Polymorphs

• US 9,266,888 B2
• Filed: 08/19/2014
• Issued: 02/23/2016
• 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: Sieger, Peter, Nicola, Thomas, Renz, Martin, Kemmer, Dirk, Kohlbauer, Peter
• Primary Examiner(s): Jarrell, Noble
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US14/462,654
• Publication Number:
  US 20140357646A1
• Time in Patent Office: 553 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:

(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:

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:

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.