Abstract:
The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.

Description:
[0001]    This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety. 
       BACKGROUND OF THE INVENTION 
       [0002]    1. Field of the Invention 
         [0003]    The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament. 
         [0004]    2. Description of the Prior Art 
         [0005]    The enzyme DPP-IV, also known by the name CD26, is a serine protease which promotes the cleaving of dipeptides in proteins with a proline or alanine group at the N-terminal end. DPP-IV inhibitors thereby influence the plasma level of bioactive peptides including the peptide GLP-1. Compounds of this type are useful for the prevention or treatment of illnesses or conditions which are associated with an increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II diabetes mellitus, prediabetes, or reduced glucose tolerance. 
         [0006]    WO 2004/018468 describes DPP-IV inhibitors with valuable pharmacological properties. One example of the inhibitors disclosed therein is 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0007]      FIG. 1  shows the thermoanalysis of the anhydrous form A/B. 
           [0008]      FIG. 2  shows a cyclic DSC diagram, in which the phase transition from −40° C. to 120° C. and vice versa has been run through a total of 3 times. 
           [0009]      FIG. 3  shows an X-ray powder diagram of the anhydrous form A. 
           [0010]      FIG. 4  shows an X-ray powder diagram of the anhydrous form B. 
           [0011]      FIG. 5  shows an X-ray powder diagram of polymorph C. 
           [0012]      FIG. 6  shows the thermoanalysis of form C. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0013]    Within the scope of the present invention it has been found that 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine may take on various polymorphous crystal modifications and that the compound prepared in WO 2004/018468 is present at ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C. (see  FIGS. 1 and 2 ). 
         [0014]    The pure high temperature form (polymorph A), which can be obtained by heating the mixture to temperatures &gt;40° C., melts at 206±3° C. In the X-ray powder diagram (see  FIG. 3 ) this form shows characteristic reflexes at the following d values: 11.49 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47 Å (cf. also Table 1 and 2). 
         [0015]    Anhydrous polymorph A may be prepared by
   (a) refluxing 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in absolute ethanol and optionally filtering the mixture,   (b) cooling the hot solution or the hot filtrate until crystallisation sets in,   (c) diluting with a solvent such as tert.-butylmethylether,   (d) suction filtering the solvent mixture and   (e) drying the polymorph A at 45° C. in vacuo.   
 
         [0021]    The low temperature form (polymorph B) is obtained by cooling to temperatures &lt;10° C. In the X-ray powder diagram (see  FIG. 4 ) this form shows characteristic reflexes at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å (cf. also Table 3 and 4). 
         [0022]    Anhydrous polymorph B may be prepared by
   (a) dissolving 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in absolute ethanol and refluxing and optionally filtering the mixture,   (b) cooling the hot solution or the hot filtrate for crystallisation to a temperature below 10° C.,   (c) diluting with a solvent such as tert.-butylmethylether,   (d) suction filtering the solvent mixture and   (e) drying the polymorph at a temperature below 10° C. in vacuo.   
 
         [0028]    Another polymorph (polymorph C) shows characteristic reflexes in the X-ray powder diagram (see  FIG. 5 ) at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å (cf. also Table 5). 
         [0029]    Polymorph C is obtained if
   (a) 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is dissolved in methanol and refluxed and optionally filtered in the presence of activated charcoal,   (b) the methanolic solution is cooled to a temperature of 40-60° C.,   (c) a solvent such as tert.-butylmethylether or diisopropylether is added,   (d) the resulting suspension is first of all cooled slowly to 15-25° C. and then later to 0-5° C.,   (e) the crystals formed are suction filtered and washed again with tert.-butylmethylether or diisopropylether and   (f) the crystals thus obtained are dried at a temperature of 70° C. in the vacuum dryer.   
 
         [0036]    Another polymorph (polymorph D) melts at 150±3° C. This polymorph is obtained if polymorph C is heated to a temperature of 30-100° C. or dried at this temperature. 
         [0037]    Finally, there is also polymorph E, which melts at a temperature of 175±3° C. Anhydrous polymorph E is formed if polymorph D is melted. On further heating, polymorph E crystallises out of the melt. 
         [0038]    The polymorphs thus obtained may be used in the same way as the mixture of the two polymorphs A and B described in WO 2004/018468 for preparing a pharmaceutical composition which is suitable for treating patients with type I and type II diabetes mellitus, prediabetes or reduced glucose tolerance, with rheumatoid arthritis, obesity, or calcitonin-induced osteoporosis, as well as patients in whom an allograft transplant has been carried out. These medicaments contain in addition to one or more inert carriers at least 0.1% to 0.5%, preferably at least 0.5% to 1.5% and particularly preferably at least 1% to 3% of one of the polymorphs A, B, or C. 
         [0039]    The following Examples are intended to illustrate the invention in more detail. 
       Example 1 
     Crystallisation of Polymorph A 
       [0040]    Crude 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is refluxed with 5 times as much absolute ethanol and the hot solution is filtered clear through activated charcoal. After the filtrate has been cooled to 20° C. and crystallisation has set in, the solution is diluted to double the volume with tert.-butylmethylether. Then the suspension is cooled to 2° C., stirred for 2 hours, suction filtered and dried in the vacuum dryer at 45° C. 
         [0041]      FIG. 1  shows the thermoanalysis of the anhydrous form A/B. 
         [0042]    Plymorph A melts at 206±3° C. In the DSC diagram another slightly endothermic signal can be seen at approx. 25° C. This is a fully reversible solid-solid phase transition between the two enantiotropic crystal modifications A and B. The form A is the thermodynamically stable modification above this transformation temperature, w| form B is the thermodynamically stable modification below this transformation temperature. 
         [0043]      FIG. 2  shows a cyclic DSC diagram, in which the phase transition from −40° C. to 120° C. and vice versa has been run through a total of 3 times. During heating, the phase transition is observed as an endothermic signal and, correspondingly, during cooling it is observed as an exothermic signal. During the first heating cycle the phase transition may also be observed as an endothermic double signal or as a very broad signal while in all the other cycles the signal occurs as a very sharp endothermic or exothermic signal, depending on whether heating or cooling is taking place. 
         [0044]      FIG. 3  shows an X-ray powder diagram of the anhydrous form A 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Labelled X-ray reflexes up to 30 °2Θ with intensities (standardised) for 
               
               
                 the anhydrous polymorph A 
               
             
          
           
               
                 2Θ 
                 intensity 
                 d hkl   
                 labelling 
                 d exp-calc   
               
             
          
           
               
                 [°] 
                 I/I o  [%] 
                 [Å] 
                 h 
                 k 
                 l 
                 [Å] 
               
               
                   
               
             
          
           
               
                 5.56 
                 1 
                 15.89 
                 1 
                 0 
                 0 
                 −0.008 
               
               
                 7.18 
                 32 
                 12.31 
                 0 
                 1 
                 1 
                 0.005 
               
               
                 7.62 
                 100 
                 11.59 
                 1 
                 1 
                 0 
                 0.007 
               
               
                 8.49 
                 20 
                 10.41 
                 −1 
                 1 
                 1 
                 0.002 
               
               
                 9.91 
                 24 
                 8.92 
                 0 
                 0 
                 2 
                 0.003 
               
               
                 10.41 
                 18 
                 8.49 
                 0 
                 2 
                 0 
                 0.024 
               
               
                 11.18 
                 24 
                 7.91 
                 2 
                 0 
                 0 
                 0.038 
               
               
                 11.63 
                 41 
                 7.60 
                 −1 
                 1 
                 2 
                 0.003 
               
               
                 12.37 
                 59 
                 7.15 
                 −1 
                 2 
                 1 
                 −0.003 
               
               
                 13.19 
                 6 
                 6.71 
                 1 
                 2 
                 1 
                 −0.014 
               
               
                 13.45 
                 3 
                 6.58 
                 −2 
                 0 
                 2 
                 0.007 
               
               
                 14.05 
                 6 
                 6.30 
                 2 
                 1 
                 1 
                 0.011 
               
               
                 14.38 
                 6 
                 6.16 
                 0 
                 2 
                 2 
                 0.003 
               
               
                 14.71 
                 10 
                 6.02 
                 −1 
                 2 
                 2 
                 −0.008 
               
               
                 15.26 
                 13 
                 5.80 
                 2 
                 2 
                 0 
                 0.001 
               
               
                 15.76 
                 10 
                 5.62 
                 −1 
                 1 
                 3 
                 0.008 
               
               
                 16.09 
                 1 
                 5.51 
                 1 
                 2 
                 2 
                 −0.010 
               
               
                 16.32 
                 1 
                 5.43 
                 2 
                 0 
                 2 
                 0.035 
               
               
                 16.69 
                 4 
                 5.31 
                 2 
                 2 
                 1 
                 −0.007 
               
               
                 17.03 
                 3 
                 5.20 
                 −1 
                 3 
                 1 
                 0.026 
               
               
                 17.63 
                 6 
                 5.03 
                 1 
                 3 
                 1 
                 0.006 
               
               
                 18.17 
                 5 
                 4.88 
                 −1 
                 2 
                 3 
                 −0.004 
               
               
                 18.78 
                 7 
                 4.72 
                 −1 
                 3 
                 2 
                 −0.014 
               
               
                 19.30 
                 1 
                 4.60 
                 −2 
                 3 
                 1 
                 −0.019 
               
               
                 19.61 
                 2 
                 4.52 
                 −3 
                 2 
                 1 
                 0.036 
               
               
                 19.86 
                 20 
                 4.47 
                 −2 
                 2 
                 3 
                 0.040 
               
               
                 20.29 
                 10 
                 4.37 
                 2 
                 0 
                 3 
                 0.019 
               
               
                 20.57 
                 4 
                 4.31 
                 0 
                 1 
                 4 
                 0.006 
               
               
                 21.12 
                 1 
                 4.20 
                 3 
                 0 
                 2 
                 0.048 
               
               
                 21.57 
                 12 
                 4.12 
                 −2 
                 1 
                 4 
                 0.028 
               
               
                 22.46 
                 10 
                 3.96 
                 1 
                 4 
                 1 
                 0.035 
               
               
                 23.03 
                 35 
                 3.86 
                 4 
                 1 
                 0 
                 0.022 
               
               
                 23.39 
                 21 
                 3.80 
                 −1 
                 4 
                 2 
                 0.019 
               
               
                 24.08 
                 2 
                 3.69 
                 −3 
                 1 
                 4 
                 −0.006 
               
               
                 24.51 
                 1 
                 3.63 
                 −4 
                 0 
                 3 
                 0.036 
               
               
                 24.91 
                 10 
                 3.57 
                 −2 
                 4 
                 2 
                 0.003 
               
               
                 25.14 
                 39 
                 3.54 
                 3 
                 1 
                 3 
                 0.043 
               
               
                 25.69 
                 36 
                 3.47 
                 −3 
                 3 
                 3 
                 0.041 
               
               
                 26.68 
                 3 
                 3.34 
                 0 
                 5 
                 1 
                 0.035 
               
               
                 26.90 
                 2 
                 3.31 
                 3 
                 4 
                 0 
                 0.027 
               
               
                 27.10 
                 2 
                 3.29 
                 0 
                 2 
                 5 
                 0.030 
               
               
                 27.42 
                 3 
                 3.25 
                 4 
                 3 
                 0 
                 0.006 
               
               
                 28.19 
                 2 
                 3.16 
                 −1 
                 5 
                 2 
                 −0.035 
               
               
                 28.54 
                 2 
                 3.12 
                 3 
                 0 
                 4 
                 0.047 
               
               
                 28.94 
                 11 
                 3.08 
                 0 
                 4 
                 4 
                 −0.036 
               
               
                 29.18 
                 5 
                 3.06 
                 −4 
                 3 
                 3 
                 0.017 
               
               
                 29.50 
                 4 
                 3.03 
                 −1 
                 0 
                 6 
                 0.041 
               
               
                 30.18 
                 7 
                 2.96 
                 −1 
                 5 
                 3 
                 −0.042 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Lattice metrics of the anhydrous form A 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Symmetry: 
                 monocline 
               
               
                   
                 spatial group: 
                 P 
               
               
                   
                 a: 
                 16.16(2) Å 
               
               
                   
                 b: 
                 17.02(1) Å 
               
               
                   
                 c: 
                 18.18(2) Å 
               
               
                   
                 β: 
                 100.95(6)° 
               
               
                   
                 cell volume: 
                     4907(11) Å 3   
               
               
                   
                   
               
             
          
         
       
     
       Example 2 
     Crystallisation of Polymorph B 
       [0045]    Polymorph B is obtained by cooling form A from Example 1 to temperatures &lt;10° C. 
         [0046]      FIG. 4  shows an X-ray powder diagram of the anhydrous form B 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Labelled X-ray reflexes up to 30 °2Θ with intensities (standardised) for 
               
               
                 the anhydrous form B 
               
             
          
           
               
                 2Θ 
                 intensity 
                 d hkl   
                 labelling 
                 d exp-calc   
               
             
          
           
               
                 [°] 
                 I/I o  [%] 
                 [Å] 
                 h 
                 k 
                 l 
                 [Å] 
               
               
                   
               
             
          
           
               
                 5.82 
                 3 
                 15.17 
                 1 
                 0 
                 0 
                 −0.007 
               
               
                 7.04 
                 33 
                 12.55 
                 0 
                 1 
                 1 
                 0.001 
               
               
                 7.82 
                 100 
                 11.3 
                 1 
                 1 
                 0 
                 −0.004 
               
               
                 8.84 
                 11 
                 10 
                 −1 
                 1 
                 1 
                 0.001 
               
               
                 9.44 
                 40 
                 9.36 
                 1 
                 1 
                 1 
                 0.011 
               
               
                 10.62 
                 14 
                 8.32 
                 −1 
                 0 
                 2 
                 0.013 
               
               
                 10.79 
                 24 
                 8.19 
                 0 
                 1 
                 2 
                 −0.005 
               
               
                 11.82 
                 39 
                 7.48 
                 −1 
                 1 
                 2 
                 −0.003 
               
               
                 12.64 
                 53 
                 7 
                 −1 
                 2 
                 1 
                 −0.009 
               
               
                 13.07 
                 11 
                 6.77 
                 1 
                 2 
                 1 
                 −0.006 
               
               
                 13.24 
                 6 
                 6.68 
                 −2 
                 1 
                 1 
                 0.004 
               
               
                 14.04 
                 16 
                 6.3 
                 2 
                 1 
                 1 
                 0.003 
               
               
                 15.23 
                 17 
                 5.81 
                 −2 
                 1 
                 2 
                 0.003 
               
               
                 15.70 
                 22 
                 5.64 
                 2 
                 2 
                 0 
                 0.016 
               
               
                 16.38 
                 2 
                 5.41 
                 0 
                 3 
                 1 
                 −0.010 
               
               
                 16.73 
                 6 
                 5.3 
                 2 
                 2 
                 1 
                 0.008 
               
               
                 17.67 
                 8 
                 5.02 
                 0 
                 2 
                 3 
                 0.014 
               
               
                 18.16 
                 3 
                 4.88 
                 −1 
                 2 
                 3 
                 0.005 
               
               
                 18.33 
                 9 
                 4.84 
                 3 
                 1 
                 0 
                 0.016 
               
               
                 18.48 
                 10 
                 4.8 
                 −3 
                 1 
                 1 
                 −0.003 
               
               
                 18.97 
                 15 
                 4.68 
                 0 
                 0 
                 4 
                 −0.001 
               
               
                 19.56 
                 6 
                 4.54 
                 1 
                 3 
                 2 
                 0.013 
               
               
                 20.00 
                 17 
                 4.44 
                 2 
                 1 
                 3 
                 0.000 
               
               
                 20.42 
                 9 
                 4.35 
                 1 
                 0 
                 4 
                 0.009 
               
               
                 20.76 
                 4 
                 4.27 
                 3 
                 0 
                 2 
                 −0.014 
               
               
                 20.97 
                 4 
                 4.23 
                 0 
                 4 
                 0 
                 0.010 
               
               
                 21.07 
                 5 
                 4.21 
                 1 
                 1 
                 4 
                 −0.009 
               
               
                 21.22 
                 12 
                 4.18 
                 0 
                 3 
                 3 
                 0.001 
               
               
                 21.40 
                 7 
                 4.15 
                 3 
                 2 
                 1 
                 0.004 
               
               
                 21.66 
                 4 
                 4.1 
                 −1 
                 3 
                 3 
                 0.018 
               
               
                 21.98 
                 7 
                 4.04 
                 2 
                 2 
                 3 
                 −0.003 
               
               
                 22.16 
                 10 
                 4.01 
                 −3 
                 1 
                 3 
                 0.008 
               
               
                 22.97 
                 3 
                 3.87 
                 1 
                 2 
                 4 
                 −0.006 
               
               
                 23.58 
                 43 
                 3.77 
                 −2 
                 3 
                 3 
                 −0.003 
               
               
                 23.78 
                 15 
                 3.74 
                 −2 
                 2 
                 4 
                 −0.004 
               
               
                 24.05 
                 6 
                 3.7 
                 4 
                 1 
                 0 
                 −0.002 
               
               
                 24.29 
                 8 
                 3.66 
                 −2 
                 4 
                 1 
                 −0.008 
               
               
                 24.46 
                 5 
                 3.64 
                 3 
                 3 
                 1 
                 0.018 
               
               
                 24.71 
                 7 
                 3.6 
                 0 
                 3 
                 4 
                 0.001 
               
               
                 24.96 
                 23 
                 3.56 
                 2 
                 3 
                 3 
                 −0.001 
               
               
                 25.45 
                 12 
                 3.5 
                 −2 
                 4 
                 2 
                 −0.010 
               
               
                 25.75 
                 35 
                 3.46 
                 4 
                 2 
                 0 
                 0.011 
               
               
                 25.99 
                 4 
                 3.43 
                 3 
                 2 
                 3 
                 0.014 
               
               
                 26.15 
                 6 
                 3.41 
                 3 
                 3 
                 2 
                 0.010 
               
               
                 26.57 
                 12 
                 3.35 
                 −2 
                 3 
                 4 
                 −0.001 
               
               
                 26.82 
                 4 
                 3.32 
                 −3 
                 2 
                 4 
                 0.011 
               
               
                 27.20 
                 6 
                 3.28 
                 1 
                 2 
                 5 
                 −0.010 
               
               
                 27.43 
                 4 
                 3.25 
                 −2 
                 4 
                 3 
                 −0.003 
               
               
                 27.60 
                 3 
                 3.23 
                 −2 
                 2 
                 5 
                 −0.005 
               
               
                 28.19 
                 4 
                 3.16 
                 3 
                 4 
                 1 
                 0.010 
               
               
                 28.40 
                 15 
                 3.14 
                 0 
                 4 
                 4 
                 −0.013 
               
               
                 28.64 
                 12 
                 3.11 
                 0 
                 0 
                 6 
                 0.016 
               
               
                 29.18 
                 6 
                 3.06 
                 −4 
                 3 
                 2 
                 0.004 
               
               
                 29.42 
                 2 
                 3.03 
                 1 
                 4 
                 4 
                 0.002 
               
               
                 29.99 
                 10 
                 2.98 
                 0 
                 5 
                 3 
                 −0.008 
               
               
                 30.77 
                 3 
                 2.9 
                 −4 
                 3 
                 3 
                 0.018 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Lattice metrics of the anhydrous form B 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Symmetry: 
                 monocline 
               
               
                   
                 spatial group: 
                 P2 1 /c (# 14) 
               
               
                   
                 a: 
                 15.23(1) Å 
               
               
                   
                 b: 
                 16.94(1) Å 
               
               
                   
                 c: 
                 18.79(1) Å 
               
               
                   
                 β: 
                 95.6(2)° 
               
               
                   
                 cell volume: 
                      4823(3) Å 3   
               
               
                   
                   
               
             
          
         
       
     
       Example 3 
     Crystallisation of Polymorph C 
       [0047]    Crude 1-[(4-methyl-quinazolin-2-ylmethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (26 kg) is refluxed with 157 l methanol, combined with 1.3 kg of activated charcoal and after 30 minutes&#39; stirring the mixture is filtered and rinsed with 26 l methanol. 122 l of methanol are distilled off from the filtrate, then the residue is cooled to 45-55° C. 52 l of tert.-butylmethylether are added to the residue over 30 minutes. Then the mixture is stirred for another 60 minutes at 45-55° C. Crystallisation takes place within this time. A further 78 l tert. butylmethylether are added to the suspension over 30 minutes and then it is stirred again for a further 60 minutes at 45-55° C. It is diluted to four times the volume. The suspension is slowly cooled to 15-25° C. and stirred overnight at this temperature. After the suspension has been cooled to 0-5° C. the crystals are suction filtered, washed with 2 batches tert.-butylmethylether and dried at 70° C. in the vacuum dryer. 
         [0048]      FIG. 5  shows an X-ray powder diagram of polymorph C 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 X-ray reflexes up to 30° 2 Θ with intensities 
               
               
                 (standardised) for the anhydrous form C 
               
             
          
           
               
                 2 Θ 
                 d hkl   
                 intensity 
               
               
                 [°] 
                 [Å] 
                 I/I o  [%] 
               
               
                   
               
             
          
           
               
                 3.38 
                 26.16 
                 4 
               
               
                 6.85 
                 12.90 
                 100 
               
               
                 7.18 
                 12.31 
                 11 
               
               
                 7.52 
                 11.74 
                 14 
               
               
                 7.96 
                 11.10 
                 36 
               
               
                 9.80 
                 9.02 
                 3 
               
               
                 11.11 
                 7.96 
                 2 
               
               
                 11.58 
                 7.64 
                 3 
               
               
                 12.30 
                 7.19 
                 5 
               
               
                 13.30 
                 6.65 
                 16 
               
               
                 13.75 
                 6.44 
                 26 
               
               
                 14.38 
                 6.16 
                 17 
               
               
                 14.74 
                 6.01 
                 11 
               
               
                 14.95 
                 5.92 
                 10 
               
               
                 15.63 
                 5.66 
                 6 
               
               
                 16.28 
                 5.44 
                 5 
               
               
                 17.81 
                 4.98 
                 10 
               
               
                 18.33 
                 4.83 
                 6 
               
               
                 18.75 
                 4.73 
                 15 
               
               
                 20.51 
                 4.33 
                 8 
               
               
                 20.77 
                 4.27 
                 8 
               
               
                 21.47 
                 4.14 
                 3 
               
               
                 21.96 
                 4.05 
                 4 
               
               
                 22.59 
                 3.93 
                 26 
               
               
                 23.76 
                 3.74 
                 29 
               
               
                 24.68 
                 3.60 
                 6 
               
               
                 25.01 
                 3.56 
                 7 
               
               
                 25.57 
                 3.48 
                 4 
               
               
                 25.96 
                 3.43 
                 4 
               
               
                 26.93 
                 3.31 
                 18 
               
               
                 27.22 
                 3.27 
                 13 
               
               
                 27.92 
                 3.19 
                 10 
               
               
                   
               
             
          
         
       
     
       Example 4 
     Crystallisation of Polymorph D 
       [0049]    Polymorph D is obtained if polymorph C from Example 3 is heated to a temperature of 30-100° C. or dried at this temperature. 
       Example 5 
     Crystallisation of Polymorph E 
       [0050]    Anhydrous polymorph E is obtained if polymorph D is melted. On further heating, polymorph E crystallises out of the melt. 
         [0051]      FIG. 6  shows a thermoanalysis of form C 
         [0052]    In the DSC diagram of form C a whole range of signals can be observed. The strongest signal is the melting point of the anhydrous form A at approx. 206° C., which is produced in the DSC experiment. Before the melting point a number of other endothermic and exothermic signals can be observed. Thus, for example, a very broad and weak endothermic signal can be seen between 30 and 100° C., which correlates with the main loss of weight in thermogravimetry (TR). A TG/IR coupling experiment provides the information that only water escapes from the sample in this temperature range. 
         [0053]    An X-ray powder diagram taken of a sample maintained at a temperature of 100° C. shows different X-ray reflexes from the starting material, suggesting that form C is a hydrate phase with stoichiometry somewhere in the region of a hemihydrate or monohydrate. The temperature-controlled sample is another anhydrous modification D, which only stable under anhydrous conditions. The D form melts at approx. 150° C. Another anhydrous crystal modification E crystallises from the melt, and when heated further melts at approx. 175° C. Finally, form A crystallises from the melt of form E. Form E is also a metastable crystal modification which occurs only at high temperatures.