Polymorphs

Patent metadata

Field	Value
Publication number	US-9493462-B2
Application number	US-201614994578-A
Country	US
Kind code	B2
Filing date	Jan 13, 2016
Priority date	May 4, 2006
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

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

First claim

The invention claimed is:

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:
heating polymorph B or a mixture of polymorphs A and B to temperatures>40° C.; 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;

and wherein
said anhydrous polymorph B transforms reversibly into the polymorph A 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, 7.0 Å and 3.77 Å.

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

3. The method of claim 1 , wherein anhydrous polymorph A is characterized in that the reflection at 11.59 Å in the X-ray powder diagram has a relative intensity of 100% and 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 7.0 Å.

4. The method according to claim 1 , wherein polymorph A is characterised by the follow 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 .

5. The method according to claim 1 wherein anhydrous polymorph B has an X-ray powder diagram as shown in FIG. 4 .

6. The method of claim 1 , wherein anhydrous polymorph B is characterized in that the reflection at 11.3 Å in the X-ray powder diagram has a relative intensity of 100% and 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.

7. The method according to claim 1 , 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 .

8. 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.

9. A method of preparing anhydrous polymorph A or B, or a mixture thereof, 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 crystallizing polymorph A or B, or a mixture thereof, from 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 ethanol,
wherein anhydrous polymorph A is characterised in that it melts at 206±3° C., and further characterised in that it 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,
wherein anhydrous polymorph B is characterised in that it transforms reversibly into polymorph A at a temperature of 10-40° C., and further characterised in that it 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.

10. A method of preparing a medicament, the method comprising
i) preparing the anhydrous polymorph A or B, or a mixture thereof, by the method of claim 9 , and
ii) combining the anhydrous polymorph A or B, or a mixture thereof, 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 or B, or a mixture thereof, based on the total weight of the polymorph A or B and the one or more inert carriers.

Assignees

• Boehringer Ingelheim Int

Inventors

• Sieger Peter
• Kemmer Dirk
• Kohlbauer Peter
• Nicola Thomas
• Renz Martin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title