Fenofibrate crystalline form and manufacturing method thereof

Abstract

The present invention relates to Form IV of fenofibrate and its preparation methods thereof. Its X-ray powder diffraction pattern expressed as 2θ angle has characteristic peaks at 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 20.21±0.2°, and 22.87±0.2°. The present invention also provides preparation methods of Form IV. The preparation methods are simple, easy to operate, short, and have good repeatability. The methods are also non-toxic and non-polluting by using water as a medium and using a pharmaceutically accepted excipient, such as polyvinylpyrrolidone or polyvinyl alcohol as an inducer. The results of stability experiments (light exposure, high humidity and grinding) and solubility tests show that Form IV is stable and has a higher solubility than the prior art crystal form.

Claims

1. Form IV of fenofibrate having the structure shown in formula (I) below, ##STR00002## wherein the X-ray powder diffraction pattern of the Form IV of fenofibrate, expressed as 2θ angles, has the following characteristic peaks: 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 20.21±0.2°, and 22.87±0.2°.

2. The Form IV of fenofibrate according to claim 1, wherein the X-ray powder diffraction pattern of the Form IV of fenofibrate, expressed as 2θ angles, has the following characteristic peaks: 7.98±0.2°, 9.82±0.2°, 12.96±0.2°, 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 17.99±0.2°, 18.79±0.2°, 20.21±0.2°, 22.87±0.2°, and 26.17±0.2°.

3. The Form IV of fenofibrate according to claim 2, wherein the X-ray powder diffraction pattern of the Form IV of fenofibrate, expressed as 2θ angles, has the following characteristic peaks with their relative intensities: TABLE-US-00002 2θ Relative intensity % 7.98 13.7 9.82 12.5 12.96 11.1 14.15 50.9 15.94 41.5 16.49 70.4 17.45 60.8 17.99 25.9 18.79 24.8 19.81 23.7 20.21 72.4 22.87 100 23.57 43.9 23.96 22.7 24.48 9.7 24.81 20.0 26.17 33.9 27.31 12.3 28.80 13.5 30.66 23.9 31.22 10.2.

4. The Form IV of fenofibrate according to claim 1, wherein the Fourier transform infrared spectrum of the Form IV of fenofibrate, has characteristic peaks at wave numbers of 2985, 2936, 1737, 1650, 1596, 1499, 1468, 1389, 1314, 1258, 1149, and 1093 cm.sup.−1.

5. A method of preparing the Form IV of fenofibrate according to claim 1, comprising the following steps: mixing Form I of fenofibrate and a polymer material, adding a solvent, stirring and mixing uniformly, heating until melting, cooling to crystallize, filtering, washing the filter cake, drying to obtain the Form IV of fenofibrate; wherein: the polymer material is 1% to 20% by weight of the fenofibrate; and the solvent is a protic solvent.

6. The method of claim 5, wherein the polymer material is polyvinylpyrrolidone or polyethylene glycol.

7. The method of claim 5, wherein the polymer material is 5% to 10% by weight of the fenofibrate.

8. The method of claim 5, wherein the solvent is water.

9. The method of claim 5, wherein the weight to volume ratio of the fenofibrate and the solvent is from 100 mg/mL to 1000 mg/mL.

10. The method of claim 9, wherein the weight to volume ratio of the fenofibrate and the solvent is from 100 mg/mL to 200 mg/mL.

11. The method of claim 5, wherein the melting temperature is from 80° C. to 100° C.

12. The method of claim 11, wherein the melting temperature is from 85° C. to 92° C.

13. The method of claim 5, wherein the cooling crystallization temperature is from −20° C. to 30° C.

14. The method of claim 13, wherein the cooling crystallization temperature is room temperature.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 is the XRPD pattern of fenofibrate Form I.

(2) FIG. 2 is the XRPD pattern of fenofibrate Form IV according to Example 1 of the present invention.

(3) FIG. 3 is the DSC pattern of fenofibrate Form IV according to Example 1 of the present invention.

(4) FIG. 4 is the IR pattern of fenofibrate Form IV according to Example 1 of the present invention.

EXAMPLES

(5) The following examples are provided to illustrate some aspects of the present invention. The examples, however, are not intended to limit the scope of any embodiment of the present invention.

(6) Instrument and Method for Data Collection:

(7) The instrument used for collecting X-ray powder diffraction (XRPD) patterns is Bruker D8 Advance diffractometer. The samples are tested at room temperature under the following conditions: 2θ scan range, 3-40°; step size, 0.02°/step; speed, 0.2 s/step.

(8) Differential scanning calorimetry data are collected on TA Instruments Q200 MDSC. The procedure is as follows: Usually take 1-10 mg sample and heat it to 100° C. under the protection of 40 ml/min dry nitrogen at a heating rate of 10° C./min.

(9) The infrared spectra are collected using Burker Tensor 27 FT-IR. Test method: Making a potassium bromide blank pellet and sample pellets, and then record infrared spectra.

(10) The solubility data are collected using the TU-1901 ultraviolet spectrophotometer at a wavelength of 289 nm.

Example 1

(11) Mixed fenofibrate Form I (100 mg) and polyvinylpyrrolidone PVP K30 (5 mg), added the mixture to water (1.0 mL), heated to 92° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (82 mg, 82% yield).

(12) FIG. 2 is the XRPD pattern of Form IV of fenofibrate. FIG. 3 is the DSC pattern of Form IV of fenofibrate. FIG. 4 is the IR spectrum of Form IV of fenofibrate.

Example 2

(13) Mixed fenofibrate Form I (100 mg) and PVP K40 (2.5 mg), added the mixture to water (1.0 mL), heated to 85° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (80 mg, 80% yield).

Example 3

(14) Mixed fenofibrate Form I (100 mg) and PVP K40 (10 mg), added the mixture to water (1.0 mL), heated to 90° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain of fenofibrate Form IV (86 mg, 86% yield).

Example 4

(15) Mixed fenofibrate Form I (100 mg) and polyethylene glycol 4000 (5 mg), added the mixture to water (1.0 mL), heated to 90° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (88 mg, 88% yield).

Example 5

(16) Mixed fenofibrate Form I (100 mg) and polyethylene glycol 6000 (1 mg), added the mixture to water (1.0 mL), heated to 100° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (75 mg, 75% yield).

Example 6

(17) Mixed fenofibrate Form I (100 mg) and polyethylene glycol 10000 (20 mg), added the mixture to water (1.0 mL), heated to 90° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (81 mg, 81% yield).

Example 7

(18) Mixed fenofibrate Form I (100 mg) and PVP K30 (2 mg), added the mixture to water (0.5 mL), heated to 90° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (81 mg, 81%).

Example 8

(19) Mixed fenofibrate Form I (200 mg) and polyethylene glycol 2000 (2 mg), added the mixture to n-butanol (0.2 mL), heated to 80° C. until fenofibrate was melted in n-butanol to form an emulsion, stirred, cooled to 0° C. until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (50 mg, 25% yield).

Example 9

(20) Mixed fenofibrate Form I (200 mg) and polyethylene glycol 4000 (20 mg), added the mixture to monoethanolamine (0.2 mL), heated to 80° C. until fenofibrate was melted in monoethanolamine to form an emulsion, stirred, cooled to −20° C. until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain of fenofibrate Form IV (74 mg, 37% yield).

Example 10

(21) Placed fenofibrate Form I (100 mg) in water (1.0 mL), heated to 92° C. until fenofibrate was melted in water to form an emulsion, stirred, cooled to 80° C. and added seed crystal of fenofibrate Form IV (1 mg), cooled to room temperature until solids were precipitated, filtered, washed the wet cake using a small amount of water and dried the wet cake under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (75 mg, 75% yield).

Example 11

(22) Dispersed fenofibrate Form I (100 mg) in ethanol (5 mL) to form a suspension, filtered to obtain a saturated solution, added seed crystal of fenofibrate Form IV (1 mg) to the saturated solution, evaporated at room temperature to remove solvent (4 mL) to crystallize, filtered, washed the wet cake using a small amount of water and dried under vacuum at room temperature for 4 hours to obtain fenofibrate Form IV (72 mg, 72% yield). The yield was 72%.

Example 12

(23) Dispersed fenofibrate Form I (100 mg) in ethanol (5 mL) to form a suspension, placed the suspension in a 50° C. water bath and stirred until dissolved, cooled to 40° C. to form a saturated solution, then slowly cooled to 10° C., filtered, washed the wet cake using a small amount of water, dried under vacuum for 4 hours at room temperature to obtain fenofibrate Form IV (51 mg, 51% yield).

(24) XRPD patterns, DSC patterns and IR patterns (not shown) of the products obtained in Examples 2 to 12 were the same or similar as the product obtained in Example 1, indicating the Forms obtained in Examples 2 to 12 were the same as that in Example 1.

Comparative Example 1

(25) Stability experiments, grinding tests and solubility experiments were performed on Form I and Form IV.

(26) Stability experiments: Form IV of fenofibrate and the known Form I were evenly distributed in open petri dishes to form a thin layer with less than 5 mm in thickness, respectively. They were placed at 4500±500 lx light exposure, and 90±5% RH humidity chamber at 25° C., respectively. The XRPD results of the 5th day and 10th day were compared with that of the 0th day. The results shown in Table 1 indicated that neither Form I nor Form IV changed its corresponding pattern.

(27) Grinding tests: placed 100 mg of Form IV of fenofibrate and the known Form I in a ball mill, respectively, grounded for 10 minutes at 20 Hz, compared its XRPD patterns with the unground samples. The results in Table 1 showed that neither Form I nor Form IV changed its corresponding pattern.

(28) Solubility test at room temperature: placed 10 mg of Form IV of fenofibrate and 10 mg of the known Form I in two separate vials. Added 5 mL 0.5% Tween 80 aqueous solution and stirred at room temperature for 1 hours at 120 r/min, filtered, and the filtrates were analyzed by ultraviolet spectrophotometry. The solubility of Form IV and Form I was 0.079 g/L and 0.049 g/L, respectively, i.e., the solubility of Form IV was 1.6 times that of Form I. The result demonstrated that Form IV of the present invention has higher solubility.

(29) TABLE-US-00001 TABLE 1 Stability experiments and grinding tests of Forms of fenofibrate. The results of stability experiments and grinding tests Starting Light exposure High humidity Grinding form for 10 days for 10 days for 10 min Form I Form I Form I Form I Form IV Form IV Form IV Form IV

(30) The results indicate that Form IV of fenofibrate has good stability and its solubility is higher than that of the known Form I.

(31) The described above are only specific embodiments for illustrating the present invention, but without limiting it thereto. Any changes or alternations, without creative work, made by those skilled in the art within the technical scope disclosed by the present invention, should fall within the scope of the present invention. Therefore, the scope of the present invention should be defined by the claims.