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.

Claims

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. 1a in X-ray powder diffraction pattern.

8. The crystalline compound of claim 3, wherein the crystalline form B is fundamentally consistent with FIG. 2a in X-ray powder diffraction pattern.

9. The crystalline compound of claim 4, wherein the crystalline form C is fundamentally consistent with FIG. 3a in X-ray powder diffraction pattern.

10. The crystalline compound of claim 5, wherein the crystalline form D is fundamentally consistent with FIG. 4a in X-ray powder diffraction pattern.

11. The crystalline compound of claim 6, wherein the crystalline form E is fundamentally consistent with FIG. 5a in X-ray powder diffraction pattern.

12. The crystalline compound of claim 2, wherein the crystalline form A is fundamentally consistent with FIG. 1b, 1c, 1d 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. 2b, 2c, 2d 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. 3b, 3c, 3d 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. 4b, 4c, 4d 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. 5b, 5c, 5d 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 suspended in an organic solvent, followed by stirring until complete dissolving, and the crystalline form A then was obtained by evaporated slowly under 25° C.; or Method 2: Crystalline form E of benfotiamine was 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 then added slowly while being stirred, and the crystalline form A was obtained by filtering and evaporating in the air; or Method 3: Crystalline form E of benfotiamine was suspended in an organic solvent, followed by stirring in a hybrid oven for at least 24 h, and the crystalline form B then was obtained by filtering and evaporating in the air; or Method 4: Crystalline form E of benfotiamine was suspended in an organic solvent and the mixture was heated to 60° C. while being stirred until complete dissolving; after the addition was complete the mixture was cooled in an ice bath, followed by stirring; and then the crystalline form C was obtained by filtering and evaporating in the air; or Method 5: Crystalline form E of benfotiamine was suspended in an organic solvent, followed by stirring using a magnetic stirrer for at least 24 h, and then the crystalline form D was 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 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.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1a is a characteristic X-ray Powder Diffraction (XRPD) pattern for crystalline form A of benfotiamine.

(2) FIG. 1b is a characteristic Differential Scanning calorimetry (DSC) thermogram for crystalline form A of benfotiamine.

(3) FIG. 1c is a characteristic infrared spectroscopy (IR) pattern for crystalline form A of benfotiamine.

(4) FIG. 1d is a characteristic raman spectroscopy pattern for crystalline form A of benfotiamine.

(5) FIG. 2a is a characteristic X-ray Powder Diffraction (XRPD) pattern for crystalline form B of benfotiamine.

(6) FIG. 2b is a characteristic Differential Scanning calorimetry (DSC) thermogram for crystalline form B of benfotiamine.

(7) FIG. 2c is a characteristic infrared spectroscopy (IR) pattern for crystalline form B of benfotiamine.

(8) FIG. 2d is a characteristic raman spectroscopy pattern for crystalline form B of benfotiamine.

(9) FIG. 3a is a characteristic X-ray Powder Diffraction (XRPD) pattern for crystalline form C of benfotiamine.

(10) FIG. 3b is a characteristic Differential Scanning calorimetry (DSC) thermogram for crystalline form C of benfotiamine.

(11) FIG. 3c is a characteristic infrared spectroscopy (IR) pattern for crystalline form C of benfotiamine.

(12) FIG. 3d is a characteristic raman spectroscopy pattern for crystalline form C of benfotiamine.

(13) FIG. 4a is a characteristic X-ray Powder Diffraction (XRPD) pattern for crystalline form D of benfotiamine.

(14) FIG. 4b is a characteristic Differential Scanning calorimetry (DSC) thermogram for crystalline form D of benfotiamine.

(15) FIG. 4c is a characteristic infrared spectroscopy (IR) pattern for crystalline form D of benfotiamine.

(16) FIG. 4d is a characteristic raman spectroscopy pattern for crystalline form D of benfotiamine.

(17) FIG. 5a is a characteristic X-ray Powder Diffraction (XRPD) pattern for crystalline form E of benfotiamine.

(18) FIG. 5b is a characteristic Differential Scanning calorimetry (DSC) thermogram for crystalline form E of benfotiamine.

(19) FIG. 5c is a characteristic infrared spectroscopy (IR) pattern for crystalline form E of benfotiamine.

(20) FIG. 5d is a characteristic raman spectroscopy pattern for crystalline form E of benfotiamine.

(21) FIG. 6 is an overlapping pattern of FIG. 1a, 2a, 3a, 4a, and 5a.

(22) FIG. 7 is an overlapping pattern of FIG. 1b, 2b, 3b, 4b, and 5b.

DETAILED DESCRIPTION OF THE INVENTION

(23) The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings.

(24) Laboratory Condition:

(25) X-ray powder diffraction (XRPD) patterns of the polymorphs are measured on a Bruker D2 phaser X-ray powder diffractometer using Cu-Ka radiation at room temperature. The tube voltage and amperage ware set to 40 kV and 40 mA, respectively. A theta-two theta continuous scan at 0.1 sec/step from 3° to 40° 2θ is used.

(26) In a further embodiment, the pattern of crystalline is characteristic in X-ray powder diffraction pattern. The band, especially in low angle, can be slightly changed in the relative intensity depending on crystallization condition, particle size, relative concentration of mixture and other measurement condition. Therefore, the relative intensity of diffraction angle 2θ of the crystalline form is not characteristic. The identification of crystalline form should be determined with the reference to the peak positions, but not their relative intensity. Additionally, the identification of crystalline form should not depend on one single peak, but comprehensive analysis of specific dI/II system. Moreover, during the identification of mixture, some deficiency of peak can occur due to decline in sample concentration. Therefore, it is not necessary to find safe bands appeared in highly pure samples. Even a single band may identify the crystalline form.

(27) Differential Scanning calorimetry (DSC) thermograms of the polymorphs are measured on a DSC8500 (perkinelemer, USA). Analysis conditions were 10° C./min with a nitrogen purge.

(28) Infrared spectroscopy (IR) pattern of the polymorphs are measured on a Nicolot-Magna FT-IR750 (Nicolot-Magna, USA) under room temperature, scanning at 4000-350 cm.sup.−1.

(29) Raman spectroscopy pattern of the polymorphs are measured on DXR (Thermo Scientific, USA) under room temperature, scanning at 3500-50 cm.sup.−1.

Example 1: Preparation of Crystalline Form E of Benfotiamine

(30) Step1: In a glass vial, 135 g of phosphoric acid (85%) was mixed with 155 g of phosphorus pentoxide, followed by stirring until complete dissolving. Then, 100 g of thiamine hydrochloride was added to the mixture, followed by stirring until no gas was observed. Hydrochloric acid was further added dropwise until no gas was observed.

(31) Step2: The resultant mixture was added to acetone. Precipitated crystals were collected by filtration. The resultant thiamine monophosphate was dissolved in water, followed by adding 30% of sodium hydroxide to pH 12. Benzoyl chloride was then added slowly to the mixture, followed by stirring at room temperature for 3 hours. Precipitated crystals were collected by filtration.

(32) Step3: Crystalline form E of benfotiamine was obtained by washing the precipitated crystals formed in step2 with ethanol.

(33) The X-ray power diffraction pattern showed the compound was crystalline form E, as described below:

(34) TABLE-US-00001 TABLE 1 Peak data list for crystalline form E of benfotiamine 2θ° d/A Intensity % 8.545 10.3399 5.1 9.334 9.4673 25.2 10.465 8.4459 7.9 10.893 8.1155 4.6 11.863 7.4539 100 12.633 7.0011 53.2 13.26 6.6717 20.8 13.484 6.5613 22.4 14.395 6.1479 25.7 15.102 5.8615 6.8 15.588 5.6802 26.5 15.891 5.5722 11.9 17.206 5.1492 46.9 18.015 4.92 20.5 18.48 4.7971 5.5 18.948 4.6798 67.4 19.635 4.5175 52.2 20.042 4.4266 16.1 21.276 4.1727 30.8 21.618 4.1073 6.6 22.025 4.0324 24.6 23.703 3.7506 20.5 24.352 3.652 40.8 24.938 3.5676 71.2 26.314 3.3841 60 27.023 3.2968 48.5 27.954 3.1891 9.8 28.358 3.1446 7.5 28.805 3.0969 4.2 29.271 3.0486 7.1 30.828 2.898 14 31.132 2.8704 5.9 31.557 2.8327 8.7 32.083 2.7875 10.5 34.248 2.6161 4.9 35.971 2.4946 4.1 37.507 2.3959 3.9 38.703 2.3246 3.7 39.045 2.305 3.5

(35) The crystalline form E of benfotiamine was measured by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and raman spectroscopy, respectively, as shown in FIG. 5b, 5c, 5d.

Example 2: Preparation of Crystalline Form A of Benfotiamine

(36) In 200 μl of a mixture organic solvent of methanol and chloroform (volume ratio 1:2) was add 3 mg of the crystalline form E of benfotiamine, followed by stirring until complete dissolving. The crystals were collected by evaporating the resultant mixture slowly at 25° C. The X-ray power diffraction pattern showed the compound was crystalline form A, as described below:

(37) TABLE-US-00002 TABLE 2 Peak data list for crystalline form A of benfotiamine 2θ/° d/A Intensity % 8.869 9.9618 14.4 9.212 9.5917 3 10.852 8.1463 6.4 11.317 7.8123 100 12.409 7.1269 2.9 13.665 6.4745 11.5 14.17 6.245 4.1 14.839 5.9651 14.1 15.385 5.7544 4.7 15.711 5.6358 8 16.377 5.4082 19.4 17.086 5.1854 8.5 17.874 4.9585 22.9 18.543 4.7811 26.7 19.313 4.5922 34.3 19.822 4.4753 5.4 20.85 4.2569 26.6 21.295 4.1689 25.2 21.861 4.0622 4.9 22.853 3.8881 12.6 23.441 3.7918 9.4 24.067 3.6946 6.5 24.858 3.5788 26 25.142 3.5391 17 25.505 3.4895 4.3 25.871 3.4411 4.4 26.517 3.3586 3.5 27.631 3.2257 10.3 27.913 3.1937 7.1 28.864 3.0906 10.3 29.39 3.0365 3.2 29.977 2.9783 3.9 30.543 2.9244 4.6 30.949 2.887 5.5 31.82 2.8099 2.9 32.77 2.7306 3.2 34.451 2.6011 4.9

(38) The crystalline form A of benfotiamine was measured by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and raman spectroscopy, respectively, as shown in FIG. 1b, 1c, 1d.

Example 3: Preparation of Crystalline Form A of Benfotiamine

(39) In 200 μl of a mixture organic solvent of methanol and dichloromethane (volume ratio 1:3) was added 10 mg of the crystalline form E of benfotiamine (solubility 50 mg/ml). Then, 1 ml of the poor solvent of ethanol was slowly added to the mixture along device wall. Precipitated crystals were collected by filtration, followed by evaporated in the air. The X-ray power diffraction pattern showed the compound was crystalline form A, as described in table 2.

Example 4: Preparation of Crystalline Form A of Benfotiamine

(40) Crystalline form A of benfotiamine was obtained in the same manner as in Example 3, except the poor solvent was isopropanol. The X-ray power diffraction pattern showed the compound was crystalline form A, as described in table 2.

Example 5: Preparation of Crystalline Form A of Benfotiamine

(41) Crystalline form A of benfotiamine was obtained in the same manner as in Example 3, except the poor solvent was pentanol. The X-ray power diffraction pattern showed the compound was crystalline form A, as described in table 2.

Example 6: Preparation of Crystalline Form A of Benfotiamine

(42) Crystalline form A of benfotiamine was obtained in the same manner as in Example 3, except the poor solvent was 2-butanone. The X-ray power diffraction pattern showed the compound was crystalline form A, as described in table 2.

Example 7: Preparation of Crystalline Form A of Benfotiamine

(43) Crystalline form A of benfotiamine was obtained in the same manner as in Example 3, except the poor solvent was methylbenzene. The X-ray power diffraction pattern showed the compound was crystalline form A, as described in table 2.

Example 8: Preparation of Crystalline Form B of Benfotiamine

(44) 25 mg of crystalline form E of benfotiamine was suspended in 1 ml of methanol, followed by stirring for at least 24 h by a stirrer at 25° C. Then, the precipitated crystals were collected by filtration, followed by evaporated in the air for 10 min. The X-ray power diffraction pattern showed the compound was crystalline form B, as described in table 3.

(45) TABLE-US-00003 TABLE 3 Peak data list for crystalline form B of benfotiamine 2θ/° d/A Intensity % 9.05 9.7636 6.8 11.459 7.7157 100 13.139 6.7326 4.4 15.122 5.8539 9.6 16.276 5.4416 4.2 16.883 5.2472 14 17.693 5.0086 9.4 18.644 4.7553 55.6 19.271 4.6019 9.6 19.699 4.503 5.8 20.222 4.3877 5.3 20.669 4.2938 11.2 21.295 4.169 36 21.821 4.0696 5.9 22.773 3.9016 35.1 24.817 3.5848 11.2 25.728 3.4597 11.2 26.235 3.3941 5.7 26.841 3.3189 5 27.327 3.2609 12.3 28.662 3.1119 7 29.128 3.0632 11.5 31.577 2.831 5.9 32.326 2.7671 2.6 32.975 2.7141 4.5 34.169 2.622 2.4 34.937 2.5661 3.6 37.79 2.3786 2.7 38.417 2.3412 2.1

(46) The crystalline form B of benfotiamine was measured by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and raman spectroscopy, respectively, as shown in FIG. 2b, 2c, 2d.

Example 9: Preparation of Crystalline Form B of Benfotiamine

(47) Crystalline form B of benfotiamine was obtained in the same manner as in Example 8, except the organic solvent was isopropanol. The X-ray power diffraction pattern showed the compound was crystalline form B, as described in table 3.

Example 10: Preparation of Crystalline Form C of Benfotiamine

(48) In 0.5 ml of mixed solution of methanol and dichloromethane (volume ratio 1:1) was added 5 mg of crystalline form E of benfotiamine powder, followed by heating to 60° C. while being stirred until complete dissolving. Then, the resultant mixture was incubated on the ice bath, followed by stirring for 4 h. The resultant mixture may be stored at 4° C. overnight, if there is no precipitate appeared. And then, the precipitated crystals were collected by filtration, followed by evaporated. The X-ray power diffraction pattern showed the compound was crystalline form C, as described in table 4.

(49) TABLE-US-00004 TABLE 4 Peak data list for crystalline form C of benfotiamine 2θ/° d/A Intensity % 8.889 9.9404 15.2 9.496 9.3063 8.2 10.811 8.1766 62.1 11.338 7.7981 84.5 12.692 6.9686 8.8 13.179 6.7123 8.5 13.908 6.3623 17.6 14.516 6.0971 100 15.223 5.8155 13.2 16.984 5.2162 28.2 17.793 4.9809 15 18.684 4.7452 37.3 19.352 4.5829 67.4 20.809 4.2652 26.4 21.336 4.161 62.8 22.854 3.888 35.7 23.276 3.8184 11.3 25.424 3.5005 72.5 27.327 3.2608 7.7 28.561 3.1227 30.4 31.152 2.8686 7.8 33.054 2.7078 10.8

(50) The crystalline form C of benfotiamine was measured by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and raman spectroscopy, respectively, as shown in FIG. 3b, 3c, 3d.

Example 11: Preparation of Crystalline Form C of Benfotiamine

(51) Crystalline form C of benfotiamine was obtained in the same manner as in Example 10, except the organic solvent was a mixture of methanol and dichloromethane (volume ratio 1:2). The X-ray power diffraction pattern showed the compound was crystalline form C, as described in table 4.

Example 12: Preparation of Crystalline Form C of Benfotiamine

(52) Crystalline form C of benfotiamine was obtained in the same manner as in Example 10, except the organic solvent was a mixture of methanol and chloroform (volume ratio 1:2). The X-ray power diffraction pattern showed the compound was crystalline form C, as described in table 4.

Example 13: Preparation of Crystalline Form D of Benfotiamine

(53) In 1 ml of ethanol was added 25 mg of crystalline form E of benfotiamine, followed by stirring at 25° C. by a stirrer for at least 24 h. The precipitated crystals were collected by filtration, followed by evaporated in the air for 10 min. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

(54) TABLE-US-00005 TABLE 5 Peak data list for crystalline form D of benfotiamine 2θ/° d/A Intensity % 6.843 12.9057 2.7 9.032 9.7828 4.3 9.353 9.448 3.7 10.69 8.2692 29.6 11.033 8.0124 100 11.743 7.53 6.8 12.431 7.1145 5.2 13.766 6.4273 7.7 14.414 6.1399 31.6 15.365 5.7619 22.8 15.952 5.5511 21.2 16.924 5.2345 5.8 17.308 5.1192 9.5 18.118 4.8922 5.7 18.725 4.7349 21.5 19.31 4.5927 12.4 19.797 4.4809 13 21.032 4.2205 14.3 21.256 4.1765 13.6 22.896 3.881 9.9 24.35 3.6523 30.6 25.081 3.5476 15.5 25.323 3.5142 26.5 27.044 3.2943 6.3 28.318 3.1489 14.5 30.606 2.9185 4.5

(55) The crystalline form D of benfotiamine was measured by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and raman spectroscopy, respectively, as shown in FIG. 4b, 4c, 4d.

Example 14: Preparation of Crystalline Form D of Benfotiamine

(56) Crystalline form D of benfotiamine was obtained in the same manner as in Example 13, except the organic solvent was pentanol. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

Example 15: Preparation of Crystalline Form D of Benfotiamine

(57) Crystalline form D of benfotiamine was obtained in the same manner as in Example 13, except the organic solvent was acetone. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

Example 16: Preparation of Crystalline Form D of Benfotiamine

(58) Crystalline form D of benfotiamine was obtained in the same manner as in Example 13, except the organic solvent was 2-butanone. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

Example 17: Preparation of Crystalline Form D of Benfotiamine

(59) Crystalline form D of benfotiamine was obtained in the same manner as in Example 13, except the organic solvent was tetrahydrofuran. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

Example 18: Preparation of Crystalline Form D of Benfotiamine

(60) Crystalline form D of benfotiamine was obtained in the same manner as in Example 13, except the organic solvent was nitromethane. The X-ray power diffraction pattern showed the compound was crystalline form D, as described in table 5.

Example 19: Hygroscopicity Comparisons Among Four Crystalline Forms of Benfotiamine

(61) Dynamic vapor sorption analysis was used for measurement of the hygroscopicity of crystalline form A, C, D, and E under the scope of relative humidity (RH) from 5% to 95%. It indicated that hygroscopicity of the four crystalline forms was all under 2.0%, wherein the crystalline form E has the lowest hygroscopicity, and the crystalline form D has the highest hygroscopicity.

(62) As used herein “basically pure” is that the crystals of the present invention preferably contains 90% or more of a crystalline substance, more preferably 95% or more, further preferably 96% or more, more further preferably 97% or more, especially preferably 98% or more, most preferably 99% or more of a crystalline substance, which used in X-ray powder diffraction (XRPD), raman spectroscopy, infrared spectroscopy (IR).