Polymorphs

Abstract

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

1 . Anhydrous polymorph A of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it melts at 206±3° C. 
   
   
       2 . Polymorph A according to  claim 1 , characterised in that in the X-ray powder diagram it has inter alia 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. 
   
   
       3 . Anhydrous polymorph B of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that at a temperature of 10-40° C. it transforms reversibly into the polymorph A of  claim 1 . 
   
   
       4 . Polymorph B according to  claim 3 , characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å. 
   
   
       5 . Polymorph C of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it loses water at a temperature of 30-100° C. and in the DSC diagram it exhibits further thermal effects at approx. 150° C. and 175° C. 
   
   
       6 . Polymorph C according to  claim 5 , characterised in that in the X-ray powder diagram it has inter alia characteristic reflexes at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å. 
   
   
       7 . Anhydrous polymorph D of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it melts at 150±3° C. 
   
   
       8 . Anhydrous polymorph E of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, characterised in that it melts at 175±3° C. 
   
   
       9 . Method of preparing the polymorph C according to  claim 5 , characterised in that
 (a) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is refluxed in methanol,   (b) the methanolic solution is cooled to a temperature of 40-60° C.,   (c) a solvent such as tert.-butylmethylether is added,   (d) the resulting suspension is cooled first of all to 15-25° C. and then to 0-5° C.,   (e) the crystals are suction filtered and   (f) dried in vacuo at a temperature of 70° C.   
   
   
       10 . Method according to  claim 9 , characterised in that after step (a) the hot solution is filtered. 
   
   
       12 . A method for the treatment of patients with type I and type II diabetes mellitus, prediabetes or reduced glucose tolerance, rheumatoid arthritis, obesity, or calcitonin-induced osteoporosis, as well as patients in whom an allograft transplant has been carried out, the method comprising the step of administering a pharmaceutical composition comprising at least one of the polymorphs A, B, and C, and one or more inert carriers, diluents, or carriers and diluents. 
   
   
       13 . A pharmaceutical composition comprising at least one of the polymorphs A, B, and C, and one or more inert carriers, diluents, or carriers and diluents.