensive study, the inventors of the
present invention found the new crystal forms of pyrroloquinoline
quinone disodium salt of the present invention, they have good
solubilities, simple crystallization process, easy operation, low
pollution, and industrialized production can be achieved. In
addition, the drugs in the crystal forms of the present invention
have the advantages of high product purities, excellent physical
and chemical properties, good chemical stabilities and can be
reproduced through processing (filtering, drying, dissolving and
tabletting).
* * * * *