Crystal forms of saxagliptin and processes for preparing same

Abstract

Physical crystal structures of a compound of the formula I: are provided including the free base monohydrate thereof (form H-1) and the hydrochloric acid salt thereof, including hydrochloric acid salt containing 0.75 equivalent of H 2 O (form H0.75-3) and hydrochloric acid salt containing 2 equivalents of H 2 O (form H2-1), and hydrochloric acid salt Pattern P-5, preferably in substantially pure form, and other forms as described herein, pharmaceutical compositions containing structures of compound I or IA, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.

1 . A crystalline compound of the structure 
       
         
           
           
               
               
           
         
       
       in the form of a hydrated monoHCl salt in substantially pure form which is a mixture of form H2-1 (1HCl) and form H0.75-3 and/or Pattern P-5, in which
 form H2-1 (1HCl) has structure 
 
       
         
           
           
               
               
           
         
       
       and has powder x-ray diffraction peaks at 2θ values (CuKαλ−1.5418 Å) of 6.8±0.1, 11.1±0.1, 13.7±0.1, 14.6±0.1, 15.2±0.1, 16.4±0.1, 17.0±0.1, 20.2±0.1, and 21.1±0.1;
 form H0.75-3 has structure 
 
       
         
           
           
               
               
           
         
       
       and has powder x-ray diffraction peaks at 2θ values (CuKαλ−1.5418 Å) of 5.0±0.1, 7.0±0.1, 8.1±0.1, 11.4±0.1, 13.4±0.1, 14.0±0.1, 14.5±0.1, 18.6±0.1, 19.4±0.1, and 20.0±0.1; and
 form P-5 has structure 
 
       
         
           
           
               
               
           
         
       
       and has powder x-ray diffraction peaks at 2θ values (CuKαλ−1.5418 Å) of 6.2±0.1, 10.7±0.1, 14.5±0.1, 15.0±0.1, 15.6±0.1, 16.2±0.1, 18.1±0.1, 18.7±0.1, and 21.1±0.1. 
     
     
         2 . The crystalline compound according to  claim 1 , wherein form H2-1 (1HCl) has an observed powder x-ray diffraction pattern as shown in  FIG. 6 . 
     
     
         3 . The crystalline compound according to  claim 1 , wherein form H0.75-3 has an observed powder x-ray diffraction pattern as shown in  FIG. 11 . 
     
     
         4 . The crystalline compound according to  claim 1 , wherein form P-5 has an observed powder x-ray diffraction pattern as shown in  FIG. 28 . 
     
     
         5 . The crystalline compound as defined in  claim 1 , wherein the form H2-1 is characterized by unit cell parameters substantially equal to the following:
 Cell dimensions for single crystal (2H 2 O)   
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Temperature ° C. 
                     
                 
                 
                 
                 
               
                     
                   at −50° C. 
                   at +22° C. 
                 
                     
                     
                 
                 
                 
                 
                 
               
                     
                   a(Å) 
                   10.994(1) 
                   11.026(4) 
                 
                     
                   b(Å) 
                   6.834(1) 
                   6.8436(2) 
                 
                     
                   c(Å) 
                   12.922(1) 
                   12.9928(4) 
                 
                     
                   α° 
                   90 
                   90 
                 
                     
                   β° 
                   95.66(1) 
                   95.734(2) 
                 
                     
                   γ° 
                   90 
                   90 
                 
                     
                   Space group 
                   P2 1   
                   P2 1   
                 
                     
                   Molecules/asymmetric unit 
                   1 
                   1 
                 
                     
                     
                 
             
                
                
               
            
             
                
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         the observed powder X-ray diffraction pattern substantially in accordance with that shown in  FIG. 6 ; or 
         positional parameters substantially as listed in Table 7A; or 
         a differential scanning calorimetry thermogram substantially in accordance with that shown in  FIG. 7 , having an endotherm in the range from at about room temperature to about 85° C.; or 
         thermal gravimetric analysis curve substantially in accordance with that shown in  FIG. 8  having a weight loss of about 5.6% up to about 85° C.; or 
         a Raman observed spectrum at room temperature as substantially shown in  FIG. 9 ; or 
         an observed infrared spectrum at room temperature as substantially shown in  FIG. 10 . 
       
     
     
         6 . The crystalline compound as defined in  claim 1 , wherein the form H0.75-3 is characterized by unit cell parameters substantially equal to the following: Cell dimensions for single crystal HCl salt (form H0.75-3)
 a=43.913 Å   b=6.759(1)Å   c=17.948 Å   α=90°   β=134.98(1)°   γ=90°   Space group C2   Molecules/asymmetric unit 2   
       as measured at about +22° C.; or
 the observed powder X-ray diffraction pattern substantially in accordance with that shown in  FIG. 11 ; or 
 positional parameters substantially as listed in Table 10; or 
 a differential scanning calorimetry thermogram substantially in accordance with that shown in  FIG. 12 , having an endotherm in the range from at about room temperature to about 150° C.; or 
 thermal gravimetric analysis curve substantially in accordance with that shown in  FIG. 13  having a weight loss of about 3.84% up to about 120° C.; or 
 a Raman observed spectrum at room temperature as substantially shown in  FIG. 14 ; or 
 an observed infrared spectrum at room temperature as substantially shown in  FIG. 15 . 
 
     
     
         7 . The crystalline compound as defined in  claim 1 , wherein the Pattern P-5 is characterized by the X-ray diffraction patterns substantially in accordance with that shown in  FIGS. 28 and 29 ; the diffraction peak positions shown in Table A′; and the FT-NIR spectrum shown in  FIG. 30 . 
     
     
         8 . The crystalline compound as defined in  claim 2 , wherein the crystalline compound is a mixture of form H2-1 (1HCl) and Pattern P-5. 
     
     
         9 . A pharmaceutical composition which comprises a crystalline compound as defined in  claim 8  and a pharmaceutically acceptable carrier therefor. 
     
     
         10 . A method for treating diabetes, insulin resistance, hyperglycemia, dyslipidemia or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, retinopathy, neuropathy, nephropathy, cataracts, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, arthritis, allograft rejection in transplantation, scleroderma, multiple sclerosis, necrotizing enteritis, microvillus inclusion disease, celiac disease, inflammatory bowel syndrome, anorexia nervosa, osteoporosis, lupus erythematosis, psoriasis, Crohn's disease or ulcerative colitis, which comprises administering to a mammalian species in need of treatment or an effective amount of a crystalline compound according to  claim 1 . 
     
     
         11 . A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment or an effective amount of a crystalline compound according to  claim 1 . 
     
     
         12 . A pharmaceutical composition which comprises a crystalline compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , further including one or more antidiabetic agent(s) other than a DPP4 inhibitor. 
     
     
         14 . The pharmaceutical composition according to  claim 13  wherein the antidiabetic agent is a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a CTEP inhibitor, a PPAR α/γ dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide. 
     
     
         15 . The pharmaceutical composition according to  claim 13  wherein the antidiabetic agent is metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, dapagliflozin, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR—H039242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902. 
     
     
         16 . The pharmaceutical composition according to  claim 13  wherein the antidiabetic agent is metformin, glyburide, glipizide, or dapagliflozin. 
     
     
         17 . The pharmaceutical composition according to  claim 13  wherein the antidiabetic agent is metformin or dapagliflozin. 
     
     
         18 . The pharmaceutical composition according to  claim 13  wherein the antidiabetic agent is dapagliflozin. 
     
     
         19 . The pharmaceutical composition according to  claim 12 , further comprising an anti-obesity agent. 
     
     
         20 . The pharmaceutical composition according to  claim 19  wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol. 
     
     
         21 . The pharmaceutical composition according to  claim 12 , further comprising a lipid modulating agent. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, ZD-4522, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427. 
     
     
         23 . A method for treating diabetes, insulin resistance, hyperglycemia, dyslipidemia or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, retinopathy, neuropathy, nephropathy, cataracts, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, arthritis, allograft rejection in transplantation, scleroderma, multiple sclerosis, necrotizing enteritis, microvillus inclusion disease, celiac disease, inflammatory bowel syndrome, anorexia nervosa, osteoporosis, lupus erythematosis, psoriasis, Crohn's disease or ulcerative colitis, which comprises administering to a mammalian species in need of treatment or an effective amount of a crystalline compound according to  claim 1 . 
     
     
         24 . A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment or an effective amount of a crystalline compound according to  claim 1 .