Polymorphs
The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.
1. A method of preparing 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, characterized in that it melts at 150±3° C., the method comprising heating 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 at a temperature of 100° C. to lose water, wherein polymorph C is characterized in that it loses water at a temperature of 30-100° C. and exhibits further thermal effects at a temperature of about 150° C. and about 175° C. in a differential scanning calorimetry (DSC) analysis.
2. The method according to claim 1 wherein polymorph C is obtained by a method comprising:
(a) refluxing a solution of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol to provide a hot methanolic solution,
(b) cooling the hot methanolic solution to a temperature of 40-60° C. to provide a cooled methanolic solution,
(c) adding tert-butylmethylether to the cooled methanolic solution to form a suspension,
(d) cooling the suspension first to a temperature of 15-25° C. and then to a temperature of 0-5° C. to provide crystals,
(e) suction filtering the crystals, and
(f) drying the crystals obtained in step (e) in vacuo at a temperature of 70° C. to provide Polymorph C.
3. The method according to claim 2 , wherein the X-ray powder diagram of Polymorph C has characteristic reflections at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å.
4. The method according to claim 2 , wherein the hot methanolic solution obtained in step (a) is filtered before cooling in step (b).