Polymorphs

• US 9,493,462 B2
• Filed: 01/13/2016
• Issued: 11/15/2016
• Est. Priority Date: 05/04/2006
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Nicola, Thomas, Sieger, Peter, Kemmer, Dirk, Kohlbauer, Peter, Renz, Martin
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/994,578
• Publication Number:
  US 20160122352A1
• Time in Patent Office: 307 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 473/04 two oxygen atoms
• CPC Class Codes: C07D 473/06 with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Abstract

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

Claims

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:

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:

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.