Note: Descriptions are shown in the official language in which they were submitted.
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3-[2-(dimethylamino)methyl-(cyclohex-l-yl)l-phenol maleate and the crystalline
forms thereof
The present invention relates to salts of maleic acid and 3-[2-
(dimethylamino)methyl-(cyclohex-l-yl)]-phenol, preferably in a 1:1
composition,
to stable crystalline forms of the salt and to processes for the production
thereof,
to a pharmaceutical composition and to the use of the salt as a pharmaceutical
active ingredient in a composition.
EP-A1-0 753 506 describes 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenols
with analgesic action. It is mentioned in the text that salts may also be
produced
from the free bases, maleic acid not, however, being mentioned as a possible
anion. In the Examples, only hydrochlorides are provided, i.e. a salt with a
monovalent anion. EP-Al-0 753 506 does not contain any indications as to the
stoichiometric ratio in which 3-[2-(dimethylamino)methyl-(cyclohex-l-yl)]-
phenols
with divalent anions may be present, for example as half- or 1:1 salts. A more
detailed investigation of 3-[2-(dimethylamino)methyl-(cyclohex-l-yl)]-phenol
hydrochloride has shown that this crystalline solid is distinguished by
pronounced polymorphism and forms a plurality of crystalline and also
metastable forms. In addition, this hydrochloride has a strong tendency to
form
hydrates and solvates, which is a considerable disadvantage with regard to the
purposeful production of a specific crystalline form. Crystalline 3-[2-
(dimethylamino)methyl-(cyclohex-l-yl)]-phenol hydrochloride has additionally
proven to be decidedly hygroscopic. This range of properties of 3-[2-
(dimethylamino)methyl-(cyclohex-l-yl)]-phenol hydrochloride makes it clear
that
it is very difficult using this active substance to provide pharmaceutical
compositions with reproducible properties which are also retained over a
period
of storage. To achieve these objectives there would at least be a need for
complex protective measures.
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It has now surprisingly been found that 3-[2-(dimethylamino)methyl-(cyclohex-1-
yl)]-phenol forms with maleic acid a maleate as a crystalline solid,
preferably in a
composition exhibiting a ratio of 1:1 of maleic acid anion and 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol. It has furthermore surprisingly
been found that the maleate is not hygroscopic, is stable in air and does not
form
any hydrates or solvates. It has also surprisingly been found that 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is able to form only a
few, namely two crystalline forms stable at low or at elevated temperature,
and
that identifiable metastable forms convert into form A, which is stable at
room
temperature. Form B, which is stable at higher temperatures, may likewise be
converted into form A, it being possible for both forms to be present in a
mixture
at low temperature. Crystalline form A is also distinguished by elevated
chemical
stability at temperatures of below 100 C. In addition, 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate also exhibits valuable
biological properties, such as for example good solubility particularly in
polar and
protic solvents including water, and good bioavailability. Due to its range of
properties, 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is
outstandingly suitable for the formulation of pharmaceutical compositions.
The present invention firstly provides salts of maleic acid with 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol, 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleates of the formula I
OH
H~ C(O)OH
CH3 II (I)
1 ~ C
2 +N-H H/ C(O)O-
CH3
being preferred.
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The compounds according to the invention, such as compounds of the formula I,
each contain a chiral C atom in positions 1 and 2 of the cyclohexane ring. The
compounds according to the invention such as the compounds of the formula I
comprise all stereoisomers and mixtures of stereoisomers. Diastereomers or
mixtures of enantiomeric diastereomers are preferred which exhibit
transconfiguration of the phenyl ring and of the dimethylaminomethyl group
(1 R,2R or 1 S,2S configuration), the enantiomer with the absolute
configuration
(1 R,2R) being very particularly preferred.
The structure of the (1 R,2R)-enantiomer of 3-[2-(dimethylamino)methyl-
(cyclohex-l-yl)1-phenol is shown below:
\ OH
I
CH3
CH3
The compounds of the formula I may be obtained, in a manner similar to the
methods described in general in EP-A1-0 753 506 for the production of salts,
from the free base and reaction with maleic acid or maleic anhydride in the
presence of water. The free base 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-
phenol may be isolated for example from the hydrochloride described in
Examples 9 and 10 of EP-A1-0 753 506. To this end, the hydrochloride is
dissolved in an organic solvent, combined with an aqueous inorganic base, for
example alkali metal bases or also alkali metal hydrogencarbonates (such as
LiOH, NaOH, KOH, NaHCO3 and KHCO3), and the organic phase is isolated.
The organic phase may be dried and the base may either be isolated in
conventional manner or optionally used directly for salt formation after
concentration by evaporation from the solvent.
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It has surprisingly been found that salt formation only results in a
crystalline form
when the temperature is monitored and no temperatures of over 100 C are
applied.
The present invention also provides a process for the production of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I,
comprising the combination of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-
phenol and maleic acid, wherein preferably at least one of the components is
present in dissolved or suspended form.
The present invention also provides a process for the production of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I,
comprising the steps
a) dissolving or suspending 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-
phenol in a solvent,
b) mixing the solution or suspension with maleic acid or a solution of maleic
acid, and
c) isolating the compound of the formula I,
the temperature preferably not being above 100 C in any process step and it
also being possible to reverse steps a) and b).
The temperature is preferably no more than 80 C, more preferably no more than
70 C and particularly preferably no more than 60 C. During dissolution
according to process step a), the temperature is generally higher than during
mixing according to process step b).
The free base and maleic acid may be used in the molar ratio of 1:1, or maleic
acid may also be used in excess, for example in a molar ratio of up to 1.3,
preferably up to 1.1. When an excess of the free base is used, no hemimaleates
are formed, even if a molar ratio of base to maleic acid of 2:1 is
established.
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The quantity of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol in the
solution may amount for example to 5 to 70 wt.%, preferably 10 to 60 wt.%,
more
preferably 10 to 50 wt.%, and particularly preferably 15 to 40 wt.%, relative
to the
solution. The solution of 3-[2-(dimethylamino)methyl-(cyclohex-1-yI)]-phenol
may
be heated and then optionally cooled to the temperature desired for mixing
with
maleic acid.
In the process for the production of 3-[2-(dimethylamino)methyl-(cyclohex-1-
yl)]-
phenol maleate described herein, the maleic acid may in each case also be used
in the form of the anhydride thereof.
Inert (compatible) solvents for 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-
phenol and maleic acid or maleic anhydride are for example aliphatic,
cycloaliphatic and aromatic hydrocarbons (hexane, heptane, petroleum ether,
cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic
halogenated hydrocarbons (methylene chloride, chloroform, di- and
tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile),
ethers (diethyl
ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether,
ethylene
glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran,
dioxane),
ketones (acetone, 2-butanone, methyl isobutyl ketone), carboxylic acid esters
and lactones (ethyl or methyl acetate, valerolactone), N-substituted lactams
(N-
methylpyrrolidone), carboxylic acid amides (dimethylacetamide,
dimethylformamide), acyclic ureas (dimethytimidazoline), and sulfoxides and
sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide,
tetramethylene sulfone) and alcohols (methanol, ethanol, 1- or 2-propanol, n-,
i-
and t-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, ethylene glycol
monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol
monomethyl- or monoethyl ether) and water. The solvents may be used alone or
in a mixture of at least two solvents. Advantageously, physiologically
unproblematic solvents are used, which are familiar to the person skilled in
the
a rt.
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Mixing in process step b) may proceed by means of the slow or rapid addition
of
one solution to the other solution. One or both solutions may be heated.
Mixing
may also be performed in such a way, however, that one or both solutions are
at
room temperature or have been cooled, for example down to -20 C and more
preferably down to -10 to +10 C, most preferably -5 to +5 C. After mixing, the
mixture may be heated and cooled again and stirring may continue for a given
period. Crystal formation may also be promoted by seeding.
As a rule, a white precipitate forms as early as during mixing, said
precipitate
being crystalline and readily filterable. Isolation may proceed by decanting,
filtration or centrifugation. The crystalline residue may then be dried again,
for
example by means of heating, vacuum drying or heating under a vacuum, or by
means of an optionally heated, inert stream of gas (air, nitrogen, noble
gases).
The compounds of the formula I are obtained in elevated yields and with
elevated purity. As a rule, no or only a few further cleaning steps, such as
for
example recrystallisation, are necessary and the product may be used directly
for the production of pharmaceutical compositions.
The present invention also provides a salt of maleic acid and 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol, in particular a salt of the
formula I, obtainable by one of the above-described processes.
The compounds of the formula I and the production process according to the
invention offer considerable and in part unexpected advantages relative to
corresponding hydrochlorides. Since no hydrates and solvates could be
characterised, the selection of usable solvents is broad and non-critical.
Open
handling without particular protective measures is possible due to the
stability in
air and against moisture. The spontaneous salt formation and formation of
crystalline deposits and their good filterability allow processes on an
industrial
scale
The compounds of the formula I are obtained in the salt formation process
according to the invention as crystalline solids predominantly in a
polymorphic
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form, which is hereinafter designated form A. Amorphous forms of the
compounds of the formula I are simple to obtain for example by means of freeze
drying or rapid cooling of solutions. Amorphous compounds of the formula I are
not very stable and tend to crystallise in the presence of moisture. They are
therefore particularly suitable as a starting material for the purposeful
production
of crystalline forms.
It has been found that the compounds of the formula I form as crystalline
solids
polymorphic forms which may be produced purposefully from 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate and, due to their
stability,
are in particular suitable as the active ingredient in the formulation of
pharmaceutical compositions. It is known [see for example Z. Jane Li et al. in
J.
Pharm. Sci., Vol. 88(3), pages 337 to 346 (1999)] that enantiomers result in
identical X-ray diffractograms and Raman spectra and thus form the same
polymorphic forms. For the purposes of the invention, polymorphic forms of all
enantiomers are thus included.
The present invention also provides a crystalline form of 3-[2-
(dimethylamino)methyl-(cycfohex-1-yl)]-phenol maleate of the formula 1, which
exhibits a characteristic X-ray diffraction pattern in the range from 2 to 35
28
with pronounced characteristic lines, expressed in d values (A):
9.4 (vs), 6.8 (m), 5.56 (s), 5.30 (s), 5.22 (s), 4.71 (s), 4.66 (s), 4.24 (m),
4.12 (m),
4.03 (m), 3.98 (s) 3.76 (m), 3.27 (m);
hereinafter designated as form A.
Both above and below, the abbreviations in brackets mean the following: (vs) _
very strong intensity, (s) = strong intensity, (m) = moderate intensity, (w) =
weak
intensity, and (vw) = very weak intensity.
The present invention also provides a crystalline form A of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
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exhibits a characteristic X-ray diffraction pattern with following pronounced
reflections.
2theta rel. intensity
9.38 100
9.94 5
10.35 8
12.76 6
13.07 20
13.49 7
15.94 43
16.72 52
16.98 40
17.54 15
18.86 61
19.04 48
19.28 8
20.01 5
20.57 6
20.96 24
21.57 23
22.03 20
22.33 30
23.69 15
24.84 8
25.01 9
25.71 11
26.35 7
26.75 13
27.24 16
27.66 9
27.95 6
28.40 5
28.68 9
29.87 6
30.76 8
31.37 4
31.67 4
31.99 6
32.53 4
32.80 5
33.55 7
35.20 5
36.93 5
37.58 5
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2theta rel. intensit
44.54 6
45.70 4
The above Table states the peak positions (in 2 theta) and the relative
intensities
of the peaks, the highest intensity peak here being normalised to a relative
intensity of 100.
The present application furthermore provides a crystalline form A of 3-[2-
(dimethyiamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I
(polymorph A), characterised by a powder diffractogram comprising one or more
the following reflections: 9.38 (100), 9.94 (5) and 10.35 (8) (in each case
0.5 in
2 theta, relative intensity in brackets). The powder diagram may preferably
additionally comprise one or more of the following reflections: 12.76 (6),
15.94
(43), 17.54 (15), 19.28 (8), 28.68 (9) and 31.99 (6) (in each case 0.2 in 2
theta,
relative intensity in brackets).
The present invention also provides a crystalline form A of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
exhibits a characteristic Raman spectrum with characteristic lines, expressed
in
wavenumbers (cm-1):
Position (cm-1) Intensity
3060 m
3040 m
3021 m
2986 m
2966 s
2933 s
2920 s
2895 m
2879 m
2856 s
2812 w
1690 m
1616 m
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Position (cm-1) Intensity
1601 m
1569 vw
1467 m
1443 m
1412 w
1389 m
1361 w
1351 m
1332 w
1322 w
1306 w
1295 w
1289 w
1273 m
1247 m
1227 w
1211 m
1177 w
1167 w
1122 vw
1106 w
1081 w
1076 w
1055 m
1047 m
1025 w
999 vs
971 vw
957 m
929 w
901 w
855 m
843 m
817 w
796 w
754 m
707 vw
676 vw
635 m
614 w
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Position (cm-1) Intensity
572 vw
536 m
514 vw
486 vw
468 vw
454 w
425 vw
400 w
359 w
345 w
328 m
292 m
272 m
247 s
188 w
118 vs
105 vs
81 vs
The invention further provides a crystalline form A of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I
comprising one or more of the following characteristic bands in the Raman
spectrum, in each case expressed in wavenumbers (cm-1): 118 (vs), 188 (w),
400 (w), 676 (w), 2812 (w), 2879 (m),
preferably one or more of the following bands:
118 (vs), 188 (w), 292 (m), 328 (m), 359 (w), 400 (w), 486 (vw), 676 (w), 901
(w),
1025 (w), 1273 (m), 1351 (m), 1412 (w), 1569 (vw), 1601 (m), 1690 (m), 2812
(w), 2879 (m), 2986 (m), 3060 (m).
The present invention also provides a crystalline form A of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula 1, which
exhibits an X-ray diffraction pattern as illustrated in Figure 1.
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The present invention also provides a crystalline form A of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
exhibits a Raman spectrum as illustrated in Figure 2.
The crystalline form A is the thermodynamically most stable form at low
temperature up to for example approx. 100 C and additionally exhibits
excellent
chemical and physical stability. Polymorph A is stable and insensitive even to
the
influence of atmospheric humidity at elevated relative atmospheric humidities
of
up to 90%, even over a relatively long period. No water absorption, no
formation
of hydrates and no conversion into other crystalline forms is observed under
normal conditions. Polymorph A also exhibits no phase transformations in air
and the presence of moisture. Polymorph A also does not change under
elevated pressure or on grinding, and conversion into other crystalline forms
on
exposure to relatively high pressure does not occur. Polymorph A is also non-
hygroscopic and absorbs only small quantities of surface water. Under these
conditions, polymorph A also does not form any solvates and no conversion is
observed in contact with solvents. Solubility in polar solvents is very good.
The
melting point is approx. 167 C and the enthalpy of fusion is approx. 135 J/g.
Polymorph A may be produced as a solid powder with desired average particle
sizes which lie as a rule in the range from 1 m to approx. 500 m. Because of
these properties, the crystalline form A is extremely well suited to the
production
of pharmaceutical formulations.
The compound of the formula I forms a further crystalline form B which is
thermodynamically stable at elevated temperatures, and which is likewise
stable
under normal conditions in air and with the exclusion of atmospheric humidity.
The crystalline form B may also be handled in such a way that it may be used
for
the production of pharmaceutical compositions.
The present invention also provides a crystalline form of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
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exhibits a characteristic X-ray diffraction pattern in the range from 2 to 35
20
with pronounced characteristic lines, expressed in d values (A):
10.6 (m), 7.5 (m), 7.3 (m), 6.1 (s), 5.29 (s) 4.88 (m), 4.72 (m), 4.47 (vs),
4.43 (m),
4.26 (m), 4.24 (m), 3.99 (s), 3.71 (m), 3.52 8m), 3.30 (s);
hereinafter designated as form B.
The present invention also provides a crystalline form B of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)J-phenol maleate of the formula I, which
exhibits a characteristic X-ray diffraction pattern with following pronounced
reflections.
theta rel. intensity
8.36 18
11.85 20
12.19 20
13.41 12
14.50 49
14.83 11
16.77 58
18.16 17
18.78 28
19.84 100
20.00 17
20.84 19
20.97 16
21.19 12
22.27 33
22.64 7
22.85 11
23.95 18
24.53 7
24.85 8
25.26 16
25.97 8
26.66 12
27.00 29
27.18 13
27.48 8
28.21 4
29.10 6
29.41 9
29.90 8
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theta rel. intensity
30.49 10
31.32 6
33.14 6
33.88 5
34.32 4
34.99 10
36.32 3
36.88 4
37.86 4
38.35 10
42.11 5
42.78 3
43.05 3
43.62 6
44.35 4
46.83 6
47.80 3
48.35 3
The above Table states the peak positions (in 2 theta) and the relative
intensities
of the peaks, the highest intensity peak here being normalised to a relative
intensity of 100.
The present invention furthermore provides polymorph B of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I,
characterised by a powder diffractogram comprising one or more the following
reflections: 8.36 (18), 14.5 (49) and 14.83 (11) (in each case 0.5 in 2
theta,
relative intensity in brackets). The powder diagram may preferably
additionally
comprise one or more of the following reflections: 11.85 (20), 12.19 (20),
18.16
(17), 22.85 (11), 29.1 (6) and 29.41 (6) (in each case 0.2 in 2 theta,
relative
intensity in brackets).
The present invention also provides a crystalline form B of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
exhibits a characteristic Raman spectrum with characteristic lines, expressed
in
wavenumbers (cm-1):
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Position (cm-1) Intensity
3045 vs
3028 m
2974 s
2953 s
2928 vs
2896 s
2856 s
2829 m
1703 s
1621 m
1612 m
1583 m
1480 vw
1459 m
1446 m
1401 vw
1385 m
1360 s
1227 vw
1324 w
1313 m
1309 m
1295 m
1282 m
1253 w
1220 w
1211 m
1197 m
1178 w
1162 m
1124 w
1104 w
1081 w
1076 w
1052 m
1010 w
999 vs
971 vw
956 w
933 w
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Position (cm-1) Intensity
890 w
875 m
858 m
841 s
816 m
794 m
750 m
708 vw
628 w
620 w
605 vw
578 w
573 w
538 m
507 vw
472 w
455 w
449 w
418 w
372 w
340 m
307 w
272 m
246 s
229 m
101 vs
83 vs
The present invention further provides a crystalline form B of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I
comprising one or more of the following characteristic bands in the Raman
spectrum, in each case expressed in wavenumbers (cm-1): 229 (vs), 875 (w)
and 2829 (m),
preferably one or more of the following bands:
229 (m), 307 (w), 372 (w), 605 (vw), 875 (m), 890 (w), 1010 (w), 1197 (m),
1401
(vw), 1480 (vw), 1583 (m), 1703 (s), 2829 (m), 2953 (s).
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The invention also provides a crystalline form B of 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate of the formula I, which exhibits an X-ray
diffraction pattern as illustrated in Figure 3.
The invention further provides a crystalline form B of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate of the formula I, which
exhibits a Raman spectrum as illustrated in Figure 4.
The polymorphic form B may convert into the crystalline form A. Forms A and B
form an enantiotropic system with a transition point or range of approx. 100
to
120 C. The present invention therefore also provides mixtures of crystalline
forms A and B in any per se desired quantity ratios.
Crystalline form B is the thermodynamically most stable form at elevated
temperatures, for example approx. at least 100 C or more. Polymorph B
additionally exhibits excellent chemical stability at elevated temperatures,
even
in the presence of atmospheric humidity. Its physical stability is lower,
since at
elevated pressure, and also at elevated temperatures with or without the
influence of moisture, conversion into polymorph A occurs. However, no water
absorption and no hydrate formation is observed. Polymorph B also does not
form any solvates. In contact with solvents, conversion into crystalline form
A
may take place. Solubility in polar solvents is very good and comparable with
the
solubility of polymorph A. The melting point is approx. 178 C and the enthalpy
of
fusion is approx. 125 J/g. Polymorph B may be produced as solid powder with
desired average particle sizes which lie as a rule in the range from 1 m to
approx. 500 m. It is advisable to store the crystalline form B under dry
protective gas (nitrogen).
The polymorphic forms may be produced using per se known crystallisation
processes from the salt 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol
maleate, for example stirring of suspensions (establishment of phase
equilibria),
precipitation, recrystallisation, or evaporation of solvents. Dilute,
saturated or
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supersaturated solutions may be used, with or without seeding with a crystal
nucleating agent. The temperatures for forming solutions may amount to up to
100 C. Crystallisation may be initiated by cooling to approx. -100 C to 30 C,
and
preferably -30 C to 20 C, it being possible for cooling to proceed
continuously or
stepwise. To produce solutions or suspensions, amorphous or crystalline
starting
materials may be used, in order to achieve high concentrations in solutions
and
to obtain other crystalline forms.
The present invention also provides a process for the production of the
crystalline form A from 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol
maleate, wherein
a) a pulverulent, solid, amorphous form of 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate is treated with a water vapour-containing
inert gas; or
b) a suspension of the amorphous form of 3-[2-(dimethylamino)methyl-
(cyclohex-1-yi)]-phenol maleate is produced in a solvent as carrier and
stirred until the crystalline form A is fully formed; or
c) 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is dissolved
in a solvent and then precipitated; or
d) 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol and maleic acid are
combined, wherein preferably at least one of these components is in
dissolved or suspended form, and the resultant product is isolated,
providing that the temperature does not exceed 100 C.
The temperature in process steps a) and b) preferably amounts to at most 40 C
and the process is particularly preferably performed at room temperature.
Inert
gases are for example air, nitrogen and noble gases, air being particularly
preferred for reasons of economic viability. The relatively humidity of the
gases
may amount for example to 40 to 90% and preferably 60 to 90%. The treatment
time in process step a) depends substantially on particle size and relative
humidity and may amount for example to 5 to 100 hours. In process step a),
polymorph B may also be formed in addition to form A, if the relative
atmospheric
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humidity is too low and/or the treatment time is too short. After isolation,
the
crystalline residue may be dried in conventional manner, temperatures of over
100 C conveniently being avoided.
Process step b) is preferably performed at approx. -20 to 40 C and
particularly
preferably at -5 C to 25 C (approx. room temperature). Solvents which may be
considered have been stated above. The treatment time in process step b) may
amount to 5 to 100 hours. After isolation, the solvent or solvent mixture used
may be removed in conventional manner by means of known drying processes.
In process step c), the crystalline form A, B or the amorphous form of 3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate may be used for the
production of solutions. The concentration of 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate in the solution depends on the selected
temperature and on the solvent. The dissolved quantity may amount to for
example from 0.5 to 50, preferably 0.5 to 30, more preferably 0.5 to 20 and
particularly preferably 1 to 15 weight percent, relative to the solvent. The
dissolution temperature may amount to up to 100 C and preferably up to 60 C.
The solution may also be produced at room temperature, if a solvent having
elevated solvency is used, for example water, acetone, dimethylformamide,
dimethyl sulfoxide, methanol, ethanol, N-methylpyrrolidone and propylene
glycol.
Precipitation may proceed by means of cooling, partial or complete removal of
the solvent, addition of a precipitating agent (non-solvent, for example
heptane
or methyl t-butyl ether) or a combination of these measures. Cooling may mean
slow cooling or also quenching to temperatures of down to -20 C and preferably
down to 0 C. The solvent may proceed by heating, in a gas stream, application
of a vacuum or a combination of these measures. Heating to remove solvent
means a temperature of at most 70 and preferably at most 50 C in process step
c). Precipitation processes according to process step c) are preferably used
to
produce the polymorphic form A.
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In process step d), the temperature is preferably no more than 80 C, more
preferably no more than 70 C and particularly preferably no more than 60 C.
During dissolution or suspension of a component, the temperature is generally
higher than during mixing.
The present invention also provides a salt of the formula I of maleic acid and
3-
[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol in crystalline form A
(polymorph A) obtainable by a process according to one of the above-described
processes.
While production of the polymorphic form A is relatively non-critical, the
polymorphic form B may only be obtained using a special process. It has
surprisingly been found that form B is obtainable reproducibly using an
evaporation process, a specific combination of solvent and elevated
evaporation
temperatures.
The present invention accordingly also provides a process for the production
of
crystalline form B of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol
maleate,
wherein 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate is
dissolved
in a mixture of tetrahydrofuran and water in the volume ratio of 0.8:1.2 to
1.2:0.8,
and then the solvent mixture is removed completely at a temperature of at
least
80 C. Lower evaporation temperatures in an open atmosphere are also possible,
for example at room temperature in an open vessel (contact with atmospheric
humidity).
Tetrahydrofuran (THF) and water preferably exhibit a volume ratio of 1:1.
Prior to
removal of the solvent mixture, the solution may be stirred for a given
period, for
example up to 24 hours at elevated temperature (approx. 80 to 100 C). To
remove the solvent mixture, a gas stream may additionally be used and/or a
vacuum applied. Heating to remove solvent means a temperature of at least
80 C and preferably up to approx. 120 C and particularly preferably 90 to 100
C.
The solvent is particularly preferably removed by distillation in a rotary
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evaporator. The quantity of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenoi
maleate in the mixture of THF and water may amount to 0.5 to 20, preferably
0.5
to 10 weight percent, relative to the THF and water mixture.
It has also been found that the establishment of phase equilibria by means of
stirring suspensions at temperatures of at least 120 C leads to the formation
of
crystalline form B.
The present invention also provides a salt of the formula I of maleic acid and
3-
[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenoi in crystalline form B
(polymorph B) obtainable by a process according to one of the above-described
processes.
Due to its favourable overall range of properties, 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate is excellent as an active ingredient for
pharmaceutical compositions and very particularly for analgesic medicines.
Accordingly, the invention also provides the use of 3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate of the formula I as an active ingredient in
pharmaceutical preparations, preferably as an active ingredient in analgesics.
Here too, as throughout the application, preferred diastereomers or mixtures
of
enantiomeric diastereomers are those which exhibit transconfiguration of the
phenyl ring and of the dimethylaminomethyl group (1 R,2R or 1 S,2S
configuration), the enantiomer with the absolute configuration (1 R,2R) being
very
particularly preferred.
The present invention also provides a pharmaceutical composition containing an
active quantity of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate
of
the formula I and a pharmaceutical excipient or a pharmaceutical diluent.
In the composition, the compound of the formula I may be present as
crystalline
form A, crystalline form B or a mixture of forms A and B. The crystalline form
A is
preferably present.
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The quantity of compounds of the formula I depends substantially on the type
of
the formulation and on the desired dosage during the period of administration.
The quantity of the particular salts according to the invention to be
administered
to the patient may vary and is for example dependent on the weight or age of
the
patient and on the mode of administration, the indication and the severity of
the
complaint. Conventionally, at least one such compound is administered in a
quantity of 0.005 to 5000 mg/kg, preferably of 0.05 to 500 mg/kg, of patient
body
weight.
Oral formulations may comprise solid formulations, for example tablets,
capsules, pills and pastilles. Oral formulations may also comprise liquid
formulations, for example solutions, suspensions, syrups or elixirs. Liquid
and
solid formulations also cover incorporation of the compounds of the formula I
in
solid or liquid foodstuffs. Liquids additionally cover solutions for
parenteral
administration, such as for example infusion or injection.
The compounds of the formula I and the crystalline forms may be used directly
as powder (micronised particles), granules, suspensions or solutions, or they
may be mixed with other pharmaceutically acceptable ingredients and
components and then pulverised, in order then to introduce the powder into
hard
or soft gelatine capsules, to press it into tablets, pills or pastilles, or in
order to
suspend or dissolve the powder in an excipient for the production of
suspensions, syrups or elixirs. Tablets, pills or pastilles may be provided
with a
coating after pressing.
Pharmaceutically acceptable ingredients and components for the various types
of the formulation are known per se. They may for example comprise binders
such as synthetic or natural polymers, pharmaceutical excipients, lubricants,
surfactants, sweeteners and aroma substances, coating agents, preservatives,
colorants, thickeners, auxiliary substances, antimicrobial agents and
excipients
for the various types of the formulation.
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Examples of binders are gum arabic, gum tragacanth, acacia gum and
biodegradable polymers such as homo- or copolyesters of dicarboxylic acids,
alkylene diols, polyalkylene glycols and/or aliphatic hydroxycarboxylic acids;
homo- or copolyamides of dicarboxylic acids, alkylene diamines, and/or
aliphatic
aminocarboxylic acids; corresponding polyester-polyamide copolymers,
polyanhydrides, polyorthoesters, polyphosphazenes and polycarbonates.
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 copolymers thereof),
polyacrylamides and hydroxyalkylated polyacrylamides, polymaleic acid and
esters or amides thereof, polyacrylic acid and esters or amides thereof,
polyvinyl
alcohol and esters or ethers thereof, polyvinylimidazole,
polyvinylpyrrolidone,
and natural polymers such as for example chitosan.
Examples of pharmaceutical excipients are phosphates such as dicalcium
phosphate.
Examples of lubricants are natural or synthetic oils, fats, waxes or fatty
acid salts
such as magnesium stearate.
Surfactants (surface-active agents) may be anionic, cationic, amphoteric or
neutral. Examples of surfactants are 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-
tetradecanoylaminoethane 2-sulfonic acid, 1-hexadecanoylaminoethan-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
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sulfate, sulfated castor oil, sodium dioctyl sulfosuccinate, cocamidopropyl
betaine and lauryl betaine, fatty alcohols, cholesterol, glycerol mono- or
distearate, glycerol mono- or dioleate, glycerol mono- or dipalmitate, and
polyoxyethylene stearate.
Examples of sweeteners are sucrose, fructose, lactose or aspartame.
Examples of aroma substances are peppermint, oil of wintergreen or fruit
essences such as cherry or orange essence.
Examples of coating agents are gelatine, waxes, shellac, sugar or
biodegradable
polymers.
Examples of preservatives are methyl- or propylparaben, sorbic acid,
chlorobutanol and phenol.
Examples of auxiliary substances are fragrance substances.
Examples of thickeners are synthetic polymers, fatty acids, fatty acid salts,
fatty
acid esters and fatty alcohols.
Examples of liquid excipients are water, alcohols (ethanol, glycerol,
propylene
glycol, liquid polyethylene glycols), polytriazines and oils. Examples of
solid
excipients are talcum, aluminas, microcrystalline cellulose, silicon dioxide,
aluminium oxide and similar solids.
The composition according to the invention may also contain isotonic agents
such as for example sugar, physiological buffers and sodium chloride.
The composition according to the invention may also be formulated as an
effervescent tablet or effervescent powder, which disintegrates in an aqueous
environment when drinkable solutions or suspensions are prepared.
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A syrup or elixir may contain the compound of the formula I, a sugar such as
sucrose or fructose as sweetener, a preservative (methylparaben), a colorant
and a flavouring agent (aroma substances).
The composition according to the invention may also comprise formulations
which exhibit delayed and controlled active ingredient release on contact with
bodily fluids of the gastrointestinal tract, in order to achieve a
substantially
constant and effective level of the active ingredient in the blood plasma. The
compounds of the formula I may to this end be embedded in a polymer matrix of
a biodegradable polymer, a water-soluble polymer or both polymers, optionally
together with a suitable surfactant. In this context, embedding may mean the
incorporation of microparticles into the polymer matrix. Formulations
exhibiting
delayed and controlled active ingredient release may be obtained by
encapsulation of dispersed microparticles or emulsified microdroplets using
known dispersion and emulsion coating technologies.
The compounds of the formula I may also be used together with at least one
further pharmaceutical active ingredient for combination therapies. To this
end,
at least one further active ingredient may additionally be dispersed or
dissolved
in the composition according to the invention.
The invention also provides the use of 3-[2-(dimethylamino)methyl-(cyclohex-1 -
yl)]-phenol maleate of the formula I to produce a pharmaceutical composition,
in
particular for the treatment of pain.
The invention further provides a method for the treatment of pain, in which an
active quantity of 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate
of
the formula I is administered to a patient suffering from pain.
The pharmaceutical preparation according to the invention (the pharmaceutical
composition according to the invention) is preferably suitable for the
treatment
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and/or prevention of pain, preferably selected from the group consisting of
acute
pain, chronic pain, neuropathic pain and visceral pain; of migraine;
depression;
neurodegenerative diseases, preferably selected from the group consisting of
Parkinson's disease, Alzheimer's disease, Huntington's chorea and multiple
sclerosis; cognitive disorders, preferably cognitive deficiency states,
particularly
preferably attention deficit syndrome (ADS), panic attacks; epilepsy;
coughing;
urinary incontinence; diarrhoea; pruritus; schizophrenia; cerebral ischaemia;
muscle spasms; cramps; disorders of food intake, preferably selected from the
group consisting of bulimia, cachexia, anorexia and obesity; alcohol and/or
drug
abuse (in particular nicotine and/or cocaine abuse) and/or abuse of medicines;
alcohol and/or drug dependency (in particular nicotine and/or cocaine
dependency) and/or dependency on medicines, preferably for prevention and/or
reduction of withdrawal symptoms associated with alcohol and/or drug
dependency (in particular nicotine and/or cocaine dependency) and/or
dependency on medicines; development of tolerance phenomena with regard to
medicines; in particular with regard to opioids; gastro-oesophageal reflux
syndrome; for diuresis; for antinatriuresis; for influencing the
cardiovascular
system; for anxiolysis; for increasing vigilance; for increasing libido, for
modulating locomotor activity, and for local anaesthesia.
The pharmaceutical preparation according to the invention (the pharmaceutical
composition according to the invention) is particularly preferably suitable
for the
treatment and/or prevention of pain, preferably of acute pain, chronic pain,
neuropathic pain or visceral pain; depression; epilepsy; Parkinson's disease;
alcohol and/or drug abuse (in particular nicotine and/or cocaine abuse) and/or
abuse of medicines; alcohol and/or drug dependency (in particular nicotine
and/or cocaine dependency) and/or dependency on medicines; preferably for
prevention and/or reduction of withdrawal symptoms associated with alcohol
and/or drug dependency (in particular nicotine and/or cocaine dependency)
and/or dependency on medicines; development of tolerance phenomena with
regard to medicines, in particular with regard to opioids, or for anxiolysis.
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The pharmaceutical preparation according to the invention is very particularly
preferably suitable for the prevention and/or treatment of pain, preferably
acute
pain, chronic pain, neuropathic pain or visceral pain.
It is particularly preferred to use at least one salt according to the
invention, in
each case optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or in the form
of
a mixture of stereoisomers, in particular the enantiomers and/or
diastereomers,
in any desired mixing ratio, and optionally one or more pharmaceutically
compatible auxiliary substances for the production of a pharmaceutical
preparation for the prevention and/or treatment of pain, preferably selected
from
the group consisting of acute pain, chronic pain, neuropathic pain and
visceral
pain, of migraine, depression, neurodegenerative diseases, preferably selected
from the group consisting of Parkinson's disease, Alzheimer's disease,
Huntington's chorea and multiple sclerosis, cognitive disorders, preferably
cognitive deficiency states, particularly preferably attention deficit
syndrome
(ADS), panic attacks, epilepsy, coughing, urinary incontinence, diarrhoea,
pruritus, schizophrenia, cerebral ischaemia, muscle spasms, cramps, disorders
of food intake, preferably selected from the group consisting of bulimia,
cachexia, anorexia and obesity, alcohol and/or drug abuse (in particular
nicotine
and/or cocaine abuse) and/or abuse of medicines; alcohol and/or drug
dependency (in particular nicotine and/or cocaine dependency) and/or
dependency on medicines; preferably for prevention and/or reduction of
withdrawal symptoms associated with alcohol and/or drug dependency (in
particular nicotine and/or cocaine dependency) and/or dependency on
medicines; development of tolerance phenomena with regard to drugs and/or
medicines, in particular with regard to opioids, gastro-oesophageal reflux
syndrome, for diuresis, for antinatriuresis, for influencing the
cardiovascular
system, for anxiolysis, for increasing vigilance, for increasing libido, for
modulating locomotor activity, and for local anaesthesia.
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The pharmaceutical preparation according to the invention may assume the form
of a liquid, semisolid or solid dosage form, for example in the form of
solutions
for injection, drops, succi, syrups, sprays, suspensions, tablets, patches,
capsules, dressings, suppositories, ointments, creams, lotions, gels,
emulsions,
aerosols or be in multiparticulate form, for example in the form of pellets or
granules, optionally press-moulded into tablets, packaged in capsules or
suspended in a liquid and also be administered as such.
In addition to at least one salt according to the invention, optionally in the
form of
the pure stereoisomers thereof, in particular enantiomers or diastereomers,
the
racemate thereof or in the form of mixtures of the stereoisomers, in
particular the
enantiomers or diastereomers, in any desired mixing ratio, the pharmaceutical
preparation according to the invention (the pharmaceutical composition
according to the invention) conventionally contains further physiologically
acceptable pharmaceutical auxiliary substances, which may preferably be
selected from the group consisting of excipient materials, fillers, solvents,
diluents, surface-active substances, colorants, preservatives, disintegrants,
slip
agents, lubricants, aromas and binders.
Selection of the physiologically acceptable auxiliary substances and the
quantities thereof which are to be used depends upon whether the
pharmaceutical preparation (pharmaceutical composition) is to be administered
orally, subcutaneously, parenterally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally, buccally, rectally or topically,
for
example onto infections of the skin, mucous membranes and eyes. Preparations
in the form of tablets, coated tablets, capsules, granules, pellets, drops,
succi
and syrups are preferred for oral administration, while solutions,
suspensions,
readily reconstitutible dried preparations and sprays are preferred for
parenteral,
topical and inhalatory administration.
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Suitable percutaneous administration preparations also include depot
preparations in dissolved form or in a dressing, optionally with the addition
of
agents promoting skin penetration.
Orally or percutaneously administrable formulations may release the particular
salts of the invention in delayed manner.
Production of the pharmaceutical preparations according to the invention
proceeds with the assistance of conventional means, devices, methods and
processes well known to the person skilled in the art, such as are described
for
example in "Remington's Pharmaceutical Sciences", ed. A.R. Gennaro, 17th ed.,
Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters
76 to 93. The corresponding description is hereby introduced as a reference
and
is deemed to be part of the disclosure.
The quantity of the particular salts according to the invention to be
administered
to the patient may vary and is for example dependent on the weight or age of
the
patient and on the mode of administration, the indication and the severity of
the
complaint. Conventionally, at least one such compound is administered in a
quantity of 0.005 to 5000 mg/kg, preferably of 0.05 to 500 mg/kg, of patient
body
weight.
The following Examples illustrate the invention in greater detail without
restricting
it thereto.
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Examples:
In all the DSC measurements (unless stated otherwise), the heating rates are
to
C/minute; the stated temperatures are peak maxima.
5
A) Production of (+)-(1 R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)1-
phenol
maleate
Example Al: Production as crystalline form A
10 0.0685 g of (+)-(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-l-yl)]-phenol
are
dissolved in 0.4 ml of ethyl acetate. In addition, a second solution of 0.0371
g of
maleic acid in 1 ml of ethyl acetate is prepared. The two solutions are
combined
at room temperature and mixed with stirring, a white precipitate forming
immediately. The mixture is heated with stirring to 50 C and thereafter cooled
again to room temperature. Then the precipitate is filtered out using a
sintered
glass filter, washed with 4 ml of ethyl acetate and the residue is dried by
having
air drawn through it for 5 minutes. 0.0870 mg (85% of theoretical) of (+)-(1
R,2R)-
3-[2-(dimethylamino)methyl-(cyclohex-l-yl)]-phenol maleate is obtained as a
white, crystalline solid with a melting point of approx. 167 C and the
enthalpy of
fusion is approx. 135 J/g, determined by Differential Scanning Calorimetry
(DSC)
at a heating rate of 10 C/minute. The crystalline solid is the polymorphic
form A,
whose X-ray diffraction pattern is shown in Figure 1. The Raman spectrum is
shown in Figure 2.
If twice the quantity of (+)-(1 R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-l-
yl)]-
phenol is used, again only the 1:1 maleate is formed.
Example A2: Production as crystalline form A
6.22 g (53.5 mmol) of maleic acid are dissolved in a glass flask in 130 ml of
ethyl
acetate and then added dropwise with stirring to a solution, adjusted to a
temperature of 50 C, of 12.48 g (53.5 mmol) of (+)-(1 R,2R)-3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol in 40 ml of ethyl acetate. After
the
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addition of 20 to 25 ml, a white precipitate forms. After addition of the
entire
solution, the finely crystalline white solid is filtered out of the warm
solution and
washed with a little cold ethyl acetate. The residue is dried by having air
drawn
through it. 18.38 g (98.3% of theoretical) of (+)-(1 R,2R)-3-[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate are obtained as
crystalline form A (according to the X-ray diffraction pattern) with a melting
point
of 177-179 C. DSC analysis reveals two peaks at 165.5 and 177.2 C.
g of the solid are dried overnight in the drying cabinet at 40 C and 80 to 90
mbar. The weight loss amounts to only 3.8 mg (ethyl acetate). The X-ray
10 diffraction pattern corresponds to form A; the DSC peaks are almost
unchanged
165.8 and 176.7.
Example A3: Production as crystalline form B
In a glass flask, 1.95 g of (+)-(1 R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-
1-
yl)]-phenol are dissolved at room temperature in 40 ml of ethyl acetate. Then
a
solution of 0.97 g of maleic acid in 25 ml of ethyl acetate is added dropwise
at
room temperature. After the addition of approx. half the solution, firstly
turbidity
forms and then a crystalline precipitate. The suspension is stirred at 70 C
for an
hour in a rotary evaporator and then cooled to room temperature. The
suspension is then cooled to 4 C in the refrigerator and the precipitate
filtered
out. The solid residue is washed once with 4 ml of ethyl acetate and dried by
having air drawn through it (5 minutes). 2.815 g (96.4% of theoretical) of (+)-
(1 R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate are
obtained as crystalline form B (according to the X-ray diffraction pattern)
with a
melting point of 177-179 C. DSC analysis reveals a peak at 177.7 C.
Example A4: Production as crystalline form A
8.92 g of maleic acid are dissolved at 55 C in a glass flask in 120 ml of
ethyl
acetate. In another glass flask 17.96 g of (+)-(1 R,2R)-3-[2-
(dimethylamino)methyl-(cyclohex-1-yi)]-phenol are likewise dissolved at 55 C
at
room temperature in 108 ml of ethyl acetate and slowly added dropwise within
30 minutes to the solution of maleic acid. After the addition of approx. half,
a
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white, voluminous, finely crystalline solid precipitates out. The suspension
is
stirred for a further 3 hours at 55 C once addition is complete. It is then
left to
cool by itself to room temperature and stirred again overnight. The
precipitate is
filtered out and washed once with 20 ml of ethyl acetate and dried by having
air
drawn through it (5 minutes). 26.26 g (97.7% of theoretical) of (+)-(1 R,2R)-3-
[2-
(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate are obtained as
crystalline form A (according to the X-ray diffraction pattern). DSC analysis
reveals two peaks at 166.03 and 177.03 C.
Example A5: Production as crystalline form A
2.33 g of (+)-(1 R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1 -yl)]-phenol are
dissolved at room temperature in 15 ml of ethyl acetate and 1.16 g of maleic
acid
are dissolved in 30 ml of ethyl acetate, each in a glass flask. In another
glass
flask, 20 ml of ethyl acetate are heated to 45 C and then both solutions are
added simultaneously dropwise with stirring. Considerable turbidity forms
spontaneously. Once addition is complete, the suspension is stirred for
another 3
hours at 50 C. Then it is left to cool by itself to room temperature. The
precipitate
is filtered out and washed once with 10 ml of ethyl acetate and dried by
having
air drawn through it (5 minutes). 3.41 g (97.7% of theoretical) of (+)-(1
R,2R)-3-
[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate are obtained as
crystalline form A (according to the X-ray diffraction pattern). DSC analysis
reveals two peaks at 166.03 and 177.03 C.
Example A6: Production of crystalline (+)-(1 R,2R)-3-[2-(dimethylamino)methyl-
(cyclohex-1-yl)]-phenol maleate
a) Production
24.64 g of (+)-(1R,2R)-3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol
(purity
according to HPLC analysis 76.8%) are dissolved in a 1 1 three-necked flask in
500 ml of ethyl acetate. The temperature is raised to 55 C and 9.44 g of
maleic
acid are added all at once with stirring. Stirring is performed at this
temperature
for 4 hours and then for 2 hours at 20 C. Then the precipitate is filtered
out,
washed once with 20 ml of ethyl acetate and then dried by drawing air through
it.
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Thermoanalysis (DSC) reveals endothermic signals at 150.4 C and 157.7 C.
Purity (relative to the phenol) amounts according to HPLC analysis to 84.4%.
The yield amounts to 27.57 g (97.0% of theoretical).
b) Purification by means of stir-washing
The resultant crude product is weighed out into glass flask, combined with
solvent and shaken in a Thermomixer at 50 C for 4 hours. Then the solutions
are cooled overnight to 23 and subsequently filtered. The yield and purity
(HPLC) of the residue are determined. Further details may be found in Table 1
below. The following abbreviations are used: EtAc is ethyl acetate, EtOH is
ethanol, PrOH is i-propanol, AcNi is acetonitrile, Tol is toluene, Hex is n-
hexane,
DiEt is diethyl ether, BuMe is t-butyl methyl ether, Ace is acetone, MeEt is
methyl
ethyl ketone, THF is tetrahydrofuran.
Table 1:
Maleate Solvent 1 Solvent 2 Yield (%) Purity (%)
quantity (mg) (mI) (mI)
56.3 EtAc (1.0) -- 97.2 84.6
55.9 PrOH (1.0) -- 73.0 96.7
56.2 Hex (1.0) -- 96.3 84.0
55.8 AcNi (1.0) -- 71.5 93.6
56.4 Tol (1.0) -- 97.2 84.0
62.6 DiEt (1.0) -- 97.0 84.6
53.5 BuMe (1.0) -- 97.4 84.2
55.2 Ace (1.0) -- 58.2 97.9
55.1 MeEt (1.0) -- 75.9 92.1
58.8 THF (1.0) -- 80.1 89.5
55.2 Ace (0.98) EtOH (0.02) 52.0 97.9
60.4 Ace (0.96) EtOH (0.04) 50.5 97.0
55.5 Ace (0.94) EtOH (0.06) 37.1 98.2
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Maleate Solvent 1 Solvent 2 Yield (%) Purity (%)
quantity (mg) (ml) (mI)
58.2 Ace (0.92) EtOH (0.08) 42.4 98.3
57.3 Ace (0.90) EtOH (0.10) 39.6 98.2
517.1 PrOH (10.0) -- 79.7 88.9
516.5 PrOH (10.0) -- 79.4 87.5
511.2 PrOH (10.0) -- 80.7 89.0
516.4 Ace (10.0) -- 62.0 98.1
515.2 Ace (10.0) -- 64.8 96.4
511.6 Ace (10.0 ) -- 68.7 94.8
506.9 THF (10.0) -- 82.9 87.9
511.2 THF (10.0) -- 81.9 87.8
507.2 THF (10.0) -- 83.8 88.5
518.3 Ace (9.70) EtOH (0.3) 48.3 98.6
514.3 Ace (9.70) EtOH (0.3) 50.9 97.8
509.8 Ace (9.70) EtOH (0.3) 50.2 98.7
The product may be obtained in good to excellent purities by purifying the
crude
product by means of stir-washing.
B) Production of amorphous (+)-(1 R,2R)-3-f2-(dimethylamino)methyl-(cyclohex-
1-yl)l-phenof maleate
Example B1: Freeze drying
81.5 mg of the maleate produced according to Example Al are dissolved in 3 ml
of water and then quenched to -75 C. Then freeze-drying is performed at this
temperature and a pressure of 0.011 mbar for 23 hours. A solid, white residue,
which has a tendency to crystallise rapidly in the presence of moisture, is
obtained quantitatively, substantially with formation of the crystalline form
A.
Differential Scanning Calorimetry (DSC, heating rate 10 C/minute) reveals a
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glass transition temperature of around 30 C. An exothermic peak at 85 C is
attributed to crystallisation. The crystalline material formed melts at 178 C.
If 20 mg of the amorphous form is stored at room temperature and 20% or 90%
atmospheric humidity for 24 hours, there is obtained respectively a mixture of
crystalline forms A and B or only crystalline form A.
C) Production of crystalline form A
The crystal shape is determined, if not stated otherwise, by comparing the
Raman spectra.
Example Cl: Precipitation with non-solvent
a) Precipitation with n-heptane
80 mg of the maleate produced according to Example Al are dissolved at room
temperature in 8 ml acetone. Thereafter 7.5 ml of n-heptane are added with
stirring. A white precipitate is formed, which is filtered out and dried in a
stream
of air at room temperature. 50 mg of white powder are obtained, which
corresponds to crystalline form A.
b) Precipitation with n-heptane
80 mg of the maleate produced according to Example Al are dissolved at room
temperature in 17 ml of tetrahydrofuran (THF). Thereafter 9 ml of n-heptane
are
added with stirring. A white precipitate is formed, which is filtered out and
dried in
a stream of air at room temperature. 52 mg of white powder are obtained, which
corresponds to crystalline form A.
c) Precipitation with tert-butyl methyl ether (TBME)
80 mg of the maleate produced according to Example Al are dissolved at room
temperature in 21 ml of THF. Thereafter 7.5 ml of TBME are added with
stirring.
A white precipitate is formed, which is filtered out and dried in a stream of
air at
room temperature. 48 mg of white powder are obtained, which corresponds to
crystalline form A.
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Exampfe C2: Phase equilibria with suspensions
a) Suspension in acetone
0.5 ml of acetone are added to 80 mg of the maleate produced according to
Example B1 and stirring is performed for 24 hours at room temperature.
Filtering
out is then performed, followed by drying at room temperature in a stream of
air.
52 mg of crystalline form A are obtained as white powder.
b) Suspension in 1,4-dioxane
0.5 ml of 1,4-dioxane are added to 80 mg of the maleate produced according to
Example B1 and stirring is performed for 24 hours at room temperature.
Filtering
out is then performed, followed by drying at room temperature in a stream of
air.
47 mg of crystalline form A are obtained as white powder.
c) Suspension in ethyl acetate
0.5 ml of ethyl acetate are added to 80 mg of the maleate produced according
to
Example B1 and stirring is performed for 24 hours at room temperature.
Filtering
out is then performed, followed by drying at room temperature in a stream of
air.
50 mg of crystalline form A are obtained as white powder.
d) Suspension in water
0.1 ml of water and then two 0.2 ml portions of water are added to 80 mg of
the
maleate produced according to Example B1 and stirring is performed for 24
hours at room temperature. Filtering out is then performed, followed by drying
at
room temperature in a stream of air. 49 mg of crystalline form A are obtained
as
white powder.
e) Suspension in isopropanol
0.5 ml of isopropanol are added to 80 mg of the maleate produced according to
Example B1 and stirring is performed for 24 hours at room temperature.
Filtering
out is then performed, followed by drying at room temperature in a stream of
air.
54 mg of crystalline form A are obtained as white powder.
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f) Suspension in tetrahydrofuran
0.5 ml of THF are added to 80 mg of the maleate produced according to
Example B1. A solid agglomerate is formed, which is comminuted with a spatula.
The resultant suspension is stirred thereafter for 24 hours at room
temperature.
Filtering out is then performed, followed by drying at room temperature in a
stream of air. 49 mg of crystalline form A are obtained as white powder.
Example C3: Crystallisation
a) Crystallisation from methanol/methylene chloride
100 mg of the maleate produced according to Example Al are dissolved in 1 ml
of methanol. After the addition of 14 ml of methylene chloride, a clear
solution is
obtained, which is left to stand for 5 days at 5 C. Then the volume is
evaporated
down to a quarter and again left to stand at 5 C for one week. Then the
solvent
is evaporated completely at room temperature. 98 mg of crystalline form A are
obtained in the form of a white powder.
b) Crystallisation from toluene and acetone
60 mg of the maleate produced according to Example Al are dissolved in 10 ml
of toluene/acetone (1:1 vol/vol) at 60 C and thereafter cooled to room
temperature. The solution is then left to stand at 5 C for 4 days. Thereafter,
the
large crystals formed are filtered out and dried. 28 mg of crystalline form A
are
obtained in the form of white crystals.
c) Crystallisation from ethyl acetate
51 mg of the maleate produced according to Example Al are dissolved at 65 C
in 31 ml of ethyl acetate. The solution is then left to cool to room
temperature
and within 2 hours acicular crystals form. The solution is left to stand for a
further
5 days at 5 C and the crystals are filtered out and dried. 33 mg of
crystalline
form A are obtained in the form of white, acicular crystals.
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d) Crystallisation from tetrahydrofuran
100 mg of the maleate produced according to Example Al are dissolved at 65 C
in 7 ml of THF and thereafter cooled to room temperature. The solution is then
left to stand at 5 C for 4 days. Thereafter, the large crystals formed are
filtered
out and dried. 28 mg of crystalline form A are obtained in the form of large,
white
crystals.
e) Crystallisation from isopropanol
In a stirring flask, 2.31 g of the maleate salt produced according to Example
A6a
are suspended in 30 ml of isopropanol and heated within 20 minutes at a speed
of rotation of the stirrer of approx. 600 rpm (revolutions per minute) to 80 C
with
formation of a clear solution. The speed of rotation is increased to 800 rpm
and
stirring is performed at this temperature for 30 minutes, the speed of
rotation
being increased briefly to 1000 rpm towards the end. Then the temperature is
lowered within 25 minutes to 65 C and stirring is performed for 35 minutes at
this
temperature. Thereafter seeding is performed with 50 mg of crystalline form A
of
the maleate salt and the temperature is lowered to 10 C with stirring within 3
hours at a rate of 0.3 K/min. The white solid is filtered out and dried in air
(2.132
g, 92.3%). According to an X-ray powder diffractogram, only lines of the
crystalline form A are measured. Thermoanalysis (DSC) reveals endothermic
signals at 165.8 C and 177.2 C. When thermogravimetric analysis is performed,
significant weight loss is observed, such that no solvated form can be
present.
Purity amounts to 99.5%, determined by HPLC.
f) Crystallisation from isopropanol
In a stirring flask, 2.32 g of the maleate salt produced according to Example
A6a
are suspended in 30 mi of isopropanol and heated within 15 minutes at a speed
of rotation of the stirrer of approx. 600 rpm (revolutions per minute) to 80 C
with
formation of a clear solution. The speed of rotation is increased to 800 rpm
and
stirring is performed at this temperature for 20 minutes, the speed of
rotation
being increased briefly to 1000 rpm towards the end. Then the temperature is
lowered within 10 minutes to 65 C and stirring is performed for 10 minutes at
this
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temperature. Thereafter seeding is performed with 50 mg of crystalline form A
of
the maleate salt and the temperature is lowered to 20 C with stirring within 3
hours at a rate of 0.25 K/min. The white solid is filtered out and dried in
air (2.132
g, 92.3%). According to an X-ray powder diffractogram, only lines of the
crystalline form A are measured. Thermoanalysis (DSC) reveals endothermic
signals at 163.4 C and 174.4 C. When thermogravimetric analysis is performed,
significant weight loss is observed, such that no solvated form can be
present.
Purity amounts to 99.5%, determined by HPLC.
Example C4: Crystallisation by means of solvent evaporation
a) Solvent acetone/THF
10 mg of the maleate produced according to Example Al are dissolved in 15 ml
of acetone/THF (1:1, vol/vol) and the solvent mixture is evaporated slowly to
dryness at room temperature in a stream of nitrogen. 9 mg of crystalline form
A
are obtained in the form of a white powder.
b) Solvent acetone/ethyl acetate
10 mg of the maleate produced according to Example Al are dissolved in 15 ml
of acetone/ethyl acetate (1:1, vol/vol) and the solvent mixture is evaporated
slowly to dryness at room temperature in a stream of nitrogen. 8 mg of
crystalline
form A are obtained in the form of a white powder.
c) Solvent methylene chloride
10 mg of the maleate produced according to Example Al are dissolved in 15 mi
of methylene chloride (1:1, vol/vol) and the solvent mixture is evaporated
slowly
to dryness at room temperature under ambient conditions in an open
atmosphere. 9 mg of crystalline form A are obtained in the form of a white
powder.
d) Solvent THF/water
200 mg of the maleate produced according to Example Al are dissolved in 4 mi
of water/THF (1:1, vol/vol) and the solution is filtered through a 0.22 pm
filter.
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The solution is introduced into a Petri dish and the solvent mixture is
evaporated
slowly to dryness at room temperature under ambient conditions in an open
atmosphere. 188 mg of crystalline form A are obtained in the form of a
acicular
crystals.
e) Solvent THF/water
200 mg of the maleate produced according to Example Al are dissolved in 4 ml
of water/THF (1:1, vol/vol) and the solution is filtered through a 0.22 pm
filter.
The solution is introduced into a Petri dish and seeded with crystals of
poiymorph B and the solvent mixture is evaporated slowly to dryness at room
temperature under ambient conditions in an open atmosphere. After one day,
acicular crystals form. 160 mg of crystalline form A are obtained in the form
of
acicular crystals.
f) Solvent THF/water
200 mg of the maleate produced according to Example Al are dissolved in 4 ml
of water/THF (1:1, vol/vol) and the solution is filtered through a 0.22 pm
filter.
The solution is introduced into a Petri dish and the solvent mixture is
evaporated
to dryness at room temperature under a stream of nitrogen. After one day,
acicular crystals form. 182 mg of crystalline form A are obtained in the form
of
acicular crystals.
g) Solvent 1,4-dioxane
11 mg of the maleate produced according to Example Al are dissolved in 15 ml
of 1,4-dioxane. The solution is introduced into an open vial and the solvent
is
evaporated to dryness under ambient conditions in an open atmosphere at room
temperature within 4 days. 9 mg of crystalline form A are obtained in the form
of
a white powder.
h) Solvent THF
10 mg of the maleate produced according to Example Al are dissolved in 15 ml
of THF. The solution is introduced into a Petri dish and the solvent mixture
is
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evaporated slowly to dryness at room temperature under ambient conditions in
an open atmosphere within 2 days. 9 mg of crystalline form A are obtained in
the
form of a white powder.
i) Solvent THF/water
150 mg of the maleate produced according to Example Al are dissolved in 3 ml
of THF/water (1:1, vol/vol). Then the solvent is evaporated at 60 C in a
rotary
evaporator. 135 mg of crystalline form A are obtained in the form of a white
powder.
j) Solvent THF/water
150 mg of the maleate produced according to Example Al are dissolved in 3 ml
of THF/water (1:1, vol/vol). Then stirring is performed at 40 C for 10 minutes
and
thereafter for 1 more minute at 60 C. Filtration is performed through a 0.22
pm
filter. The solution is introduced into a Petri dish and the solvent mixture
is
evaporated to dryness at room temperature under a stream of nitrogen. 125 mg
of crystalline form A are obtained in the form of a white powder.
k) Solvent THF
50 mg of the maleate produced according to Example Al are dissolved at 60 C
in 40 mi of THF. Then the solution is cooled with dry ice and left to stand at
-
20 C, turbidity forming. After 3 days, a white precipitate has formed, which
is
filtered out and dried. 21 mg of crystalline form A are obtained in the form
of a
white powder.
Example C5: Conversion of crystalline form B into form A
a) Phase equilibrium with suspension in ethyl acetate
mg of the crystalline form B produced according to Example Dl are
suspended in 2 ml of ethyl acetate and stirred for 18 hours at 23 C. Then
30 filtration is performed and the residue dried. 15 mg of crystalline form A
are
obtained in the form of a white powder.
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b) Phase equilibrium with suspension in toluene
30 mg of the crystalline form B produced according to Example Dl are
suspended in 2 ml of toluene and stirred for 18 hours at 23 C. Then filtration
is
performed and the residue dried. 22 mg of crystalline form A are obtained in
the
form of a white powder.
D) Production of crystalline form B
Example Dl:
250 mg of the maleate produced according to Example Al are dissolved in 5 ml
of THF/water (1:1, vol/vol). Then the solvent mixture is evaporated at 90 C in
a
rotary evaporator. 208 mg of crystalline form B are obtained in the form of a
white powder. The melting point is approx. 178 C and the enthalpy of fusion is
approx. 125 J/g, measured with DSC at a heating rate of 10 C/minute. The X-ray
diffraction pattern is shown in Figure 3 and the Raman spectrum in Figure 4.
Example D2:
The procedure is as for Example Dl, except that the solvent is left to stand
for
22 hours prior to evaporation. The residue is crystalline form B.
Example D3:
100 mg of the maleate produced according to Example Al are dissolved in 2 ml
of THF/water (1:1, vol/vol). Then the solution is left to stand for 3.5 hours
at room
temperature. Thereafter the solvent mixture is evaporated at 90 C in a rotary
evaporator. 84 mg of crystalline form B are obtained in the form of a white
powder.
Example D4:
Two 250 mg portions of the maleate produced according to Example Al are
dissolved in each case in 5 ml of THF/water (1:1, vol/vol). One solution is
filtered
through a 0.22 pm filter and the second solution is filtered through a 0.45 pm
filter. The solutions are each introduced into a Petri dish and the solvent
mixture
is evaporated slowly at room temperature under ambient conditions in an open
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atmosphere. After one day, spherical crystals are observed to form. After 3
days,
the solvent mixture is evaporated and the residues consist of crystalline form
B
in the form of spherical crystals.
E) Stability investigations
Example El: Storage of the amorphous form under elevated atmospheric
humidity
The amorphous form according to Example B1 is stored at room temperature
and 75% relative atmospheric humidity and samples are investigated after 2
days, 1, 2, 3, 4 and 8 weeks using Raman spectroscopy. After 2 days, a mixture
of crystalline forms A and B is present. The same mixture is still observed
after 8
weeks.
Example E2: Storage of crystalline form A under elevated atmospheric humidity
The maleate produced according to Example Al is stored at room temperature
and 75% relative atmospheric humidity and samples are investigated after 3
days, 1, 2, 3, 4, 8 and 10 weeks using Raman spectroscopy. The samples are
virtually unchanged even after 10 weeks.
Example E3: Storage of crystalline form B under elevated atmospheric humidity
The crystalline form B produced according to Example Dl is stored at room
temperature and 75% relative atmospheric humidity and samples are
investigated after 3 days, 1, 2, 3, 4 and 8 weeks using Raman spectroscopy.
The
samples are virtually unchanged even after 8 weeks.
Example E4: Stability under grinding conditions
a) Crystalline form A on trituration
The maleate produced according to Example Al is triturated with a pestle in a
mortar for 5 minutes. Thereafter, the crystalline form A is present in
unchanged
form. Amorphous fractions are not observed.
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b) Crystalline form B on trituration
Crystalline form B according to Example Dl is triturated with a pestle in a
mortar
for 5 minutes. Thereafter a mixture of crystalline forms A and B is present.
c) Crystalline form A on grinding
The maleate produced according to Example Al is introduced into an agate ball
mill (Retsch MM200 mixing mill with 5 mm agate ball) and ground at 20 Hz and
room temperature for 180 minutes. Thereafter, the crystalline form A is
present
in unchanged form. Amorphous fractions are not observed.
c) Crystalline form B on grinding
The procedure is carried out in accordance with Example E4c) with crystalline
form B according to Example Dl. After 180 minutes, a mixture of crystalline
forms A and B is present.
Example E5: Stability under pressure
a) Crystalline form A on tablet pressing
The maleate produced according to Example Al is introduced into a tablet press
and pressed under a vacuum at a pressure of 100 MPa for 60 minutes to form a
tablet. Thereafter, the crystalline form A is present in unchanged form.
b) Crystalline form B on tablet pressing
The procedure is carried out in accordance with Example E5a) with crystalline
form B according to Example Dl. After 60 minutes, a mixture of crystalline
forms
A and B is present.
Example E6: Water absorption
Water absorption is determined by means of dynamic water vapour absorption
(Dynamic Vapour Sorption, DVS) using apparatus DVS-1 from Surface
Measurement System Ltd.. The sample is placed in a platinum crucible at the
tip
of a microchemical balance. Then the sample is firstly equilibrated at 50%
relative atmospheric humidity and then subjected to a predefined measuring
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program. The temperature is 25 C. The change in weight of the sample is
determined.
a) Amorphous form
The amorphous form exhibits pronounced water absorption of approx. 2.2 wt.%
up to approx. 33% relative atmospheric humidity. At higher atmospheric
humidity, the weight drops again, which is caused by crystallisation. After
the
end of the test, a mixture of crystalline forms A and B is present.
b) Crystalline form A
Crystalline form A exhibits water absorption of only approx. 0.2 wt.%. At the
end
of the measuring cycle, the unchanged crystalline form A is substantially
present.
c) Crystalline form B
Crystalline form B exhibits water absorption of only approx. 0.2 wt.%. At the
end
of the measuring cycle, however, a mixture of crystalline forms A and B is
present.
Example E7: Stability at elevated temperature
The crystalline forms are stored in open and closed vessels and, after a
predetermined time, possible changes are measured chromatographically
(HPLC) as stability parameters. Crystalline form A proves very stable with
regard
to chemical stability and crystal shape. Crystalline form A proves very stable
with
regard to chemical stability. The results are shown in Table 2 below.
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Table 2:
Polymorph Conditions Time HPLC FT Raman')
A 40 C/75% R.H. 1 week 100.2% A
A 60 C/75% R.H. 4 weeks 100.3% A
A 60 C (closed) 1 week 100.2% A
A 60 C (closed) 4 weeks 100.5% A
A -18 C reference 4 weeks 100% A
B 40 C/75% R.H. 1 week 100.3% A and B
B 60 C/75% R.H. 4 weeks 101.1% A and B
B 60 C (closed) 1 week 100.6% A and B
B 60 C (closed) 4 weeks 100.9% A and B
B -18 C (reference) 4 weeks 100% A and B
Determination of crystalline form
Example E8: Water absorption of maleate and hydrochloride (comparison)
Water absorption is determined by means of dynamic water vapour absorption
(Dynamic Vapour Sorption, DVS) using apparatus DVS-1 from Surface
Measurement System Ltd.. The sample is placed in a platinum crucible at the
tip
of a microchemical balance. Then the sample is firstly equilibrated at 50%
relative atmospheric humidity and then subjected to a predefined measuring
program. The temperature is 25 C. The change in weight of the sample is
determined after a stepwise increase in relative atmospheric humidity by 10%
steps up to 90%.
a) (+)-(1R,2R)-3-f2-(dimethylamino)methyl-(cyclohex-1-yl)1-phenol maleate
(form
A)
Decidedly low water absorption of 0.06% is revealed. The absorbed moisture is
released again completely at approx. 10% relative atmospheric humidity.
b) (+)-(1 R,2R)-3-f2-(dimethylamino)methyl-(cyclohex-1-yl)1 phenol
hydrochloride
(form D
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When the relative atmospheric humidity is increased to approx. 75%, water
absorption of approx. 2 wt.% is observed. A further increase to 90% relative
atmospheric humidity results in water absorption of altogether approx. 5 wt.%.
In
the case of desorption by lowering the relative atmospheric humidity in 10%
steps, more water is released than was previously absorbed, namely 8.5%
altogether. It is suspected that a variable hydrate is present.
Example E9: Damp storage and drying of maleate and hydrochloride
(comparison)
Maleate and hydrochloride according to Example E8 are stored firstly at 25 C
and 75% and 95% relative atmospheric humidity for 7 days and thereafter are
dried for 7 days in the drying cabinet at 50 C under a vacuum. Before storage
begins, X-ray diffraction patterns (XRD) are recorded, DSC performed to
determine transition points (Tp), dry weight (DW) and the Karl-Fischer water
content (WC) are determined and the same values again after damp storage and
drying. The X-ray diffraction patterns show no change in crystalline forms A
and
D after damp storage and drying. The initial vales for the hydrochloride are
Tp =
116.27 C, DW = 6.35% and WC 8.00%. The initial values for the maleate are Tp
= 170.4 C and 179.85 C, DW = 0 and WC = 0.2%. The results are given in
Tables 3 (75% relative atmospheric humidity) and 4 (95% relative atmospheric
humidity).
Table 3 (75%):
Salt Tp ( C) DW (%) WC (%) Tp ( C) DW (%) WC (%)
Maleate 165.41 -- 0.20 165.33 -- 0.20
Hydrochloride 116.22 5.92 8.50 113.83 6.12 6.00
Table 4 (95%):
Salt Tp ( C) DW (%) WC (%) Tp ( C) DW WC (%)
Maleate 165.92 -- 0.20 165.47 -- 0.50
177.82 177.55
Hydrochloride 116.52 7.84 8.50 114.47 6.74 6.60
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Eguipment, methods:
Differential Scanning Calorimetry (DSC): model Perkin Elmer DSC 7 or Perkin
Elmer Pyris 1. Variable measurements (heating rate) in gold or aluminium
crucibles.
Powder X-ray diffraction patterns (PXRD):
PXRD is performed using a Philips 1710 Powder X-ray diffractometer, CuKa
radiation being used. D spacing is calculated from the 20 values, the
wavelength
of 1.54060 A being taken as basis. It is the case in general that the 20
values
have an error rate of 0.1-0.2 . In the case of the d spacing values,
therefore,
the experimental error depends on the location of the line (of the peak).
Raman spectroscopy:
FT Raman spectra are recorded using a Bruker RFS 100 FT-Raman system,
which is operated with an Nd:YAG laser (wavelength 1064 nm) and a
germanium detector cooled with liquid nitrogen. For each sample, 64 scans are
accumulated with a resolution of 2 cm-'. In general, a laser power of 100 mW
is
used.
Description of the Figures
Figure 1 shows the X-ray diffraction pattern of polymorphic form A
Figure 2 shows the Raman spectrum of polymorphic form A
Figure 3 shows the X-ray diffraction pattern of polymorphic form B
Figure 4 shows the Raman spectrum of polymorphic form B
