Polymorphs

  *US09815837B2*
  US009815837B2                                 
(12)United States Patent(10)Patent No.: US 9,815,837 B2
  et al. (45) Date of Patent:Nov.  14, 2017

(54)Polymorphs 
    
(75)Inventor: Boehringer Ingelheim International GmbH,  Ingelheim am Rhein (DE) 
(73)Assignee:Boehringer Ingelheim International GmbH,  Ingelheim am Rhein (DE), Type: Foreign Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
(21)Appl. No.: 15/285,871 
(22)Filed: Oct.  5, 2016 
(65)Prior Publication Data 
 US 2017/0022203 A1 Jan.  26, 2017 
 Related U.S. Patent Documents 
(63) .
Continuation of application No. 14/994,578, filed on Jan.  13, 2016, now Pat. No. 9,493,462 , which is a continuation of application No. 14/462,654, filed on Aug.  19, 2014, now Pat. No. 9,266,888 , which is a continuation of application No. 13/563,767, filed on Aug.  1, 2012, now abandoned , which is a continuation of application No. 11/744,700, filed on May  4, 2007, now abandoned .
 
(30)Foreign Application Priority Data 
 May  4, 2006     (EP)   06009202
Jan.  1, 2013 C 07 D 473 06 F I Nov.  14, 2017 US B H C Jan.  1, 2013 C 07 D 473 04 L I Nov.  14, 2017 US B H C Jan.  1, 2013 C 07 B 2200 13 L A Nov.  14, 2017 US B H C
(51)Int. Cl. C07D 473/06 (20060101); C07D 473/04 (20060101)

 
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 2012//0040982  A1  2/2012    Himmelsbach et al.     
 2012//0053173  A1  3/2012    Banno et al.     
 2012//0094894  A1  4/2012    Graefe-Mody et al.     
 2012//0107398  A1  5/2012    Schneider et al.     
 2012//0121530  A1  5/2012    Klein et al.     
 2012//0122776  A1  5/2012    Graefe-Mody et al.     
 2012//0129874  A1  5/2012    Sieger et al.     
 2012//0142712  A1  6/2012    Pfrengle et al.     
 2012//0165251  A1  6/2012    Klein et al.     
 2012//0208831  A1  8/2012    Himmelsbach et al.     
 2012//0219622  A1  8/2012    Kohlrausch et al.     
 2012//0219623  A1  8/2012    Meinicke     
 2012//0252782  A1  10/2012    Himmelsbach et al.     
 2012//0252783  A1  10/2012    Himmelsbach et al.     
 2012//0296091  A1  11/2012    Sieger et al.     
 2013//0064887  A1  3/2013    Ito et al.     
 2013//0122089  A1  5/2013    Kohlrausch et al.     
 2013//0172244  A1  7/2013    Klein et al.     
 2013//0184204  A1  7/2013    Pfrengle et al.     
 2013//0196898  A1  8/2013    Dugi et al.     
 2013//0236543  A1  9/2013    Ito et al.     
 2013//0303554  A1  11/2013    Klein et al.     
 2013//0315975  A1  11/2013    Klein et al.     
 2013//0317046  A1  11/2013    Johansen     
 2013//0324463  A1  12/2013    Klein et al.     
 2014//0100236  A1  4/2014    Busl et al.     
 2014//0274889  A1  9/2014    Johansen et al.     
 2014//0343014  A1  11/2014    Klein et al.     
 2014//0371243  A1  12/2014    Klein et al.     
 2015//0196565  A1  7/2015    Klein et al.     
 2015//0246045  A1  9/2015    Klein et al.     
 2015//0265538  A1  9/2015    Balthes et al.     
 2016//0082011  A1  3/2016    Klein et al.     
 2016//0106677  A1  4/2016    Boeck et al.     
 2016//0310435  A1  10/2016    Friedl et al.     

 
 FOREIGN PATENT DOCUMENTS 
 
       AU       2003280680       A1                6/2004      
       AU       2009224546       A1                9/2009      
       CA       1123437       A1                5/1982      
       CA       2136288       A1                5/1995      
       CA       2418656       A1                2/2002      
       CA       2435730       A1                9/2002      
       CA       2496249       A1                3/2004      
       CA       2496325       A1                3/2004      
       CA       2498423       A1                4/2004      
       CA       2505389       A1                5/2004      
       CA       2508233       A1                6/2004      
       CA       2529729       A1                12/2004      
       CA       2543074       A1                6/2005      
       CA       2555050       A1                9/2005      
       CA       2556064       A1                9/2005      
       CA       2558067       A1                10/2005      
       CA       2558446       A1                10/2005      
       CA       2561210       A1                10/2005      
       CA       2562859       A1                11/2005      
       CA       2576294       A1                3/2006      
       CA       2590912       A1                6/2006      
       CA       2599419       A1                11/2006      
       CA       2651019       A1                11/2007      
       CA       2651089       A1                11/2007      
       CA       2720450       A1                10/2009      
       CN       101234105       A                8/2008      
       DE       2205815       A1                8/1973      
       DE       2758025       A1                7/1979      
       DE       19705233       A1                8/1998      
       DE       10109021       A1                9/2002      
       DE       10117803       A1                10/2002      
       DE       10238243       A1                3/2004      
       DE       102004019540       A1                11/2005      
       DE       102004024454       A1                12/2005      
       DE       102004044221       A1                3/2006      
       DE       102004054054       A1                5/2006      
       EA       201300121                         10/2009      
       EP       0023032       A1                1/1981      
       EP       0149578       A2                7/1985      
       EP       0223403       A2                5/1987      
       EP       0237608       A1                9/1987      
       EP       0248634       A2                12/1987      
       EP       0342675       A2                11/1989      
       EP       0389282       A2                9/1990      
       EP       0399285       A1                11/1990      
       EP       0400974       A2                12/1990      
       EP       409281       A1                1/1991      
       EP       0412358       A1                2/1991      
       EP       443983       A1                8/1991      
       EP       0475482       A1                3/1992      
       EP       0524482       A1                1/1993      
       EP       0638567       A1                2/1995      
       EP       0657454       A1                6/1995      
       EP       0775704       A1                5/1997      
       EP       0950658       A1                10/1999      
       EP       1054012       A1                11/2000      
       EP       1066265       A1                1/2001      
       EP       1310245       A1                5/2003      
       EP       1333033                         8/2003      
       EP       1338595       A2                8/2003      
       EP       1406873       A2                4/2004      
       EP       1500403       A1                1/2005      
       EP       1514552       A1                3/2005      
       EP       1523994       A1                4/2005      
       EP       1535906       A1                6/2005      
       EP       1537880       A1                6/2005      
       EP       1557165       A1                7/2005      
       EP       1586571       A1                10/2005      
       EP       1743655       A1                1/2007      
       EP       1760076                         3/2007      
       EP       1829877       A1                9/2007      
       EP       1852108       A1                11/2007      
       EP       1897892       A2                3/2008      
       EP       2143443       A1                1/2010      
       EP       2166007       A1                3/2010      
       ES       385302       A1                4/1973      
       ES       2256797       T3                7/2006      
       ES       2263057       T3                12/2006      
       FR       2707641       A1                1/1995      
       GB       2084580       A                4/1982      
       HU       9003243                         5/1990      
       HU       9902308       A2                7/2000      
       JP       S374895       A                6/1962      
       JP       770120                         3/1995      
       JP       8333339                         12/1996      
       JP       11193270                         7/1999      
       JP       2000502684       A                3/2000      
       JP       2001213770       A                8/2001      
       JP       2001278812       A                10/2001      
       JP       2001292388       A                10/2001      
       JP       2002348279       A                12/2002      
       JP       2003286287       A                10/2003      
       JP       2003300977       A                10/2003      
       JP       2004161749       A                6/2004      
       JP       2004250336       A                9/2004      
       JP       2006045156       A                2/2006      
       JP       2010053576       A                3/2010      
       JP       2010070576       A                4/2010      
       JP       2010524580       A                7/2010      
       KR       20070111099       A                11/2007      
       WO       8706941       A1                11/1987      
       WO       9107945       A1                6/1991      
       WO       9205175       A1                4/1992      
       WO       9219227       A2                11/1992      
       WO       9402150       A1                2/1994      
       WO       9403456       A1                2/1994      
       WO       9532178       A1                11/1995      
       WO       9609045       A1                3/1996      
       WO       9611917       A1                4/1996      
       WO       9636638       A1                11/1996      
       WO       9718814       A1                5/1997      
       WO       9723447       A1                7/1997      
       WO       9723473       A1                7/1997      
       WO       9746526       A1                12/1997      
       WO       98007725                         2/1998      
       WO       9811893                         3/1998      
       WO       9818770       A1                5/1998      
       WO       9822464       A1                5/1998      
       WO       9828007       A1                7/1998      
       WO       9840069       A2                9/1998      
       WO       98046082       A1                10/1998      
       WO       9856406       A1                12/1998      
       WO       9929695       A1                6/1999      
       WO       9938501       A2                8/1999      
       WO       9950248       A1                10/1999      
       WO       9956561       A1                11/1999      
       WO       9967279       A1                12/1999      
       WO       0034241       A1                6/2000      
       WO       0069464       A1                11/2000      
       WO       0072799       A2                12/2000      
       WO       0073307       A2                12/2000      
       WO       0078735       A1                12/2000      
       WO       0107441       A1                2/2001      
       WO       0132158       A2                5/2001      
       WO       0140180       A2                6/2001      
       WO       0147514       A1                7/2001      
       WO       0151919                         7/2001      
       WO       0152825                         7/2001      
       WO       0152852       A1                7/2001      
       WO       0166548       A1                9/2001      
       WO       0168603                         9/2001      
       WO       0168646       A1                9/2001      
       WO       0172290       A2                10/2001      
       WO       0177110       A1                10/2001      
       WO       0196301       A1                12/2001      
       WO       0197808       A1                12/2001      
       WO       0202560       A2                1/2002      
       WO       0214271       A1                2/2002      
       WO       0224698       A1                3/2002      
       WO       02053516       A2                7/2002      
       WO       02068420       A1                9/2002      
       WO       03000241       A2                1/2003      
       WO       03000250                         1/2003      
       WO       03002531       A2                1/2003      
       WO       03002553       A2                1/2003      
       WO       03004496       A1                1/2003      
       WO       03024965       A2                3/2003      
       WO       03033686       A2                4/2003      
       WO       03034944       A1                5/2003      
       WO       03035177       A2                5/2003      
       WO       03037327       A1                5/2003      
       WO       03053929       A1                7/2003      
       WO       03055881       A1                7/2003      
       WO       03057200       A2                7/2003      
       WO       03059327                         7/2003      
       WO       03064454       A1                8/2003      
       WO       03074500       A2                9/2003      
       WO       03088900       A2                10/2003      
       WO       03094909       A2                11/2003      
       WO       03099279       A1                12/2003      
       WO       03099836       A1                12/2003      
       WO       03104229       A1                12/2003      
       WO       03106428       A1                12/2003      
       WO       2004002924       A1                1/2004      
       WO       2004011416       A1                2/2004      
       WO       2004016587       A1                2/2004      
       WO       2004018467       A2                3/2004      
       WO       2004018468       A2                3/2004      
       WO       2004018469       A1                3/2004      
       WO       2004028524       A1                4/2004      
       WO       2004033455       A1                4/2004      
       WO       2004035575       A1                4/2004      
       WO       2004037169       A2                5/2004      
       WO       2004041820       A1                5/2004      
       WO       2004043940                         5/2004      
       WO       2004046148       A1                6/2004      
       WO       2004048379       A1                6/2004      
       WO       2004050658       A1                6/2004      
       WO       2004052362       A1                6/2004      
       WO       2004058233       A1                7/2004      
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       WO       2004074246       A2                9/2004      
       WO       2004081006       A1                9/2004      
       WO       2004082402       A1                9/2004      
       WO       2004096806       A1                11/2004      
       WO       2004096811       A1                11/2004      
       WO       2004106279       A2                12/2004      
       WO       2004108730       A1                12/2004      
       WO       2004111051       A1                12/2004      
       WO       2005000846       A1                1/2005      
       WO       2005000848       A1                1/2005      
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       WO       2005007658       A2                1/2005      
       WO       2005012288       A1                2/2005      
       WO       2005023179       A2                3/2005      
       WO       2005049022       A2                6/2005      
       WO       2005051950       A1                6/2005      
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       WO       2005082906       A1                9/2005      
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       WO       2005095381       A1                10/2005      
       WO       2005097798       A                10/2005      
       WO       2005116000       A1                12/2005      
       WO       2005116014       A1                12/2005      
       WO       2005117861       A1                12/2005      
       WO       2005117948       A1                12/2005      
       WO       2006005613       A1                1/2006      
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       WO       2006135693       A2                12/2006      
       WO       2006137085       A1                12/2006      
       WO       2007007173       A2                1/2007      
       WO       2007014886       A1                2/2007      
       WO       2007014895       A2                2/2007      
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       WO       2007120702       A2                10/2007      
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       WO       2007128721       A                11/2007      
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       WO       2007128761       A2                11/2007      
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       WO       2008005569       A2                1/2008      
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       WO       2008022267       A2                2/2008      
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       WO       2008070692       A2                6/2008      
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     * cited by examiner
 
     Primary Examiner —Noble Jarrell
     Assistant Examiner —John S Kenyon
     Art Unit — 1625
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — Marc Began; David L. Kershner

(57)

Abstract

The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.
3 Claims, 6 Drawing Sheets, and 6 Figures


BACKGROUND OF THE INVENTION

[0001] This Application claims priority of EP 06 009 202, which is hereby incorporated by reference in its entirety.
[0002] 1. Field of the Invention
[0003] The invention relates to polymorphous crystal modifications of a DPP-IV inhibitor, the preparation thereof and the use thereof for preparing a medicament.
[0004] 2. Description of the Prior Art
[0005] The enzyme DPP-IV, also known by the name CD26, is a serine protease which promotes the cleaving of dipeptides in proteins with a proline or alanine group at the N-terminal end. DPP-IV inhibitors thereby influence the plasma level of bioactive peptides including the peptide GLP-1. Compounds of this type are useful for the prevention or treatment of illnesses or conditions which are associated with an increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, particularly type I or type II diabetes mellitus, prediabetes, or reduced glucose tolerance.
[0006] WO 2004/018468 describes DPP-IV inhibitors with valuable pharmacological properties. One example of the inhibitors disclosed therein is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows the thermoanalysis of the anhydrous form A/B.
[0008] FIG. 2 shows a cyclic DSC diagram, in which the phase transition from −40° C. to 120° C. and vice versa has been run through a total of 3 times.
[0009] FIG. 3 shows an X-ray powder diagram of the anhydrous form A.
[0010] FIG. 4 shows an X-ray powder diagram of the anhydrous form B.
[0011] FIG. 5 shows an X-ray powder diagram of polymorph C.
[0012] FIG. 6 shows the thermoanalysis of form C.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Within the scope of the present invention it has been found that 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine may take on various polymorphous crystal modifications and that the compound prepared in WO 2004/018468 is present at ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C. (see FIGS. 1 and 2).
[0014] The pure high temperature form (polymorph A), which can be obtained by heating the mixture to temperatures >40° C., melts at 206±3° C. In the X-ray powder diagram (see FIG. 3) this form shows characteristic reflections at the following d values: 11.49 Å, 7.60 Å, 7.15 Å, 3.86 Å, 3.54 Å and 3.47 Å (cf. also Table 1 and 2).
[0015] Anhydrous polymorph A may be prepared by
[0016] (a) refluxing 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 and optionally filtering the mixture,
[0017] (b) cooling the hot solution or the hot filtrate until crystallisation sets in,
[0018] (c) diluting with a solvent such as tert.-butylmethylether,
[0019] (d) suction filtering the solvent mixture and
[0020] (e) drying the polymorph A at 45° C. in vacuo.
[0021] The low temperature form (polymorph B) is obtained by cooling to temperatures <10° C. In the X-ray powder diagram (see FIG. 4) this form shows characteristic reflections at the following d values: 11.25 Å, 9.32 Å, 7.46 Å, 6.98 Å and 3.77 Å (cf. also Table 3 and 4).
[0022] Anhydrous polymorph B may be prepared by
[0023] (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 and refluxing and optionally filtering the mixture,
[0024] (b) cooling the hot solution or the hot filtrate for crystallisation to a temperature below 10° C.,
[0025] (c) diluting with a solvent such as tert.-butylmethylether,
[0026] (d) suction filtering the solvent mixture and
[0027] (e) drying the polymorph at a temperature below 10° C. in vacuo.
[0028] Another polymorph (polymorph C) shows characteristic reflections in the X-ray powder diagram (see FIG. 5) at the following d values: 12.90 Å, 11.10 Å, 6.44 Å, 3.93 Å and 3.74 Å (cf. also Table 5).
[0029] Polymorph C is obtained if
[0030] (a) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is dissolved in methanol and refluxed and optionally filtered in the presence of activated charcoal,
[0031] (b) the methanolic solution is cooled to a temperature of 40-60° C.,
[0032] (c) a solvent such as tert.-butylmethylether or diisopropylether is added,
[0033] (d) the resulting suspension is first of all cooled slowly to 15-25° C. and then later to 0-5° C.,
[0034] (e) the crystals formed are suction filtered and washed again with tert.-butylmethylether or diisopropylether and
[0035] (f) the crystals thus obtained are dried at a temperature of 70° C. in the vacuum dryer.
[0036] Another polymorph (polymorph D) melts at 150±3° C. This polymorph is obtained if polymorph C is heated to a temperature of 30-100° C. or dried at this temperature.
[0037] Finally, there is also polymorph E, which melts at a temperature of 175±3° C. Anhydrous polymorph E is formed if polymorph D is melted. On further heating, polymorph E crystallises out of the melt.
[0038] The polymorphs thus obtained may be used in the same way as the mixture of the two polymorphs A and B described in WO 2004/018468 for preparing a pharmaceutical composition which is suitable for treating patients with type I and type II diabetes mellitus, prediabetes or reduced glucose tolerance, with rheumatoid arthritis, obesity, or calcitonin-induced osteoporosis, as well as patients in whom an allograft transplant has been carried out. These medicaments contain in addition to one or more inert carriers at least 0.1% to 0.5%, preferably at least 0.5% to 1.5% and particularly preferably at least 1% to 3% of one of the polymorphs A, B, or C.
[0039] The following Examples are intended to illustrate the invention in more detail.

EXAMPLE 1: CRYSTALLISATION OF POLYMORPH A

[0040] Crude 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is refluxed with 5 times as much absolute ethanol and the hot solution is filtered clear through activated charcoal. After the filtrate has been cooled to 20° C. and crystallisation has set in, the solution is diluted to double the volume with tert.-butylmethylether. Then the suspension is cooled to 2° C., stirred for 2 hours, suction filtered and dried in the vacuum dryer at 45° C.
[0041] FIG. 1 shows the thermoanalysis of the anhydrous form A/B.
[0042] Polymorph A melts at 206±3° C. In the DSC diagram another slightly endothermic signal can be seen at approx. 25° C. This is a fully reversible solid-solid phase transition between the two enantiotropic crystal modifications A and B. The form A is the thermodynamically stable modification above this transformation temperature, w| form B is the thermodynamically stable modification below this transformation temperature.
[0043] FIG. 2 shows a cyclic DSC diagram, in which the phase transition from −40° C. to 120° C. and vice versa has been run through a total of 3 times. During heating, the phase transition is observed as an endothermic signal and, correspondingly, during cooling it is observed as an exothermic signal. During the first heating cycle the phase transition may also be observed as an endothermic double signal or as a very broad signal while in all the other cycles the signal occurs as a very sharp endothermic or exothermic signal, depending on whether heating or cooling is taking place.
[0044] FIG. 3 shows an X-ray powder diagram of the anhydrous form A
[0045] 
[00001] [TABLE-US-00001]
  TABLE 1
 
  Labelled X-ray reflections up to 30° 2 Θ with intensities
  (standardised) for the anhydrous polymorph A
  2 Θ   intensitydhkl   labellingdexp-calc
  [°]I/Io [%]   [Å]   h   k   l   [Å]
 
  5.56   1   15.89   1   0   0   −0.008
  7.18   32   12.31   0   1   1   0.005
  7.62   100   11.59   1   1   0   0.007
  8.49   20   10.41   −1   1   1   0.002
  9.91   24   8.92   0   0   2   0.003
  10.41   18   8.49   0   2   0   0.024
  11.18   24   7.91   2   0   0   0.038
  11.63   41   7.60   −1   1   2   0.003
  12.37   59   7.15   −1   2   1   −0.003
  13.19   6   6.71   1   2   1   −0.014
  13.45   3   6.58   −2   0   2   0.007
  14.05   6   6.30   2   1   1   0.011
  14.38   6   6.16   0   2   2   0.003
  14.71   10   6.02   −1   2   2   −0.008
  15.26   13   5.80   2   2   0   0.001
  15.76   10   5.62   −1   1   3   0.008
  16.09   1   5.51   1   2   2   −0.010
  16.32   1   5.43   2   0   2   0.035
  16.69   4   5.31   2   2   1   −0.007
  17.03   3   5.20   −1   3   1   0.026
  17.63   6   5.03   1   3   1   0.006
  18.17   5   4.88   −1   2   3   −0.004
  18.78   7   4.72   −1   3   2   −0.014
  19.30   1   4.60   −2   3   1   −0.019
  19.61   2   4.52   −3   2   1   0.036
  19.86   20   4.47   −2   2   3   0.040
  20.29   10   4.37   2   0   3   0.019
  20.57   4   4.31   0   1   4   0.006
  21.12   1   4.20   3   0   2   0.048
  21.57   12   4.12   −2   1   4   0.028
  22.46   10   3.96   1   4   1   0.035
  23.03   35   3.86   4   1   0   0.022
  23.39   21   3.80   −1   4   2   0.019
  24.08   2   3.69   −3   1   4   −0.006
  24.51   1   3.63   −4   0   3   0.036
  24.91   10   3.57   −2   4   2   0.003
  25.14   39   3.54   3   1   3   0.043
  25.69   36   3.47   −3   3   3   0.041
  26.68   3   3.34   0   5   1   0.035
  26.90   2   3.31   3   4   0   0.027
  27.10   2   3.29   0   2   5   0.030
  27.42   3   3.25   4   3   0   0.006
  28.19   2   3.16   −1   5   2   −0.035
  28.54   2   3.12   3   0   4   0.047
  28.94   11   3.08   0   4   4   −0.036
  29.18   5   3.06   −4   3   3   0.017
  29.50   4   3.03   −1   0   6   0.041
  30.18   7   2.96   −1   5   3   −0.042
 
[0046] 
[00002] [TABLE-US-00002]
  TABLE 2
 
  Lattice metrics of the anhydrous form A
 
 
    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) Å3
   

EXAMPLE 2: CRYSTALLISATION OF POLYMORPH B

[0047] Polymorph B is obtained by cooling form A from Example 1 to temperatures <10° C.
[0048] FIG. 4 shows an X-ray powder diagram of the anhydrous form B
[0049] 
[00003] [TABLE-US-00003]
  TABLE 3
 
  Labelled X-ray reflections up to 30° 2 Θ with intensities
  (standardised) for the anhydrous form B
  2 Θ   intensitydhkl   labellingdexp-calc
  [°]I/Io [%]   [Å]   h   k   l   [Å]
 
  5.82   3   15.17   1   0   0   −0.007
  7.04   33   12.55   0   1   1   0.001
  7.82   100   11.3   1   1   0   −0.004
  8.84   11   10   −1   1   1   0.001
  9.44   40   9.36   1   1   1   0.011
  10.62   14   8.32   −1   0   2   0.013
  10.79   24   8.19   0   1   2   −0.005
  11.82   39   7.48   −1   1   2   −0.003
  12.64   53   7   −1   2   1   −0.009
  13.07   11   6.77   1   2   1   −0.006
  13.24   6   6.68   −2   1   1   0.004
  14.04   16   6.3   2   1   1   0.003
  15.23   17   5.81   −2   1   2   0.003
  15.70   22   5.64   2   2   0   0.016
  16.38   2   5.41   0   3   1   −0.010
  16.73   6   5.3   2   2   1   0.008
  17.67   8   5.02   0   2   3   0.014
  18.16   3   4.88   −1   2   3   0.005
  18.33   9   4.84   3   1   0   0.016
  18.48   10   4.8   −3   1   1   −0.003
  18.97   15   4.68   0   0   4   −0.001
  19.56   6   4.54   1   3   2   0.013
  20.00   17   4.44   2   1   3   0.000
  20.42   9   4.35   1   0   4   0.009
  20.76   4   4.27   3   0   2   −0.014
  20.97   4   4.23   0   4   0   0.010
  21.07   5   4.21   1   1   4   −0.009
  21.22   12   4.18   0   3   3   0.001
  21.40   7   4.15   3   2   1   0.004
  21.66   4   4.1   −1   3   3   0.018
  21.98   7   4.04   2   2   3   −0.003
  22.16   10   4.01   −3   1   3   0.008
  22.97   3   3.87   1   2   4   −0.006
  23.58   43   3.77   −2   3   3   −0.003
  23.78   15   3.74   −2   2   4   −0.004
  24.05   6   3.7   4   1   0   −0.002
  24.29   8   3.66   −2   4   1   −0.008
  24.46   5   3.64   3   3   1   0.018
  24.71   7   3.6   0   3   4   0.001
  24.96   23   3.56   2   3   3   −0.001
  25.45   12   3.5   −2   4   2   −0.010
  25.75   35   3.46   4   2   0   0.011
  25.99   4   3.43   3   2   3   0.014
  26.15   6   3.41   3   3   2   0.010
  26.57   12   3.35   −2   3   4   −0.001
  26.82   4   3.32   −3   2   4   0.011
  27.20   6   3.28   1   2   5   −0.010
  27.43   4   3.25   −2   4   3   −0.003
  27.60   3   3.23   −2   2   5   −0.005
  28.19   4   3.16   3   4   1   0.010
  28.40   15   3.14   0   4   4   −0.013
  28.64   12   3.11   0   0   6   0.016
  29.18   6   3.06   −4   3   2   0.004
  29.42   2   3.03   1   4   4   0.002
  29.99   10   2.98   0   5   3   −0.008
  30.77   3   2.9   −4   3   3   0.018
 
[0050] 
[00004] [TABLE-US-00004]
  TABLE 4
 
  Lattice metrics of the anhydrous form B
 
 
    Symmetry:   monoclinic
    space group:P21/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) Å3
   

EXAMPLE 3: CRYSTALLISATION OF POLYMORPH C

[0051] Crude 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (26 kg) is refluxed with 157 l methanol, combined with 1.3 kg of activated charcoal and after 30 minutes' stirring the mixture is filtered and rinsed with 26 l methanol. 122 l of methanol are distilled off from the filtrate, then the residue is cooled to 45-55° C. 52 l of tert.-butylmethylether are added to the residue over 30 minutes. Then the mixture is stirred for another 60 minutes at 45-55° C. Crystallisation takes place within this time. A further 78 l tert. butylmethylether are added to the suspension over 30 minutes and then it is stirred again for a further 60 minutes at 45-55° C. It is diluted to four times the volume. The suspension is slowly cooled to 15-25° C. and stirred overnight at this temperature. After the suspension has been cooled to 0-5° C. the crystals are suction filtered, washed with 2 batches tert.-butylmethylether and dried at 70° C. in the vacuum dryer.
[0052] FIG. 5 shows an X-ray powder diagram of polymorph C
[0053] 
[00005] [TABLE-US-00005]
  TABLE 5
 
  X-ray reflections up to 30° 2 Θ with intensities (standardised) for the
  anhydrous form C
  2 Θdhkl   intensity
  [°]   [Å]I/Io [%]
 
  3.38   26.16   4
  6.85   12.90   100
  7.18   12.31   11
  7.52   11.74   14
  7.96   11.10   36
  9.80   9.02   3
  11.11   7.96   2
  11.58   7.64   3
  12.30   7.19   5
  13.30   6.65   16
  13.75   6.44   26
  14.38   6.16   17
  14.74   6.01   11
  14.95   5.92   10
  15.63   5.66   6
  16.28   5.44   5
  17.81   4.98   10
  18.33   4.83   6
  18.75   4.73   15
  20.51   4.33   8
  20.77   4.27   8
  21.47   4.14   3
  21.96   4.05   4
  22.59   3.93   26
  23.76   3.74   29
  24.68   3.60   6
  25.01   3.56   7
  25.57   3.48   4
  25.96   3.43   4
  26.93   3.31   18
  27.22   3.27   13
  27.92   3.19   10
 

EXAMPLE 4: CRYSTALLISATION OF POLYMORPH D

[0054] Polymorph D is obtained if polymorph C from Example 3 is heated to a temperature of 30-100° C. or dried at this temperature.

EXAMPLE 5: CRYSTALLISATION OF POLYMORPH E

[0055] Anhydrous polymorph E is obtained if polymorph D is melted. On further heating, polymorph E crystallises out of the melt.
[0056] FIG. 6 shows a thermoanalysis of form C
[0057] In the DSC diagram of form C a whole range of signals can be observed. The strongest signal is the melting point of the anhydrous form A at approx. 206° C., which is produced in the DSC experiment. Before the melting point a number of other endothermic and exothermic signals can be observed. Thus, for example, a very broad and weak endothermic signal can be seen between 30 and 100° C., which correlates with the main loss of weight in thermogravimetry (TR). A TG/IR coupling experiment provides the information that only water escapes from the sample in this temperature range.
[0058] An X-ray powder diagram taken of a sample maintained at a temperature of 100° C. shows different X-ray reflections from the starting material, suggesting that form C is a hydrate phase with stoichiometry somewhere in the region of a hemihydrate or monohydrate. The temperature-controlled sample is another anhydrous modification D, which only stable under anhydrous conditions. The D form melts at approx. 150° C. Another anhydrous crystal modification E crystallises from the melt, and when heated further melts at approx. 175° C. Finally, form A crystallises from the melt of form E. Form E is also a metastable crystal modification which occurs only at high temperatures.
(57)

Claims

1. A method of preparing 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, the 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,
wherein Polymorph C 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 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.
3. The method according to claim 1, wherein the hot methanolic solution obtained in step (a) is filtered before cooling in step (b).
*****

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