Polymorphs

1. A method of preparing an 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, the method comprising:

(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 to provide a solution;

(b) refluxing the solution to provide a hot solution and, optionally filtering the hot solution to provide a hot filtrate,

(c) cooling the hot solution or the hot filtrate until crystallisation sets in,

(d) diluting the cooled solution or the cooled filtrate with a solvent to provide a solvent mixture,

(e) suction filtering the solvent mixture, and

(f) drying the solids collected by filtration at 45° C. in vacuo to provide said anhydrous polymorph A; wherein

said anhydrous polymorph A melts at 206±3° C., and

said anhydrous polymorph A exhibits an X-ray powder diagram having characteristic reflections at the following d values: 11.59 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47 Å.

2. The method of claim 1 , wherein the solvent used in Step (d) is tertiary-butylmethylether.

3. The method according to claim 1 , wherein anhydrous polymorph A has an X-ray powder diagram as shown in FIG. 3 .

4. The method of claim 1 , further characterized in that the reflection at 11.59 Å in the X-ray powder diagram has a relative intensity of 100% and further characterized in that the X-ray powder diagram exhibits no reflections having a relative intensity of 1% or more at the following d values: 11.3 Å, 9.36 Å, 7.48 Å, and 7 Å.

5. The method according to claim 1 , wherein polymorph A is characterised by its lattice metrics:

Symmetry:

monoclinic

space 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 .

6. A method of preparing 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, the method comprising:

(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 to provide a solution,

(b) refluxing the solution to provide a hot solution and, optionally filtering the hot solution to provide a hot filtrate,

c) cooling the hot solution or the hot filtrate for crystallisation to a temperature below 10° C. to provide a cold solution or cold filtrate,

(d) diluting the cold solution or cold filtrate with a solvent to provide a solvent mixture,

(e) suction filtering the solvent mixture, and

(f) drying the collected solids at a temperature below 10° C. in vacuo to provide anhydrous polymorph B;

or

cooling polymorph A or a mixture of polymorphs A and B to temperatures <10° C.; wherein

said anhydrous polymorph B transforms reversibly into the polymorph A of claim 1 at temperature of 10-40° C., and

said anhydrous polymorph B exhibits an X-ray powder diagram having characteristic reflections at the following d values: 11.3 Å, 9.36 Å, 7.48 Å, 7 Å and 3.77 Å.

7. The method of claim 6 , wherein the solvent in Step (d) is tertiary-butylmethylether.

8. The method according to claim 6 wherein anhydrous polymorph B has an X-ray powder diagram as shown in FIG. 4 .

9. The method of claim 6 , further characterized in that the reflection at 11.3 Å in the X-ray powder diagram has a relative intensity of 100% and further characterized in that the X-ray powder diagram exhibits no reflections having a relative intensity of 1% or more at the following d values: 11.59 Å, 7.60 Å, and 7.15 Å.

10. The method according to claim 6 , wherein polymorph B is characterised by its lattice metrics:

Symmetry:

monoclinic

space 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 .

11. A method of preparing a medicament, the method comprising

i) preparing the anhydrous polymorph A by the method of claim 1 , and

ii) combining the anhydrous polymorph A with one or more inert carriers to provide a medicament containing 0.1% to 0.5%, or 0.5% to 1.5%, or 1% to 3% of the anhydrous polymorph A based on the total weight of the polymorph A and the one or more inert carriers.

12. A method of preparing a medicament, the method comprising

i) preparing the anhydrous polymorph B by the method of claim 6 , and

ii) combining the anhydrous polymorph B with one or more inert carriers to provide a medicament containing 0.1% to 0.5%, or 0.5% to 1.5%, or 1% to 3% of the anhydrous polymorph B based on the total weight of the polymorph B and the one or more inert carriers.