Crystal form of dezocine and preparation method therefor

Abstract

Disclosed is a crystal form of dezocine. The X-ray powder diffraction (XRD) pattern thereof is determined using Cu/K-1 and has diffraction peaks at the 2 value of 9.10.2 and 12.20.2, with the height % of these diffraction peaks greater than 20. Also disclosed are a preparation method for the crystal form, a pharmaceutical composition and use thereof. The crystal form of dezocine has good solubility, the preparation method has simple operations, good reproducibility, suitability for industrial production and the like.

Claims

1. A crystal form of dezocine, wherein the X-ray powder diffraction (XRD) pattern of the crystal form of dezocine is determined using Cu/K-al and has diffraction peaks at 2 value of 9.10.2, 12.20.2, 13.00.2, 13.60.2, 14.00.2, 14.70.2, 15.20.2, 19.60.2, 23.10.2, 24.4.40.2, and 27.20.2, with the height % of the diffraction peaks greater than 20.

2. The crystal form of dezocine according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form of dezocine is determined using Cu/K-1, and has the following diffraction peak profile: TABLE-US-00008 Peak number 2 d value Height % Area % FWHM 1 9.100 9.7102 51.4 66.1 0.460 2 12.161 7.2716 100.00 100.0 0.358 3 13.008 6.8003 23.0 9.2 0.143 4 13.556 6.5265 41.8 22.3 0.191 5 13.973 6.3329 52.2 26.2 0.179 6 14.743 6.0038 98.7 72.5 0.263 7 15.197 5.8252 56.3 44.9 0.285 8 16.656 5.3183 4.2 2.5 0.208 9 17.051 5.1958 7.7 3.9 0.183 10 18.118 4.8923 12.1 9.2 0.271 11 18.452 4.8043 14.7 17.4 0.424 12 19.186 4.6222 13.0 9.7 0.266 13 19.598 4.5259 19.8 12.8 0.231 14 21.808 4.0720 14.8 8.4 0.202 15 22.675 3.9182 8.1 6.2 0.273 16 23.111 3.8452 74.9 42.2 0.201 17 23.444 3.7914 8.9 7.9 0.318 18 24.355 3.6516 25.5 22.9 0.321 19 24.865 3.5779 6.9 5.9 0.307 20 25.580 3.4794 6.0 4.7 0.276 21 27.159 3.2807 19.9 12.4 0.223 22 27.549 3.2351 3.0 3.6 0.425 23 28.043 3.1792 4.5 4.2 0.337 24 28.281 3.1530 5.6 3.7 0.236 25 29.859 2.9899 1.8 1.1 0.215 26 30.274 2.9498 5.9 5.1 0.311 27 30.773 2.9031 2.6 2.1 0.281 28 31.635 2.8259 1.2 0.6 0.178 29 32.467 2.7554 2.7 2.1 0.275 30 33.201 2.6962 1.6 0.5 0.108 31 33.865 2.6448 3.7 2.2 0.215 32 34.519 2.5962 1.1 0.8 0.271 33 36.000 2.4927 5.6 4.5 0.286 34 37.715 2.3832 5.4 4.6 0.310 35 39.298 2.2908 3.3 1.5 0.158.

3. The crystal form of dezocine according to claim 1, wherein a DSC test of the crystal form of dezocine shows an endothermic peak near 168.40 C.

4. The crystal form of dezocine according to claim 1, wherein IR data characteristics of the crystal form of dezocine is substantially as shown in FIG. 3.

5. The crystal form of dezocine according to claim 1, wherein TGA data characteristics of the crystal form of dezocine is substantially as shown in FIG. 4.

6. A preparation method for the crystal form of dezocine according to claim 1, comprising the following steps of: 1) under heating, dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble; 2) precipitating crystals by cooling and heat keeping, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

7. The preparation method according to claim 6, wherein the solvent A is selected from one or both of dioxane and ethyl acetate, and is optionally dioxane.

8. The preparation method according to claim 6, wherein the solvent B is selected from one or more of acetonitrile, toluene, petroleum ether, and ethyl ether, and is optionally petroleum ether.

9. The preparation method according to claim 6, wherein, the ratio of the amount of the solvent A to the amount of dezocine in step 1) is dissolving 1 gram of dezocine in 1 ml to 30 ml, optionally in 2 ml to 10 ml, of the solvent A; wherein the volume ratio of the solvent A to the solvent B is 1:0.3 to 1:10, optionally 1:1 to 1:2.5.

10. The preparation method according to claim 6, wherein the temperature for dissolving under heating in step 1) is 30 C. to 100 C., optionally 70 C. to 80 C.

11. The preparation method according to claim 6, wherein the temperature for precipitating by cooling in step 2) is 0 C. to 20 C., optionally 0 C. to 10 C.

12. The preparation method according to claim 6, wherein the drying in step 2) is drying under vacuum, and the temperature for the drying is 60 C. to 90 C., optionally 60 C. to 80 C.

13. A preparation method for the crystal form of dezocine according to claim 2, comprising the following steps of: 1) under heating, dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble; 2) precipitating crystals by cooling and heat preservation, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

14. A preparation method for the crystal form of dezocine according to claim 3, comprising the following steps of: 1) under heating, dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble; 2) precipitating crystals by cooling and heat preservation, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

15. A preparation method for the crystal form of dezocine according to claim 4, comprising the following steps of: 1) under heating, dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble; 2) precipitating crystals by cooling and heat preservation, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

16. A preparation method for the crystal form of dezocine according to claim 5, comprising the following steps of: 1) under heating, dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble; 2) precipitating crystals by cooling and heat preservation, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1a shows the XRD pattern of the new crystal form of dezocine according to Example 1 of the present application.

(2) FIG. 1b shows the XRD pattern of the sample obtained from Example 1 of the Patent No. CN102503840A.

(3) FIG. 2a shows the DSC pattern of the new crystal form of dezocine according to Example 1 of the present application.

(4) FIG. 2b shows the DSC pattern of the sample obtained from Example 1 of the Patent NO. CN102503840A.

(5) FIG. 3 shows the IR pattern of the new crystal form of dezocine according to Example 1 of the present application.

(6) FIG. 4 shows the TGA pattern of the new crystal form of dezocine according to Example 1 of the present application.

DETAILED DESCRIPTION

(7) In one embodiment of the present application, there is provided a new crystal form of dezocine, the X-ray powder diffraction pattern of the new crystal form is determined using Cu/K-1 and has diffraction peaks at 2 value of 9.10.2 and 12.20.2, with the height % of these diffraction peaks greater than 20.

(8) In one embodiment of the present application, there is provided a new crystal form of dezocine, the X-ray powder diffraction pattern of the new crystal form of dezocine is determined using Cu/K-1, and may have diffraction peaks at 2 value of 9.10.2, 12.20.2, 13.60.2, and 23.10.2, with the height % of these diffraction peaks greater than 20. In one embodiment of the present application, there is provided a new crystal form of dezocine, the X-ray powder diffraction pattern of the new crystal form of dezocine is determined using Cu/K-1, and may have diffraction peaks at 2 value of 9.10.2, 12.20.2, 13.00.2, 13.60.2, 14.00.2, 14.70.2, 15.20.2, 19.60.2, 23.10.2, 24.40.2, and 27.20.2, with the height % of these diffraction peaks greater than 20.

(9) In one embodiment of the present application, there is provided a new crystal form of dezocine, the X-ray powder diffraction pattern of the new crystal form of dezocine is determined using Cu/K-1, and may have the following diffraction peak profile:

(10) TABLE-US-00001 Peak number 2 d value Height % Area % FWHM 1 9.100 9.7102 51.4 66.1 0.460 2 12.161 7.2716 100.00 100.0 0.358 3 13.008 6.8003 23.0 9.2 0.143 4 13.556 6.5265 41.8 22.3 0.191 5 13.973 6.3329 52.2 26.2 0.179 6 14.743 6.0038 98.7 72.5 0.263 7 15.197 5.8252 56.3 44.9 0.285 8 16.656 5.3183 4.2 2.5 0.208 9 17.051 5.1958 7.7 3.9 0.183 10 18.118 4.8923 12.1 9.2 0.271 11 18.452 4.8043 14.7 17.4 0.424 12 19.186 4.6222 13.0 9.7 0.266 13 19.598 4.5259 19.8 12.8 0.231 14 21.808 4.0720 14.8 8.4 0.202 15 22.675 3.9182 8.1 6.2 0.273 16 23.111 3.8452 74.9 42.2 0.201 17 23.444 3.7914 8.9 7.9 0.318 18 24.355 3.6516 25.5 22.9 0.321 19 24.865 3.5779 6.9 5.9 0.307 20 25.580 3.4794 6.0 4.7 0.276 21 27.159 3.2807 19.9 12.4 0.223 22 27.549 3.2351 3.0 3.6 0.425 23 28.043 3.1792 4.5 4.2 0.337 24 28.281 3.1530 5.6 3.7 0.236 25 29.859 2.9899 1.8 1.1 0.215 26 30.274 2.9498 5.9 5.1 0.311 27 30.773 2.9031 2.6 2.1 0.281 28 31.635 2.8259 1.2 0.6 0.178 29 32.467 2.7554 2.7 2.1 0.275 30 33.201 2.6962 1.6 0.5 0.108 31 33.865 2.6448 3.7 2.2 0.215 32 34.519 2.5962 1.1 0.8 0.271 33 36.000 2.4927 5.6 4.5 0.286 34 37.715 2.3832 5.4 4.6 0.310 35 39.298 2.2908 3.3 1.5 0.158

(11) In one embodiment of the present application, there is provided a new crystal form of dezocine, the X-ray powder diffraction pattern of the new crystal form of dezocine is determined using Cu/K-1, which can be substantially as shown in FIG. 1a.

(12) In one embodiment of the present application, there is provided a new crystal form of dezocine, and a DSC test of the new crystal form of dezocine can show an endothermic peak near 168.40 C.

(13) In one embodiment of the present application, there is provided a new crystal form of dezocine, and the characteristics of the DSC pattern of the new crystal form of dezocine can be substantially as shown in FIG. 2a.

(14) In one embodiment of the present application, there is provided a new crystal form of dezocine, and the IR data characteristics of the new crystal form of dezocine can be substantially as shown in FIG. 3.

(15) In one embodiment of the present application, there is provided a new crystal form of dezocine, and the TGA data characteristics of the new crystal form of dezocine may be substantially as shown in FIG. 4.

(16) In another aspect, in another embodiment of the present application, there is provided a preparation method for the new crystal form of dezocine described above, including the following steps of:

(17) 1) under heating, dissolving dezocine in a solvent A in which dezocine has higher solubility, under stirring, then adding another solvent B in which dezocine has lower solubility;

(18) 2) precipitating crystals by cooling and heat keeping, after filtering, collecting the crystals, and drying to obtain the crystal form of dezocine.

(19) As used in the present application, the phrase dissolving dezocine in a solvent A in which dezocine has higher solubility, under stirring, then adding another solvent B in which dezocine has lower solubility (or dissolving dezocine in a solvent A in which dezocine is soluble, under stirring, then adding another solvent B in which dezocine is insoluble) means that two solvents with different solubility for dezocine can be selected, the solvent A in which dezocine has high solubility is firstly used for dissolution, and then the other solvent B in which dezocine has low solubility relative to solvent A is added, the claimed new crystal form of dezocine is thereby precipitated.

(20) Specifically, solvent A in which dezocine has higher solubility (or solvent A in which dezocine is soluble) may be a solvent that dissolves more than 0.1 g of dezocine per milliliter of solvent A; and solvent B in which dezocine has lower solubility (or solvent B in which dezocine is insoluble) may be a solvent that dissolves less than 0.03 g of dezocine per milliliter of solvent B.

(21) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the solvent A in which dezocine has a higher solubility in step 1) can be selected from one or both of dioxane and ethyl acetate.

(22) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the solvent A in which dezocine has a higher solubility in step 1) can be dioxane.

(23) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the solvent B in which dezocine has a lower solubility in step 1) can be selected from one or more of acetonitrile, toluene and petroleum ether.

(24) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the solvent B in which dezocine has a lower solubility in step 1) can be petroleum ether.

(25) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the ratio of the amount of solvent A to the amount of dezocine in step 1) can be dissolving 1 gram of dezocine in 1 ml to 30 ml of solvent A.

(26) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the ratio of the amount of solvent A to the amount of dezocine in step 1) can be dissolving 1 gram of dezocine in 2 ml to 10 ml of solvent A.

(27) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the volume ratio of solvent A to solvent B in step 1) can be 1:0.3 to 1:10.

(28) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the volume ratio of solvent A to solvent B in step 1) can be 1:0.4 to 1:10.

(29) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the volume ratio of solvent A to solvent B in step 1) can be 1:0.5 to 1:10.

(30) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the volume ratio of solvent A to solvent B in step 1) can be 1:1 to 1:2.5.

(31) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the temperature for dissolving under heating in step 1) can be 30 C. to 100 C.

(32) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the temperature for dissolving under heating in step 1) can be 70 C. to 80 C.

(33) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the temperature for precipitating by cooling in step 2) can be 0 C. to 20 C.

(34) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the temperature for precipitating by cooling in step 2) can be 0 C. to 10 C.

(35) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the drying in step 2) is drying under vacuum (0.1 MPa), and the temperature for the drying can be 60 C. to 90 C.

(36) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the drying in step 2) is drying under vacuum (0.1 MPa), and the temperature for the drying can be 60 C. to 80 C.

(37) In an embodiment of the present application, in the preparation method for the new crystal form of dezocine, the dezocine used in step 1) can be prepared by the method according to the Patent No. CN102503840A.

(38) In the third aspect, the present application provides a pharmaceutical composition including the new crystal form of dezocine described above. For the administration mode and dosage of the pharmaceutical composition, the teaching in U.S. Pat. No. 4,001,331 can be referred to.

(39) In the fourth aspect, the present application provides use of the new crystal form of dezocine or a pharmaceutical composition thereof described above in analgesics.

(40) Hereinafter, the technical solution of the present application will be further explained by specific Examples, in order to enable those skilled in the art to better understand the application, but the scope of protection of the present application is not limited thereto.

(41) The dezocine used in Examples is prepared according to the method of Example 1 in Patent No. CN102503840A.

(42) XRD Test Conditions:

(43) Equipment model: BrukerD8advance, Germany; X-ray tube: Cu tube; radiation used: K (1); voltage and current of generator: 40 kV and 40 mA; step size: 0.02; scanning speed: 0.5 s/time; scanning range: 3-40;

(44) DSC Test Conditions:

(45) Equipment model: TA Q200; equilibrium temperature: 25 C.; temperature rise condition:

(46) the temperature rises to 250 C. at a rate of 10 C./min; nitrogen flow rate: 40 ml/min; aluminum dish, cover;

(47) IR Test Conditions:

(48) Equipment model: Bruker Tensor 27; KBr pellet; scanning range: 4000-400 cm.sup.1;

(49) TGA Test Conditions:

(50) Equipment model: NETZSCH TG 209; temperature rise rate: 10 C./min; temperature range: 30-250 C.; crucible material: Al.sub.2O.sub.3.

Example 1

(51) To a clean 50 ml reaction flask, 2 g of dezocine and 7.5 ml of dioxane were added, after heating to 80 C. with stirring for complete dissolution, 7.5 ml of acetonitrile was added, cooled to about 5 C. and precipitated for 2 h, filtered to obtain a solid, dried at 80 C. under vacuum to give 1.7 g of dry dezocine with a yield of 85%. The XRD pattern of the crystal form of dezocine is determined as shown in FIG. 1a, the DSC pattern is as shown in FIG. 2a, the IR pattern is as shown in FIG. 3, and the TGA pattern is as shown in FIG. 4.

Example 2

(52) To a clean 50 ml reaction flask, 2 g of dezocine and 9 ml of dioxane were added, after heating to 60 C. with stirring for complete dissolution, 6 ml of petroleum ether was added, cooled to about 5 C. and precipitated for 2 h, filtered to obtain a solid, dried at 60 C. under vacuum to give 1.9 g of dry dezocine with a yield of 95%.

Example 3

(53) To a clean 50 ml reaction flask, 2 g of dezocine and 15 ml of ethyl acetate were added, after heating to 60 C. with stirring for complete dissolution, 6 ml of petroleum ether was added, cooled to about 15 C. and precipitated for 2 h, filtered to obtain a solid, dried at 80 C. under vacuum to give 1.3 g of dry dezocine with a yield of 65%.

Example 4

(54) To a clean 50 ml reaction flask, 2 g of dezocine and 15 ml of ethyl acetate were added, after heating to 65 C. with stirring for complete dissolution, 10 ml of toluene was added, cooled to about 10 C. and precipitated for 2 h, filtered to obtain a solid, dried at 70 C. under vacuum to give 1.6 g of dry dezocine with a yield of 80%.

Example 5

(55) To a clean 50 ml reaction flask, 2 g of dezocine and 9 ml of dioxane were added, after heating to 75 C. with stirring for complete dissolution, 15 ml of toluene was added, cooled to about 5 C. and precipitated for 2 h, filtered to obtain a solid, dried at 90 C. under vacuum to give 1.4 g of dry dezocine with a yield of 70%.

(56) The typical XRD pattern of the crystal form of dezocine obtained in Examples of the present application is as shown in FIG. 1a, the DSC pattern is as shown in FIG. 2a, the IR pattern is as shown in FIG. 3, and the TGA pattern is as shown in FIG. 4.

(57) The dezocine crystal obtained in the Patent No. CN102503840A (hereinafter referred to as crystal form I of dezocine) is tested in the present application, its X-ray powder diffraction pattern is determined using Cu/K-1, as shown in FIG. 1b, and has the following diffraction peak profile:

(58) TABLE-US-00002 Peak number 2 d value Height % Area % FWHM 1 9.750 9.0639 3.5 3.6 0.148 2 10.398 8.5007 8.4 8.4 0.147 3 11.585 7.6319 16.4 17.0 0.152 4 13.008 6.8000 75.1 74.6 0.145 5 14.150 6.2537 100.0 100.0 0.146 6 14.604 6.0606 5.9 6.6 0.164 7 15.688 5.6439 38.6 28.7 0.109 8 16.615 5.3313 6.6 9.7 0.215 9 17.188 5.1548 4.5 3.8 0.122 10 17.938 4.9408 3.8 5.4 0.212 11 18.200 4.8704 5.5 6.3 0.166 12 18.888 4.6945 9.4 11.8 0.185 13 19.403 4.5710 3.7 4.3 0.173 14 19.773 4.4863 19.7 26.4 0.196 15 20.918 4.2433 27.1 31.8 0.172 16 21.531 4.1238 27.1 32.5 0.175 17 22.399 3.9659 7.9 6.6 0.122 18 23.798 3.7358 26.4 48.9 0.271 19 24.173 3.6787 4.3 5.9 0.202 20 24.828 3.5831 2.6 2.6 0.150 21 25.302 3.5171 4.9 7.5 0.222 22 25.950 3.4307 4.9 13.8 0.410 23 26.286 3.3876 16.2 25.6 0.231 24 26.564 3.3528 4.3 8.1 0.273 25 27.827 3.2034 3.2 3.9 0.179 26 29.958 2.9802 4.3 7.9 0.272 27 31.024 2.8802 11.4 19.0 0.244 28 31.657 2.8240 8.6 10.9 0.187 29 32.818 2.7267 5.4 6.2 0.168 30 33.548 2.6691 0.7 1.5 0.304 31 34.615 2.5892 2.2 2.7 0.180 32 35.029 2.5595 2.1 3.5 0.240 33 35.526 2.5248 5.3 5.2 0.143 34 36.431 2.4642 2.1 2.9 0.208 35 36.851 2.4371 0.8 1.1 0.203 36 37.850 2.3750 2.9 7.1 0.359 37 38.362 2.3444 2.2 5.3 0.348 38 39.471 2.2811 1.7 1.8 0.154

(59) After solubility and stability tests, the inventors surprisingly found that the solubility and stability of the new crystal form of dezocine of the present application (hereinafter referred to as crystal Form II of dezocine) are significantly better than those of crystal Form I of dezocine.

(60) i. Compared with the sample of crystal Form I of dezocine, the new crystal form of dezocine according to the present application has better solubility in 0.1 mol/L hydrochloric acid solution, and the solubility is increased by about 32%, as shown in the following table:

(61) TABLE-US-00003 Amount Amount Sample of sample of solvent Solubility Crystal Form II of dezocine 50 mg 1.5 ml 0.033 g/ml Crystal Form I of dezocine 50 mg 2.0 ml 0.025 g/ml

(62) ii. Compared with the sample of crystal Form I of dezocine, the content of related substances in the new crystal Form of dezocine according to the present application is lower, as shown in the following table for details:

(63) TABLE-US-00004 Crystal Form Example Example Example Example Example Sample I 1 2 3 4 5 Related 0.08% 0.06% 0.07% 0.04% 0.06% 0.04% substances

(64) iii. Compared with the sample of crystal Form I of dezocine, the new crystal form of dezocine prepared according to the present application has better stability, and changes of the related substances within the new crystal form of dezocine over 6 months are as follows:

(65) TABLE-US-00005 Sample 0 days 1 month 3 months 6 months Crystal Form I 0.08% 0.15% 0.21% 0.28% of dezocine Example 1 0.06% 0.07% 0.10% 0.13% Example 2 0.07% 0.09% 0.10% 0.12% Example 3 0.04% 0.05% 0.8% 0.10% Example 4 0.06% 0.08% 0.10% 0.12% Example 5 0.04% 0.06% 0.07% 0.09%

(66) iv. Compared with the sample of crystal Form I of dezocine, the new crystal form of dezocine prepared according to the present application has better stability, and changes of the content of impurity B over 6 months are as follows:

(67) TABLE-US-00006 Sample 0 days 1 month 3 months 6 months Crystal Form I 0.03% 0.04% 0.04% 0.05% of dezocine Example 1 Not detected Not detected Not detected Not detected Example 2 Not detected Not detected Not detected Not detected Example 3 Not detected Not detected Not detected Not detected Example 4 Not detected Not detected Not detected Not detected Example 5 Not detected Not detected Not detected Not detected

(68) v. Crystal Form I of dezocine has been refined for many times according to Patent No. CN102503840A, while the content of impurity B is constant, as shown in the following table:

(69) TABLE-US-00007 Crystal Form I Primary Secondary Triple of dezocine refining refining refining Content of 0.03% 0.03% 0.03% 0.03% impurity B

(70) Therefore, the new crystal form of dezocine provided by the present application has better solubility and is beneficial to medication dissolution and absorption by human body; it has better stability and lower content of related substances during storage; meanwhile, the preparation method for the new crystal form has the advantages such as simple operations, good reproducibility, suitability for industrial mass production and the like.