U.S. patent application number 13/563767 was filed with the patent office on 2012-11-22 for polymorphs.
This patent application is currently assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG. Invention is credited to Dirk KEMMER, Peter KOHLBAUER, Thomas NICOLA, Martin RENZ, Peter SIEGER.
Application Number | 20120296091 13/563767 |
Document ID | / |
Family ID | 38335646 |
Filed Date | 2012-11-22 |
United States Patent
Application |
20120296091 |
Kind Code |
A1 |
SIEGER; Peter ; et
al. |
November 22, 2012 |
POLYMORPHS
Abstract
The invention relates to polymorphous crystal modifications of a
DPP-IV inhibitor, the preparation thereof and the use thereof for
preparing a medicament.
Inventors: |
SIEGER; Peter;
(Mittelbiberach, DE) ; KEMMER; Dirk; (Guldental,
DE) ; KOHLBAUER; Peter; (Biberach an der Riss,
DE) ; NICOLA; Thomas; (Ingelheim am Rhein, DE)
; RENZ; Martin; (Eberhardzell-Dietenwengen, DE) |
Assignee: |
BOEHRINGER INGELHEIM PHARMA GMBH
& CO. KG
Ingelheim am Rhein
DE
|
Family ID: |
38335646 |
Appl. No.: |
13/563767 |
Filed: |
August 1, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11744700 |
May 4, 2007 |
|
|
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13563767 |
|
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Current U.S.
Class: |
544/268 |
Current CPC
Class: |
A61P 3/00 20180101; C07B
2200/13 20130101; C07D 473/06 20130101; A61P 19/00 20180101; A61P
29/00 20180101; A61P 19/02 20180101; C07D 473/04 20130101; A61P
3/04 20180101; A61P 43/00 20180101; A61P 3/08 20180101; A61P 3/10
20180101; A61P 37/06 20180101; A61P 19/10 20180101 |
Class at
Publication: |
544/268 |
International
Class: |
C07D 473/04 20060101
C07D473/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2006 |
EP |
06009202 |
Claims
1. An isolated form of an anhydrous polymorph A of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, characterised in that it melts at
206.+-.3.degree. C., and further characterised in that it exhibits
an X-ray powder diagram having inter alia characteristic reflexes
at the following d values: 11.59 .ANG., 7.60 .ANG., 7.15 .ANG.,
3.86 .ANG., 3.54 .ANG. and 3.47.
2. (canceled)
3. An isolated form of an anhydrous polymorph B of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, characterised in that it exhibits an
X-ray powder diagram having inter alia characteristic reflexes at
the following d values: 11.25 .ANG., 9.32 .ANG., 7.46 .ANG., 6.98
.ANG. and 3.77 .ANG..
4-13. (canceled)
14. The isolated form of polymorph A of claim 1, further
characterised in that the reflex at 11.59 .ANG. in the X-ray powder
diagram has a relative intensity of 100% and further characterized
in that the X-ray powder diagram exhibits no reflexes having a
relative intensity of 1% or more at the following d values: 11.25
.ANG., 9.32 .ANG., 7.46 .ANG., and 6.98 .ANG..
15. The isolated form of polymorph B of claim 3, further
characterised in that the reflex at 11.3 .ANG. in the X-ray powder
diagram has a relative intensity of 100% and further characterized
in that the X-ray powder diagram exhibits no reflexes having a
relative intensity of 1% or more at the following d values: 11.59
.ANG., 7.60 .ANG., and 7.15 .ANG..
16. An isolated form of an anhydrous polymorph B of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine according to claim 3, further
characterised in that at a temperature of 10-40.degree. C. it
transforms reversibly into the polymorph A, said polymorph A
characterised in that it melts at 206.+-.3.degree. C., and further
characterised in that it exhibits an X-ray powder diagram having
inter alia characteristic reflexes at the following d values: 11.59
.ANG., 7.60 .ANG., 7.15 .ANG., 3.86 .ANG., 3.54 .ANG. and 3.47.
17. Anhydrous polymorph A of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, said polymorph A characterised in
that it melts at 206.+-.3.degree. C., and further characterised in
that it exhibits an X-ray powder diagram having inter alia
characteristic reflexes at the following d values: 11.59 .ANG.,
7.60 .ANG., 7.15 .ANG., 3.86 .ANG., 3.54 .ANG. and 3.47, unmixed
with polymorph B, said polymorph B characterised in that it
exhibits an X-ray powder diagram having inter alia characteristic
reflexes at the following d values: 11.25 .ANG., 9.32 .ANG., 7.46
.ANG., 6.98 .ANG. and 3.77 .ANG..
18. Anhydrous polymorph B of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, said polymorph B characterised in
that at a temperature of 10-40.degree. C. it transforms reversibly
into the polymorph A, and further characterised in that it exhibits
an X-ray powder diagram having inter alia characteristic reflexes
at the following d values: 11.25 .ANG., 9.32 .ANG., 7.46 .ANG.,
6.98 .ANG. and 3.77 .ANG., unmixed with polymorph A, said polymorph
A characterised in that it exhibits an X-ray powder diagram having
inter alia characteristic reflexes at the following d values: 11.59
.ANG., 7.60 .ANG., 7.15 .ANG., 3.86 .ANG., 3.54 .ANG. and 3.47.
19. An isolated form of an anhydrous polymorph A of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, characterised by its lattice
metrics: TABLE-US-00006 Symmetry: monocline spatial group: P a:
16.16(2) .ANG. b: 17.02(1) .ANG. c: 18.18(2) .ANG. .beta.:
100.95(6).degree. cell volume: .sup. 4907(11) .ANG..sup.3
20. An isolated form of an anhydrous polymorph B of the compound
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, characterised by its lattice
metrics: TABLE-US-00007 Symmetry: monocline spatial group:
P2.sub.1/c (# 14) a: 15.23(1) .ANG. b: 16.94(1) .ANG. c: 18.79(1)
.ANG. .beta.: 95.6(2).degree. cell volume: .sup. 4823(3)
.ANG..sup.3
Description
[0001] This Application claims priority of EP 06 009 202, which is
hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to polymorphous crystal modifications
of a DPP-IV inhibitor, the preparation thereof and the use thereof
for preparing a medicament.
[0004] 2. Description of the Prior Art
[0005] The enzyme DPP-IV, also known by the name CD26, is a serine
protease which promotes the cleaving of dipeptides in proteins with
a proline or alanine group at the N-terminal end. DPP-IV inhibitors
thereby influence the plasma level of bioactive peptides including
the peptide GLP-1. Compounds of this type are useful for the
prevention or treatment of illnesses or conditions which are
associated with an increased DPP-IV activity or which can be
prevented or alleviated by reducing the DPP-IV activity,
particularly type I or type II diabetes mellitus, prediabetes, or
reduced glucose tolerance.
[0006] WO 2004/018468 describes DPP-IV inhibitors with valuable
pharmacological properties. One example of the inhibitors disclosed
therein is
1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-am-
ino-piperidin-1-yl)-xanthine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 shows the thermoanalysis of the anhydrous form
A/B.
[0008] FIG. 2 shows a cyclic DSC diagram, in which the phase
transition from -40.degree. C. to 120.degree. C. and vice versa has
been run through a total of 3 times.
[0009] FIG. 3 shows an X-ray powder diagram of the anhydrous form
A.
[0010] FIG. 4 shows an X-ray powder diagram of the anhydrous form
B.
[0011] FIG. 5 shows an X-ray powder diagram of polymorph C.
[0012] FIG. 6 shows the thermoanalysis of form C.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Within the scope of the present invention it has been found
that
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine may take on various polymorphous
crystal modifications and that the compound prepared in WO
2004/018468 is present at ambient temperature as a mixture of two
enantiotropic polymorphs. The temperature at which the two
polymorphs transform into one another is 25.+-.15.degree. C. (see
FIGS. 1 and 2).
[0014] The pure high temperature form (polymorph A), which can be
obtained by heating the mixture to temperatures >40.degree. C.,
melts at 206.+-.3.degree. C. In the X-ray powder diagram (see FIG.
3) this form shows characteristic reflexes at the following d
values: 11.49 .ANG., 7.60 .ANG., 7.15 .ANG., 3.86 .ANG., 3.54 .ANG.
and 3.47 .ANG. (cf. also Table 1 and 2).
[0015] Anhydrous polymorph A may be prepared by [0016] (a)
refluxing
1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-am-
ino-piperidin-1-yl)-xanthine in absolute ethanol and optionally
filtering the mixture, [0017] (b) cooling the hot solution or the
hot filtrate until crystallisation sets in, [0018] (c) diluting
with a solvent such as tert.-butylmethylether, [0019] (d) suction
filtering the solvent mixture and [0020] (e) drying the polymorph A
at 45.degree. C. in vacuo.
[0021] The low temperature form (polymorph B) is obtained by
cooling to temperatures <10.degree. C. In the X-ray powder
diagram (see FIG. 4) this form shows characteristic reflexes at the
following d values: 11.25 .ANG., 9.32 .ANG., 7.46 .ANG., 6.98 .ANG.
and 3.77 .ANG. (cf. also Table 3 and 4).
[0022] Anhydrous polymorph B may be prepared by [0023] (a)
dissolving
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine in absolute ethanol and refluxing and
optionally filtering the mixture, [0024] (b) cooling the hot
solution or the hot filtrate for crystallisation to a temperature
below 10.degree. C., [0025] (c) diluting with a solvent such as
tert.-butylmethylether, [0026] (d) suction filtering the solvent
mixture and [0027] (e) drying the polymorph at a temperature below
10.degree. C. in vacuo.
[0028] Another polymorph (polymorph C) shows characteristic
reflexes in the X-ray powder diagram (see FIG. 5) at the following
d values: 12.90 .ANG., 11.10 .ANG., 6.44 .ANG., 3.93 .ANG. and 3.74
.ANG. (cf. also Table 5).
[0029] Polymorph C is obtained if [0030] (a)
1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-am-
ino-piperidin-1-yl)-xanthine is dissolved in methanol and refluxed
and optionally filtered in the presence of activated charcoal,
[0031] (b) the methanolic solution is cooled to a temperature of
40-60.degree. C., [0032] (c) a solvent such as
tert.-butylmethylether or diisopropylether is added, [0033] (d) the
resulting suspension is first of all cooled slowly to 15-25.degree.
C. and then later to 0-5.degree. C., [0034] (e) the crystals formed
are suction filtered and washed again with tert.-butylmethylether
or diisopropylether and [0035] (f) the crystals thus obtained are
dried at a temperature of 70.degree. C. in the vacuum dryer.
[0036] Another polymorph (polymorph D) melts at 150.+-.3.degree. C.
This polymorph is obtained if polymorph C is heated to a
temperature of 30-100.degree. C. or dried at this temperature.
[0037] Finally, there is also polymorph E, which melts at a
temperature of 175.+-.3.degree. C. Anhydrous polymorph E is formed
if polymorph D is melted. On further heating, polymorph E
crystallises out of the melt.
[0038] The polymorphs thus obtained may be used in the same way as
the mixture of the two polymorphs A and B described in WO
2004/018468 for preparing a pharmaceutical composition which is
suitable for treating patients with type I and type II diabetes
mellitus, prediabetes or reduced glucose tolerance, with rheumatoid
arthritis, obesity, or calcitonin-induced osteoporosis, as well as
patients in whom an allograft transplant has been carried out.
These medicaments contain in addition to one or more inert carriers
at least 0.1% to 0.5%, preferably at least 0.5% to 1.5% and
particularly preferably at least 1% to 3% of one of the polymorphs
A, B, or C.
[0039] The following Examples are intended to illustrate the
invention in more detail.
Example 1
Crystallisation of Polymorph A
[0040] Crude
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine is refluxed with 5 times as much
absolute ethanol and the hot solution is filtered clear through
activated charcoal. After the filtrate has been cooled to
20.degree. C. and crystallisation has set in, the solution is
diluted to double the volume with tert.-butylmethylether. Then the
suspension is cooled to 2.degree. C., stirred for 2 hours, suction
filtered and dried in the vacuum dryer at 45.degree. C.
[0041] FIG. 1 shows the thermoanalysis of the anhydrous form
A/B.
[0042] Plymorph A melts at 206.+-.3.degree. C. In the DSC diagram
another slightly endothermic signal can be seen at approx.
25.degree. C. This is a fully reversible solid-solid phase
transition between the two enantiotropic crystal modifications A
and B. The form A is the thermodynamically stable modification
above this transformation temperature, w| form B is the
thermodynamically stable modification below this transformation
temperature.
[0043] FIG. 2 shows a cyclic DSC diagram, in which the phase
transition from -40.degree. C. to 120.degree. C. and vice versa has
been run through a total of 3 times. During heating, the phase
transition is observed as an endothermic signal and,
correspondingly, during cooling it is observed as an exothermic
signal. During the first heating cycle the phase transition may
also be observed as an endothermic double signal or as a very broad
signal while in all the other cycles the signal occurs as a very
sharp endothermic or exothermic signal, depending on whether
heating or cooling is taking place.
[0044] FIG. 3 shows an X-ray powder diagram of the anhydrous form
A
TABLE-US-00001 TABLE 1 Labelled X-ray reflexes up to 30
.degree.2.THETA. with intensities (standardised) for the anhydrous
polymorph A 2.THETA. intensity d.sub.hkl labelling d.sub.exp-calc
[.degree.] I/I.sub.o [%] [.ANG.] h k l [.ANG.] 5.56 1 15.89 1 0 0
-0.008 7.18 32 12.31 0 1 1 0.005 7.62 100 11.59 1 1 0 0.007 8.49 20
10.41 -1 1 1 0.002 9.91 24 8.92 0 0 2 0.003 10.41 18 8.49 0 2 0
0.024 11.18 24 7.91 2 0 0 0.038 11.63 41 7.60 -1 1 2 0.003 12.37 59
7.15 -1 2 1 -0.003 13.19 6 6.71 1 2 1 -0.014 13.45 3 6.58 -2 0 2
0.007 14.05 6 6.30 2 1 1 0.011 14.38 6 6.16 0 2 2 0.003 14.71 10
6.02 -1 2 2 -0.008 15.26 13 5.80 2 2 0 0.001 15.76 10 5.62 -1 1 3
0.008 16.09 1 5.51 1 2 2 -0.010 16.32 1 5.43 2 0 2 0.035 16.69 4
5.31 2 2 1 -0.007 17.03 3 5.20 -1 3 1 0.026 17.63 6 5.03 1 3 1
0.006 18.17 5 4.88 -1 2 3 -0.004 18.78 7 4.72 -1 3 2 -0.014 19.30 1
4.60 -2 3 1 -0.019 19.61 2 4.52 -3 2 1 0.036 19.86 20 4.47 -2 2 3
0.040 20.29 10 4.37 2 0 3 0.019 20.57 4 4.31 0 1 4 0.006 21.12 1
4.20 3 0 2 0.048 21.57 12 4.12 -2 1 4 0.028 22.46 10 3.96 1 4 1
0.035 23.03 35 3.86 4 1 0 0.022 23.39 21 3.80 -1 4 2 0.019 24.08 2
3.69 -3 1 4 -0.006 24.51 1 3.63 -4 0 3 0.036 24.91 10 3.57 -2 4 2
0.003 25.14 39 3.54 3 1 3 0.043 25.69 36 3.47 -3 3 3 0.041 26.68 3
3.34 0 5 1 0.035 26.90 2 3.31 3 4 0 0.027 27.10 2 3.29 0 2 5 0.030
27.42 3 3.25 4 3 0 0.006 28.19 2 3.16 -1 5 2 -0.035 28.54 2 3.12 3
0 4 0.047 28.94 11 3.08 0 4 4 -0.036 29.18 5 3.06 -4 3 3 0.017
29.50 4 3.03 -1 0 6 0.041 30.18 7 2.96 -1 5 3 -0.042
TABLE-US-00002 TABLE 2 Lattice metrics of the anhydrous form A
Symmetry: monocline spatial group: P a: 16.16(2) .ANG. b: 17.02(1)
.ANG. c: 18.18(2) .ANG. .beta.: 100.95(6).degree. cell volume:
.sup. 4907(11) .ANG..sup.3
Example 2
Crystallisation of Polymorph B
[0045] Polymorph B is obtained by cooling form A from Example 1 to
temperatures <10.degree. C.
[0046] FIG. 4 shows an X-ray powder diagram of the anhydrous form
B
TABLE-US-00003 TABLE 3 Labelled X-ray reflexes up to 30
.degree.2.THETA. with intensities (standardised) for the anhydrous
form B 2.THETA. intensity d.sub.hkl labelling d.sub.exp-calc
[.degree.] I/I.sub.o [%] [.ANG.] h k l [.ANG.] 5.82 3 15.17 1 0 0
-0.007 7.04 33 12.55 0 1 1 0.001 7.82 100 11.3 1 1 0 -0.004 8.84 11
10 -1 1 1 0.001 9.44 40 9.36 1 1 1 0.011 10.62 14 8.32 -1 0 2 0.013
10.79 24 8.19 0 1 2 -0.005 11.82 39 7.48 -1 1 2 -0.003 12.64 53 7
-1 2 1 -0.009 13.07 11 6.77 1 2 1 -0.006 13.24 6 6.68 -2 1 1 0.004
14.04 16 6.3 2 1 1 0.003 15.23 17 5.81 -2 1 2 0.003 15.70 22 5.64 2
2 0 0.016 16.38 2 5.41 0 3 1 -0.010 16.73 6 5.3 2 2 1 0.008 17.67 8
5.02 0 2 3 0.014 18.16 3 4.88 -1 2 3 0.005 18.33 9 4.84 3 1 0 0.016
18.48 10 4.8 -3 1 1 -0.003 18.97 15 4.68 0 0 4 -0.001 19.56 6 4.54
1 3 2 0.013 20.00 17 4.44 2 1 3 0.000 20.42 9 4.35 1 0 4 0.009
20.76 4 4.27 3 0 2 -0.014 20.97 4 4.23 0 4 0 0.010 21.07 5 4.21 1 1
4 -0.009 21.22 12 4.18 0 3 3 0.001 21.40 7 4.15 3 2 1 0.004 21.66 4
4.1 -1 3 3 0.018 21.98 7 4.04 2 2 3 -0.003 22.16 10 4.01 -3 1 3
0.008 22.97 3 3.87 1 2 4 -0.006 23.58 43 3.77 -2 3 3 -0.003 23.78
15 3.74 -2 2 4 -0.004 24.05 6 3.7 4 1 0 -0.002 24.29 8 3.66 -2 4 1
-0.008 24.46 5 3.64 3 3 1 0.018 24.71 7 3.6 0 3 4 0.001 24.96 23
3.56 2 3 3 -0.001 25.45 12 3.5 -2 4 2 -0.010 25.75 35 3.46 4 2 0
0.011 25.99 4 3.43 3 2 3 0.014 26.15 6 3.41 3 3 2 0.010 26.57 12
3.35 -2 3 4 -0.001 26.82 4 3.32 -3 2 4 0.011 27.20 6 3.28 1 2 5
-0.010 27.43 4 3.25 -2 4 3 -0.003 27.60 3 3.23 -2 2 5 -0.005 28.19
4 3.16 3 4 1 0.010 28.40 15 3.14 0 4 4 -0.013 28.64 12 3.11 0 0 6
0.016 29.18 6 3.06 -4 3 2 0.004 29.42 2 3.03 1 4 4 0.002 29.99 10
2.98 0 5 3 -0.008 30.77 3 2.9 -4 3 3 0.018
TABLE-US-00004 TABLE 4 Lattice metrics of the anhydrous form B
Symmetry: monocline spatial group: P2.sub.1/c (# 14) a: 15.23(1)
.ANG. b: 16.94(1) .ANG. c: 18.79(1) .ANG. .beta.: 95.6(2).degree.
cell volume: .sup. 4823(3) .ANG..sup.3
Example 3
Crystallisation of Polymorph C
[0047] Crude
1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-am-
ino-piperidin-1-yl)-xanthine (26 kg) is refluxed with 157 l
methanol, combined with 1.3 kg of activated charcoal and after 30
minutes' stirring the mixture is filtered and rinsed with 26 l
methanol. 122 l of methanol are distilled off from the filtrate,
then the residue is cooled to 45-55.degree. C. 52 l of
tert.-butylmethylether are added to the residue over 30 minutes.
Then the mixture is stirred for another 60 minutes at 45-55.degree.
C. Crystallisation takes place within this time. A further 78 l
tert. butylmethylether are added to the suspension over 30 minutes
and then it is stirred again for a further 60 minutes at
45-55.degree. C. It is diluted to four times the volume. The
suspension is slowly cooled to 15-25.degree. C. and stirred
overnight at this temperature. After the suspension has been cooled
to 0-5.degree. C. the crystals are suction filtered, washed with 2
batches tert.-butylmethylether and dried at 70.degree. C. in the
vacuum dryer.
[0048] FIG. 5 shows an X-ray powder diagram of polymorph C
TABLE-US-00005 TABLE 5 X-ray reflexes up to 30.degree. 2 .THETA.
with intensities (standardised) for the anhydrous form C 2 .THETA.
d.sub.hkl intensity [.degree.] [.ANG.] I/I.sub.o [%] 3.38 26.16 4
6.85 12.90 100 7.18 12.31 11 7.52 11.74 14 7.96 11.10 36 9.80 9.02
3 11.11 7.96 2 11.58 7.64 3 12.30 7.19 5 13.30 6.65 16 13.75 6.44
26 14.38 6.16 17 14.74 6.01 11 14.95 5.92 10 15.63 5.66 6 16.28
5.44 5 17.81 4.98 10 18.33 4.83 6 18.75 4.73 15 20.51 4.33 8 20.77
4.27 8 21.47 4.14 3 21.96 4.05 4 22.59 3.93 26 23.76 3.74 29 24.68
3.60 6 25.01 3.56 7 25.57 3.48 4 25.96 3.43 4 26.93 3.31 18 27.22
3.27 13 27.92 3.19 10
Example 4
Crystallisation of Polymorph D
[0049] Polymorph D is obtained if polymorph C from Example 3 is
heated to a temperature of 30-100.degree. C. or dried at this
temperature.
Example 5
Crystallisation of Polymorph E
[0050] Anhydrous polymorph E is obtained if polymorph D is melted.
On further heating, polymorph E crystallises out of the melt.
[0051] FIG. 6 shows a thermoanalysis of form C
[0052] In the DSC diagram of form C a whole range of signals can be
observed. The strongest signal is the melting point of the
anhydrous form A at approx. 206.degree. C., which is produced in
the DSC experiment. Before the melting point a number of other
endothermic and exothermic signals can be observed. Thus, for
example, a very broad and weak endothermic signal can be seen
between 30 and 100.degree. C., which correlates with the main loss
of weight in thermogravimetry (TR). A TG/IR coupling experiment
provides the information that only water escapes from the sample in
this temperature range.
[0053] An X-ray powder diagram taken of a sample maintained at a
temperature of 100.degree. C. shows different X-ray reflexes from
the starting material, suggesting that form C is a hydrate phase
with stoichiometry somewhere in the region of a hemihydrate or
monohydrate. The temperature-controlled sample is another anhydrous
modification D, which only stable under anhydrous conditions. The D
form melts at approx. 150.degree. C. Another anhydrous crystal
modification E crystallises from the melt, and when heated further
melts at approx. 175.degree. C. Finally, form A crystallises from
the melt of form E. Form E is also a metastable crystal
modification which occurs only at high temperatures.
* * * * *