U.S. patent application number 13/874851 was filed with the patent office on 2013-09-19 for hcl polymorphs of 3-((2-(dimethylamino)methyl(cyclohex-1-yl))phenol.
This patent application is currently assigned to GRUENENTHAL GmbH. The applicant listed for this patent is GRUENENTHAL GMBH. Invention is credited to Joerg BERGHAUSEN, Susan Margaret DE PAUL, Andreas FISCHER, Michael GRUSS, Wolfgang HELL, Markus KEGEL, Markus VON RAUMER.
Application Number | 20130245125 13/874851 |
Document ID | / |
Family ID | 37101337 |
Filed Date | 2013-09-19 |
United States Patent
Application |
20130245125 |
Kind Code |
A1 |
GRUSS; Michael ; et
al. |
September 19, 2013 |
HCl Polymorphs of
3-((2-(Dimethylamino)methyl(cyclohex-1-yl))phenol
Abstract
A crystalline salt of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]
phenol and hydrogen chloride, preferably in a 1:1 composition,
including various crystalline forms of this salt, processes for
preparing the various crystalline forms of this salt,
pharmaceutical compositions containing the various crystalline
forms of this salt, and the use of this salt as a pharmacologically
active agent in a pharmaceutical composition to treat or inhibit
pain or other disorders or disease states.
Inventors: |
GRUSS; Michael; (Aachen,
DE) ; FISCHER; Andreas; (Huertgenwald, DE) ;
KEGEL; Markus; (Aachen, DE) ; HELL; Wolfgang;
(Aachen, DE) ; VON RAUMER; Markus; (Arlesheim,
CH) ; BERGHAUSEN; Joerg; (Loerrach, DE) ; DE
PAUL; Susan Margaret; (Zuerich, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUENENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUENENTHAL GmbH
Aachen
DE
|
Family ID: |
37101337 |
Appl. No.: |
13/874851 |
Filed: |
May 1, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12627190 |
Nov 30, 2009 |
|
|
|
13874851 |
|
|
|
|
12016506 |
Jan 18, 2008 |
8058476 |
|
|
12627190 |
|
|
|
|
PCT/EP2006/007163 |
Jul 20, 2006 |
|
|
|
12016506 |
|
|
|
|
Current U.S.
Class: |
514/646 ;
564/280 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 29/00 20180101; A61P 25/04 20180101; C07C 213/10 20130101;
C07C 215/64 20130101; C07C 215/66 20130101; C07C 2601/14 20170501;
C07B 2200/13 20130101 |
Class at
Publication: |
514/646 ;
564/280 |
International
Class: |
C07C 215/66 20060101
C07C215/66; C07C 213/10 20060101 C07C213/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 22, 2005 |
DE |
102005034973.0 |
Jul 22, 2005 |
DE |
102005034974.9 |
Claims
1. A crystalline salt of hydrogen chloride and
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol.
2. A crystalline salt according to claim 1, wherein said salt is
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
corresponding to formula (1) ##STR00003##
3. A crystalline salt according to claim 1, wherein said salt is in
the form of a diastereomer or a mixture of enantiomeric
diastereomers wherein the phenol ring and the dimethylaminomethyl
group are in a trans configuration.
4. A crystalline salt according to claim 3, wherein said salt is in
the form of an enantiomer with a (1R,2R) absolute
configuration.
5. A crystalline salt according to claim 1, wherein said salt
exhibits a characteristic X-ray diffraction pattern within the
range from 2.degree. to 35.degree. 2.theta. with characteristic
lines corresponding to the following 2theta values: 11.2 (w), 14.1
(m), 17.1 (w), 19.5 (w), 19.8 (vs), 20.5 (w), 21.5 (m), 24.1 (m),
26.1 (s), 26.8 (w), and 31.3 (m).
6. A crystalline salt according to claim 1, which exhibits the
X-ray diffraction pattern of FIG. 1.
7. A crystalline salt according to claim 1, which exhibits the
Raman spectrum of FIG. 2.
8. A crystalline salt according to claim 1, wherein said salt is
crystalline form III and exhibits a characteristic X-ray
diffraction pattern within the range from 2.degree. to 35.degree.
2.theta. with pronounced characteristic lines corresponding to the
following 2theta values: 6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w),
20.9 (vs), 22.1 (w), 22.5 (w), and 27.8 (w).
9. A crystalline salt according to claim 1, wherein said salt is
crystalline form III and exhibits the X-ray diffraction pattern of
FIG. 5.
10. A crystalline salt according to claim 1, wherein said salt is
crystalline form III and exhibits the Raman spectrum of FIG. 6.
11. A crystalline salt according to claim 1, wherein said salt
exhibits a characteristic X-ray diffraction pattern within the
range from 2.degree. to 35.degree. 2.theta. with pronounced
characteristic lines corresponding to the following 2theta values:
12.0 (m), 13.0 (m), 17.3 (m), 17.7 (m), 19.2 (s), 19.7 (m), 20.2
(m), 21.3 (m), 23.4 (m), 24.2 (m), 24.6 (m), 43.1 (vs), and 44.2
(vs).
12. A crystalline salt according to claim 1, wherein said salt
exhibits the X-ray diffraction pattern of FIG. 7.
13. A crystalline salt according to claim 1, wherein said salt
exhibits the Raman spectrum of FIG. 8.
14. A crystalline salt according to claim 1, wherein said salt is a
hydrate which exhibits a proportion of water of crystallization
within the range from 1% to 10%, relative to the weight of
hydrate.
15. A crystalline salt according to claim 14, wherein the
proportion of water of crystallization lies within the range from
5% to 9%.
16. A crystalline salt according to claim 14, wherein the
proportion of water of crystallization lies within the range from
6% to 8.5%.
17. A crystalline salt according to claim 14, wherein the
proportion of water of crystallization lies within the range from
7% to 8%.
18. A crystalline salt according to claim 1, wherein said salt is
crystalline form V and is a hydrate which exhibits a characteristic
X-ray diffraction pattern within the range from 2.degree. to
35.degree. 20 with pronounced characteristic lines corresponding to
the following 2theta values: 11.4 (m), 12.1 (m), 16.7 (w), 19.2
(m), 19.4 (w), 20.1 (m), 21.1 (m), 22.4 (vs), 24.0 (m), and 31.3
(w).
19. A crystalline salt according to claim 1, wherein said salt is
crystalline form V and exhibits the X-ray diffraction pattern of
FIG. 9.
20. A crystalline salt according to claim 1, wherein said salt is
crystalline form V and exhibits the Raman spectrum of FIG. 10.
21. A process for preparing crystalline form I of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
according to claim 5, said process comprising: a) stirring
crystalline form III of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride and
crystalline form IV or V of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent until complete formation of crystalline form I occurs, or
b) stirring crystalline form II of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride and
crystalline form I of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent until complete formation of crystalline form I occurs.
22. Crystalline form I of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
obtained by the process of claim 21.
23. A process for preparing crystalline form III of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
according to claim 11, said process comprising: a) dissolving
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the form of an ethanol solvate or acetone solvate in a solvent,
stirring the resulting solution and subsequently precipitating
crystalline form III; or b) stirring a suspension of amorphous
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent as a carrier at a temperature between 30.degree. C. and
80.degree. C. until complete formation of crystalline form III
occurs.
24. A process according to claim 23, wherein said solvent in b) is
a solvent that does not form solvates, and said stirring in b) is
effected at a temperature between 35.degree. C. and 50.degree.
C.
25. Crystalline form III of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
obtained by the process of claim 23.
26. A process for preparing crystalline form IV of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
according to claim 11, said process comprising: a) heat treating
crystalline form III of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride at a
temperature between 150.degree. C. and 160.degree. C. until
complete formation of crystalline form IV occurs, or b) stirring a
suspension of amorphous
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent as a carrier at a temperature between 40.degree. C. and
120.degree. C. until complete formation of crystalline form IV
occurs; or c) stirring crystalline form IV of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride and
crystalline form III of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in
a solvent until complete formation of crystalline form IV
occurs.
27. A process according to claim 26, wherein: the heat treatment in
a) is effected at a temperature between 154.degree. C. and
158.degree. C.; or the solvent in b) is a solvent that does not
form solvates, and the heat treatment in b) is effected at a
temperature between 40.degree. C. and 100.degree. C.
28. Crystalline form IV of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
obtained by the process of claim 26.
29. A process for preparing crystalline form V of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
according to claim 18, said process comprising: a) allowing
crystalline form I, II, III or IV of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride to
stand in air, or treating crystalline form I, II, III or IV of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
with water vapor, or b) stirring a suspension of amorphous
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride in
water optionally mixed with at least one solvent as a carrier at a
temperature between 20.degree. C. and 60.degree. C., and
subsequently removing remaining water and solvent.
30. A process according to claim 29, wherein the stirring in b) is
carried out at a temperature between 20.degree. C. and 30.degree.
C.
31. Crystalline form V of
3-[2-(dimethylamino)methyl(cyyclohex-1-yl)]phenol hydrochloride
obtained by the process of claim 29.
32. A pharmaceutical composition comprising a crystalline salt of
3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochloride
according to claim 1 and at least one pharmaceutical carrier or
diluent.
33. A pharmaceutical composition according to claim 32, wherein
said salt is present as crystalline faun I, crystalline form II,
crystalline form III, crystalline form IV, crystalline form V or a
mixture of two or more of crystalline forms I, II, III, IV and
V.
34. A pharmaceutical composition according to claim 32, wherein
said salt is present as crystalline form V.
35. A method of treating pain in a subject in need thereof, said
method comprising administering to said subject an analgesically
effective amount of a crystalline salt according to claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending application
Ser. No. 12/627,190, filed Nov. 30, 2009 which is a continuation of
application Ser. No. 12/016,506, filed Jan. 18, 2008, now U.S. Pat.
No. 8,058,476, which in turn was a continuation of international
patent application no. PCT/EP2006/007163, filed Jul. 20, 2006
designating the United States of America and published in German on
Jan. 25, 2007 as WO 2007/0009794, the entire disclosure of which is
hereby incorporated herein by reference. Priority is claimed based
on Federal Republic of Germany patent application nos. DE 10 2005
034 973.0 and DE 10 2005 034 974.9, both filed Jul. 22, 2005.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a crystalline salt of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol and hydrogen
chloride, preferably in a composition of 1:1, to various
crystalline forms of this salt and also to processes for
preparation thereof, to a pharmaceutical composition, and to the
use of the salt as pharmaceutical active substance in a
medicament.
[0003] 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenols having
analgesic activity are described in published European patent
application no. EP 753,506. In the description it is mentioned that
salts--such as hydrochlorides, for example--can also be prepared
from the free bases of these compounds. But EP 753 506 contains no
references to the fact that these hydrochlorides can be obtained in
the form of a crystalline solid substance.
[0004] It has now surprisingly been found that
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol forms with
hydrogen chloride an addition salt in the form of a crystalline
solid substance, preferably in a composition in the ratio 1:1. It
has furthermore been found that
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl in the form of
crystalline solids form polymorphous forms which can each be
selectively prepared and which are particularly suitable, at least
partly by reason of their stability, as active substance for
formulating pharmaceutical compositions. For example, the
crystalline form II is suitable, by reason of its kinetic
stability, as active substance for formulating pharmaceutical
compositions. Moreover, the crystalline form V is suitable, by
reason of its stability in the presence of water, for example in
the form of atmospheric moisture, as active substance for
formulating pharmaceutical compositions. Furthermore it has been
found that the hydrochloride salts are distinguished by very good
solubility in water. A first subject of the invention is therefore
constituted by crystalline salts of hydrogen chloride with
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol, whereby
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
the following formula (1) is preferred.
##STR00001##
[0005] The compounds of the formula (1) contain a chiral C atom in
the 1-position and 2-position of the cyclohexane ring. The
compounds of the formula (1) encompass all the stereoisomers and
mixtures of stereoisomers. Preferred are diastereomers or mixtures
of enantiomeric diastereomers with trans configuration of the
phenyl ring and of the dimethylaminomethyl group (1R,2R
configuration and 1S,2S configuration, respectively), the
enantiomer with the absolute configuration (1R,2R) being quite
particularly preferred.
[0006] The structure of the (1R,2R) enantiomer of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol is reproduced
below:
##STR00002##
[0007] The invention also relates to a process for preparing
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), the process comprising: [0008] a) dissolving or
suspending 3-[2-(dimethylamino)methyl(cyclohex-1-ye]phenol in a
solvent, or charging
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk, [0009] b)
mixing the solution, the solid substance or the suspension with a
solution of hydrogen chloride, in particular hydrochloric acid,
optionally cooling or heating and holding at a temperature between
-80.degree. C. and 150.degree. C., preferably between -20.degree.
C. and 30.degree. C., particularly preferably between -5.degree. C.
and 5.degree. C., up until the complete formation of a solid
substance, and [0010] c) isolating the compound of the formula
(1).
[0011] Alternatively, of course,
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in solution, in
the form of a suspension, or in bulk may also be introduced into a
solution or gas containing hydrogen chloride.
[0012] The hydrochloric acid in step b) of the process stated above
may, in particular, be present in the form of an aqueous solution
or in the form of a solution in an organic solvent, preferably in a
solvent selected from the group consisting of diethyl ether,
tert.-butylmethyl ether and tetrahydrofuran.
[0013] The invention also relates to a process for preparing
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), the process comprising: [0014] a) dissolving
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in a solvent, or
charging 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol in bulk,
and [0015] b) introducing hydrogen-chloride gas into the solution
or suspension, or passing hydrogen-chloride gas over the solid
substance.
[0016] In the salification process according to the invention, the
compounds of the formula (1) are also obtained in an amorphous
form. Amorphous forms of the compounds of the formula (1) are
obtainable, for example, simply by freeze drying or rapid cooling
of solutions. Amorphous compounds of the formula (1) are not very
stable, and in the presence of moisture tend to form hydrates.
Likewise, amorphous forms of the compounds of the formula (1) in
solvating solvents--such as, for example, acetone, ethanol,
methanol, methyl ethyl ketone, isopropanol, n-propanol and
n-octanol--are suitable for preparing the corresponding solvates.
The amorphous form of the compounds of the formula (1) can likewise
be used for selective preparation of crystalline forms.
[0017] It has been found that the compounds of the formula (1) in
the form of crystalline solids form polymorphous forms which can be
selectively prepared from
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride and
which by reason of their stability are particularly suitable as
active substance for formulating pharmaceutical compositions. The
crystalline form II is preferably suitable, by reason of its
kinetic stability, as active substance for formulating
pharmaceutical compositions. Likewise the crystalline form V, by
reason of its stability in the presence of water, for example in
the form of atmospheric moisture, is preferably suitable as active
substance for formulating pharmaceutical compositions.
[0018] It is known--inter alia, from Z. Jane Li et al. in J. Pharm.
Sci., 1999, Vol. 88(3), pages 337 to 346--that enantiomers yield
identical X-ray diffractograms and Raman spectra, and consequently
form the same polymorphous forms. Polymorphous forms of all
enantiomers are consequently encompassed within the scope of this
invention.
[0019] The invention further relates to a crystalline form of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern within the range from 2.degree. to 35.degree. 2.theta. with
pronounced characteristic signals (peaks), expressed in 2-theta
values: [0020] 11.2 (w), 14.1 (m), 17.1 (w), 19.5 (w), 19.8 (vs),
20.5 (w), 21.5 (m), 24.1 (m), 26.1 (s), 26.8 (w), 31.3 (m);
designated hereinafter as form I.
[0021] The invention further relates to another crystalline form I
of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula
(1), which exhibits a characteristic X-ray diffraction pattern with
the following pronounced reflections.
[0022] The measuring accuracy of the 2theta values lies within the
range of .+-.0.2.
TABLE-US-00001 2Theta Intensity (relative) 9.09 1 10.22 1 11.22 24
12.21 4 13.03 2 13.47 3 14.12 43 14.90 15 16.69 3 17.16 24 18.05 10
18.89 14 19.53 26 19.78 100 20.22 12 20.48 28 21.46 43 22.24 11
22.50 21 22.71 19 24.12 34 26.09 73 26.81 43 27.68 22 28.26 25
28.51 14 29.96 14 31.28 46 32.58 8 33.03 6 34.52 15 35.44 28 35.67
15 36.38 8 37.94 8 38.59 8 39.66 18 40.13 15 40.88 14 41.72 21
42.44 9 43.15 44 44.35 47 45.70 10 46.55 11 47.13 8 47.84 15 48.69
10 49.68 14
[0023] In this application, the abbreviations in brackets signify:
[0024] (vs)=very strong intensity, [0025] (s)=strong intensity,
[0026] (m)=medium intensity,
[0027] (w)=weak intensity, and
[0028] (vw)=very weak intensity.
The abbreviation `sh` in the tables of the Raman spectra signifies
`shoulder`.
[0029] The crystalline form I of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1) exhibits a characteristic Raman spectrum with
characteristic bands, which is described by the following wave
numbers (cm.sup.-1):
TABLE-US-00002 Wave number [cm.sup.-1] Intensity 82 S 107 VS 177 W
251 M 284 VW 346 W 362 VW 423 VW 434 VW 479 VW 533 W 626 VW 634 VW
754 VW 762 W 787 VW 794 VW 823 W 838 W 861 VW 884 VW 936 VW 954 VW
972 VW 1001 VS 1056 W 1070 W 1080 VW 1102 VW 1122 VW 1154 VW 1162
VW 1184 VW 1208 VW 1227 VW 1274 W 1286 W 1293 W 1306 W 1316 W 1335
VW 1350 VW 1367 VW 1439 W 1449 W 1470 W 1584 W 1611 W 2633 VW 2662
VW 2714 VW 2805 VW 2856 M 2901 M 2922 M 2942 M 2957 M 2983 W 3008 W
3017 W 3025 W 3042 W 3051 M 3074 VW 3196 VW
In the tables, wave numbers are stated with a precision of .+-.4
cm.sup.-1.
[0030] The invention further relates to a crystalline form I of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which possesses a characteristic X-ray diffraction
pattern as represented in FIG. 1.
[0031] The invention also relates to a crystalline form I of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which is characterized by a Raman spectrum as
represented in FIG. 2.
[0032] The crystalline form I is thermodynamically the most stable
form at low temperatures up to approximately 40.degree. C. The
crystalline form I in the presence of atmospheric moisture with a
relative air humidity >50% irreversibly forms hydrates of the
crystalline form V. At a relative air humidity >95%, hydrates
result having a proportion of water of crystallization, relative to
the total weight of the hydrate, within the range from 8% to 10%.
In order to avoid the formation of hydrates, the compounds of the
crystalline form I can advantageously be stored in a low-moisture
environment, for example in a vessel over phosphorus pentoxide or
molecular sieve. Likewise, a storage of the crystalline form I
under dry protective gas (for example, nitrogen) is advisable. The
melting-point amounts to approximately 150.degree. C.
[0033] Polymorph I can be prepared in the form of solid powder
having desired mean particle sizes, which, as a rule, lie within
the range from 1 .mu.m to approximately 500 .mu.m. The compound of
the formula (1) forms a further crystalline form II which is
thermodynamically stable at higher temperatures and which is
likewise stable under normal conditions in air and with exclusion
of atmospheric moisture. The crystalline form II is also capable of
being handled in such a way that it can be employed for the
preparation of pharmaceutical compositions.
[0034] The invention further includes a crystalline form of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern within the range from 2.degree. to 35.degree. 2.theta. with
pronounced characteristic lines, expressed in 2theta values: [0035]
11.1 (m), 12.9 (w), 16.1 (m), 17.1 (w), 19.1 (s), 19.6 (w), 19.9
(m), 23.2 (w), 25.8 (w), 26.1 (s), 33.6 (w); designated hereinafter
as form II.
[0036] The invention also includes a crystalline form II of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the
formula (1), which exhibits a characteristic X-ray diffraction
pattern with the following pronounced reflections.
TABLE-US-00003 2Theta Intensity (relative) 11.06 56 11.55 12 12.97
27 13.70 18 14.10 6 15.03 9 16.15 55 17.07 25 18.48 4 19.10 100
19.56 25 19.90 36 21.13 11 21.95 9 22.21 4 22.66 15 23.26 26 24.64
15 24.95 4 25.43 7 25.82 22 26.12 82 26.71 4 27.02 19 27.66 8 28.44
6 28.72 5 29.07 3 29.65 7 30.34 6 31.44 5 31.95 6 32.42 14 33.62 15
33.99 7 34.64 7 35.21 5 36.17 10 37.39 2 38.30 3 38.96 3 39.24 4
39.62 10 40.35 2 41.26 4 41.82 3 42.38 3 42.89 5 44.16 3 44.76 4
45.35 11 45.85 4 46.18 2 47.09 3 48.45 3
[0037] A further subject of the invention is a crystalline form II
of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
of the formula (1), which exhibits a characteristic Raman spectrum
with characteristic bands, which is described by the following wave
numbers (cm.sup.-1):
TABLE-US-00004 Wave number [cm.sup.-1] Intensity 90 S 123 VS 171 W
230 VW 248 M 341 W 384 VW 457 VW 475 VW 505 VW 532 W 573 VW 624 VW
638 W 682 VW 706 VW 761 W 795 W 817 VW 844 W 857 VW 894 VW 936 VW
957 VW 971 VW 989 VW 997 S 1010 VW 1054 W 1075 W 1085 VW 1124 VW
1168 VW 1212 VW 1250 VW 1276 W 1294 W 1317 VW 1339 VW 1355 VW 1361
W 1391 VW 1414 VW 1441 W 1462 W 1529 VW 1586 W 1614 W 2477 VW 2519
VW 2665 VW 2734 VW 2768 VW 2814 VW 2850 M 2889 M 2920 M 2929 S 2938
S 2968 M 3019 M 3040 W 3067 W 3103 VW 3181 VW 3229 VW 3248 VW
[0038] The invention also relates to a crystalline form II of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which possesses a characteristic X-ray diffraction
pattern as represented in FIG. 3.
[0039] The invention also includes a crystalline form II of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which is characterized by a Raman spectrum as
represented in FIG. 4.
[0040] The compounds of the crystalline form II are less
hygroscopic than the compounds of the crystalline forms I, III and
IV, and form hydrates of the crystalline form V only at a relative
air humidity >70%. For instance, after 5 hours of storage of the
crystalline form II at a relative air humidity of 60% no
appreciable absorption of water can be established (proportion of
water <0.15 wt. %). The crystalline form II is converted only
slowly, by stir-mixing in ethyl acetate at a temperature between
20.degree. C. and 30.degree. C., preferably at a temperature of
23.degree. C., into the form I which is thermodynamically more
stable at this temperature, so that only after 32 days has the
crystalline form II been completely converted into the crystalline
form I. A small proportion of the crystalline form I can be
detected after three days of stir-mixing. The conversion of the
crystalline form II into the crystalline form I by stir-mixing
takes place only slowly also in the presence of seed crystals of
the crystalline form I. The low hygroscopicity and the kinetic
stability make the crystalline form II a suitable active substance
in pharmaceutical formulations.
[0041] The compounds of the crystalline form II possess good
chemical stability. In the presence of atmospheric moisture with a
relative air humidity >70.degree. C. they form hydrates of the
crystalline form V only slowly. At a relative air humidity >95%,
hydrates result having a proportion of water of crystallization,
relative to the total weight of the hydrate, within the range from
8% to 10%. In order to avoid the formation of hydrates, the
compounds of the crystalline form II are advantageously stored in a
low-moisture environment, for example in a vessel stored over
phosphorus pentoxide or molecular sieve. Likewise, a storage of the
crystalline form II under dry protective gas (for example,
nitrogen) is advisable.
[0042] The melting-point lies within the range between 175.degree.
C. and 178.degree. C., and the enthalpy of fusion amounts to
approximately 93.3 J/g, deter mined by DSC at a heating-rate of
10.degree. C./minute. Polymorph III can be prepared in the form of
solid powder having desired mean particle sizes, which, as a rule,
lie within the range from 1 .mu.m to approximately 500 .mu.m.
[0043] The compound of the formula (1) forms a further stable
crystalline form III, which is thermodynamically stable at higher
temperatures, preferably at a temperature between 70.degree. C. and
155.degree. C., particularly preferably at a temperature between
75.degree. C. and 151.degree. C., and which is likewise stable
under normal conditions in air and with exclusion of atmospheric
moisture.
[0044] The invention also relates to a crystalline form of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern within the range from 2.degree. to 35.degree. 20 with
pronounced characteristic lines, expressed in 2theta values:
6.9 (s), 13.9 (m), 16.3 (m), 17.7 (w), 20.9 (vs), 22.1 (w), 22.5
(w), 27.8 (w); designated hereinafter as form III.
[0045] The invention also includes a crystalline form III of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of formula I,
which exhibits a characteristic X-ray diffraction pattern with the
following pronounced reflections:
TABLE-US-00005 2Theta Intensity (relative) 6.94 71 8.85 3 10.93 5
11.41 8 12.18 4 13.88 44 16.26 42 16.67 2 17.70 24 18.34 10 18.79 9
19.18 5 19.63 6 20.07 5 20.88 100 21.41 10 21.60 8 22.04 21 22.53
24 23.03 6 23.59 8 24.02 4 24.73 4 25.48 2 26.04 6 26.49 9 27.54 8
27.84 16 28.85 3 29.23 7 29.99 7 30.92 2 31.23 4 31.65 6 32.04 2
32.47 5 32.84 6 33.95 3 34.47 2 35.11 5 35.83 3 36.36 2 37.07 3
37.90 4 38.67 6 39.22 3 39.81 3 40.49 3 41.24 3 42.45 3 43.67 2
45.90 2 47.19 2 48.67 3
[0046] A further subject of the invention is a crystalline form III
of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
of the formula (1), which exhibits a characteristic Raman spectrum
with characteristic bands, which is described by the following wave
numbers (cm.sup.-1):
TABLE-US-00006 Wave number [cm.sup.-1] Intensity 75.65 S 94.93 VS
194.25 VW 244.39 M 286.33 VW 338.40 W 386.13 VW 443.99 VW 456.04 VW
481.59 VW 533.66 W 573.67 VW 624.30 VW 635.87 VW 702.88 VW 755.91 W
784.36 VW 793.52 VW 797.86 VW 819.07 VW 840.29 W 848.00 W 852.34 W
869.21 VW 897.66 VW 936.71 VW 958.89 W 974.31 VW 999.87 VS 1051.45
W 1071.70 W 1103.52 VW 1124.25 VW 1147.88 VW 1159.45 VW 1167.16 W
1213.44 VW 1232.25 VW 1249.60 VW 1264.55 VW 1277.08 VW 1293.48 W
1307.94 W 1311.80 W 1335.42 VW 1367.24 VW 1399.06 VW 1431.84 VW
1444.86 W 1466.07 W 1479.09 W 1529.71 VW 1587.08 W 1605.40 W
1653.62 VW 1661.33 VW 1704.24 VW 2675.22 W 2700.29 VW 2707.04 VW
2722.95 VW 2812.14 W 2852.16 S 2858.91 S 2891.21 M 2912.91 M
2924.48 M 2939.42 S 2949.55 M 2960.63 M 3019.45 M 3048.86 M 3071.04
W 3174.69 VW 3204.10 VW 3236.41 VW
[0047] A further subject of the invention is a crystalline form III
of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
of the formula (1), which exhibits a characteristic X-ray
diffraction pattern as shown in FIG. 5.
[0048] The invention further relates to a crystalline form III of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), which is characterized by a Raman spectrum as shown in
FIG. 6.
[0049] The crystalline form III in the presence of atmospheric
moisture with a relative air humidity >50% irreversibly forms
hydrates of the crystalline form V. At a relative air humidity
>95%, hydrates result having a proportion of water of
crystallization, relative to the total weight of the hydrate,
within the range from 8% to 10%. In order to avoid the formation of
hydrates, the compounds of the crystalline form III can
advantageously be stored in a low-moisture environment, for example
in a vessel over phosphorus pentoxide or a molecular sieve.
Likewise, it is advisable to store the crystalline form III under
dry protective gas (for example, nitrogen).
[0050] The melting-point lies within the range between 155.degree.
C. and 158.degree. C., and the enthalpy of fusion amounts to
approximately 87 J/g, determined by DSC at a heating-rate of
10.degree. C./minute. Polymorph III can be prepared in the form of
solid powder having desired mean particle sizes, which, as a rule,
lie within the range from 1 .mu.m to approximately 500 .mu.m.
[0051] The compound of the formula (1) forms a further stable
crystalline form IV which is thermodynamically stable at higher
temperatures, preferably at a temperature between 70.degree. C. and
155.degree. C., particularly preferably at a temperature between
75.degree. C. and 130.degree. C., still more preferably at a
temperature between 75.degree. C. and 122.degree. C., and which is
also stable under normal conditions in air and with exclusion of
atmospheric moisture.
[0052] The invention also relates to a crystalline form of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), which exhibits a characteristic X-ray diffraction
pattern within the range from 2.degree. to 35.degree. 20 with the
following pronounced characteristic lines, expressed in 2theta
values: [0053] 12.0 (m), 13.0 (m), 17.3 (m), 17.7 (m), 19.2 (s),
19.7 (m), 20.2 (m), 21.3 (m), 23.4 (m), 24.2 (m), 24.6 (m), 43.1
(vs), 44.2 (vs); designated hereinafter as form IV.
[0054] The invention also relates to a crystalline form IV of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol HCl of the
formula (1), which exhibits a characteristic X-ray diffraction
pattern with the following pronounced reflections:
TABLE-US-00007 2Theta Intensity (relative) 10.73 6 12.04 42 12.38
32 13.02 59 13.78 6 14.71 6 14.96 5 15.62 21 15.91 8 16.65 12 17.28
42 17.73 47 18.78 23 19.22 86 19.67 39 20.16 51 20.59 17 21.30 47
22.07 78 23.40 43 24.25 47 24.56 41 25.04 14 25.44 19 25.72 31
27.22 22 27.82 35 28.53 14 29.13 24 29.62 31 29.99 21 30.58 12
31.33 21 31.57 18 31.91 16 32.45 18 32.85 13 33.33 10 33.75 15
34.48 25 34.92 18 35.46 16 36.44 12 37.36 18 38.15 18 38.58 20
39.67 14 40.56 17 41.05 15 41.63 14 41.85 14 42.57 15 43.14 96
43.25 60 44.24 100 45.99 23 46.81 16 49.06 22
[0055] The invention also includes a crystalline form IV of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic Raman spectrum
with characteristic bands described by the following wave numbers
(cm.sup.-1):
TABLE-US-00008 Wave number [cm.sup.-1] Intensity 85 S 115 S 123 S
190 VW 243 M 337 W 386 VW 448 VW 476 VW 502 VW 534 W 574 VW 625 W
637 VW 709 VW 724 VW 748 W 761 W 794 VW 819 VW 833 W 844 W 858 VW
891 VW 913 VW 936 VW 957 VW 970 VW 988 VW 999 VS 1052 W 1071 VW
1083 VW 1104 VW 1123 VW 1160 W 1211 VW 1251 VW 1278 W 1293 W 1321 W
1337 VW 1366 W 1401 VW 1444 W 1463 W 1476 VW 1585 W 1614 W 2665 VW
2684 VW 2697 VW 2701 VW 2817 W 2853 M 2897 M 2914 M 2925 M 2938 S
2964 M 3017 W 3028 W 3043 M 3074 VW 3083 VW
[0056] The invention also relates to a crystalline form IV of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern as shown in FIG. 7.
[0057] The invention additionally includes a crystalline form IV of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), which is characterized by a Raman spectrum as shown in
FIG. 8.
[0058] In the presence of atmospheric moisture at a relative air
humidity >50%, the crystalline form IV irreversibly forms
hydrates of the crystalline form V. At a relative air humidity
>95%, hydrates result having a proportion of water of
crystallization, relative to the total weight of the hydrate,
within the range from 8% to 10%. In order to avoid the formation of
hydrates, the compounds of the crystalline form IV can
advantageously be stored in a low-moisture environment, for example
in a vessel over phosphorus pentoxide or over a molecular sieve.
Likewise, it is advisable to store the crystalline form IV under
dry protective gas (for example, nitrogen).
[0059] The melting-point lies within the range between 166.degree.
C. and 172.degree. C., and the enthalpy of fusion amounts to
approximately 78 J/g, determined by DSC at a heating-rate of
10.degree. C./minute. Polymorph IV can be prepared in the form of
solid powder having desired mean particle sizes, which, as a rule,
lie within the range from 1 .mu.m to approximately 500 .mu.m.
[0060] The compound of the formula (1) furthermore forms stable
hydrates of the crystalline form V, which are stable in air under
normal conditions.
[0061] The hydrates of the crystalline form V preferably exhibit a
content of water of crystallization within the range from 1% to
10%, particularly preferably within the range from 5% to 9%, quite
particularly preferably within the range from 6% to 8.5%, still
more preferably within the range from 7% to 8%, relative to the
weight of the hydrate.
[0062] The invention also relates to a crystalline form, of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern within the range from 2.degree. to 35.degree. 20 with
pronounced characteristic lines, expressed in 2theta values: [0063]
11.4 (m), 12.1 (m), 16.7 (w), 19.2 (m), 19.4 (w), 20.1 (m), 21.1
(m), 22.4 (vs), 24.0 (m), 31.3 (w); designated in the following as
form V.
[0064] The invention further relates to a crystalline form V of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol HCl of formula
(1), which exhibits a characteristic X-ray diffraction pattern with
the following pronounced reflections.
TABLE-US-00009 2Theta Intensity (relative) 9.06 6 11.47 60 12.15 36
13.43 9 14.32 11 14.89 6 16.72 17 17.42 4 18.12 5 18.82 6 19.23 46
19.44 31 20.07 50 20.68 8 21.09 50 21.88 8 22.42 100 23.00 5 23.53
6 24.04 46 24.37 33 24.54 26 24.58 27 25.05 7 25.89 29 26.52 7
26.99 6 27.32 12 27.91 13 28.65 10 30.11 13 30.93 17 31.29 20 32.43
17 32.96 11 33.74 5 34.11 6 34.46 7 34.84 9 35.89 7 36.31 6 36.88 7
37.38 12 37.71 8 38.06 5 38.99 7 40.01 7 40.72 5 41.70 4 42.35 5
42.94 8 43.86 5 44.15 5 44.70 4 45.07 6 45.65 6 46.24 5 47.31 6
48.23 4 49.12 4
[0065] The invention also includes a crystalline form V of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), which exhibits a characteristic Raman spectrum with
characteristic bands described by the following wave numbers
(cm.sup.-1):
TABLE-US-00010 Wave number [cm.sup.-1] Intensity 96.38 VS 252.59 W
270.91 W 337.44 W 371.67 VW 448.81 VW 469.06 VW 507.14 VW 535.11 W
572.23 VW 624.30 VW 704.81 VW 751.58 W 794.48 VW 817.14 VW 837.39 W
857.16 VW 886.09 VW 915.01 VW 935.26 VW 952.62 VW 999.38 S 1053.38
W 1100.15 VW 1120.40 VW 1159.45 VW 1211.03 VW 1251.05 VW 1271.78 VW
1294.44 W 1308.42 VW 1336.87 VW 1355.19 VW 1368.69 W 1405.81 VW
1440.52 W 1459.81 W 1502.71 VW 1600.58 W 2667.03 VW 2702.70 VW
2728.74 VW 2811.66 VW 2855.05 M 2895.55 M 2934.60 M 2966.42 M
3032.47 W
[0066] The invention also relates to a crystalline form V of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), which exhibits a characteristic X-ray diffraction
pattern as shown in FIG. 9.
[0067] The invention additionally relates to a crystalline form V
of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
of the formula (1), which is characterized by a Raman spectrum as
represented in FIG. 10.
[0068] The crystalline form V is stable at ambient temperature in
air and is therefore particularly suitable as an active substance
in pharmaceutical formulations.
[0069] The crystalline form V can be dehydrated only with
difficulty. The use of vacuum and/or of hygroscopic reagents--such
as phosphorus pentoxide, for example--results only in an incomplete
release of water from the crystalline form V. In the presence of
water--which may be present, for example, in the form of water
vapor or atmospheric moisture--the partially dehydrated compound of
the crystalline form V quickly absorbs said water again. The
compounds of the crystalline form V do not change under elevated
pressure--for example, at a pressure of 8000 bar for a period of 60
minutes--or in the course of grinding, and no conversion into the
crystalline forms I, II, III or IV is observed under the influence
of elevated pressure.
[0070] The melting-point of the compounds of the crystalline form V
lies within the temperature range from 105.degree. C. to
115.degree. C., and the enthalpy of fusion determined by DSC at a
heating-rate of 10.degree. C./minute amounts to approximately 77
J/g.
[0071] The compound of the formula (1) forms stable solvates in
solvating solvents such as, for example, ethanol, methanol, methyl
ethyl ketone, isopropanol, n-propanol, n-octanol and acetone. The
solvates are isomorphous to one another and likewise to the hydrate
having the crystalline form V. The solvent cannot be removed, or
cannot be completely removed, by vacuum.
[0072] The replacement of ethanol in an appropriate solvate of
compounds of the formula (1) is possible by storage at elevated air
humidity, for example by storage in the presence of a
supersaturated aqueous solution of magnesium nitrate or in the
presence of a supersaturated aqueous solution of sodium chloride
for a period of at least two months, preferably for a period of at
least four months.
[0073] The polymorphous forms I, II, III, IV and V can each be
converted into other crystalline forms. For example, the
polymorphous forms II, III and IV can be converted into the
polymorphous form I; the polymorphous forms III and IV can be
converted into the polymorphous form II; the polymorphous forms III
can be converted into the polymorphous form IV, and the
polymorphous forms I and II can be converted into the polymorphous
forms III or IV. A further subject of the invention is therefore
also constituted by mixtures of the crystalline forms I, II, III,
IV and V in, as such, arbitrary mixing ratios.
[0074] The crystal lattices of forms I, II, III, IV and V are
clearly different from one another, so that the Raman spectra and
X-ray diffraction patterns exhibit great differences. For instance,
form I exhibits a peak with strong intensity within the range of
19.degree. 2.theta., form III exhibits peaks with strong intensity
within the ranges of 7.degree., 14.degree. and 21.degree. 2.theta.,
and form V exhibits peaks with strong intensity within the ranges
of 12.degree. and 22.degree. 2.theta..
[0075] The polymorphous forms I, II, III and IV can be prepared by
crystallization procedures known as such from the salt
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, for
example by stirring of suspensions (adjustment of phase
equilibria), precipitation, recrystallization, evaporation of
solvents or crystallization from the melt. Diluted, saturated or
supersaturated solutions may be used, with or without seeding with
a crystal nucleator. The temperatures for forming solutions may
amount to up to 100.degree. C. The crystallization can be initiated
by cooling to approximately -100.degree. C. to 30.degree. C., and
preferably -30.degree. C. to 20.degree. C., whereby cooling may
take place continuously or in stepwise manner. For the purpose of
preparing solutions or suspensions, use may be made of amorphous or
crystalline starting materials, in order to achieve high
concentrations in solutions and to obtain other crystalline
forms.
[0076] The invention therefore also relates to a process for
preparing the crystalline form I of 3-[2
(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, wherein:
[0077] a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride in the crystalline form III and
3-[2-(dimethylamino)methyl(cyclohex-1-ye]phenol hydrochloride in
the crystalline form IV or
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)phenol hydrochloride in
the crystalline form V are stirred in a solvent, preferably in a
quantitative ratio between 1:100 and 100:1, particularly preferably
in a quantitative ratio between 1:10 and 10:1, quite particularly
preferably in a quantitative ratio between 1:5 and 5:1, up until
the complete formation of the crystalline form I, or [0078] b)
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form II and
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form I are stirred in a solvent, preferably in a
quantitative ratio between 100:1 and 8:1, particularly preferably
in a quantitative ratio between 11:1 and 9:1, up until the complete
formation of the crystalline form I, whereby the temperature in
processes a) and b) is at most 40.degree. C., preferably at most
30.degree. C., particularly preferably at most 25.degree. C.
[0079] Processes a) and b) can be carried out in the presence of
air or in the presence of inert gases such as, for example,
nitrogen and noble gases. It is preferred to work in an air
environment for economic reasons. The relative humidity of the
gases preferably is <50%, particularly preferably <20%,
especially preferably <5%.
[0080] The duration of processes a) and b) depends substantially on
the size of the crystals and on the concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and
may preferably amount to from 1 hour to 250 hours, particularly
preferably 3 hours to 72 hours, and especially preferably 5 hours
to 25 hours. The concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride
preferably amounts to 0.5% to 50%, particularly preferably 2% to
30%, quite particularly preferably 5% to 20%, still more preferably
5% to 8%, in each instance relative to the weight of the
solvent.
[0081] After isolation, the crystalline residue can be dried in
conventional manner, whereby temperatures above 40.degree. C. are
advantageously avoided.
[0082] Processes a) and b) are preferably carried out in
non-solvating solvents. Particularly preferred are solvents
selected from the group consisting of aliphatic, cycloaliphatic and
aromatic hydrocarbons (hexane, heptane, petroleum ether,
cyclohexane, methyl cyclohexane, benzene, toluene, xylene),
aliphatic halogenated hydrocarbons (dichloromethane, chloroform,
dichloroethane and tetrachloroethane), nitriles (acetonitrile,
propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether,
tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene
glycol diethyl ether, diethylene glycol dimethyl ether,
tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain
alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and
carboxylic-acid esters and lactones (propyl acetate, ethyl acetate
or methyl acetate, valerolactone). The solvent ethyl acetate is
especially preferred.
[0083] The solvents can be used individually or in a mixture of at
least two solvents. It is preferred to use physiologically harmless
solvents that are known to persons skilled in the art. After
isolation, the solvent or solvent mixture that has been used can be
removed in conventional manner by known drying processes.
[0084] The invention also relates to a crystalline form I of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), obtainable by one of the processes described
above.
[0085] The invention additionally includes a process for preparing
the crystalline form II of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride,
wherein [0086] a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride in the crystalline form IV or a mixture of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form III and
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form V is heat-treated at a temperature between
150.degree. C. and 160.degree. C., preferably at a temperature
between 154.degree. C. and 158.degree. C., up until the complete
formation of the crystalline form II, or [0087] b)
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form II and
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form III or
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form IV is stirred in a solvent, preferably in a
quantitative ratio between 1:100 and 1:8, particularly preferably
in a quantitative ratio between 1:11 and 1:9, up until the complete
formation of the crystalline form II, or [0088] c) a suspension of
the amorphous form of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent, preferably a solvent that does not form solvates, as a
carrier is stirred at a temperature between 30.degree. C. and
50.degree. C., preferably at a temperature between 35.degree. C.
and 45.degree. C., particularly preferably at a temperature of
40.degree. C., until the complete formation of the crystalline form
II occurs; or [0089] d)
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form III and
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form IV are stirred in a solvent, preferably in a
quantitative ratio between 1:100 and 100:1, particularly preferably
in a quantitative ratio between 1:10 and 10:1, especially
preferably in a quantitative ratio between 1:5 and 5:1, until the
complete formation of the crystalline form II occurs; whereby the
temperature in processes b) and d) is at most 60.degree. C.,
preferably at most 40.degree. C., particularly preferably at most
30.degree. C., especially preferably at most 25.degree. C.
[0090] Processes b), c) and d) can be carried out in the presence
of air or in the presence of inert gases such as, for example,
nitrogen and noble gases. It is preferred to work in an air
environment for economic reasons. The relative humidity of the
gases preferably is <50%, particularly preferably <20%,
especially preferably <5%.
[0091] The duration of processes b) and d) depends substantially on
the size of the crystals and on the concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and
may preferably amount to from 1 hour to 250 hours, particularly
preferably 3 hours to 72 hours, especially preferably 5 hours to 25
hours. The duration of process c) preferably amounts to at least
300 hours, particularly preferably at least 350 hours, especially
preferably at least 400 hours. The concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydro-chloride in
processes b), c) and d) preferably is 0.5% to 50%, particularly
preferably 2% to 30%, quite particularly preferably 5% to 20%,
still more preferably 5% to 8%, in each instance relative to the
weight of the solvent.
[0092] Processes b), c) and d) are preferably carried out in
non-solvating solvents. Particularly preferred are solvents
selected from the group consisting of aliphatic, cycloaliphatic and
aromatic hydrocarbons (hexane, heptane, petroleum ether,
cyclohexane, methyl cyclohexane, benzene, toluene, xylene),
aliphatic halogenated hydrocarbons (dichloromethane, chloroform,
dichloroethane and tetrachloroethane), nitriles (acetonitrile,
propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether,
tert.-butyl methyl ether, ethylene glycol dimethyl ether, ethylene
glycol diethyl ether, diethylene glycol dimethyl ether,
tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain
alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and
carboxylic-acid esters and lactones (propyl acetate, ethyl acetate
or methyl acetate, valerolactone). The solvent ethyl acetate is
especially preferred.
[0093] The solvents can be used individually or in a mixture of at
least two solvents. It is advantageous to use physiologically
harmless solvents that are known to persons skilled in the art.
After isolation, the solvent and/or solvent mixture that has been
used can be removed in conventional manner by known drying
processes.
[0094] The invention also relates to a crystalline form II of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), obtainable by one of the processes described
above.
[0095] The invention likewise relates to a process for preparing
the crystalline form III of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride,
wherein [0096] a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride in the form of an ethanol solvate or acetone solvate
is dissolved in a solvent and stirred and subsequently
precipitated, or [0097] b) a suspension of the amorphous form of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent, preferably in a solvent that does not form solvates, as a
carrier carrier, is stirred at a temperature between 30.degree. C.
and 80.degree. C., preferably at a temperature between 35.degree.
C. and 50.degree. C., particularly preferably at a temperature of
40.degree. C., until complete formation of the crystalline form III
occurs.
[0098] In process step a) the crystalline forms I; II, IV, the
amorphous form of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride or corresponding mixtures can be used for preparing
solutions. The concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the solution depends on the chosen temperature and on the solvent.
The dissolved quantity may preferably amount to from 0.5% to 50%,
particularly preferably from 2% to 30%, quite particularly
preferably 3% to 25%, and still more preferably 5% to 20%, relative
to the solvent. The dissolution temperature may be up to 70.degree.
C. and preferably up to 60.degree. C. Ethyl acetate is preferably
used as solvent for preparing solutions.
[0099] Precipitation can be effected by cooling, partial or
complete removal of the solvent, addition of a solvent in which
3-[2-(dimethylamino)methyl(cyclohex-1-ye]phenol hydrochloride
exhibits only a low solubility--such as, for example, heptane,
tert.-butylmethyl ether or ethyl acetate and corresponding
mixtures--or by a combination of these measures. `Cooling` may
signify slow cooling or chilling to temperatures down to
-20.degree. C. and preferably to 0.degree. C. The solvent can be
removed by heating, in a stream of gas, applying a vacuum, or a
combination of these measures. In process stage a), heating for the
purpose of removing solvent implies a temperature of at most
40.degree. C., and preferably of at most 30.degree. C.
[0100] Process b) can be carried out in the presence of air or in
the presence of inert gases such as, for example, nitrogen and
noble gases. It is preferred to work in an air environment for
economic reasons. The relative humidity of the gases preferably is
<50%, particularly preferably <40%, especially preferably
<20%.
[0101] The duration of process b) depends substantially on the size
of the crystals and on the concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and
may preferably amount to from 1 hour to 350 hours, particularly
preferably 10 hours to 300 hours, especially preferably 20 hours to
300 hours. The concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride in
process b) preferably amounts to 0.5% to 50%, particularly
preferably 2% to 30%, quite particularly preferably 5% to 20%,
still more preferably 5% to 15%, in each instance relative to the
weight of the solvent. After isolation, the crystalline residue can
be dried in conventional manner, whereby temperatures above
40.degree. C. are advantageously avoided.
[0102] Process b) is preferably carried out in non-solvating
solvents. Particularly preferred are solvents selected from the
group consisting of aliphatic, cycloaliphatic and aromatic
hydrocarbons (hexane, heptane, petroleum ether, cyclohexane, methyl
cyclohexane, benzene, toluene, xylene), aliphatic halogenated
hydrocarbons (dichloromethane, chloroform, dichloroethane and
tetrachloroethane), nitriles (acetonitrile, propionitrile,
benzonitrile), ethers (diethyl ether, dibutyl ether,
tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene
glycol diethyl ether, diethylene glycol dimethyl ether,
tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain
alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and
carboxylic-acid esters and lactones (propyl acetate, ethyl acetate
or methyl acetate, valerolactone). The solvents heptane,
tert.-butylmethyl ether and ethyl acetate are especially
preferred.
[0103] The invention also relates to a crystalline form III of
3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1), obtainable by one of the processes described
above.
[0104] The invention likewise relates to a process for preparing
the crystalline form IV of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride,
wherein [0105] a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride in the crystalline form III is heat-treated at a
temperature between 150.degree. C. and 160.degree. C., preferably
at a temperature between 154.degree. C. and 158.degree. C., until
complete formation of the crystalline form IV occurs, or [0106] b)
a suspension of the amorphous form of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
solvent, preferably in a solvent that does not form solvates, as a
carrier, is stirred at a temperature between 40.degree. C. and
120.degree. C., preferably at a temperature between 40.degree. C.
and 100.degree. C., particularly preferably at a temperature
between 40.degree. C. and 80.degree. C., until complete formation
of the crystalline form IV occurs; or [0107] c)
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form IV and
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in
the crystalline form III are stirred in a solvent, preferably in a
quantitative ratio between 1:100 and 1:8, particularly preferably
in a quantitative ratio between 1:11 and 1:9, until complete
formation of the crystalline form IV occurs; whereby the
temperature in process c) is at most 40.degree. C., preferably at
most 30.degree. C., particularly preferably at most 25.degree.
C.
[0108] Processes b) and c) can be carried out in the presence of
air or in the presence of inert gases such as, for example,
nitrogen and noble gases. It is preferred to work in an air
environment for economic reasons. The relative humidity of the
gases preferably is <50%, particularly preferably <40%,
especially preferably <20%.
[0109] The duration of processes b) and c) depends substantially on
the size of the crystals and on the concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride, and
may preferably amount to from 1 hour to 250 hours, particularly
preferably 10 hours to 200 hours, especially preferably 30 hours to
150 hours. The concentration of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]-phenol hydrochloride
preferably amounts to 0.5% to 50%, particularly preferably 0.5% to
20%, quite particularly preferably 0.5% to 10%, still more
preferably 1% to 8%, in each instance relative to the weight of the
solvent. After isolation, the crystalline residue can be dried in
conventional manner, whereby temperatures above 40.degree. C. are
advantageously avoided.
[0110] Processes b) and c) are preferably implemented in
non-solvating solvents. Particularly preferred are solvents
selected from the group consisting of aliphatic, cycloaliphatic and
aromatic hydrocarbons (hexane, heptane, petroleum ether,
cyclohexane, methyl cyclohexane, benzene, toluene, xylene),
aliphatic halogenated hydrocarbons (dichloromethane, chloroform,
dichloroethane and tetrachloroethane), nitriles (acetonitrile,
propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether,
tert.-butylmethyl ether, ethylene glycol dimethyl ether, ethylene
glycol diethyl ether, diethylene glycol dimethyl ether,
tetrahydrofuran, methyl tetrahydrofuran, dioxan), long-chain
alcohols (butanol, tert.-butanol, pentanol, octanol, decanol) and
carboxylic-acid esters and lactones (propyl acetate, ethyl acetate
or methyl acetate, valerolactone). The solvent tert.-butylmethyl
ether is especially preferred.
[0111] The solvents can be used individually or in a mixture of at
least two solvents. It is advantageous to use physiologically
harmless solvents that are known to persons skilled in the art.
After isolation, the solvent and/or solvent mixture that has been
used can be removed in conventional manner by known drying
processes.
[0112] The invention further relates to a crystalline form IV of
3-[2-(dimethyl-amino)methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1), obtainable by one of the processes described
above.
[0113] The invention likewise includes a process for preparing the
crystalline form V of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride,
wherein [0114] a) 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride in the crystalline form I, II, III or IV is left to
stand in air or is treated with water vapor, or [0115] b) a
suspension of the amorphous form of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride in a
mixture of water and optionally at least one solvent as a carrier,
is stirred at a temperature between 20.degree. C. and 60.degree.
C., preferably at a temperature between 20.degree. C. and
30.degree. C., and subsequently the remaining water or solvent is
removed.
[0116] The invention also includes a crystalline form V of
3-[2-(dimethylamino)-methyl(cyclohex-1-ye]phenol hydrochloride of
formula (1), obtainable by one of the processes described
above.
[0117] Due to its favorable overall profile of properties,
3-[2-(dimethylamino)-methyl(cyclohex-1-ye]phenol hydrochloride, in
particular 3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol
hydrochloride in the crystalline forms II and V, is outstandingly
suitable as an active substance for pharmaceutical compositions and
quite particularly suitable for pain-relieving medicaments.
Accordingly, the invention also includes the use of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1) as an active substance in a pharmaceutical composition
or medicament, preferably as an active substance in an
analgesic.
[0118] Preferred here also, as in the entire application, are
diastereomers or mixtures of enantiomeric diastereomers with trans
configuration of the phenyl ring and of the dimethylaminomethyl
group (1R,2R configuration and 1S,2S configuration, respectively),
the enantiomer with the absolute configuration (1R,2R) being quite
particularly preferred.
[0119] The invention also includes a pharmaceutical composition
containing a pharmacologically effective amount of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
formula (1) and at least one pharmaceutical carrier or diluent.
[0120] In the composition the compound of the formula (1) may be
present as crystalline form I, II, III, IV, V or as a mixture of
forms I, H, III, IV and V. The crystalline form II and/or I and/or
V is preferably included. The crystalline form II and/or V is
particularly preferably included.
[0121] The conversion of the compounds of the crystalline form II
into the crystalline form I in pharmaceutical compositions can be
prevented through the use of pharmaceutically acceptable
ingredients and components or through the use of suitable
formulation auxiliaries known to a person skilled in the art.
[0122] The quantity of the compounds of the formula (1) depends
substantially on the type of formulation and on the desired dosage
during the period of administration. The quantity of the respective
compounds of the formula (1) to be administered to the patient may
vary and is, for example, dependent on the weight or age of the
patient and also on the manner of administration, on the indication
and on the degree of severity of the illness. Preferably 0.005
mg/kg to 5000 mg/kg, particularly preferably 0.05 mg/kg to 500
mg/kg, quite particularly preferably 0.5 mg/kg to 100 mg/kg, still
more preferably 2 mg/kg to 20 mg/kg of body weight of the patient
of at least one such compound are administered.
[0123] Oral formulations may be solid formulations, for example
tablets, capsules, pills and pastilles, but oral formulations may
also be liquid formulations, for example solutions, suspensions,
syrups or elixirs. Liquid and solid formulations also encompass the
incorporation of the compounds of the formula (1) into solid or
liquid foodstuffs. Furthermore, liquids also encompass solutions
for parenteral applications, such as, for example, solutions for
infusion or injection.
[0124] The compounds of the formula (1) and the crystalline forms
can be used directly as powders (micronized particles), granulates,
suspensions or solutions, or they may be mixed with other
pharmaceutically acceptable ingredients and components and then
pulverized, in order then to fill the powders into capsules
consisting of hard or soft gelatin, to press tablets, pills or
pastilles, or in order to suspend or dissolve the powders in a
carrier for the purpose of preparing suspensions, syrups or
elixirs. Tablets, pills or pastilles can be provided with a coating
after pressing.
[0125] Pharmaceutically acceptable ingredients and components for
the various types of formulation are known as such. It may, for
example, be a question of binding agents such as synthetic or
natural polymers, medicinal carriers, lubricating agents,
surfactants, sweetening agents and flavoring agents, coating
agents, preserving agents, dyestuffs, thickening agents, ancillary
agents, antimicrobial agents and carriers for the various types of
formulation.
[0126] Examples of suitable binding agents include gum arabic, gum
tragacanth, acacia gum and biodegradable polymers such as
homopolyesters or copolyesters of dicarboxylic acids, alkylene
diols, polyalkylene glycols and/or aliphatic hydroxycarboxylic
acids; homopolyamides or copolyamides of dicarboxylic acids,
alkylenediamines and/or aliphatic aminocarboxylic acids;
corresponding polyester-polyamide copolymers, polyanhydrides,
polyorthoesters, polyphosphazenes and polycarbonates. The
biodegradable polymers may be linear, branched or crosslinked.
Specific examples are polyglycolic acid, polylactic acid and
poly-d,l-lactic/glycolic acid. Other examples of polymers are
water-soluble polymers such as, for example, polyoxaalkylenes
(polyoxaethylene, polyoxapropylene and mixed polymers thereof),
polyacrylamides and hydroxyl-alkylated polyacrylamides, polymaleic
acid and esters or amides thereof, polyacrylic acid and esters or
amides thereof, polyvinyl alcohol and esters or ethers thereof,
polyvinyl imidazole, polyvinyl pyrrolidone and natural polymers,
such as chitosan, for example.
[0127] Examples of medicinal carriers include phosphates, such as
dicalcium phosphate.
[0128] Examples of suitable lubricating agents include natural or
synthetic oils, fats, waxes or fatty-acid salts such as magnesium
stearate.
[0129] Surfactants (surface-active agents) may be anionic,
cationic, amphoteric or neutral. Examples of useful surfactants
include lecithin, phospholipids, octyl sulfate, decyl sulfate,
dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and
octadecyl sulfate, sodium oleate or sodium caprate,
1-acylaminoethane-2-sulfonic acids such as
1-octanoylaminoethane-2-sulfonic acid,
1-decanoylaminoethane-2-sulfonic acid,
1-dodecanoylaminoethane-2-sulfonic acid,
1-tetradecanoylamino-ethane-2-sulfonic acid,
1-hexadecanoylaminoethane-2-sulfonic acid and
1-octadecanoylaminoethane-2-sulfonic acid, bile acids, salts and
derivatives thereof, such as, for example, cholic acid, deoxycholic
acid, taurocholic acid, taurodeoxycholic acid and sodium
glycocholates, sodium caprate, sodium laurate, sodium oleate,
sodium lauryl sulfate, sodium cetyl sulfate, sulfated castor oil,
sodium dioctyl sulfosuccinate, cocamidopropyl betaine and lauryl
betaine, fatty alcohols, cholesterols, glycerin monostearate or
distearate, glycerin monooleate or dioleate, glycerin monopalmitate
or dipalmitate and polyoxyethylene stearate.
[0130] Examples of suitable sweetening agents include sucrose,
fructose, lactose and aspartame.
[0131] Examples of useful flavoring agents include peppermint, oil
of wintergreen or fruit flavor such as cherry or orange flavor.
[0132] Examples of suitable coating agents include gelatins, waxes,
shellac, sugars and biodegradable polymers.
[0133] Examples of preservation agents include methylparaben or
propylparaben, sorbic acid, chlorobutanol and phenol.
[0134] Examples of ancillary agents include aromatic
principles.
[0135] Examples of suitable thickening agents include synthetic
polymers, fatty acids, fatty-acid salts, fatty-acid esters and
fatty alcohols.
[0136] Examples of suitable liquid carriers include water, alcohols
(ethanol, glycerol, propylene glycol, liquid polyethylene glycols),
polytriazines and oils. Examples of solid carriers are talc,
aluminas, microcrystalline cellulose, silicon dioxide, aluminium
oxide and similar solid substances.
[0137] The composition according to the invention may also contain
isotonic agents such as, for example, sugars, physiological buffers
and sodium chloride.
[0138] The composition according to the invention may also be
formulated as an effervescent tablet or effervescent powder which
decomposes in an aqueous environment, thereby formulating solutions
or suspensions for drinking.
[0139] A syrup or a elixir may contain the compound of the formula
(1), a sugar such as sucrose or fructose by way of sweetening
agent, a preserving agent (such as methylparaben), a dyestuff and a
flavoring agent (such as flavoring substances).
[0140] The composition according to the invention may also be a
formulation with delayed and/or controlled release of the active
substance upon contact with body fluids of the gastrointestinal
tract, in order to achieve a substantially constant and effective
level of the active substance in the blood plasma. For this purpose
the compounds of the formula (1) can be embedded in a polymer
matrix of a biodegradable polymer, of a water-soluble polymer or of
both types of polymers, optionally together with a suitable
surfactant. In this context, `embedding` may signify the
incorporation of microparticles into the polymer matrix.
Formulations with delayed and controlled release of active
substance can also be obtained by encapsulation of dispersed
microparticles or emulsified microdroplets with the aid of known
techniques for coating dispersions and emulsions.
[0141] The compounds of the formula (1) can also be used together
with at least one further pharmaceutical active substance for
combination therapies. To this end, at least one further active
substance may be additionally dispersed or dissolved in the
composition according to the invention.
[0142] The invention also relates to the use of
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride of
formula (1) for preparing a pharmaceutical composition, in
particular for the treatment of pain.
[0143] The invention thus also relates to a process for treating
pain conditions, wherein an effective quantity of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride of
the formula (1) is administered to a patient suffering from
pain.
[0144] The medicament or pharmaceutical composition according to
the invention preferably is suitable for the treatment or
inhibition of pain, preferentially pain selected from the group
consisting of acute pain, chronic pain, neuropathic pain and
visceral pain; of migraine; depressions; neurodegenerative
diseases, preferentially selected from the group consisting of
Parkinson's disease, Alzheimer's disease, Huntington's disease and
multiple sclerosis; cognitive illnesses, preferentially cognitive
deficiency conditions, particularly preferably attention-deficit
syndrome (ADS), panic attacks; epilepsy; coughing; urinary
incontinence; diarrhoea; pruritus; schizophrenia; cerebral
ischaemias; muscular spasms; cramps; food-intake disorders,
preferentially selected from the group consisting of bulimia,
cachexia, anorexia and obesity; abuse of alcohol and/or drugs (in
particular, nicotine and/or cocaine) and/or medicaments; dependence
on alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments, preferentially for the prophylaxis and/or
reduction of withdrawal symptoms in the case of dependence on
alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments; development of tolerance phenomena in relation
to medicaments, particularly in relation to opioids;
gastro-oesophageal reflux syndrome; for diuresis; for
antinatriuresis; for influencing the cardiovascular system; for
anxiolysis; for heightening wakefulness; for heightening libido,
for modulating motor activity and for local anaesthesia.
[0145] In particularly preferred manner, the pharmaceutical
composition according to the invention is suitable for the
treatment and/or inhibition of pain, preferentially of acute pain,
chronic pain, neuropathic pain or visceral pain; depressions;
epilepsy; Parkinson's disease; abuse of alcohol and/or drugs (in
particular, nicotine and/or cocaine) and/or medicaments; dependence
on alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments; preferentially for the prophylaxis and/or
reduction of withdrawal symptoms in the case of dependence on
alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments; of the development of tolerance phenomena in
relation to medicaments, in particular in relation to opioids, or
for anxiolysis.
[0146] In quite particularly preferred manner, the medicament
according to the invention is suitable for the treatment and/or
inhibition of pain, preferentially of acute pain, chronic pain,
neuropathic pain or visceral pain.
[0147] Particularly preferred is the use of at least one salt
according to the invention, in each case optionally in the form of
a purified or isolated stereoisomer, in particular enantiomers or
diastereomers, or a racemate or in the form of a mixture of
stereoisomers, in particular of the enantiomers and/or
diastereomers, in an arbitrary mixing ratio, and also, optionally,
of one or more pharmaceutically compatible ancillary substances for
preparing a pharmaceutical composition for treating and/or
inhibiting pain, preferentially pain selected from the group
consisting of acute pain, chronic pain, neuropathic pain and
visceral pain, or for the treatment and/or inhibition of migraine,
depression, neurodegenerative diseases, preferentially a
neurodegenerative disease selected from the group consisting of
Parkinson's disease, Alzheimer's disease, Huntington's disease and
multiple sclerosis, cognitive illnesses, preferentially cognitive
deficiency conditions, particularly preferably of attention-deficit
syndrome (ADS), panic attacks, epilepsy, coughing, urinary
incontinence, diarrhoea, pruritus, schizophrenia, cerebral
ischaemias, muscular spasms, cramps, food-intake disorders,
preferentially selected from the group consisting of bulimia,
cachexia, anorexia and obesity, abuse of alcohol and/or drugs (in
particular, nicotine and/or cocaine) and/or medicaments; dependence
on alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments; preferentially for the prophylaxis and/or
reduction of withdrawal symptoms in the case of dependence on
alcohol and/or drugs (in particular, nicotine and/or cocaine)
and/or medicaments; development of tolerance phenomena in relation
to drugs and/or medicaments, particularly in relation to opioids,
gastro-oesophageal reflux syndrome, for diuresis, for
antinatriuresis, for influencing the cardiovascular system, for
anxiolysis, for heightening wakefulness, for heightening libido,
for modulating motor activity and for local anaesthesia.
[0148] The pharmaceutical composition according to the invention
may exist as a liquid, semisolid or solid medicinal form, for
example in the form of injection solutions, drops, juices, syrups,
sprays, suspensions, tablets, patches, capsules, plasters,
suppositories, ointments, creams, lotions, gels, emulsions,
aerosols, or in multiparticulate form, for example in the form of
pellets or granulates, optionally pressed into tablets, filled in
capsules or suspended in a liquid, and may also be administered as
such.
[0149] In addition to at least one salt according to the invention,
optionally in the form of an isolated and/or purified stereoisomer,
in particular enantiomers or diastereomers, its racemate or in the
form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixing ratio, the
pharmaceutical composition according to the invention) ordinarily
contains further physiologically compatible pharmaceutical
ancillary substances, which may preferably be selected from the
group consisting of carrier materials, fillers, solvents, diluents,
surface-active substances, dyestuffs, preserving agents,
disintegrants, lubricating agents, lubricants, flavors and binding
agents.
[0150] The selection of the physiologically compatible ancillary
substances and also the quantities of such substances to be
employed depend on whether the pharmaceutical composition is to be
administered orally, subcutaneously, parenterally, intravenously,
intraperitoneally, intradermally, intramuscularly, intranasally,
buccally, rectally or locally, for example onto infections on the
skin, of the mucous membranes and in the eyes. Particularly
suitable for oral administration are preparations in the form of
tablets, dragees, capsules, granulates, pellets, drops, juices and
syrups; for parenteral, topical and inhalational application,
solutions, suspensions, dry preparations capable of being
reconstituted easily and also sprays.
[0151] Suitable preparations for percutaneous application include
also sustained-release preparations in dissolved form or in a
plaster, optionally with addition of agents which promote the
penetration of the skin.
[0152] Orally or percutaneously administerable forms of preparation
are able to release the respective salts according to the invention
in delayed manner.
[0153] The pharmaceutical compositions according to the invention
are prepared using conventional means, appliances and methods,
following processes well-known from the state of the art, such as
are described, for example, in Remington's Pharmaceutical Sciences,
editor A. R. Genarro, 17th Edition, Mack Publishing Company,
Easton, Pa., 1985, in particular in Part 8, Chapters 76 to 93,
which chapters are hereby incorporated by reference as part of the
original disclosure.
[0154] The quantity of the respective salts according to the
invention to be administered to the patient may vary and will
depend, for example, on the weight or age of the patient and also
on the manner of administration, on the indication and on the
degree of severity of the illness. Ordinarily, 0.005 mg/kg to 5000
mg/kg, preferentially 0.05 mg/kg to 500 mg/kg, of body weight of
the patient of at least one such compound are applied.
BRIEF DESCRIPTION OF THE DRAWINGS
[0155] FIG. 1 shows the X-ray diffraction pattern of the
polymorphous form I;
[0156] FIG. 2 shows the Raman spectrum of the polymorphous form
I;
[0157] FIG. 3 shows the X-ray diffraction pattern of the
polymorphous form II;
[0158] FIG. 4 shows the Raman spectrum of the polymorphous form
II;
[0159] FIG. 5 shows the X-ray diffraction pattern of the
polymorphous form III;
[0160] FIG. 6 shows the Raman spectrum of the polymorphous form
III;
[0161] FIG. 7 shows the X-ray diffraction pattern of the
polymorphous form IV;
[0162] FIG. 8 shows the Raman spectrum of the polymorphous form
IV;
[0163] FIG. 9 shows the X-ray diffraction pattern of the
polymorphous form V; and
[0164] FIG. 10 shows the Raman spectrum of the polymorphous form
V.
EXAMPLES
[0165] The following Examples are intended to illustrate the
invention in further detail without limiting its scope. Unless
state otherwise, all DSC measurements were carried out at a
heating-rate of 10.degree. C./minute; the stated temperatures are
peak maxima.
Example 0.1
Synthesis of the Base
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
Procedure a)
[0166] In a 1000 ml single-necked flask 52 g (183 mmole) of the
precursor 14243-methoxyphenyl)cyclohexyl)-N,N-dimethylmethaneamine
(purity according to GC: 97.5% of the trans diastereomer) and 250
ml hydrobromic acid (47%, in water) were charged together and
stirred for 2 hours with a magnetic stirrer, subject to reflux.
After conclusion of the reaction, the hydrogen bromide was
distilled off by applying a vacuum (water-jet pump). The base
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol was released from
the distillation residue with ethyl acetate and aqueous
potassium-carbonate solution. The organic phase was dried with
MgSO.sub.4, and the base
3-[2-(dimethylamino)methyl(cyclohex-1-ye]phenol was isolated as a
yellowish oil (crude yield: 42 g, which corresponded to 98.6% of
the theoretical value). The base
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol was added to 250
ml ethyl acetate and stored overnight in a refrigerator. Since no
solid substance precipitated out, the solution was inspissated
again, whereby strong foaming was observed.
Procedure b)
[0167] 125 g (440 mmole) of the precursor
1-(2-(3-methoxyphenyecyclohexyl)-N,N-dimethylmethaneamine and 500
ml of hydrobromic acid (47%, in water) were introduced together
into a single necked flask and stirred under reflux for 2 hours
using a magnetic stirrer. After conclusion of the reaction, the
hydrogen bromide was distilled off by applying a vacuum (water-jet
pump). The distillation residue was added to 250 ml water, and the
suspension was covered with a layer of 1000 ml ethyl acetate. The
pH of the reaction mixture was adjusted to pH 8 with aqueous
sodium-hydroxide solution (c=32% w/w), accompanied by cooling of
the reaction mixture with ice. Organic and aqueous phases were
separated, the aqueous phase was extracted three times with 350 ml
portions of ethyl acetate. In the process, the pH value was
monitored and maintained at a value of at least pH 8 using aqueous
sodium-hydroxide solution (c=32% w/w). The mixture was extracted
two more times with 150 ml portions of ethyl acetate, and the
organic phase was dried with MgSO.sub.4. The solvent was removed in
a rotary evaporator (bath temperature 44.degree. C., vacuum <20
mbar). The yield of crude product
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol amounted to 101 g.
The crude product 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
was added to 100 ml acetone and stirred until the light-brown
material solidified. Subsequently the material was filtered out by
suction and washed with a little diethyl ether. The yield amounted
to 48%, relative to the quantity of crude product employed.
Example 0.2
Preparation of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride
[0168] In order to prepare the hydrochloride salt, 42 g of the base
3-[2-(dimethylamino)methyl(cyclohex-1-yl)phenol were added to 210
ml methyl ethyl ketone. Subsequently 2 ml water and 23 ml
trimethylchlorosilane, dissolved in 45 ml methyl ethyl ketone, were
added. The reaction mixture was cooled down to 0.degree. C. by
cooling with ice and was kept cold overnight (in a refrigerator at
about 4.degree. C.). The solid substance that precipitated out was
filtered out by suction using a suction filter, with application of
a vacuum, and then washed with 30 ml of acetone. The yield of
3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride was
49 g (corresponding to 100% of the theoretical value). According to
NMR and GC analyses, the produce was >95% trans diastereomer.
The melting-point was 122-126.degree. C.
Example 1a
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
hydrochloride
[0169] In order to prepare the hydrochloride salt, 48.5 g (208
mmole) of the base 3-[2-(dimethylamino)methyl(cyclohex-1-yl)phenol,
prepared as in Example 0.1, were added to 250 ml acetone in
accordance with Procedure b). Subsequently 2 ml water and 27 ml
trimethylchlorosilane (TMCS), dissolved in 125 ml acetone, were
added. The solid substance that precipitated out was filtered off
by suction with a vacuum filter, with application of a vacuum, and
then washed with diethyl ether. The yield amounted to 53 g
(according to GC analysis 100% of the trans diastereomer).
[0170] Further batches of the hydrochloride salt
3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol hydrochloride
were prepared in an analogous manner:
TABLE-US-00011 HBr TMCS (in (47%)/ Acetone/ Water/ acetone)/ Trans
Batch Precursor/g ml Base/g ml ml ml Yield/g diastereomer/% 1-12
129 520 109 550 4.5 55.7 (275) 124 98.8 1-13 143 600 117 585 5 63.5
(290) 119 98.6 1-14 121 520 101 500 4 55 (250) 119 98.7 1-15 163
650 130 650 6 72 (325) 153 97.4 1-16 148 600 121 610 5.5 65.5 (300)
138 98.8
[0171] The solid substances of batches 1-12 to 1-16 were combined
and intimately blended. In order to remove residual solvent
(acetone and diethyl ether), the combined solids were predried (1
day at room temperature under vacuum <150 mbar), and
subsequently dried over Sicacide for 6 days at 70.degree. C. and
under a vacuum of <20 mbar. According to GC analysis, the
proportion of residual solvent (acetone, diethyl ether) amounted to
less than 200 ppm in each instance.
Example 1b
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
hydrochloride
[0172] In a 100 liter double-walled reactor with electric impeller
stirrer, Pt100 temperature-measuring device and oil-based
cooling/heating system, 37 kg (137.12 mol) of
(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol hydrochloride
were dissolved in 55 l water at a stirring speed of 100 rpm. The
solution was heated to 40.degree. C.-60.degree. C. until a clear
solution arose. At reduced pressure (about 30-50 mbar), 38 l-41 l
of the water were removed. The solution was stirred at 7.degree. C.
for about 16 hours. The resulting suspension was separated out via
a centrifuge. The product was dried in a drying cabinet at
45.degree. C. for 18 hours under a vacuum up to a final pressure of
130 mbar. 25.9 kg (70% of the theoretical value) of
(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol hydrochloride
were obtained with a residual-water content of 5.9%.
Example 2
Preparation of amorphous
(1R,2R)-3-[2-(dimethylamino)-methyl(cyclohex-1-yl)]phenol
hydrochloride
Example 2.1
Freeze Drying
[0173] 500.4 mg of the hydrochloride prepared in accordance with
Example 1b were dissolved in 5 ml water and then chilled to
-74.degree. C. The solution was then freeze dried at this
temperature and at a pressure of <0.1 mbar for 20 hours. A
solid, white residue was obtained quantitatively which, according
to evaluation of the Raman spectrum, is amorphous.
Example 2.2
Freeze Drying
[0174] 212.5 mg of the hydrochloride prepared in accordance with
Example 1b were dissolved in 2 ml water and then chilled to
-89.degree. C. The solution was then freeze dried at this
temperature and at a pressure of <0.01 mbar for 66 hours. A
solid, white residue was obtained quantitatively, which, according
to evaluation of the Raman spectrum, is amorphous.
Example 2.3
Freeze Drying
[0175] 651.5 mg of the hydrochloride prepared in accordance with
Example 1b were dissolved in 6.5 ml water and then chilled to
-80.degree. C. The solution was then freeze dried at this
temperature and at a pressure of 0.6 mbar for 21 hours. A solid,
white residue was obtained quantitatively, which, according to
evaluation of the Raman spectrum, is amorphous.
Example 3
Preparation of
(1R,2R)-3[-2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
hydrochloride as crystalline Form I
Example 3.1
[0176] 209.7 mg of the hydrochloride prepared in accordance with
Example 1a were suspended in 6 ml ethyl acetate and stirred for ten
days at a stirrer speed of approximately 600 rpm (revolutions per
minute) and at a temperature from 23.degree. C. to 28.degree. C.,
whereby the temperature for the first two days was 23.degree. C.,
for the next two days was 28.degree. C., and for the remaining
duration 23.degree. C. The resulting white solid substance was
separated out and analyzed. According to the Raman spectrum, only
bands of the crystalline form I were measured.
Example 3.2
[0177] 101.4 mg of the hydrochloride prepared in accordance with
Example 1a were suspended in 3 ml ethyl acetate, added to 14.5 mg
of the hydrochloride in the crystalline form I and stirred for ten
days at a stirrer speed of approximately 600 rpm (revolutions per
minute) and at a temperature of 23.degree. C. The resulting white
solid substance was separated out by vacuum filtration (5 minutes)
and dried in air. According to the X-ray powder diffractogram, only
signals of the crystalline form I were measured. A melting-point of
approximately 150.degree. C. was ascertained by differential
scanning calorimetry (DSC, heating-rate 10.degree. C./minute). An
endothermic peak is observed within the range from 121.degree. C.
to 122.degree. C.
Example 4
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
hydrochloride as crystalline Form II
Example 4.1
[0178] 191.8 mg of the hydrochloride prepared in accordance with
Example 1b were heat-treated for 23.5 hours in an open vessel at
155.degree. C. According to the X-ray powder diffractogram, only
signals of the crystalline form II are measured. A melting-point of
approximately 177.degree. C. is ascertained by differential
scanning calorimetry (DSC, heating-rate 10.degree. C./minute).
Example 4.2
[0179] 600 mg of the hydrochloride of the crystalline form III were
added to 100 mg of the hydrochloride in the crystalline form II,
intimately blended, and suspended in 10 ml of ethyl acetate. The
suspension was stirred for six days at room temperature. The
resulting white solid substance was separated out by vacuum
filtration and dried for 1.5 hours in a drying cabinet at a
temperature of 45.degree. C. and under a vacuum <150 mbar.
According to DSC analysis (heating-rate 10 K/minute), the resulting
solid substance exhibits an endothermy at 177.2.degree. C., which
is associated with the crystalline form II.
Example 4.3
[0180] 4.0 g hydrochloride of the crystalline form V were stirred
in a vessel without solvent at a temperature of 154.degree. C.
(temperature of the oil bath 154.degree. C. to 162.degree. C.). The
Raman spectrum of the resulting solid substance exhibits only bands
of the crystalline form II.
Example 5
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol
hydrochloride as crystalline Form III
Example 5.1
[0181] 76.9 mg of the amorphous hydrochloride prepared in
accordance with Example 2 were suspended in 1 ml ethyl acetate and
stirred for three days at a stirrer speed of approximately 400 rpm
(revolutions per minute) and at a temperature of 25.degree. C., for
one day at 40.degree. C., for one day at 60.degree. C., for one day
at 50.degree. C., for one day at 45.degree. C., for one day at
70.degree. C., and for 9 days at 75.degree. C., whereby starting
from the third day the stirring speed was 600 rpm in each instance.
The resulting white solid substance was separated out by vacuum
filtration (about 5 minutes) and dried in air. According to the
X-ray powder diffractogram, only signals of the crystalline form
III are measured.
Example 5.2
[0182] 70.5 mg of the amorphous hydrochloride prepared in
accordance with Example 2 were suspended in 1.5 ml
tert.-butylmethyl ether and stirred for seven days at a stirrer
speed of approximately 600 rpm (revolutions per minute) and at a
temperature of 40.degree. C. The resulting white solid substance
was separated by vacuum filtration (about 5 minutes) and dried in
air. According to the Raman spectrum, only bands of the crystalline
form III were measured. A glass transition temperature between
66.degree. C. and 67.degree. C. and a melting-point of
approximately 155.degree. C. were ascertained by differential
scanning calorimetry (DSC, heating-rate 10.degree. C./minute). A
further endothermic peak was observed at 88.degree. C.
Example 5.3
[0183] 147.8 mg of the amorphous hydrochloride prepared in
accordance with Example 2 were suspended in 1.5 ml ethyl acetate
and stirred for one day at a stirrer speed of approximately 600 rpm
(revolutions per minute) and at a temperature of 40.degree. C. The
resulting white solid substance was separated by vacuum filtration
(about 5 minutes) and dried in air. According to the Raman
spectrum, only bands of the crystalline form III were measured.
Example 5.4
[0184] 1 g of an acetone solvate or ethanol solvate of the
hydrochloride is suspended in 18 ml ethyl acetate and stirred at a
temperature of 23.degree. C. The white solid substance is separated
off by vacuum filtration (5 minutes) and dried in air. According to
the Raman spectrum, only bands of the crystalline form III are
measured.
Example 6
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride as crystalline Form IV
Example 6.1
[0185] 178.2 mg of the amorphous hydrochloride prepared in
accordance with Example 2 were suspended in 3.6 ml
tert.-butylmethyl ether and stirred for one day at a stirrer speed
of approximately 600 rpm (revolutions per minute) and at a
temperature of 40.degree. C. The resulting white solid substance
was separated by vacuum filtration (about 5 minutes) and dried in
air. According to the X-ray powder diffractogram, only lines of the
crystalline form IV were measured. A slight exothermy is observed
by differential scanning calorimetry (DSC, heating-rate 10.degree.
C./minute) at about 122.degree. C., which indicates a monotropic
conversion into another form. In the further course of the DSC
experiment, initially an endothermic peak at approximately
162.degree. C., and a further peak at approximately 171.degree. C.,
were observed.
Example 6.2
[0186] 153.2 mg of the amorphous hydrochloride prepared in
accordance with Example 2 were suspended in 3.5 ml heptane and
stirred for 26 days at a stirrer speed of approximately 600 rpm
(revolutions per minute) and at a temperature within the range from
40.degree. C. to 90.degree. C., whereby the temperature for the
first eight days was 40.degree. C., for the next six days
50.degree. C., for one day 75.degree. C., for three days 80.degree.
C., and for eight days 90.degree. C. The white solid substance was
separated by centrifuging (10 minutes at 10,000 revolutions) and
dried in air. According to the Raman spectrum, only bands of the
crystalline form IV were measured.
Example 6.3
[0187] 4.0 g hydrochloride of the crystalline form III were stirred
in a 100 ml round-necked flask without solvent for five hours at a
temperature of 154.degree. C. (temperature of the oil bath
154.degree. C. to 162.degree. C.).
[0188] Upon DSC analysis (heating-rate 10.degree. K/minute), the
resulting solid substance exhibits an endothermy at 168.8.degree.
C., which is associated with the crystalline form IV.
Example 7
Preparation of
(1R,2R)-3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol
hydrochloride as crystalline Form V
Example 7.1
[0189] 53.7 mg of the hydrochloride prepared in accordance with
Example 1b were dissolved in 1 ml ethanol and water (volume ratio:
1:1) at room temperature and left to stand in air at room
temperature until the solvent mixture had completely evaporated and
a solid substance remained. According to the X-ray powder
diffractogram, only lines of the crystalline form V were measured.
The solid residue was therefore determined to be the crystalline
form V.
Example 8
Stability at Room Temperature
Example 8.1
[0190] 51.4 mg of the hydrochloride in the crystalline form 1 and
49.8 mg of the hydrochloride in the crystalline form II were
suspended in 2 ml ethyl acetate and stirred for eleven days at a
temperature of 25.degree. C. The solid substance was separated by
vacuum filtration and dried in air. According to the Raman
spectrum, the sample predominantly contained the crystalline form I
and small amounts of form V.
Example 8.2
[0191] 33.6 mg of the hydrochloride in the crystalline form III and
31.5 mg of the hydrochloride in the crystalline form IV were
suspended in 2 ml ethyl acetate and stirred for twelve days at a
temperature of 23.degree. C. The solid substance was separated by
vacuum filtration and dried in air. According to the Raman
spectrum, only bands of the crystalline form I were measured.
Example 8.3
[0192] 30.6 mg of the hydrochloride in the crystalline form III and
30.7 mg of the hydrochloride in the crystalline form II are
suspended in 2 ml ethyl acetate and stirred for three days at a
temperature of 23.degree. C. The white solid substance is separated
off by vacuum filtration and dried in air. According to the Raman
spectrum, only bands of the crystalline form II are measured.
Example 8.4
[0193] 31.1 mg of the hydrochloride in the crystalline form IV and
28.9 mg of the hydrochloride in the crystalline form II are
suspended in 2 ml ethyl acetate and stirred for 32 days at a
temperature of 23.degree. C. The white solid substance is separated
out by vacuum filtration and dried in air. According to the Raman
spectrum, initially only bands of the crystalline form II were
measured. After the first three days of the experiment had passed,
the first traces of the crystalline form I were detected, and after
32 days almost exclusively the crystalline form I was detected.
[0194] From Examples 8.1 to 8.4, for the stability of the
crystalline compounds I, II, III and IV at room temperature under
conditions for avoiding the formation of solvates this sequence
arises: I>II>III.apprxeq.IV.
Example 9
Absorption of Water
[0195] The absorption of water is ascertained by dynamic vapour
sorption (DVS) with a DVS-1 instrument manufactured by Surface
Measurement Systems Ltd. The sample is placed in a platinum
crucible at the pivot of a microbalance. The sample is then
initially equilibrated at 50% relative air humidity and then
subjected to a predefined measuring program. The temperature was
25.degree. C. The change in weight of the sample is determined.
A) Crystalline Form I
[0196] The crystalline form absorbs water very quickly at a
relative air humidity >50%. If the relative air humidity is
reduced to 0%, the water content of the sample is reduced to 3.2
wt. %. The water content at 50% relative air humidity at the end of
the measuring cycle is 7.2%, and the recorded Raman spectrum
corresponds to the Raman spectrum of the crystalline form V.
B) Crystalline Form II
[0197] The crystalline form absorbs water very quickly at a
relative air humidity >75%. If the relative air humidity is
reduced to 0%, the water content of the sample is reduced to 3.3
wt. %. The water content at 50% relative air humidity at the end of
the measuring cycle is 7.9%, and the recorded Raman spectrum
corresponds to the Raman spectrum of the crystalline form V.
C) Crystalline Form III
[0198] The crystalline form absorbs water very quickly at a
relative air humidity >55%. If the relative air humidity is
reduced to 0%, the water content of the sample is reduced to 3.1
wt. %. The water content at 50% relative air humidity at the end of
the measuring cycle is 7.8%, and the recorded Raman spectrum
corresponds to the Raman spectrum of the crystalline form V.
D) Crystalline Form IV
[0199] The crystalline form absorbs water very quickly at a
relative air humidity >60%. If the relative air humidity is
reduced to 0%, the water content of the sample is reduced to 3.1
wt. %. The water content at 50% relative air humidity at the end of
the measuring cycle is 7.6%, and the recorded Raman spectrum
corresponds to the Raman spectrum of the crystalline form V.
Example 10
Humid Storage of the Crystalline Forms II and III
[0200] Storage conditions: 25.degree. C. and 60% relative air
humidity for 5 hrs, 24 hrs and 7 days
Test Conditions:
First Test Series:
[0201] The substances were weighed directly into DSC and TGA
crucibles, and these crucibles were stored in a climate
chamber.
Second Test Series:
[0202] 50 mg of the substances were weighed into 1 ml vials, three
times in each case, and these vials were then stored openly in a
climate chamber.
[0203] The two crystalline forms II and III display differing
water-absorption behavior. Modification II absorbs water more
slowly in both tests than modification III. Whereas, after 5 hours,
modification III has already absorbed 6.70% water in the first test
series, and 1.92% water in the second test series, in the case of
modification II no appreciable absorption of water can be
established (0.04% and 0.12%, respectively).
[0204] After 24 hours, in the case of modification III in the first
test series the water equivalent has not increased further (6.28%),
whereas in the second test series after 24 hours a rise in the
water content to 6.08% has occurred. On the other hand, after 24
hours in the first test series, modification II has absorbed 3.28%
water, and in the second test series 6.08% water.
[0205] After one week of storage at 60% relative air humidity, in
the case of modification III--both in the first test series and in
the case of the second test series--no significant absorption of
water can any longer be registered (water content: 6.74% and 6.83%,
respectively). In the case of modification II, a water content of
7.03% and 7.04%, respectively, arises after one week in both test
series.
Example 11
Example 11.1
Formation of Ethanol Solvate
[0206] 67.1 mg of the hydrochloride prepared in accordance with
Example 1b are stirred in suspension in 0.25 ml ethanol at
25.degree. C. for one day. According to Raman and TG-FTIR analyses,
an ethanol solvate is present.
[0207] The loss of mass determined by TG-FTIR amounted to 8.9%,
whereby ethanol and a little water were detected.
Example 11.2
Formation of Ethanol Solvate
[0208] 99.7 mg of the hydrochloride prepared in accordance with
Example 1b are stirred in suspension in 0.2 ml ethanol at
25.degree. C. for one day. According to Raman analyses, an ethanol
solvate is present.
[0209] Storage of the solvate obtained in such a way at room
temperature in a vacuum overnight does not result in desolvation.
Further storage of the sample for 2 months in the presence of a
saturated Mg(NO.sub.3).sub.2 solution and subsequent storage for 2
months in the presence of a saturated NaCl solution resulted in the
hydrate form V.
Example 11.3
Formation of Acetone Solvate
[0210] 100 mg of the hydrochloride prepared in accordance with
Example 1b were heat-treated for 23.5 hours at 155.degree. C. As
Raman analysis shows, form II arose. 51 mg of the material obtained
in this way were suspended in 0.1 ml of an acetone/water mixture
(95:5 volume/volume) at 25.degree. C. for 2 days. Raman analysis
showed the formation of a solvated form. The loss of mass
determined by TG-FTIR amounted to 9.4%, whereby acetone and a
little water were detected.
Instruments and Methods
Differential Scanning Calorimetry (DSC):
[0211] Instrument designation Perkin Elmer DSC 7 or Perkin Elmer
Pyris 1. Variable measurements (heating-rate) in gold or aluminium
crucibles.
[0212] Mettler Toledo DSC 821, perforated 40 .mu.m aluminium
standard crucible, variable temperature range and variable
heating-rate, nitrogen atmosphere.
[0213] Unless otherwise stated, amounts of material within the
range from 2 mg to 20 mg were employed.
Powder X-Radiation Diffraction (PXRD) Patterns:
[0214] PXRD is carried out with a Philips 1710 powder X-radiation
diffractometer or with a Phillips X'Pert PW 3040, using
CuK.sub..alpha. radiation. D-spacings are computed from the
2.theta. values, the wavelength of 1.54060 .ANG. being used as a
basis. The 2.theta. values generally have an error-rate of
.+-.0.1-0.2.degree.. The experimental error in the case of the
D-spacing values is therefore dependent on the location of the
peak.
Raman Spectroscopy:
[0215] FT Raman spectra are recorded with a Bruker RFS 100 FT Raman
system which is operated with an Nd:YAG laser (wavelength 1064 nm)
and with a germanium detector cooled with liquid nitrogen. For each
sample, 64 scans with a resolution of 2 cm.sup.-1 are accumulated.
A laser power of 100 mW is generally used.
TG-FTIR
[0216] Netsch Thermo-Microbalance TG209 with Bruke FT-IR
Spektrometer Vektor 22. The measurements were carried out in an
aluminium crucible (open or with microhole) under nitrogen
atmosphere. The heating-rate amounted to 10 K/minute within a range
of 25-250.degree. C.
[0217] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and quivalents thereof.
* * * * *