Crystalline polymorphs of benfotiamine, process for preparation and its use thereof

Abstract

The present invention is directed to crystalline polymorphs of benfotiamine, its methods of preparation and its use thereof. Five crystalline polymorphs of benfotiamine are designated as crystalline forms A, B, C, D and E, and may be distinguished by their respective patterns of X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), infrared spectroscopy (IR), raman spectroscopy, moreover by their diverse preparing process. The crystalline polymorphs of the present invention are useful as they act in treating Vitamin B1 deficiency, metabolic disorders, mental illness and disorders, diabetes complications, neurodegerative diseases. Further the present invention is a process for preparing and transforming diverse crystalline form of benfotiamine through different synthesis routes and varied solvents and combinations. The crystalline polymorphs of the present invention are basically pure. The present invention not only provides new crystalline forms of benfotiamine, but also provides its new solvates, especially hydrates.

What is claimed is: 
     
       1. A benfotiamine crystal, wherein the form can be any one of the crystalline forms below:
 Crystalline form A, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 11.317°, 16.377°, 17.874°, 18.543°, 19.313°, 20.850°, 21.295°, 24.858°, 25.142°; 
 Crystalline form B, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 11.459°, 16.883°, 18.644°, 20.669°, 21.295°, 22.773°, 24.817°, 25.728°, 27.327°; 
 Crystalline form C, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 10.811°, 11.338°, 14.516°, 16.984°, 18.684°, 19.352°, 20.809°, 21.336°, 22.854°; 
 Crystalline form D, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 10.690°, 11.033°, 14.414°, 15.365°, 15.952°, 18.725°, 24.350°, 25.081°, 25.323°; or 
 Crystalline form E, characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 9.334°, 11.863°, 12.633°, 13.260°, 13.484°, 14.395°, 15.588°, 17.206°, 18.015°, 18.948°, 19.635°, 21.276°, 22.025°, 23.703°, 24.352°, 24.938°, 26.314°, 27.023°. 
 
     
     
       2. The crystalline compound of  claim 1 , wherein the crystalline form A is further characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 8.869°, 11.317°, 13.665°, 14.839°, 16.377°, 17.874°, 18.543°, 19.313°, 20.850°, 21.295°, 22.853°, 24.858°, 25.142°, 27.631°, 28.864°. 
     
     
       3. The crystalline compound of  claim 1 , wherein the crystalline form B is further characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 11.459°, 15.122°, 16.883°, 17.693°, 18.644°, 19.271°, 20.669°, 21.295°, 22.773°, 24.817°, 25.728°, 27.327°, 29.128°. 
     
     
       4. The crystalline compound of  claim 1 , wherein the crystalline form C is further characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 8.889°, 10.811°, 11.338°, 13.908°, 14.516°, 15.223°, 16.984°, 17.793°, 18.684°, 19.352°, 20.809°, 21.336°, 22.854°, 23.276°, 25.424°, 28.561°, 33.054°. 
     
     
       5. The crystalline compound of  claim 1 , wherein the crystalline form D is further characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 10.690°, 11.033°, 14.414°, 15.365°, 15.952°, 18.725°, 19.310°, 19.797°, 21.032°, 21.256°, 24.350°, 25.081°, 25.323°, 28.318°. 
     
     
       6. The crystalline compound of  claim 1 , wherein the crystalline form E is further characterized by an X-ray powder diffraction pattern with significant peaks at diffraction angles (20 values) of about 9.334°, 11.863°, 12.633°, 13.260°, 13.484°, 14.395°, 15.588°, 17.206°, 18.015°, 18.948°, 19.635°, 20.042°, 21.276°, 22.025°, 23.703°, 24.352°, 24.938°, 26.314°, 27.023°, 30.828°, 32.083°. 
     
     
       7. The crystalline compound of  claim 2 , wherein the crystalline form A is fundamentally consistent with  FIG.  1 a  in X-ray powder diffraction pattern. 
     
     
       8. The crystalline compound of  claim 3 , wherein the crystalline form B is fundamentally consistent with  FIG.  2 a  in X-ray powder diffraction pattern. 
     
     
       9. The crystalline compound of  claim 4 , wherein the crystalline form C is fundamentally consistent with  FIG.  3 a  in X-ray powder diffraction pattern. 
     
     
       10. The crystalline compound of  claim 5 , wherein the crystalline form D is fundamentally consistent with  FIG.  4 a  in X-ray powder diffraction pattern. 
     
     
       11. The crystalline compound of  claim 6 , wherein the crystalline form E is fundamentally consistent with  FIG.  5 a  in X-ray powder diffraction pattern. 
     
     
       12. The crystalline compound of  claim 2 , wherein the crystalline form A is fundamentally consistent with  FIG.  1 b,  1 c,  1 d  in differential scanning calorimetry (DSC), infrared spectroscopy (IR), and raman spectroscopy, respectively. 
     
     
       13. The crystalline compound of  claim 3 , wherein the crystalline form B is fundamentally consistent with  FIG.  2 b,  2 c,  2 d  in differential scanning calorimetry (DSC), infrared spectroscopy (IR), and raman spectroscopy, respectively. 
     
     
       14. The crystalline compound of  claim 4 , wherein the crystalline form C is fundamentally consistent with  FIG.  3 b,  3 c,  3 d  in differential scanning calorimetry (DSC), infrared spectroscopy (IR), and raman spectroscopy, respectively. 
     
     
       15. The crystalline compound of  claim 5 , wherein the crystalline form D is fundamentally consistent with  FIG.  4 b,  4 c,  4 d  in differential scanning calorimetry (DSC), infrared spectroscopy (IR), and raman spectroscopy, respectively. 
     
     
       16. The crystalline compound of  claim 6 , wherein the crystalline form E is fundamentally consistent with  FIG.  5 b,  5 c,  5 d  in differential scanning calorimetry (DSC), infrared spectroscopy (IR), and raman spectroscopy, respectively. 
     
     
       17. The process of preparing the crystalline compound of  claim 1  comprising the methods of:
 Method 1: Crystalline form E of benfotiamine was is suspended in an organic solvent, followed by stirring until complete dissolving, and the crystalline form A then was is obtained by evaporated slowly under 25° C.; or 
 Method 2: Crystalline form E of benfotiamine was is suspended in an organic solvent mixture of methanol and dichloromethane (volume ratio 1:3), followed by stirring until complete dissolving; another poor organic solvent was is then added slowly while being stirred, and the crystalline form A was is obtained by filtering and evaporating in the air; or 
 Method 3: Crystalline form E of benfotiamine was is suspended in an organic solvent, followed by stirring in a hybrid oven for at least 24 h, and the crystalline form B then was is obtained by filtering and evaporating in the air; or 
 Method 4: Crystalline form E of benfotiamine was is suspended in an organic solvent and the mixture was is heated to 60° C. while being stirred until complete dissolving; after the addition was is complete the mixture was is cooled in an ice bath, followed by stirring; and then the crystalline form C was is obtained by filtering and evaporating in the air; or 
 Method 5: Crystalline form E of benfotiamine was is suspended in an organic solvent, followed by stirring using a magnetic stirrer for at least 24 h, and then the crystalline form D was is obtained by filtering and evaporating in the air. 
 
     
     
       18. The process for preparing crystalline polymorphs of benfotiamine obtained by the process of  claim 17 , wherein the organic solvent includes at least one member selected from the group including consisting of methanol, ethanol, isopropanol, pentanol, acetone, 2-butanone, tetrahydrofuran, nitromethane, acetonitrile, chloroform, dichloromethane, methyl tertbutyl ether and mixtures thereof. 
     
     
       19. A pharmaceutical composition comprising a therapeutically effective amount of crystalline benfotiamine according to  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
       20. The pharmaceutical composition of  claim 19 , wherein excipients comprise at least one member selected from fillers, disintegrants, binders, lubricants and mixtures thereof. 
     
     
       21. The pharmaceutical composition of  claim 20 , wherein fillers comprise at least one member selected from starch, lactose, crystalline cellulose, dextrin, mannitol, oxidase, calcium sulfate and mixtures thereof. 
     
     
       22. The pharmaceutical composition of  claim 20 , wherein disintegrants comprise at least one member selected from carboxymethylcellulose and its salt, crosslinked carboxymethylcellulose and its salt, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose and mixtures thereof. 
     
     
       23. The pharmaceutical composition of  claim 20 , wherein binders comprise at least one member selected from polyvinylpyrrolidone, hydroxypropyl methyl cellulose, starch slurry and mixtures thereof. 
     
     
       24. The pharmaceutical composition of  claim 20 , wherein lubricants comprise at least one member selected from magnesium stearate, calcium stearate and mixtures thereof.