6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-d iol

The present invention relates to crystalline modifications of (1 R,3R,6R)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol, (1S,3S,6S)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol and mixtures thereof, pharmaceutical compositions and medicaments comprising these

modifications, the use of these modifications as well as to a process for the

enrichment of (1 R,3R,6R)- or (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexane-1 ,3-diol.

(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclo hexane-1 ,3-diol - also known as Axomadol (e.g. WHO Drug Information, Vol. 16, No. 2, 2002, List 87) - is a synthetic, centrally active analgesic that is suitable for the treatment of moderate to severe, acute or chronic pain. Axomadol and methods for its production are known from US RE37.355 E.

One object of the present invention was to make the individual enantiomers of Axomadol, i.e. (1 R,3R,6R)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexane-1 ,3-diol and (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexane-1 ,3-diol and thus also (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)-cyclohexane-1 ,3-diol accessible per se, i.e. in the form of the free base, with high yields and high purity.

This object was achieved by the subject-matter of the claims.

It has surprisingly been found that under suitable conditions (1 R,3R,6R)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol and (1S,3S,6S)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol can be obtained in crystalline form, in particular in form of polymorphs A, B and C disclosed hereinafter. These crystalline forms make it possible to obtain (1 R,3R,6R)-6- DimethylaminomethyM-(3-methoxy-phenyl)-cyclohexane-1 ,3-diol and (1S,3S,6S)-6- Dimethylaminomethyl-l T(3-methoxy-phenyl)-cyclohexane-1 ,3-diol and therefore also mixtures thereof, in particular racemic (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)-cyclohexane-1 ,3-diol in the form of the free base, with high yields and high purity. These forms are further distinguished in that they are very easy to handle and allow an exact metering of the active ingredient.

Moreover, different polymorphs of (1 R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexane-1 ,3-diol and (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexane-1 ,3-diol have fundamentally different properties, which may provide further advantages.

On the one hand, the advantages may be based on a particular physical property of a particular modification, for example in relation to the handling or storage thereof, for example thermodynamic stability; crystal morphology, in particular structure, size, colour; density; bulk density; hardness; deformability; calorimetric characteristics, in particular melting point; solubility properties, in particular intrinsic rate of dissolution and equilibrium solubility; hygroscopicity; relative moisture profile; adhesion etc.

On the other hand, the crystalline modifications may also have improved chemical properties. For example, it is known that a lower hygroscopicity can lead to improved chemical stability and longer storage lives for chemical compounds.

One aspect of the present invention relates to a crystalline modification of

(1 R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohex ane-1 ,3-diol, or (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cycloh exane-1 ,3-diol, or a mixture thereof.

If the enantiomers are present in a mixture such a mixture may contain the

enantiomers in racemic or non-racemic amounts. A non-racemic amount can contain the enantiomers in any possible ratio, for example, in a ratio of 60±5:40±5;

70±5:30±5; 80±5:20±5 or 90±5:10±5. A further aspect of the present invention relates to a crystalline modification A (polymorph A). Said crystalline modification A has an X-ray diffraction peak at 10,69±0,20 (2Θ).

Preferably, the crystalline modification A according to the present invention may additionally have at least one X-ray diffraction peak selected from the group consisting of 12,81 ±0,20 (2Θ), 13,82±0,20 (2Θ), 13,88±0,20 (2Θ), 16,71 ±0,20 (2Θ), 18,31 ±0,20 (2Θ), 18,76±0,20 (2Θ), 19,52±0,20 (2Θ), 20,56±0,20 (2Θ), 20,60±0,20 (2Θ), 20,61 ±0,20 (2Θ), 21 ,42±0,20 (2Θ), 22,63±0,20 (2Θ), 23,85±0,20 (2Θ) and 26,34±0,20 (2Θ).

The crystalline modification A according to the present invention may further be characterised in that as well as the X-ray diffraction peak at 10,69±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 12,81 ±0,20 (2Θ), 13,82±0,20 (2Θ), 13,88±0,20 (2Θ), 16,71 ±0,20 (2Θ), 18,31 ±0,20 (2Θ), 18,76±0,20 (2Θ), 19,52±0,20 (2Θ), 20,56±0,20 (2Θ), 20,60±0,20 (2Θ),

20,61 ±0,20 (2Θ), 21 ,42±0,20 (2Θ), 22,63±0,20 (2Θ), 23,85±0,20 (2Θ) and

26,34±0,20 (2Θ), it additionally has at least one X-ray diffraction peak selected from the group consisting of 18,32±0,20 (2Θ), 24,79±0,20 (2Θ), 25,08±0,20 (2Θ),

28,66±0,20 (2Θ), 30,33±0,20 (2Θ), 33,05±0,20 (2Θ) and 38,36±0,20 (2Θ).

Furthermore, the crystalline modification A according to the present invention may be characterised in that as well as the X-ray diffraction peak at 10,69±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of

12,81 ±0,20 (2Θ), 13,82±0,20 (2Θ), 13,88±0,20 (2Θ), 16,71 ±0,20 (2Θ), 18,31 ±0,20

(2Θ), 18,76±0,20 (2Θ), 19,52±0,20 (2Θ), 20,56±0,20 (2Θ), 20,60±0,20 (2Θ),

20,61 ±0,20 (2Θ), 21 ,42±0,20 (2Θ), 22,63±0,20 (2Θ), 23,85±0,20 (2Θ) and

26,34±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 18,32±0,20 (2Θ), 24,79±0,20 (2Θ), 25,08±0,20 (2Θ), 28,66±0,20

(2Θ), 30,33±0,20 (2Θ), 33,05±0,20 (2Θ) and 38,36±0,20 (2Θ), it additionally has at least one X-ray diffraction peak selected from the group consisting of 10,24±0,20

(2Θ), 10,77±0,20 (2Θ), 14,22±0,20 (2Θ), 17,52±0,20 (2Θ), 19,89±0,20 (2Θ), 21 ,48±0,20 (2Θ), 21 ,64±0,20 (2Θ), 23,22±0,20 (2Θ), 23,37±0,20 (2Θ), 25,67±0,20 (2Θ), 25,77±0,20 (2Θ), 26,33±0,20 (2Θ), 27,85±0,20 (2Θ), 28,59±0,20 (2Θ),

28,82±0,20 (2Θ), 29,43±0,20 (2Θ), 29,67±0,20 (2Θ), 29,93±0,20 (2Θ), 30,11 ±0,20 (2Θ), 30,17±0,20 (2Θ), 30,52±0,20 (2Θ), 31 ,62±0,20 (2Θ), 32,31 ±0,20 (2Θ),

32,46±0,20 (2Θ), 32,59±0,20 (2Θ), 32,71 ±0,20 (2Θ), 33,67±0,20 (2Θ), 33,71 ±0,20 (2Θ), 33,79±0,20 (2Θ), 33,92±0,20 (2Θ), 33,92±0,20 (2Θ), 34,23±0,20 (2Θ),

34,28±0,20 (2Θ), 34,39±0,20 (2Θ), 35,02±0,20 (2Θ), 35,24±0,20 (2Θ), 35,46±0,20 (2Θ), 35,61 ±0,20 (2Θ), 35,80±0,20 (2Θ), 36,53±0,20 (2Θ), 36,75±0,20 (2Θ),

36,92±0,20 (2Θ), 37,14±0,20 (2Θ), 37,16±0,20 (2Θ), 37,34±0,20 (2Θ), 38,08±0,20 (2Θ), 38,38±0,20 (2Θ), 38,45±0,20 (2Θ), 38,82±0,20 (2Θ), 39,29±0,20 (2Θ),

39,36±0,20 (2Θ), 39,47±0,20 (2Θ) and 39,63±0,20 (2Θ).

The crystalline modification A according to the invention may also be characterised in that as well as the X-ray diffraction peak at 10,69±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 12,81 ±0,20 (2Θ), 13,82±0,20 (2Θ), 13,88±0,20 (2Θ), 16,71 ±0,20 (2Θ), 18,31 ±0,20 (2Θ), 18,76±0,20 (2Θ), 19,52±0,20 (2Θ), 20,56±0,20 (2Θ), 20,60±0,20 (2Θ), 20,61 ±0,20 (2Θ),

21 ,42±0,20 (2Θ), 22,63±0,20 (2Θ), 23,85±0,20 (2Θ) and 26,34±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 18,32±0,20 (2Θ), 24,79±0,20 (2Θ), 25,08±0,20 (2Θ), 28,66±0,20 (2Θ), 30,33±0,20 (2Θ), 33,05±0,20 (2Θ) and 38,36±0,20 (2Θ), and optionally one or more X-ray diffraction peaks selected from the group consisting of 10,24±0,20 (2Θ), 10,77±0,20 (2Θ), 14,22±0,20 (2Θ), 17,52±0,20 (2Θ), 19,89±0,20 (2Θ), 21 ,48±0,20 (2Θ),

21 ,64±0,20 (2Θ), 23,22±0,20 (2Θ), 23,37±0,20 (2Θ), 25,67±0,20 (2Θ), 25,77±0,20 (2Θ), 26,33±0,20 (2Θ), 27,85±0,20 (2Θ), 28,59±0,20 (2Θ), 28,82±0,20 (2Θ),

29,43±0,20 (2Θ), 29,67±0,20 (2Θ), 29,93±0,20 (2Θ), 30,11 ±0,20 (2Θ), 30,17±0,20 (2Θ), 30,52±0,20 (2Θ), 31 ,62±0,20 (2Θ), 32,31 ±0,20 (2Θ), 32,46±0,20 (2Θ),

32,59±0,20 (2Θ), 32,71 ±0,20 (2Θ), 33,67±0,20 (2Θ), 33,71 ±0,20 (2Θ), 33,79±0,20 (2Θ), 33,92±0,20 (2Θ), 33,92±0,20 (2Θ), 34,23±0,20 (2Θ), 34,28±0,20 (2Θ),

34,39±0,20 (2Θ), 35,02±0,20 (2Θ), 35,24±0,20 (2Θ), 35,46±0,20 (2Θ), 35,61 ±0,20 (2Θ), 35,80±0,20 (2Θ), 36,53±0,20 (2Θ), 36,75±0,20 (2Θ), 36,92±0,20 (2Θ), 37,14±0,20 (2Θ), 37,16±0,20 (2Θ), 37,34±0,20 (2Θ), 38,08±0,20 (2Θ), 38,38±0,20 (2Θ), 38,45±0,20 (2Θ), 38,82±0,20 (2Θ), 39,29±0,20 (2Θ), 39,36±0,20 (2Θ),

39,47±0,20 (2Θ) and 39,63±0,20 (2Θ), it additionally has at least one X-ray diffraction peak selected from the group consisting of 18,62±0,20 (2Θ), 20,73±0,20 (2Θ), 23,47±0,20 (2Θ), 26,96±0,20 (2Θ), 27,97±0,20 (2Θ), 28,07±0,20 (2Θ), 28,37±0,20 (2Θ), 28,56±0,20 (2Θ), 28,57±0,20 (2Θ), 30,02±0,20 (2Θ), 31 ,06±0,20 (2Θ),

32,51 ±0,20 (2Θ), 33,03±0,20 (2Θ), 33,48±0,20 (2Θ), 35,89±0,20 (2Θ), 37, 11 ±0,20 (2Θ), 37,62±0,20 (2Θ), 39,1 1 ±0,20 (2Θ), 39,28±0,20 (2Θ), 39,48±0,20 (2Θ) and 39,50±0,20 (2Θ).

Figure 1 shows a calculated x-ray powder diffractogram of crystalline modification A. Figure 2 shows a measured x-ray powder diffractogram of crystalline modification A. Figure 3 shows a comparison of the calculated x-ray powder diffractogram according to Figure 1 and the measured x-ray powder diffractogram according to Figure 2 of crystalline modification A.

In DSC analyses, the crystalline modification A according to the present invention preferably exhibits an endothermal event with a peak temperature at 113-121 °C, more preferably at 1 14-120 °C, even more preferably at 1 15-119 °C and in particular at 115-118 °C

The crystalline form A according to the present invention may further be

characterized in that it has at least a Raman band at 993±4 cm ^"1 (VS) and/or a Raman band at 241 ±4 cm ^"1 (M).

The crystalline form A according to the present invention may further be

characterized in that it has a Raman band at 993±4 cm ^"1 (VS) and/or a Raman band at 241 ±4 cm ^"1 (M) and/or one or more Raman bands selected from the group consisting of 200±4 cm ^"1 (W), 279±4 cm ^"1 (W), 633±4 cm ^"1 (W), 701 ±4 cm ^"1 (W), 726±4 cm ^"1 (W), 843±4 cm ^"1 (W), 855±4 cm ^"1 (W), 1065±4 cm ^"1 (W), 1082±4 cm ^"1 (W), 1 194±4 cm ^"1 (W), 1258±4 cm ^"1 (W), 1431 ±4 cm ^"1 (W), 1445±4 cm ^"1 (W), 1458±4 cm ^"1 (W), 1468±4 cm ^"1 (W), 1596±4 cm ^"1 (W), 1699±4 cm ^"1 (W), 2786±4 cm ^"1 (W), 2834±4 cm ^"1 (W), 2875±4 cm ^"1 (W), 2928±4 cm ^"1 (W), 2943±4 cm ^"1 (W) and 3062±4 cm ^"1 (W) and/or one or more Raman bands selected from the group consisting of 148±4 cm ^"1 (VW), 338±4 cm ^"1 (VW), 365±4 cm ^"1 (VW), 400±4 cm ^"1 (VW), 428±4 cm ^"1 (VW), 486±4 cm ^"1 (VW), 537±4 cm ^"1 (VW), 555±4 cm ^"1 (VW), 621 ±4 cm ^"1 (VW), 796±4 cm ^"1 (VW), 869±4 cm ^"1 (VW), 885±4 cm ^"1 (VW), 925±4 cm ^"1 (VW), 956±4 cm ^"1 (VW), 970±4 cm ^"1 (VW), 1011 ±4 cm ^"1 (VW), 1038±4 cm ^"1 (VW), 1091 ±4 cm ^"1 (VW), 1096±4 cm ^"1 (VW), 1109±4 cm ^"1 (VW), 1156±4 cm ^"1 (VW), 1171 ±4 cm ^"1 (VW), 1218±4 cm ^"1 (VW), 1282±4 cm ^"1 (VW), 1305±4 cm ^"1 (VW), 1323±4 cm ^"1 (VW), 1343±4 cm ^"1 (VW), 1355±4 cm ^"1 (VW), 1385±4 cm ^"1 (VW), 1407±4 cm ^"1 (VW), 1422±4 cm ^"1 (VW), 1653±4 cm ^"1 (VW), 1759±4 cm ^"1 (VW), 1769±4 cm ^"1 (VW), 2899±4 cm ^"1 (VW), 2953±4 cm ^"1 (VW), 2970±4 cm ^"1 (VW), 2993±4 cm ^"1 (VW), 3011 ±4 cm ^"1 (VW), and 3087±4 cm ^"1 (VW).

The crystalline form A according to the present invention may further be

characterised in that it has one or more Raman bands selected from the group consisting of 148±4 cm ^"1 (VW), 200±4 cm ^"1 (W), 241 ±4 cm ^"1 (M), 279±4 cm ^"1 (W), 338±4 cm ^"1 (VW), 365±4 cm ^"1 (VW), 400±4 cm ^"1 (VW), 428±4 cm ^"1 (VW), 452±4 cm ^"1 (W), 486±4 cm ^"1 (VW), 537±4 cm ^"1 (VW), 555±4 cm ^"1 (VW), 621 ±4 cm ^"1 (VW), 633±4 cm ^"1 (W), 701 ±4 cm ^"1 (W), 726±4 cm ^"1 (W), 796±4 cm ^"1 (VW), 843±4 cm ^"1 (W), 855±4 cm ^"1 (W), 869±4 cm ^"1 (VW), 885±4 cm ^"1 (VW), 925±4 cm ^"1 (VW), 956±4 cm ^"1 (VW), 970±4 cm ^"1 (VW), 993±4 cm ^"1 (VS), 1011 ±4 cm ^"1 (VW), 1038±4 cm ^"1 (VW), 1065±4 cm ^"1 (W), 1082±4 cm ^"1 (W), 1091 ±4 cm ^"1 (VW), 1096±4 cm ^"1 (VW), 1109±4 cm ^"1 (VW), 1156±4 cm ^"1 (VW), 1171 ±4 cm ^"1 (VW), 1194±4 cm ^"1 (W), 1218±4 cm ^"1 (VW), 1258±4 cm ^"1 (W), 1282±4 cm ^"1 (VW), 1305±4 cm ^'1 (VW), 1323±4 cm ^"1 (VW), 1343±4 cm ^"1 (VW), 1355±4 cm ^"1 (VW), 1385±4 cm ^"1 (VW), 1407±4 cm ^"1 (VW), 1422±4 cm ^"1 (VW), 1431 ±4 cm ^"1 (W), 1445±4 cm ^"1 (W), 1458±4 cm ^"1 (W), 1468±4 cm ^"1 (W), 1596±4 cm ^"1 (W), 1653±4 cm ^"1 (VW), 1699±4 cm ^"1 (W), 1759±4 cm ^'1 (VW), 1769±4 cm ^"1 (VW), 2786±4 cm ^"1 (W), 2834±4 cm ^"1 (W), 2875±4 cm ^"1 (W), 2899±4 cm ^"1 (VW), 2928±4 cm ^"1 (W), 2943±4 cm ^"1 (W), 2953±4 cm ^"1 (VW), 2970±4 cm ^"1 (VW), 2993±4 cm ^"1 (VW), 3011 ±4 cm ^"1 (VW), 3062±4 cm ^"1 (W) and 3087±4 cm ^"1 (VW).

The peak intensities are described by VW (very weak), W (weak), M (medium) and VS (very strong). Figure 4 shows a Raman spectrum of crystalline modification A.

Another aspect of the present . invention relates to a method for the production of the crystalline modification A described above comprising the step of

(a) dissolving (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in an ester.

Preferably, in the method according to the invention the ester is ethyl acetate.

Preferably, in the method according to the invention, step (a) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably the method according to the invention comprises the step

(b) precipitation of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol or one of its individual enantiomers from the solution obtained in step (a).

Suitable methods of precipitation are known to a person skilled in the art. Preferably, in the method according to the invention, step (b) may be carried out by reducing the volume of the solution obtained according to step (a) and/or by cooling of the solution, preferably to a temperature of at most 15°C, more preferably at most 10°C, even more preferably at most 4-8°C and/or by cooling of the solution, preferably to a temperature of at least 10 °C, more preferably at least 30 °C, even more preferably at least 60 °C below the temperature according to step (a).

Preferably, in the method according to the invention, after the precipitation in step (b), all other steps are carried out at a temperature between 40 and 0°C, preferably between 35 and 5°C, more preferably between 25 and 15°C. Preferably the method according to the invention may comprise the step

(c) drying of the precipitate obtained in step (b).

Preferably, in the method according to the invention, step (c) takes place under air. However, drying under vacuum, more preferably at a vacuum of 1.0 to 900 mbar, even more preferably at a vacuum of 10 to 500 mbar, and in particular at a vacuum of 20 to 200 mbar is also possible.

Preferably, in the method according to the invention, step (c) takes place in a temperature range from 0 to 60°C, preferably from 10°C to 50°C more preferably from 20 to 40°C.

Another aspect of the present invention relates to a method for the production of the crystalline modification A described above comprising the step of

(a-1 ) dissolving (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in an ester.

Preferably, in the method according to the invention the ester is ethyl acetate.

Preferably, in the method according to the invention, step (a-1 ) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably the method according to the invention comprises the step

(b-1 ) evaporating off the solvent of the solution obtained in step (a-1 ).

Suitable methods for evaporating off the solvent are known to a person skilled in the art. Preferably, in the method according to the invention, the solvent is evaporated off in air or air flow. Another aspect of the present invention relates to a method for the production of the crystalline modification A described above comprising the step of

(a-2) dissolving (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in an alcohol.

Preferably, in the method according to the invention the alcohol is selected from methanol, ethanol, 1-propanol and 2-propanol, whereby methanol is particularly preferred.

Preferably, in the method according to the invention, step (a-2) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably the method according to the invention comprises the step

(b-2) evaporating off the solvent of the solution obtained in step (a-2).

Suitable methods for evaporating off the solvent are known to a person skilled in the art. Preferably, in the method according to the invention, the solvent is evaporated off in air or air flow.

Another aspect of the present invention relates to a method for the production of the crystalline modification A described above comprising the step of

(a-3) dissolving (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in an alcohol.

Preferably, in the method according to the invention the alcohol is selected from methanol, ethanol, 1-propanol and 2-propanol, whereby methanol is particularly preferred. Preferably, in the method according to the invention, step (a-3) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably the method according to the invention comprises the step

(b-3) precipitation of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol or one of its individual enantiomers from the solution obtained in step (a-3).

Suitable methods of precipitation are known to a person skilled in the art. Preferably, in the method according to the invention, step (b-3) may be carried out by reducing the volume of the solution obtained according to step (a) and/or by cooling of the solution, preferably to a temperature of at most 15°C, more preferably at most 10°C, even more preferably at most 4-8°C and/or by cooling of the solution, preferably to a temperature of at least 10 °C, more preferably at least 30 °C, even more preferably at least 60 °C below the temperature according to step (a-3).

Preferably, in the method according to the invention, after the precipitation in step (b- 3), all other steps are carried out at a temperature between 40 and 0°C, preferably between 35 and 5°C, more preferably between 25 and 15°C.

Preferably the method according to the invention may comprise the step (c-3) drying of the precipitate obtained in step (b-3).

Preferably, in the method according to the invention, step (c-3) takes place under air. However, drying under vacuum, more preferably at a vacuum of 1.0 to 900 mbar, even more preferably at a vacuum of 10 to 500 mbar, and in particular at a vacuum of 20 to 200 mbar is also possible. Preferably, in the method according to the invention, step (c-3) takes place in a temperature range from 0 to 60°C, preferably from 10°C to 50°C more preferably from 20 to 40°C.

A further aspect of the present invention relates to a crystalline modification A that can be obtained as described above.

Crystalline modification A is the most thermodynamically stable form, in particular in the temperature range of -20 °C to 120 °C, preferably 0 - 100 °C, more preferably 25 - 75 °C. Accordingly, it may generally be obtained by slower crystallisation and/or by slower evaporation techniques.

The thermodynamic stability is important. By using the most stable modification in a medicament it may specifically be ensured that, during storage, no polymorphic conversion of the active ingredient in the pharmaceutical formulation takes place. This is advantageous, because otherwise the properties of the medicament could change as a consequence of a conversion of a less stable modification into a more stable modification. In relation to the pharmacological properties of an administration form, this could lead for example to the solubility of the active ingredient changing, accompanied by a change in the release characteristics and thus also a change in the bioavailability. Lastly, this could result in inadequate storage stability of the medicament.

A further subject-matter of the present invention relates to a crystalline modification B (polymorph B). Said crystalline modification B according to the present invention has at least one X-ray diffraction peak selected from the group consisting of 1 1 ,35±0,20 (2Θ) and 24,30±0,20 (2Θ).

Preferably, the crystalline modification B according to the present invention may additionally have at least one X-ray diffraction peak selected from the group consisting of 12,75±0,20 (2Θ), 14,04±0,20 (2Θ), 16,51 ±0,20 (2Θ), 18,79±0,20 (2Θ), 19,74±0,20 (2Θ), 20,09±0,20 (2Θ) and 21 ,20±0,20 (2Θ). The crystalline modification B according to the present invention may further be characterised in that as well as the one or more X-ray diffraction peaks selected from the group consisting of 1 1 ,35±0,20 (2Θ) and 24,30±0,20 (2Θ), and optionally one or more X-ray diffraction peaks selected from the group consisting of 12,75±0,20 (2Θ), 14,04±0,20 (2Θ), 16,51 ±0,20 (2Θ), 18,79±0,20 (2Θ), 19,74±0,20 (2Θ), 20,09±0,20 (2Θ) and 21 ,20±0,20 (2Θ), it additionally has at least one X-ray diffraction peak selected from the group consisting of 15,23±0,20 (2Θ), 19,20±0,20 (2Θ), 21 ,42±0,20 (2Θ), 23,69±0,20 (2Θ), 23,76±0,20 (2Θ), 24,30±0,20 (2Θ), 25,66±0,20 (2Θ),

25,74±0,20 (2Θ), 25,84±0,20 (2Θ), 28,30±0,20 (2Θ) and 31 ,81 ±0,20 (2Θ).

Furthermore, the crystalline modification B according to the invention may be characterised in that as well as one or more X-ray diffraction peaks selected from the group consisting of 1 1 ,35±0,20 (2Θ) and 24,30±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 12,75±0,20 (2Θ), 14,04±0,20 (2Θ), 16,51 ±0,20 (2Θ), 18,79±0,20 (2Θ), 19,74±0,20 (2Θ), 20,09±0,20 (2Θ) and 21 ,20±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 15,23±0,20 (2Θ), 19,20±0,20 (2Θ), 21 ,42±0,20 (2Θ), 23,69±0,20 (2Θ), 23,76±0,20 (2Θ), 24,30±0,20 (2Θ), 25,66±0,20 (2Θ), 25,74±0,20 (2Θ), 25,84±0,20 (2Θ), 28,30±0,20 (2Θ), 31 , 81 ±0,20 (2Θ) it additionally has at least one X-ray diffraction peak selected from the group consisting of 9,72±0,20 (2Θ), 12,79±0,20 (2Θ), 22,82±0,20 (2Θ), 26,55±0,20 (2Θ), 26,77±0,20 (2Θ), 27,07±0,20 (2Θ), 27,83±0,20 (2Θ), 28,07±0,20 (2Θ), 28,49±0,20 (2Θ), 29,44±0,20 (2Θ),

29,74±0,20 (2Θ), 30,21 ±0,20 (2Θ), 30,27±0,20 (2Θ), 30,62±0,20 (2Θ), 30,74±0,20 (2Θ), 31 ,96±0,20 (2Θ), 32,01 ±0,20 (2Θ), 32,09±0,20 (2Θ), 33,18±0,20 (2Θ),

33,39±0,20 (2Θ), 33,94±0,20 (2Θ), 34,01 ±0,20 (2Θ), 34,25±0,20 (2Θ), 34,52±0,20 (2Θ), 34,85±0,20 (2Θ), 35,37±0,20 (2Θ), 35,55±0,20 (2Θ), 35,70±0,20 (2Θ),

35,83±0,20 (2Θ), 37,21 ±0,20 (2Θ), 37,29±0,20 (2Θ), 37,63±0,20 (2Θ), 38,12±0,20 (2Θ), 38,20±0,20 (2Θ), 38,48±0,20 (2Θ), 38,50±0,20 (2Θ), 38,96±0,20 (2Θ),

39,04±0,20 (2Θ), 39,47±0,20 (2Θ) and 39,97±0,20 (2Θ). The crystalline modification B according to the invention may also be characterised in that as well as the at least one X-ray diffraction peak selected from the group consisting of 11 ,35±0,20 (2Θ) and 24,30±0,20 (2Θ) and optionally one or more X-ray diffraction peak selected from the group consisting of 12,75±0,20 (2Θ), 14,04±0,20 (2Θ), 16,51 ±0,20 (2Θ), 18,79±0,20 (2Θ), 19,74±0,20 (2Θ), 20,09±0,20 (2Θ) and optionally one or more X-ray diffraction peak selected from the group consisting of 15,23±0,20 (2Θ), 19,20±0,20 (2Θ), 21 ,42±0,20 (2Θ), 23,69±0,20 (2Θ), 23,76±0,20 (2Θ), 24,30±0,20 (2Θ), 25,66±0,20 (2Θ), 25,74±0,20 (2Θ), 25,84±0,20 (2Θ),

28,30±0,20 (2Θ), 31 ,81 ±0,20 (2Θ), and optionally one or more X-ray diffraction peak selected from the group consisting of 9,72±0,20 (2Θ), 12,79±0,20 (2Θ), 22,82±0,20 (2Θ), 26,55±0,20 (2Θ), 26,77±0,20 (2Θ), 27,07±0,20 (2Θ), 27,83±0,20 (2Θ),

28,07±0,20 (2Θ), 28,49±0,20 (2Θ), 29,44±0,20 (2Θ), 29,74±0,20 (2Θ), 30,21 ±0,20 (2Θ), 30,27±0,20 (2Θ), 30,62±0,20 (2Θ), 30,74±0,20 (2Θ), 31 ,96±0,20 (2Θ),

32,01 ±0,20 (2Θ), 32,09±0,20 (2Θ), 33,18±0,20 (2Θ), 33,39±0,20 (2Θ), 33,94±0,20 (2Θ), 34,01 ±0,20 (2Θ), 34,25±0,20 (2Θ), 34,52±0,20 (2Θ), 34,85±0,20 (2Θ),

35,37±0,20 (2Θ), 35,55±0,20 (2Θ), 35,70±0,20 (2Θ), 35,83±0,20 (2Θ), 37,21 ±0,20 (2Θ), 37,29±0,20 (2Θ), 37,63±0,20 (2Θ), 38,12±0,20 (2Θ), 38,20±0,20 (2Θ),

38,48±0,20 (2Θ), 38,50±0,20 (2Θ), 38,96±0,20 (2Θ), 39,04±0,20 (2Θ), 39,47±0,20 (2Θ) and 39,97±0,20 (2Θ) it additionally has at least one X-ray diffraction peak selected from the group consisting of 19,50±0,20 (2Θ), 20,94±0,20 (2Θ), 22,24±0,20 (2Θ), 25,19±0,20 (2Θ), 27,23±0,20 (2Θ), 27,42±0,20 (2Θ), 28,52±0,20 (2Θ),

33,14±0,20 (2Θ), 33,62±0,20 (2Θ), 34,11 ±0,20 (2Θ), 34,51 ±0,20 (2Θ), 35,15±0,20 (2Θ), 35,54±0,20 (2Θ), 35,89±0,20 (2Θ), 36,11±0,20 (2Θ), 36,30±0,20 (2Θ),

38,06±0,20 (2Θ), 38,75±0,20 (2Θ), 38,91 ±0,20 (2Θ), 39,01 ±0,20 (2Θ), 39,08±0,20 (2Θ) and 39,60±0,20 (2Θ).

Figure 5 shows a calculated diffractogram of crystalline modification B. In DSC analyses, the crystalline modification B according to the present invention preferably exhibits an endothermal event with a peak temperature at 109-120 °C, more preferably at 110-119 °C, even more preferably at 111-118 °C and in particular at 112-115 °C.

Another aspect of the present invention relates to a method for the production of the crystalline modification B described above comprising the step of

(a) dissolving (1 RS,3RS,6RS )-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in a chlorinated hydrocarbon.

Preferably, in the method according to the invention the chlorinated hydrocarbon is dichloromethane.

Preferably, in the method according to the invention, step (a) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably, in the method according to the invention, step (a) is carried out under application of energy, e.g. via ultrasound.

Preferably the method according to the invention comprises the step

(b) adding an antisolvent to the solution obtained in step (a).

An antisolvent as used herein designates a organic medium in which

(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)-cyclohexan-1 ,3-diol or its individual enantiomer shows a lower solubility as in the chlorinated hydrocarbon used in step (a), for example, n-hexane or n-pentane. The amount of the antisolvent can preferably be selected in such a manner that upon its addition precipation of the dissolved component begins.

The temperature of the solution at which the antisolvent is added and the

temperature of the antisolvent that is added can preferably be selected in such a manner that upon its addition precipation of the dissolved component begins immediately. Preferably there may be a difference between the temperature of the solution and the temperature of the antisolvent of at least 10°C, more preferably of at least 15°C, yet more preferably of at least 20°C, whereby it may be preferred that the solution has the higher temperature and the antisolvent the lower temperature.

Preferably the method according to the invention comprises the step

(c) precipitation of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol or one of its individual enantiomers from the solution obtained in step (a) or in step (b).

Suitable methods of initiating immediate precipitation are known to a person skilled in the art. Preferably, in the method according to the invention, step (c) is carried out by cooling the solution. Preferably it is cooled rapidly to a temperature of at most 15°C, more preferably at most 10°C, even more preferably at most 4-8°C.

Rapid cooling can be realised e.g. by transferring the vial or flask with the solution into an icebath or into a suspension of dry ice in methanol.

Preferably, in the method according to the invention, after the precipitation in step (c), all other steps are carried out at a temperature between 40 and 0°C, preferably between 35 and 5°C, more preferably between 25 and 15°C. Preferably the method according to the invention comprises the step

(d) drying of the precipitate obtained in step (c).

Preferably, in the method according to the invention, step (d) takes place under air. However, drying under vacuum, more preferably at a vacuum of 1.0 to 900 mbar, even more preferably at a vacuum of 10 to 500 mbar, and in particular at a vacuum of 20 to 200 mbar is also possible.

Preferably, in the method according to the invention, step (d) takes place in a temperature range from 0 to 60°C, preferably from 10°C to 50°C more preferably from 20 to 40°C.

A further aspect of the present invention relates to a crystalline modification B that can be obtained as described above.

Another aspect of the present invention relates to a method for the production of the crystalline modification B described above comprising the step of

(a-1 ) dissolving (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in an ether.

Preferably, in the method according to the invention the ether is selected from the group consisting of diethylether, diisopropylether and tert-Butylmethylether.

Preferably, in the method according to the invention, step (a) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C. Preferably the method according to the invention comprises the step

(b-1 ) evaporating off the solvent of the solution obtained in step (a-1 ).

Suitable methods of evaporating off the solvent are known to a person skilled in the art. Preferably, in the method according to the invention, the solvent is evaporated off in air or air flow, more preferably by evaporating off the solvent applying a vacuum.

It seems that generally crystalline modification B can be obtained by faster

crystallisation and/or at higher temperatures.

A further subject-matter of the present invention relates to a crystalline modification C (polymorph C). Said crystalline modification C according to the present invention has at least one X-ray diffraction peak selected from the group consisting of 9,05±0,20 (2Θ), 14,64±0,20 (2Θ), 15,83±0,20 (2Θ) and 16,07±0,20 (2Θ).

Preferably, the crystalline modification C according to the present invention may additionally have at least one X-ray diffraction peak selected from the group consisting of 15,47±0,20 (2Θ), 16,84±0,20 (2Θ), 18,07±0,20 (2Θ), 19,64±0,20 (2Θ), 20,23±0,20 (2Θ), 21 ,04±0,20 (2Θ), 21 ,49±0,20 (2Θ), 22,04±0,20 (2Θ), 24,79±0,20 (2Θ), 25,69±0,20 (2Θ), 27,80±0,20 (2Θ), 28,22±0,20 (2Θ) and 31 ,17±0,20 (2Θ).

Furthermore, the crystalline modification C according to the present invention may be characterised in that as well as one or more X-ray diffraction peaks selected from the group consisting of 9,05±0,20 (2Θ), 14,64±0,20 (2Θ), 15,83±0,20 (2Θ) and

16,07±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 15,47±0,20 (2Θ), 16,84±0,20 (2Θ), 18,07±0,20 (2Θ), 19,64±0,20 (2Θ), 20,23±0,20 (2Θ), 21 ,04±0,20 (2Θ), 21 ,49±0,20 (2Θ), 22,04±0,20 (2Θ),

24,79±0,20 (2Θ), 25,69±0,20 (2Θ), 27,80±0,20 (2Θ), 28,22±0,20 (2Θ) and

31 ,17±0,20 (2Θ) it additionally has at least one X-ray diffraction peak selected from the group consisting of 12,54±0,20 (2Θ), 15,02±0,20 (2Θ), 17,77±0,20 (2Θ),

24,94±0,20 (2Θ), 25,18±0,20 (2Θ), 25,82±0,20 (2Θ), 26,34±0,20 (2Θ), 26,82±0,20 (2Θ), 29,25+0,20 (2Θ), 29,46±0,20 (2Θ), 29,89±0,20 (2Θ), 30,07±0,20 (2Θ),

34,00±0,20 (2Θ), 35,90±0,20 (2Θ), 36,34±0,20 (2Θ) and 39,12±0,20 (2Θ).

Furthermore, the crystalline modification C according to the present invention may be characterised in that as well as one or more X-ray diffraction peaks selected from the group consisting of 9,05±0,20 (2Θ), 14,64±0,20 (2Θ), 15,83±0,20 (2Θ) and

16,07±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group consisting of 15,47±0,20 (2Θ), 16,84±0,20 (2Θ), 18,07±0,20 (2Θ), 19,64±0,20 (2Θ), 20,23±0,20 (2Θ), 21 ,04±0,20 (2Θ), 21 ,49±0,20 (2Θ), 22,04±0,20 (2Θ),

24,79±0,20 (2Θ), 25,69±0,20 (2Θ), 27,80±0,20 (2Θ), 28,22±0,20 (2Θ) and

31 ,17±0,20 (2Θ) and optionally one or more X-ray diffraction peaks selected from the group of 12,54±0,20 (2Θ), 15,02±0,20 (2Θ), 17,77±0,20 (2Θ), 24,94±0,20 (2Θ), 25,18±0,20 (2Θ), 25,82±0,20 (2Θ), 26,34±0,20 (2Θ), 26,82±0,20 (2Θ), 29,25±0,20 (2Θ), 29,46±0,20 (2Θ), 29,89±0,20 (2Θ), 30,07±0,20 (2Θ), 34,00±0,20 (2Θ),

35,90±0,20 (2Θ), 36,34±0,20 (2Θ) and 39,12±0,20 (2Θ) it additionally comprises at least one X-ray diffraction peak selected from the group consisting of 10,04±0,20 (2Θ), 23,7810,20 (2Θ), 30,31 ±0,20 (2Θ), 30,64±0,20 (2Θ), 32,47±0,20 (2Θ),

32,94±0,20 (2Θ), 33,21 ±0,20 (2Θ), 34,40±0,20 (2Θ), 38,13±0,20 (2Θ) and

39,31 ±0,20 (2Θ).

Figure 6 shows a measured diffractogram of crystalline modification C.

In DSC analyses, the crystalline modification C according to the present invention preferably exhibits an endothermal event with a peak temperature at 1 13-124 °C, more preferably at 1 14-123 °C, even more preferably at 115-122 °C and in particular at 116-121 °C. Another aspect of the present invention relates to a method for the production of the crystalline modification C described above comprising the step of

(a) . dissolving (1 RS,3RS,6RS )-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol in a ketone.

Preferably, in the method according to the invention the ketone is selected from the group consisting of acetone, butan-2-one, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one. Acetone is particularly preferred.

Preferably, in the method according to the invention, step (a) is carried out at a temperature not higher than 80°C, more preferably not higher than 60°C, even more preferably not higher than 40°C and/or in particular in a temperature range of 20-40 °C.

Preferably, in the method according to the invention, step (a) is carried out under application of energy, e.g. via ultrasound.

Preferably the method according to the invention comprises the step

(b) adding an antisolvent to the solution obtained in step (a).

An antisolvent as used herein designates a organic medium in which

(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclo hexan-1 ,3-diol or one of its enantiomers shows a lower solubility as in the ketone used in step (a), for example, n-hexane or n-pentane.

The amount of the antisolvent can preferably be selected in such a manner that upon its addition precipation of the dissolved component begins. Preferably the method according to the invention comprises the step

(c) precipitation of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol or one of its individual enantiomers from the solution obtained in step (a) or in step (b).

Suitable methods of precipitation are known to a person skilled in the art. Preferably, in the method according to the invention, step (c) is carried out by cooling the solution, preferably to a temperature of at most 15°C, more preferably at most 10°C, even more preferably at most 4-8°C and/or by cooling of the solution, preferably to a temperature of at least 10°C, more preferably at least 30°C, even more preferably at least 60°C below the temperature according to step (a) or step (b).

Preferably, in the method according to the invention, after the precipitation in step (c), all other steps are carried out at a temperature between 40 and 0°C, preferably between 35 and 5°C, more preferably between 25 and 15°C.

Preferably the method according to the invention comprises the step (d) drying of the precipitate obtained in step (c).

Preferably, in the method according to the invention, step (d) takes place under air. However, drying under vacuum, more preferably at a vacuum of 1.0 to 900 mbar, even more preferably at a vacuum of 10 to 500 mbar, and in particular at a vacuum of 20 to 200 mbar is also possible.

Preferably, in the method according to the invention, step (d) takes place in a temperature range from 0 to 60°C, preferably from 10°C to 50°C more preferably from 20 to 40°C.

A further aspect of the present invention relates to a crystalline modification C that can be obtained as described above. The modifications A, B and C according to the invention may optionally also form co- crystals and solvates. These are all included within the scope of the present invention.

It is known to anyone skilled in the art, e.g. from Jane Li et al. in J. Pharm. Sci., 1999, Vol. 88(3),pages 337-346 that enantiomers form identical crystalline modifications (polymorphs) and accordingly show identical X-ray-diffractograms and Raman spectra. Thus, the present invention comprises crystalline modifications of both enantiomers (1 R,3R,6R)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)-cyclohexan- 1 ,3-diol and (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cycloh exan- 1 ,3-diol as mixtures thereof, such as the racemate (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1 -(3-methoxy-phenyl)-cyclohexan-1 ,3-diol.

It was surprisingly found that the compound (1 RS,3RS,6RS)-6-Dimethylaminomethyl- 1-(3-methoxy-phenyl)-cyclohexan-1 ,3-diol forms a conglomerate, i.e. the resulting individual crystals do not comprise a racemic composition but the individual enantiomers.

Accordingly, the individual enantiomers (1 R,3R,6R)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)-cyclohexan-1 ,3-diol and (1S,3S,6S)-6-Dimethylaminomethyl-1-(3- methoxy-phenyl)-cyclohexan-1 ,3-diol may be obtained via preferential crystallisation from a solution comprising these comounds, which is an effective and cheap method and allows for the production of the pure enantiomers at different scales.

Thus, in yet a further aspect the present invention relates to a process for obtaining or enriching (1 R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohex ane- 1 ,3-diol or (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cycloh exane- 1 ,3-diol, which comprises the step of cooling a solution comprising these compounds.

Said inventive process may be carried out starting from a solution that contains the individual enantiomers in a racemic mixture or a non-racemic mixture, whereby the latter is preferred. A non-racemic mixture can contain the enantiomers in any possible ratio, for example, in a ratio of 60±5:40±5; 70±5:30±5; 80±5:20±5 or 90±5:10±5. Preferably, the non-racemic mixture may contain at least 55 %, preferably at least 60 % of one enantiomer, even more preferably at least 70 % of one enantiomer, preferably the enantiomer that is to be obtained or enriched.

Suitable media for carrying out the inventive process are any conventional organic solvents known to the person skilled in the art or mixtures of two or more of such solvents, for example, alcohols such as methanol, ethanol, 1-propanol and 2- propanol, esters such as ethyl acetate, ketones such as acetone and ethylmethyl ketone, ethers such as diethyl ether, diisopropylether, 1 ,4-dioxane and

tetrahydrofuran, nitriles such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, aromatic hydrocarbons such as toluene, and also dimethyl formamide and dimethyl sulphoxide. Preferably ethers such as diisopropylether may be used in the process according to the present invention.

The solution may be seeded with crystalline material of one of the enantiomers, preferably of the enantiomer that is to be obtained or enriched. Such crystals of the enantiomer may be obtained by methods well-known to those skilled in the art, for example, via chromatographic methods such as HPLC or via diastereomeric salt formation and subsequent release and crystallisation of the free base.

The solution may be cooled by a temperature difference that varies over a broad range, e.g. at least 75 °C, preferably at least 65 °C, more preferably at least 55 °C, even more preferably at least 50 °C and in particular 40-50°C.

For example, the solution may be cooled from a temperature of 50-65 °C to a room temperature, for example, 15-25 °C.

In another aspect the present invention relates to a crystalline modification as described herein for the treatment of pain. The term pain as used herein preferably includes but is not limited to pain selected from the group consisting of inflammatory pain, postoperative pain, neuropathic pain, diabetic neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain and cancer pain.

Different types of pain associated with arthrosis are described, for example, in WO 2008/138558 the respective contents of which hereby being incorporated by reference and forming part of the disclosure of the present invention.

In another aspect the present invention relates to a pharmaceutical composition comprising a crystalline modification as described herein and optionally one or more suitable additives and/or adjuvants such as described below. Preferably said pharmaceutical composition may be used for the treatment of pain.

In still another aspect the present invention relates to a medicament comprising a crystalline modification as described herein. In a preferred embodiment, the medicament is a solid drug form. The medicament is preferably manufactured for oral administration. However, other forms of administration are also possible, e.g. for buccal, sublingual, transmucosal, rectal, intralumbal, intraperitoneal, transdermal, intravenous, intramuscular, intragluteal, intracutaneous and subcutaneous

application.

Depending on the configuration, the medicament (dosage form) preferably contains suitable additives and/or adjuvants. Suitable additives and/or adjuvants in the sense of the invention are all substances known to a person skilled in the art for the formation of galenic formulations. The choice of these adjuvants and also the quantities to be used are dependent on how the medication is to be administered, i.e. orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally.

Preparations suitable for oral administration are those in the form of tablets, chewable tablets, lozenges, capsules, granules, drops, liquids or syrups, and those suitable for parenteral, topical and inhalatory administration are solutions, suspensions, easily reconstituted dry preparations and sprays. A further possibility is suppositories for rectal administration. The application in a depot in dissolved form, a patch or a. plaster, possibly with the addition of agents promoting skin penetration, are examples of suitable percutaneous forms of application.

Examples of adjuvants and additives for oral forms of application are disintegrants, lubricants, binders, fillers, mould release agents, possibly solvents, flavourings, sugar, in particular carriers, diluents, colouring agents, antioxidants etc.

Waxes or fatty acid esters, amongst others, can be used for suppositories and carrier substances, preservatives, suspension aids etc. can be used for parenteral forms of application.

Adjuvants can be, for example: water, ethanol, 2-propanol, glycerine, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose, molasses, starch, modified starch, gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl- cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic rubbers, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulphate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene fatty acid esters, sorbitane fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulphate, zinc sulphate, calcium sulphate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidon, agar and bentonite.

The production of these medicaments and pharmaceutical compositions is conducted using means, devices, methods and processes that are well known in the art of pharmaceutical technology, as described, for example, in "Remington's Pharmaceutical Sciences" , A.R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93.

Thus, for example, for a solid formulation such as a tablet, the active substance of the drug can be granulated with a pharmaceutical carrier substance, e.g.

conventional tablet constituents such as cornstarch, lactose, saccharose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable rubbers, and pharmaceutical diluents such as water, for example, in order to form a solid composition that contains the active substance in a homogenous dispersion. Homogenous dispersion is understood here to mean that the active substances are uniformly dispersed throughout the composition, so that this can be readily divided into identically effective standard dosage forms such as tablets, capsules, lozenges. The solid composition is then divided into standard dosage forms. The tablets or pills can also be coated or otherwise compounded to prepare a slow release dosage form. Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and/or cellulose acetate, for example.

In one embodiment of the present invention the crystalline modification as described herein is present in immediate release form.

In another embodiment of the present invention the crystalline modification as described herein is at least partially present in controlled-release form. In particular, the active ingredient can be released slowly from preparations that can be applied orally, rectally or percutaneously.

The medicament can preferably be manufactured for administration once daily, twice daily (bid), or three times daily, the once daily or twice daily administration (bid) being preferred.

The term controlled release as used herein refers to any type of release other than immediate release such as delayed release, sustained release, slow release, extended release and the like. These terms are well known to any person skilled in the art as are the means, devices, methods and processes for obtaining such type of release.

A controlled release of the active ingredient can be achieved, for example, by retardation using a matrix, a coating or osmotically active release systems such as described for axomadol in WO 2005/009329, for example. The respective parts of the description are hereby incorporated by reference and form part of the present disclosure.

In another embodiment of the present invention

• the medicament is manufactured for oral administration; and/or

• the medicament is a solid and/or compressed and/or film-coated drug form;

and/or

• the medicament releases the microcrystalline modification as described herein slowly from a matrix; and/or

• the medicament contains the microcrystalline modification in a quantity of 0.001 to 99.999% by wt., more preferred 0.1 to 99.9% by wt., still more preferred 1.0 to 99.0% by wt., even more preferred 2.5 to 80% by wt., most preferred 5.0 to 50% by wt. and in particular 7.5 to 40% by wt., based on the total weight of the medicament; and/or

• the medicament contains a pharmaceutically compatible carrier and/or

pharmaceutically compatible adjuvants; and/or

• the medicament has a total mass in the range of 25 to 2000 mg, more preferred 50 to 1800 mg, still more preferred 60 to 1600 mg, more preferred 70 to 1400 mg, most preferred 80 to 1200 mg and in particular 100 to 1000 mg; and/or

• the medicament is selected from the group comprising tablets, capsules, pellets and granules. The medicament can be provided as a simple tablet and as a coated tablet (e.g. as film-coated tablet or lozenge). The tablets are usually round and biconvex, but oblong forms are also possible. Granules, spheres, pellets or microcapsules, which are contained in sachets or capsules or are compressed to form disintegrating tablets, are also possible.

In yet another one of its aspects, the present invention relates to the use of the crystalline modification as described herein for the production of a medicament.

Preferably said medicament is suitable for the treatment of pain.

In still another one of its aspects, the present invention relates to the use of the crystalline modification as described herein for the treatment of pain.

Furthermore, the present invention relates to a method for treating pain in a patient, preferably in a mammal, which comprises administering an effective amount of a crystalline modification as described herein to a patient.

Figure 1 shows a calculated diffractogram of crystalline modification A.

Figure 2 shows a measured diffractogram of crystalline modification A.

Figure 3 shows a comparison of the calculated diffractogram according to Figure 1 and the measured diffractogram of crystalline modification A.

Figure 4 shows a Raman spectrum of crystalline modification A.

Figure 5 shows a calculated diffractogram of crystalline modification B.

Figure 6 shows a measured diffractogram of crystalline modification C.

The following examples serve to explain the invention in more detail, but should not be interpreted as restrictive. Examples

1. Synthesis of. crystalline modification A

1.1

27.69 g (87.66 mmol) of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy- phenyl)-cyclohexan-1 ,3-diol hydrochloride were dissolved in 140 m'L of destilled water and cooled to 25 °C. At a temperature of 25 °C an aqueous solution of sodium hydroxide (32 %) was added until a pH of 11 was obtained. Subsequent to the addition of 10 ml of said solution precipitation of a white, oily solid was observed, which was dissolved by adding 10 ml ethyl acetate. After the addition of 20 ml of the aqueous solution of sodium hydroxide (32 %) a pH of 11 was obtained.

(1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)-cyclohexan-1 ,3-diol was extracted with ethyl acetate, the resulting organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to about half its volume by means of a rotary evaporator. The resulting solution was kept at room temperature for 5 days, upon which large, colorless orthorhombic crystals were obtained, which were filtered of and washed with a small amount of cooled ethyl acetate (Yield 6.07 g). The remaining solution was evaporated to dryness to yield a light brown solid (Yield 16.49).

The obtained products were characterized by ¹ H-NMR spectroscopy.

According to x-ray powder diffraction (XRPD) the product obtained was crystalline modification A. 1.2

10 mg of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)-cyclohexan- 1 ,3-diol obtained according to 1.1 were pestled, given into a vial and 1 ml of ethyl acetate was added. The vial was given into a Desyre reaction block that was vortexted by means of an IKA-Vibrax ^® for 16 hours at room temperature and 400 rpm. Subsequently, the reaction block was kept in a refrigerator at 4 °C. After 72 hours at 4°C the vial still contained a clear solution and the reactor block was cooled to -18°C. After 72 hours at this temperature still no solid was observed. The sample was then kept at room temperature to evaporate off the solvent. After 3 days the sample was dried under nitrogen flow and crystals were obtained. (Yield 100 %).

According to x-ray powder diffraction (XRPD) the product obtained is crystalline modification A.

2. Synthesis of crystalline modification B

50.97 mg of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol were given into a vial. At a temperature of 22 °C the solid was dissolved in 0.2 ml dichloromethane under ultrasound. Subsequently n-pentane was added until the beginning of precipitation could be observed (7 ml). The resulting clear solution was then kept in a refrigerator at a temperature of 4-8°C.

After 28 hours crystalline material was obtained. After 52 hours the crystalline material was filtered off and dried under air flow.

The product obtained was characterized by ¹ H-NMR spectroscopy.

According to x-ray powder diffraction (XRPD) the product obtained is crystalline modification B with minor impurities of crystalline modification A.

3. Synthesis of crystalline modification C

49.53 mg of (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)- cyclohexan-1 ,3-diol were given into a vial. At a temperature of 22 °C the solid was dissolved in 0.7 ml acetone under ultrasound. Subsequently n-hexane was added until the beginning of precipitation could be observed (7 ml). The resulting clear solution was then kept in a refrigerator at a temperature of 4-8°C.

After 28 hours single crystals were obtained. After 52 hours the crystals were filtered off and dried under air flow.

The product obtained was characterized by ¹ H-NMR spectroscopy.

According to x-ray powder diffraction (XRPD) the product obtained is crystalline modification C.

Moreover, two single crystals were used to determine the absolute configuration via X-ray single crystal diffraction. These two single crystals contained the different enantiomers (1 R,3R,6R)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohex an- 1 ,3-diol and (1S,3S,6S)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cycloh exan- 1 ,3-diol.

4. Crystallisation experiments

In each of the following crystallisation experiments 40 mg of (1 RS,3RS,6RS)-6- Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexan-1 ,3-diol were dissolved or suspended in the respective solvent as summerized in the i the following table 1 :

Table 1 :

Subsequently, the samples were kept at room temperature. After 5 days some single crystals had formed. After an additional 3 days the crystals were seperated and subjected to further analysis. Tetrahydrofurane did not yield clear crystals; diisopropyl ether yielded large crystals, methanol yielded good crystals and ethyl acetate yielded small, clear cristals.

Surprisingly, the crystallisation experiments did not yield single crystals comprising the racemate (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1 -(3-methoxy-phenyl)- cyclohexan-1 ,3-diol. Rather, the single crystals obtained in these cristallisation experiments consisted of the enantiomers as was verified via x-ray single crystal diffraction .

Thus, upon crystallisation, the compound (1 RS,3RS,6RS)-6-Dimethylaminomethyl-1-

(3-methoxy-phenyl)-cyclohexan-1 ,3-diol formed a conglomerate. Analysis - x-ray diffraction (XRD)

(a) Measurements

X-ray diffraction (XRD):

X-ray powder diffraction (XRPD) analyses were carried out in transmission geometry with a STOE Stadi P X-ray diffractometer, monochromatised CuKc radiation being used by means of a germanium monocrystal. D-distances were calculated from the 2Θ values, establishing the wavelength of 1.540598 A. In general, the 2Θ values have an error rate of ±0.2° in 2Θ. The experimental error in the d-distance values is therefore dependent on the location of the peak. b) Calculations

The peak tables and graphical representations of the diffractograms were produced on basis of the single crystal data using the programm WinXPow (THEO 1.1 1 , version PKS_2.01 ) of the company STOE.

The parameters that were used for the calculations of the diffractograms as well as the peak lists in the computer program WinXPow are given in the following table 2.

Table 2:

Peak tables and diffractoprams

The values with regard to the relative intensities I (rel) were rounded. Thus, also peaks with an l(rel) of 0 may be seen in the diffractogram.

Due to the parameters chosen for the calculation of the diffractograms differences between the relative intensities (l(rel)) in the peak tables and the graphical representation of the calculated diffractogram may occur.

This is the case, for example, for form A: In the peak list the reflex at 16.71 (2Theta) is listed with l(rel) = 100 as the most intensive peak. However, in the graphical representation of the diffractogram the broad reflex in the range of 20.5 - 20.7 (2Theta) appears to be the reflex with the highest intensity. The reason for this is the overlap of the reflexes at 20.56; 20.60, 20.61 and 20.73 (2Theta).

The uncertainty in the 2Θ values is ±0.2° in 2Θ. The link between the d-values and the 2Theta values are known from the Bragg equation, which is well known to any person skilled in the art:

2*d*sin (Theta) = n ^* lamda wherein d: d-value

Theta: incident angle Theta

n: integral number ( n= 1 , 2, 3, ... )

lambda: Wave length (CuKa (1.540598)) Comparison between calculated and measured diffractogram:

For reasons of comparison with the calculated diffractogram of form A (Figure 1 ) an experimentally measured diffractogram (Figure 2) is analysed with regard to the peak positions.

Parameter of Measurement (Device: STOE, Stadi P):

Diffractometer: Transmission

Monochromator: Curved Germanium (111 )

Wavelength: 1.540598 Cu

Detector: Linear PSD

Scan Mode: Transmission / Moving PSD / Fixed omega

Scan Type: 2Theta:Omega

The peak positions of the measured diffractograms was carried out with the program WinXPow of the company Stoe.

The parameters used for peak-search

Expected halfwidth : 0.150

Significance level : 2.5

Peak height level : 50

The peak lists were checked and processed manually.

The calculated diffractogram and the measured diffractogram are in very good agreement (Figure 3.) Crystalline modification A

(a) The following table 3 shows the peak list for crystalline modification A as measured for the product obtained according to example 1.2. The. uncertainty in the 2Θ values is ±0.2° in 2Θ; rel. I (or Rl) is the relative intensity of the respective peaks. Maximum intensity is 100.

Table 3:

(b) The following table 4 shows the peak list for crystalline modification A as calculated from the single crystal data for the product obtained according to example 4-1 . The uncertainty in the 2Θ values is ±0.2° in 2Θ; rel. I (or Rl) is the relative intensity of the respective peaks. Maximum intensity is 100. Table 4:

Crystalline modification B

The following table 5 shows the peak list for crystalline modification B as calculated from the single crystal data for the product obtained according to example 4-5. The uncertainty in the 2Θ values is ±0.2° in 2Θ; rel. I (or Rl) is the relative intensity of the respective peaks. Maximum intensity is 100.

Table 5:

Crystalline modification C

The following table 6 shows the peak list for crystalline modification C as measured for the product obtained according to example 3. The uncertainty in the 2Θ values is ±0.2° in 2Θ; rel. I (or Rl) is the relative intensity of the respective peaks. Maximum intensity is 100.

Table 6:

Analysis - X-ray Single Crystal Structure Determination

X-ray single crystal diffraction analyses of the modification A (tables 7 to 11 ) and B (tables 12 to 16) were performed with STOE IPDS.

radiation source: fine-focus sealed tube

radiation type: Mo Ka

wavelength: 0,71073 A

measurement method: Phi-rotation

Tube power [kW]: 1.00

Tube voltage [kV]: 50

Tube current [mA]: 20

Collimator size [mm]: 0.3

Temperature [K]: 293

Software:

Data collection: STOE IPDS-EXPOSE Vers. 2.87 (1997)'

Cell refinement: STOE IPDS-RECIPE/CELL Vers. 287 (1997)

Data reduction: STOE IPDS-PROFILE/INTEGRATE Vers.2.87 (1997) Structure solution: SHELXS-86 (Sheldrick, 1990)

SIR97(Cascarano al.,Acta Cryst.,1996,A52,C-79)

Structure refinement: SHELXL-93 (Sheldrick, 1993)

X-ray single crystal diffraction analyses for determination of the absolute configuration were either performed with NONIUS CAD4 using radiation type Fe Ka wavelength 1.93604 A, at 291 ±2 K, graphite monochromator, and/or Bruker D8 Goniometer with SMART-APEX-detector, Mo Ka, at 100 K.

Software:

Data collection: CAD4_(Enraf-Nonius,_1977)

Cell refinement: CAD4_(Enraf-Nonius,_1977)

Data reduction: PROCESS_MolEN_(Fair,_1990)

Structure solution: SHELXS-97 (Sheldrick, 1990)

Structure refinement: SHELXL-97 (Sheldrick, 1997)

The correct assignment of the absolute configuration was proved by calculation of the Flack-Parameter and/or analysis of Bijvoet differences by means of Bayesian statistics (Platon 2006)

Crystalline Modification A:

Crystal data and structure refinement for crystalline modification A obtained according to example 4-1

Empirical formula C16 H25 N 03

Formula weight 279.37

Temperature 293(2) K

Wavelength 0.71073 A

Crystal system, space group 1st, P212121

Unit cell dimensions a = 9.453(2) A alpha = 90 deg.

b = 10.118 (2) A beta = 90 deg. c = 16.538 (3) A gamma = 90 deg.

Volume 1581.8(5) Α ^Λ 3

Z, Calculated density 4, 1.173 Mg/m"3

Absorption coefficient 0.080 mm ^A -l

F(000) 608

Theta range for data collection 2.36 to 24.15 deg.

Limiting indices -10<=h<=10, -ll<=k<=ll -18<=1<=18

Reflections collected / unique 12014 / 2424 [R(int) = 0.0904]

Absorption correction No correction

Refinement method Full-matrix least-squares F 2

Data / restraints / parameters 2424 / 0 / 282

Goodness-of-fit on F"2 0.635

Final R indices [ I>2sigma ( I ) ] Rl 0.0373, wR2 0.0867

R indices (all data) Rl = 0.0511, wR2 = 0.0948

Absolute structure parameter -0.22 (141)

Extinction coefficient 0.0132 (29)

Largest diff. peak and hole 0.137 and -0.180 e.A ^A -3

Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters (Α ^Λ 2 x 10 ^Λ 3). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

X Y z U(eq)

C(l) -43 (2) 265 (2) -1844 (1) 39(1)

C(2) -98 (3) 1204 (2) -1256 (1) 44 (1)

C(3) 1246 (3) 1248 (3) -930 (1) 51 (1)

C(4) 2288 (3) 400 (3) -1198 (2) 61(1)

C(5) 195 (3) -542(3) -1769 (2) 58 (1)

C(6) 605 (2) -610 (2) -2088 (1) 48(1)

C(7) -1914 (2) 236 (2) -2221 (1) 39(1)

C(8) -2648 (2) -1114 (2) -2123 (1) 42(1)

C(9) -4061 (3) -1146(3) -2570 (1) 54(1)

C(10) -3920 (3) -765 (3) -3463 (1) 52 (1)

C(ll) -3188 (3) 53 (2) -3576 (1) 49(1)

C(12) -1777 (2) 563 (3) -3134 (1) 44 (1)

C(13) -2847 (3) -1447 (3) -1222 (1) 51 (1)

C(14) 643(4) 3014 (4) -30 (2) 71(1)

C(15) -3761 (5) -2873 (5) -193 (2) 81(1)

C(16) -2330 (4) -3782 (4) -1245 (2) 80(1)

0(1) 1655 (2) 2116(2) -333 (1) 76(1)

0(2) -2744 (2) 1231 (2) -1832 (1) 52(1)

0(3) -3989 (2) 1616 (2) -3269 (1) 65 (1)

N(l) -3381 (2) -2770 (2) -1055 (1) 50(1)

Table 9: Bond lengths [A] and angles [deg]:

C(l)-C(6) 1 .384 (3)

C(l)-C(2) 1 .397 (3)

C(l)-C{7) 1 .528 (3)

C(2)-C(3) 1 .381 (3)

C(3)-0(l) 1 .377 (3)

C(3)-C(4) 1 .380(4)

C(4)-C(5) 1 .379(4)

C(5)-C{6) 1 .381 (3)

C(7)-0(2) 1 .430 (2)

C(7)-C(8) 1 541(3)

C(7)-C(12) 1 552 (3)

C(8)-C(9) 1 526 (3)

C(8)-C(13) 1 540 (3)

C(9)-C(10) 1 532 (3)

C (10) -C (11) 1 497 (4 )

C(ll)-0(3) 1 425 (3)

C(ll)-C(12) 1 522 (3)

C(13)-N(l) 1 457 (3)

C(14)-0(l) 1 411(4)

C(15)-N(l) 1 475 (3)

C(16)-N(l) 1 461 (4 )

C(6)-C(l)-C(2) 118 3(2)

C(6)-C(l)-C(7) 121 3 (2)

C(2)-C(l)-C(7) 120 4 (2)

C (3) -C (2) -C (1) 120 4 (2)

0(1)-C(3)-C(4) 115 3(2)

0(1)-C(3)-C(2) 124 0(2)

C(4) -C(3) -C(2) 120 7 (2)

C(5)-C(4)-C(3) 119 1 (2)

C(4)-C(5)-C(6) 120 4 (2)

C (5) -C (6) -C (1) 121 0(2)

0(2) -C (7) -C (1) 107 72 (15)

0(2) -C (7) -C (8) 109 2(2)

C(l)-C(7)-C(8) 112 7 (2)

0(2)-C(7)-C(12) 109. 5 (2)

C (1) -C (7) -C (12) 108. 4 (2)

C (8) -C (7) -C (12) 109. 2(2)

C(9)-C(8)-C(13) 110. 9(2)

C(9)-C(8)-C(7) Ill . 2(2)

C(13)-C(8)-C(7) 110. 5(2)

C (8) -C (9) -C (10) 112. 7 (2)

C(ll)-C(10)-C(9) 112. 5(2)

O(3)-C(ll)-C(10) 112. 6(2)

0(3) -C(ll) -C(12) 106. 2 (2)

C (10) -C (11) -C (12) 111. 2 (2)

C(ll)-C(12)-C(7) 113. 0(2)

N (1) -C (13) -C (8) 115. 2(2)

C(3)-0(l)-C(14) 118. 3(2)

C (13) - (1) -C (16) 111. 5(2)

C(13)-N(l)-C(15) 109. 4 (2)

C(16)-N(l)-C(15) 108. 9(3) Symmetry transformations used to generate equivalent atoms: Table 10: Anisotropic displacement parameters (Α ^Λ 2 x 10 ^Λ 3)

The anisotropic displacement factor exponent takes the form:

-2 pi 2 [ h ^A 2 a* ^A 2 U11 + ... + 2 h k a ^* b* U12 ]

Ull U22 U33 U23 U13 U12

C(l) 39(1) 38 (1) 42 (1) 2(1) 2 (1) -2(1)

C(2) 46(1) 43(1) 43(1) 0(1) 2 (1) -5(1)

C(3) 48 (1) 58 (2) 47 (1) 5(1) -8 (1) -14 (1)

C(4) 45(2) 73(2) 64 (1) 11 (1) -15 (1) -10(1)

C(5) 41 (1) 59(2) 74 (2) 9(1) 1 (1) 9(1)

C(6) 45 (1) 45 (1) 55(1) -1(1) 2 (1) 3(1)

C(7) 36(1) 41 (1) 39(1) -9(1) 4 (1) 1(1)

C(8) 42 (1) 50(1) 35 (1) -7 (1) 5 (1) -2 (1)

C(9) 46(1) 71 (2) 45 (1) -4 (1) -2 (1) -18 (1)

C(10) 48 (1) 63 (2) 44 (1) -12 (1) -8 (1) -1 (1)

C(ll) 50(1) 54 (1) 44 (1) -4 (1) -1 (1) 5 (1)

C(12) 42 (1) 48 (1) 42 (1) 1 (1) 3(1) 5(1)

C(13) 55(2) 62 (2) 36(1) -5(1) 3(1) -14 (1)

C(14) 89(2) 74 (2) 49(1) -10(2) -6(2) -19(2)

C(15) 99 (3) 99 (3) 44 (1) 14 (2) 3(2) -32 (3)

C(16) 70(2) 73 (2) 97 (2) 9(2) -4 (2) 11 (2)

0(1) 69(1) 92 (2) 68 (1) -21 (1) -1 (1) -20 (1)

0(2) 43(1) 60(1) 54 (1) -23(1) -2 (1) 12 (1)

0(3) 54 (1) 59(1) 81 (1) -19(1) -23(1) 16(1)

N(l) 51 (1) 59(1) 41 (1) 2 (1) -1 (1) -8 (1)

Table 11 : Hydrogen coordinates ( x 10 ) and isotropic displacement parameters

U(eq)

H(2) -824 (27) 1813 (26) -1117 (14) 56 (7)

H(4) 3288 (27) 506(23) -990 (14) 52 (6)

H(5) 2616 (27) -1179 (27) -1906 (16) 65 (7)

H{6) 351 (27) -1345 (30) -2468 (17) 66 (7)

H(8) -1994 (24) -1796(23) -2345 (13) 50 (6)

H(91) -5501 (27) -7060 (30) -2504 (13) 60 (7)

H (92) -4817 (27) -531 (26) -2294 (13) 55 (6)

H(101) -3282 (28) -1476 (27) -3738 (15) 68 (7)

H (102) -4892 (28) -858 (22) -3679 (13) 49 (6)

H(ll) -3009 (28) 670 (26) -4162 (17) 77 (8)

H (121) -1321 (22) 1465 (25) -3176 (14) 45 (6)

H(122) -1165 (22) -161 (23) -3409 12) 42 (5)

H (131) -3582 (29) -759 (26) -1022 (16) 67 (8)

H (132) -1958 (30) -1361 (25) -949 (15) 63 (7)

H (141) -234 (42) 2535 (46) 153 (21) 121 (13)

H(142) 359 (29) 3658 (29) -423 (18) 75 (9)

H(143) 1223 (37) 3480 (38) 408 (21) 110 (12)

H (151) -4207 (29) -3709 (33) -103 (17) 73 (8)

H (152) -2902 (36) -2772 (34) 140 (20) 92 (10)

H (153) -4571 (40) -2318 (44) -104 (22) 106 (14)

H (161) -2722 (40) -4638 (39) -1053 (22) 114 (12)

H(162) -1420 (45) -3575 (40) -968 (24) 118 (13)

H(163) -1938 (40) -3750 (39) -1790 (27) 115 (12)

H (20) -3362 (32) 1599 (29) -2135 (17) 71 (9)

H (30) -4942 (35) 1642 (30) -3482 (17) 82 (9)

Crystalline Modification B:

Crystal data and structure refinement for crystalline modification B obtained according to example 4-5

Empirical formula C16 H25 N 03

Formula weight 279.37

Temperature 293(2) K

Wavelength 0.71073 A

Crystal system, space group 1st, P21

Unit cell dimensions a = 8.0920 (9) alpha = 90 deg.

b = 10.727 (2) beta = 105.751(13) deg.

c = 9. 510 (10) A gamma = 90 deg.

Volume 789.6(2) Α ^Λ 3

Z, Calculated density 2, 1.175 Mg/m"3

Absorption coefficient 0.080 i ^A— 1

F(000) 304

Theta range for data collection 2.24 to 23.85 deg.

Limiting indices -9<=h<=9, -I2<=k<=12, -10<=1<

Reflections collected / unique 8316 / 2360 [R(int) = 0.0702]

Absorption correction No correction

Refinement method Full-matrix least-squares F 2

Data / restraints / parameters 2360 / 1 / 281

Goodness-of-fit on F 2 0.651

Final R indices [ I>2sigma ( I ) ] Rl = 0.0296, wR2 = 0.0781

R indices (all data) Rl = 0.0334, wR2 = 0.0817

Absolute structure parameter -0.72 (102)

Largest diff. peak and hole 0.137 and -0.121 e.A -3

Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters (Α ^Λ 2 x 10 ^Λ 3). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

X y z U(eq)

C(l) 3732 (2) 989 (1) 9252 (2) 34 (1)

C(2) 2593 (2) 1904 (2) 9434 (2) 38 (1)

C(3) 2039 (2) 1946 (2) 10701 (2) 46(1)

C(4) 2623 (3) 1071 (2) 1180 (2) 54 (1)

C(5) 3736 (3) 154 (2) 11625 (2) 49(1)

C(6) 4290 (2) 104 (2) 10365 (2) 41(1)

C(7) 4435 (2) 1013 (1) 7909 (2) 33 (1)

C(8) 4248(2) -259 (2) 7101 (2) 37 (1)

C(9) 5129 (3) -219(2) 5866 (2) 48(1)

C(10) 7002 (2) 17 (2) 6386 (2) 45(1)

C(ll) 7222 (2) 1409 (2) 7191 (2) 44 (1)

C(12) 6350 (2) 1382 (2) 8425 (2) 38 (1)

C(13) 2352 (2) -629 (2) 6525 (2) 45(1)

C(14) 248(3) 3720 (2) 9889 (3) 62 (1)

C(15) 2534 (4) -2818 (2) 7195 (3) 66 (1)

C(16) 235 (3) -2093 (3) 5205 (3) 70 (1)

0(1) 927 (2) 2817 (2) 10968 (2) 71(1)

0(2) 3493 (2) 1941 (1) 6921 (1) 46(1)

0(3) 6467 (2) 2425(1) 6261 (2) 59 (1)

N(l) 2065 (2) -1922 (1) 5988 (2) 45(1)

Table 14: Bond lengths [A] and angles [deg]. c (1)-C(2) 1 .388 (2) c (1)-C(6) 1 .398 (2) c (1)-C(7) 1 .526(2) c (2)-C(3) 1 .388 (2) c (3)-0(l) 1 367 (2) c (3)-C(4) 1 388 (3) c (4)-C{5) 1 37 (3) c (5)-C(6) 1 383 (3) c (7)-0(2) 1 434 (2) c (7)-C(12) 1 545 (2) c (7)-C(8) 1 550 (2) c (8)-C(9) 1 525 (2) c (8) -C (13) 1 535 (2) c (9) -C(10) 1 520 (3) c (10) -C (11) 1 513 (3) c (ll)-0(3) 1 429(2) c (11)-C(12) 1 519 (2) c (13)-N(1) 1 473(2) c (14)-0(1) 1 406(3) c (15) -N (1) 1 461 (3) c (16) - (1) 1 477 (3) c 2)-C(l)-C(6) 118 5(2) c 2)-C(l)-C(7) 120 07 (13) c 6)-C(l)-C(7) 121 29(14) c 1)-C(2)-C(3) 120 7 (2)

0 1)-C(3)-C(4) 115 5 (2)

0 1)-C(3)-C(2) 124 4 (2) c 4)-C(3)-C(2) 120 2(2) c 5)-C(4)-C{3) 119 5(2) c 4)-C(5)-C(6) 120 7(2) c 5)-C(6)-C(l) 120 4 (2)

0 2)-C(7)-C(l) 107 49 (12)

0 2)-C(7)-C(12) 109 75 (12) c 1)-C(7)-C(12) 108 04 (12)

0 2)-C(7)-C(8) 109 09 (12) c 1)-C(7)-C(8) 112 76 (12) c 12)-C(7)-C(8) 109 66 (13) c 9)-C(8)-C(13) 111 44 (14) c 9)-C(8)-C(7) 110 42 (14) c 13)-C(8)-C(7) 110 90 (13) c 10)-C(9)-C(8) 113 07 (14) c 11) -C (10) -C (9) 112 1(2)

0 3) -C(ll) -C (10) 112 70 (14)

0 3) -C (11) -C (12) 106 05 (14) c 10)-C(11)-C(12) 110. 69 (15) c 11)-C(12)-C(7) 113. 42 (13)

N 1)-C(13)-C(8) 114. 51 (14) c 3)-0(l)-C(14) 118. 9(2) c 15)-N(1)-C(13) 111. 5 (15) c 15)-N(1)-C(16) 108. 8(2) c 13)-N(1)-C(16) 109. 4 (2) Symmetry transformations used to generate equivalent atoms:

Anisotropic displacement parameters (Α ^Λ 2 x 10 ^Λ 3). The anisotropic displacement factor exponent takes the form:

-2 pi ^A 2 [ h ^A 2 a* ^A 2 U11 + ... + 2 h k a ^* b ^* U12 ]

—

Ull U22 U33 U23 U13 U12

C(l) 38 (1) 35 (1) 28 (1) -1(1) 7(1) -3(1)

C(2) 41 (1) 41(1) 31(1) -3(1) 10 (1) 0(1)

C(3) 45(1) 53 (1) 43(1) -10(1) 17 (1) -1(1)

C{4) 65(1) 66(1) 36(1) -3(1) 22 (1) -6(1)

C(5) 62(1) 52(1) 33(1) 6(1) 14 (1) -4(1)

C(6) 48(1) 41(1) 35 (1) 1(1) 12 (1) 2(1)

C(7) 38 (1) 36(1) 27 (1) 4(1) 9(1) 7(1)

C(8) 35 (1) 44 (1) 31 (1) -1(1) 6(1) 7(1)

C(9) 49(1) 60(1) 37 (1) -11(1) 16(1) 3(1)

C(10) 44 (1) 50(1) 46(1) 1(1) 21 (1) 8(1)

C(ll) 45(1) 44 (1) 46(1) 4 (1) 18 (1) 2(1)

C(12) 41(1) 39(1) 34 (1) 3(1) 10 (1) 0(1)

C(13) 38 (1) 54 (1) 43(1) -13(1) 9(1) 4 (1)

C(14) 53(1) 65 (1) 67 (1) -19(1) 12(1) 11(1)

C(15) 78 (2) 59(1) 65 (1) 4 (1) 26(1) -9(1)

C(16) 42(1) 85 (2) 79(2) -32 (2) 11(1) -11(1)

0(1) 77 (1) 84 (1) 61 (1) -7(1) 35 (1) 25(1)

0(2) 51(1) 53(1) 34 (1) 15(1) 13 (1) 21(1)

0(3) 80(1) 51(1) 62 (1) 22 (1) 45(1) 19(1)

N(l) 36(1) 57 (1) 42(1) -14 (1) 12(1) -5(1)

Table 16: Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Α ^Λ 2 x 10 ^Λ 3).

X y z U(eq)

H (2) 2292 (26) 2489 (19) 8728 (23) 47 (5)

H (4) 2267 (31) 1123 (20) 12698 (26) 63 (6)

H (5) 4091 (29) -504 (24) 12298 (26) 65 (6)

H 6) 5086 (26) -504 (19) 10213 (20) 39(4)

H 8) 4801 (24) -870 (18) 7773(21) 38 (4)

H (91) 5047 (26) -1089 (20) 5429 (21) 49(5)

H (92) 4480 (27) 346 (21) 5076 (26) 55 (6)

H (101) 7458 (31) 231 (21) 5497 (27) 66 (6)

H 102) 7605 (26) -526 (20) 7008 (22) 46(5)

H 11) 8509 (26) 1586 (16) 7589 (20) 46(5)

H 121) 6453 (24) 2258 (20) 8843 (20) 44 (5)

H 122) 6960 (2 ) 711 (17) 9220 (22) 42 (5)

H 131) 1865 (27) -42 (19) 5691 (23) 51(5)

H 132) 1713 (27) -484 (19) 7304 (24) 53(5)

H 141) -391 (37) 4244 (28) 10305 (31) 83(8)

H 142) 1107 (37) 4219 (25) 9546 (27) 77 (7)

H 143) -338 (33) 3380 (25) 8943 (27) 76(7)

H 151) 2213 (35) -3760 (26) 6838 (28) 81 (7)

H 152) 3796 (47) -2729 (27) 7747 (35) 104 (10)

H 153) 1861 (40) -2763 (26) 7862 (32) 91 (9)

H 161) 41 (44) -3006 (33) 4807 (36) 102 (9)

H 162) -573 (36) -1888 (25) 5813 (28) 80(7)

H 163) 81(31) -1512 (24) 4389 (28) 64 (7)

H 30) 7064 (36) 2493 (26) 5514 (31) 86(8)

H 20) 4176 (42) 2297 (32) 6436 (36) 103 (10)

Analysis - DSC

Differential Scanning Calorimetry (DSC): device reference Mettler Toledo DSC 821 , perforated 40 μηι aluminium standard crucible, variable temperature range and variable heating-rate, nitrogen atmosphere. Unless otherwise stated, substance quantities within the range from 2 mg to 20 mg were employed.

The measurement took place in a nitrogen flow in a temperature range from 30±5 °C to 200 °C with a heating rate of 10 °C/min. The temperatures specified in relation to DSC analyses are, unless otherwise specified, the temperatures of the peak maxima (peak temperature T _P ). Onset temperatures of peaks are indicated by To.

Crystalline modification A according to example 1.2:

To 115.96 °C; T _P 118.53 °C; J/g 126.60. Crystalline modification B according to example 2:

To 09.82 °C; T _P 114.12 °C; J/g 168.54. Crystalline modification C according to example 3:

To 115.66 °C; T _P 118.72 °C; J/g 111.54.

Analysis - FT Raman spectroscopy

Crystalline modification A was characterised by means of Fourier transform (FT) Raman spectrometry.

For this purpose, the FT Raman spectra were recorded on a Bruker RFS100 Raman spectrometer (Nd-YAG 100 mW laser, excitation 1064 nm, Ge detector, 64 scans, 25-3500 cm ^"1 , resolution 4 cm ^"1 ).