CRYSTAL OF CYCLIC PEPTIDE COMPOUND, PREPARATION METHOD FOR SAME AND USES THEREOF
20170198013 ยท 2017-07-13
Inventors
- Shidong Liu (Shanghai, CN)
- Xiusheng WANG (Shanghai, CN)
- Jicheng Hu (Shanghai, CN)
- Xiaoming Ji (Shanghai, CN)
Cpc classification
C07K7/56
CHEMISTRY; METALLURGY
A61K38/12
HUMAN NECESSITIES
International classification
Abstract
Disclosed is a novel polymorph of a cyclic peptide compound, the structure whereof is represented by formula I; also disclosed are a preparation method for same and uses thereof.
##STR00001##
Claims
1. Crystal A of a cyclic peptide compound, the structure of which is shown in formula I, wherein said crystal A has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 3.60.2, 6.40.2, 6.80.2, 9.50.2; ##STR00004##
2. The crystal A of a cyclic peptide compound according to claim 1, wherein said crystal A has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 7.50.2, 11.00.2, 12.40.2.
3. The crystal A of a cyclic peptide compound according to claim 2, wherein said crystal A has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 13.40.2, 20.20.2.
4. Crystal B of a cyclic peptide compound, the structure of which is shown in formula I, wherein said crystal B has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.40.2, 5.20.2, 8.50.2, 9.60.2; ##STR00005##
5. The crystal B of a cyclic peptide compound according to claim 4, wherein said crystal B has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 7.50.2, 8.80.2, 16.60.2, 13.70.2, 22.50.2.
6. The crystal B of a cyclic peptide compound according to claim 5, wherein said crystal B has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 12.60.2, 14.90.2, 15.60.2, 25.10.2.
7. Crystal C of a cyclic peptide compound, the structure of which is shown in formula I, wherein said crystal C has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.50.2, 5.30.2, 8.60.2, 9.60.2; ##STR00006##
8. A preparation method for crystal A of the cyclic peptide compound according to claim 1, comprising the steps of: (a) dissolving the compound of formula I in an aqueous mixed solution of alcohols; (b) obtaining crystal A of the cyclic peptide compound according to claim 1 by reducing the temperature and/or adding an organic solvent (i).
9. The preparation method according to claim 8, wherein the mixed solution of alcohols in step (a) is selected from a group consisting of methanol/isobutanol, methanol/isopropanol, and methanol/n-propanol.
10. The preparation method according to claim 9, wherein, in the aqueous mixed solution of alcohols in step (a), the volume ratio of the two alcohols is 0.01-100, preferably 0.05-20, more preferably 0.1-10.
11. The preparation method according to claim 8, wherein, in the aqueous mixed solution of alcohols in step (a), the ratio of total volume of the alcohol to the volume of water is 0.1 to 100, preferably 0.5 to 10, more preferably 1 to 7.
12. The preparation method according to claim 8, wherein, in step (b), the organic solvent (i) is selected from a group consisting of n-propanol, isopropanol, isobutanol, methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.
13. The preparation method according to claim 8, wherein, in step (b), the temperature is reduced to 40 to 35 C., preferably 20 to 35 C., more preferably 10 to 30 C., most preferably 5 to 15 C.
14. The preparation method according to claim 8, wherein the volume ratio of organic solvent (i) in step (b) to the aqueous mixed solution of alcohols in step (a) is 0.1 to 50, preferably 0.1 to 10, and more preferably 1-5.
15. A preparation method for crystal B of the cyclic peptide compound according to claim 4, comprising the steps of: vacuum-drying crystal A of a cyclic peptide compound, the structure of which is shown in formula I, wherein said crystal A has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 3.60.2, 6.40.2, 6.80.2, 9.50.2; ##STR00007## together with a water system and controlling the content of water, thereby obtaining crystal B of the cyclic peptide compound according to claim 4.
16. The preparation method according to claim 15, wherein the water system is selected from a group consisting of tap water, pure water, ice-water mixture, and other substances capable of releasing water vapor.
17. The preparation method according to claim 15, wherein the content of water is controlled at 4%-22%, thereby obtaining crystal B of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal B has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.40.2, 5.20.2, 8.50.2, 9.60.2; ##STR00008##
18. A preparation method for crystal C of the cyclic peptide compound according to claim 7, comprising the step of: vacuum-drying crystal B of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal B has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.40.2, 5.20.2, 8.50.2, 9.60.2; ##STR00009## and controlling the content of water, thereby obtaining crystal C of the cyclic peptide compound according to claim 7.
19. The preparation method according to claim 18, wherein the content of water is controlled at less than 4%, thereby obtaining crystal C of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal C has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.50.2, 5.30.2, 8.60.2, 9.60.2; ##STR00010##
20. Use of the crystals of the cyclic peptide compound according to claim 1 in the manufacture of a medicament for treating fungal infections.
21. A pharmaceutical composition comprising the crystals of the cyclic peptide compound according to claim 1 and a pharmaceutically acceptable carrier.
22. A preparation method for the pharmaceutical composition according to claim 21, comprising the step of: mixing the crystals of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal A has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 3.60.2, 6.40.2, 6.80.2, 9.50.2; ##STR00011## and a pharmaceutically acceptable carrier, thereby obtaining the pharmaceutical composition according to claim 21.
23. A composition of a cyclic peptide compound, wherein the composition comprises one or more crystals selected from a group consisting of crystal A of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal A has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 3.60.2, 6.40.2, 6.80.2, 9.50.2; ##STR00012## Formula I; crystal B of a cyclic peptide compound; the structure of which is shown in formula I, wherein said crystal B has characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.40.2, 5.20.2, 8.50.2, 9.60.2; ##STR00013## crystal C of the cyclic peptide compound according to claim 7.
24. The crystal B of a cyclic peptide compound according to claim 4, wherein said crystal B has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 4.40.1, 5.20.1, 8.50.1, 9.60.1.
25. The crystal B of a cyclic peptide compound according to claim 24, wherein said crystal B has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 7.50.1, 8.80.1, 16.60.1, 13.70.1, 22.50.1.
26. The crystal B of a cyclic peptide compound according to claim 25, wherein said crystal B has additional characteristic peaks at the following 2 angles in the X-ray power diffraction pattern (XRPD): 12.60.1, 14.90.1, 15.60.1, 25.10.1.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0095]
TABLE-US-00001 Number of peak 2 d(A) I % (Relative Intensity) 1 3.6 24.7974 100.0 2 6.4 13.7127 84.0 3 6.8 12.9885 42.9 4 7.5 11.7774 14.0 5 9.4 9.3605 42.8 6 10.8 8.1551 15.5 7 12.4 7.1206 15.8 8 13.6 6.5156 16.7 9 20.4 4.3580 24.6
[0096]
[0097]
TABLE-US-00002 Number of peak 2 d(A) I % (Relative Intensity) 1 4.4 19.8888 100.0 2 5.2 17.0426 46.0 3 7.5 11.8100 20.3 4 8.5 10.3938 55.2 5 8.8 10.0411 46.5 6 9.6 9.2244 69.7 7 12.6 7.0200 19.3 8 13.7 6.4581 25.4 9 14.9 5.9329 20.4 10 15.7 5.6400 25.4 11 16.7 5.3169 41.9 12 22.5 3.9443 43.0 13 25.1 3.5395 38.0
[0098]
TABLE-US-00003 Number of peak 2 d(A) I % (Relative Intensity) 1 4.4 20.1588 100.0 2 5.1 17.2445 49.4 3 7.4 11.9038 24.8 4 8.4 10.5159 54.1 5 8.7 10.1314 83.6 6 9.5 9.3212 66.8 7 12.6 7.0423 25.9 8 13.6 6.4868 31.3 9 14.8 5.9638 24.6 10 15.5 5.7043 26.0 11 16.6 5.3426 52.3 12 22.4 3.9724 51.0 13 25.0 3.5535 46.1
[0099]
[0100]
TABLE-US-00004 Number of peak 2 d(A) I % (Relative Intensity) 1 4.5 19.7047 100.0 2 5.2 16.8487 40.0 3 8.5 10.3453 33.1 4 9.6 9.2051 37.3
[0101]
[0102]
[0103]
MODE FOR CARRYING OUT THE INVENTION
[0104] The invention will be further illustrated with reference to the following specific examples. It is to be understood that these examples are only intended to illustrate the invention, but not to limit the scope of the invention. In the following examples, the experimental methods without articulating specific experimental conditions are performed under routine conditions or as instructed by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions or parts are by weight.
[0105] The unit of the weight/volume percentages in the invention is well known to the skilled in the art, for example, the weight of a solute in a 100 mL solution.
[0106] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by the skilled in the art. Furthermore, any process or material similar or equivalent to those described herein can be used in the process of the present invention. The preferred embodiments and materials described herein are merely provided for illustration.
[0107] In the following Comparative Examples and Examples, residual solvent in the crystal was determined by GC (Gas Chromatography) according to the second method in Appendix VIIIP of Part II of Chinese Pharmacopoeia (2010 edition), wherein the column used was a capillary chromatography column with polyethylene glycol as stationary phase; the initial temperature was 40 C. for 5 min, raised to 60 C. at 5 C./min, and further raised to 240 C. at 30 C./min for 3 min; the temperature at the inlet was 200 C.; the temperature at the detector was 260 C.; the equilibrium temperature of headspace bottle was 120 C.; and the equilibrium time was 20 min.
COMPARATIVE EXAMPLE 1
[0108] Preparation of the Crystal of B82 Type
[0109] Needle-like crystals, i.e., crystals of B82 type, were obtained according to the method of Example 1 of WO03/018615. The total amount of residual solvent in the crystal of B82 type was determined as 72.8% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 1
[0110] Preparation of Compound
[0111] The solid amorphous powder of the compound of formula I was prepared according to the method of U.S. Pat. No. 7,199,248, and the X-ray powder diffraction pattern thereof is shown in
EXAMPLE 2
[0112] Preparation of Crystal A of the Compound of Formula I
[0113] At 25 C., 1 g of the compound of formula I in amorphous form prepared in Example 1 was dissolved into 50 ml of an aqueous methanollisobutanol solution (isobutanol:water:methanol=8:2:1). The resultant solution was slowly cooled to 8 C., crystals precipitated from the solution. The system was stirred for 3.5 hours at this temperature, so that a large amount of crystals precipitated. 90 ml of ethyl acetate were slowly added, and the crystals were sampled before filtration and observed under a microscope (1540), photograph of which can be found in
EXAMPLE 3
[0114] Preparation of Crystal A of the Compound of Formula I
[0115] At 30 C., 2.5 g of the crystals of B82 type prepared in Comparative Example 1 were dissolved into 50 ml of an aqueous methanollisobutanol solution (isobutanol:water:methanol=1:1:1), 50 ml of methyl acetate were slowly added, and crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 28.4% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 4
[0116] Preparation of Crystal A of the Compound of Formula I
[0117] At 10 C., 3 g of the compound of formula 1 in amorphous form prepared in Example 1 were dissolved into 600 ml of an aqueous methanol/isobutanol solution (isobutanol:water:methanol=5:1:2), the resultant solution was cooled to 20 C., crystals precipitated from the solution, and the system was stirred for 12 hours, so that a large amount of crystals precipitated. Crystal A was obtained by filtration, and the total amount of residual solvent in crystal A was determined as 25.1% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 5
[0118] Preparation of Crystal A of the Compound of Formula I
[0119] At 50 C., 3 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 1.20 ml of an aqueous methanoliisopropanol solution (isopropanol:water:methanol=1:4:1), the resultant solution was cooled to 30 C., crystals precipitated from the solution, and the system was stirred for 30 mins, so that a large amount of crystals precipitated. 200 ml of isopropanol were slowly added, and crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 27.1% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 6
[0120] Preparation of Crystal A of the Compound of Formula I
[0121] At 20 C. 1 g of the compound of formula I in amorphous form prepared in Example 1 was dissolved into 20 ml of an aqueous methanol/isopropanol solution (isopropanol:water:methanol=10:2:1), 200 ml of n-propyl acetate were slowly added, and crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 26.9% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 7
[0122] Preparation of Crystal A of the Compound of Formula I
[0123] At 18 C., 1.0 g of the compound of formula in amorphous form prepared in Example 1 was dissolved into 100 ml of an aqueous methanol isopropanol solution (isopropanol:water:methanol=1:2:20), the resultant solution was cooled to 5 C., crystals precipitated from the solution, and the system was stirred for 4 hours, so that a large amount of crystals precipitated. Crystal A was obtained by filtration, and the total amount of residual solvent in crystal A was determined as 33.4% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 8
[0124] Preparation of Crystal A of the Compound of Formula I
[0125] At 30 C., 2 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 20 ml of an aqueous methanol/n-propanol solution (n-propanol:water:methanol=1:15:10), the resultant solution was cooled to 15 C., crystals precipitated from the solution, and the system was stirred for 2 hours, so that a large amount of crystals precipitated. 100 ml of isopropyl acetate were slowly added, and crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 32.0% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 9
[0126] Preparation of Crystal A of the Compound of Formula I
[0127] At 25 C., 4 of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 300 ml of an aqueous methanotin-propanol solution (n-propanol:water:methanol=20:2:1), 30 ml of isobutanol were slowly added, and crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 35.1% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 10
[0128] Preparation of Crystal A of the Compound of Formula I
[0129] At 40 C., 2.7 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 80 ml of an aqueous methanolin-propanol solution (n-propanol:water:methanol=10:3:1), the resultant solution was cooled to 10 C., crystals precipitated from the solution, and the system was stirred for 1 hour, so that a large amount of crystals precipitated. Crystal A was obtained by filtration. The total amount of residual solvent in crystal A was determined as 30.0% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 11
[0130] Preparation of Crystal B of the Compound of Formula I
[0131] At 20 C., 1.5 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 70 ml of an aqueous methanol/isobutanol solution (isobutanol:water:methanol=8:2:1), the resultant solution was cooled to 0 C., crystals precipitated from the solution, and the system was stirred for 4.5 hours, so that a large amount of crystals precipitated. 100 ml of ethyl acetate were slowly added, and crystal A was obtained by filtration. The obtained crystals were placed into a vacuum-dryer, and a plate of pure water was put on the bottom of the vacuum-dryer. The content of water was controlled at 17.9%, and crystal B was obtained by vacuum-drying. The XRPD pattern and IR spectrum of crystal B are shown in
EXAMPLE 12
[0132] Preparation of Crystal B of the Compound of Formula I
[0133] At 35 C., 2.3 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 100 ml of an aqueous ethanolin-propanol solution (n-propanol:water:methanol=6:2:1), the resultant solution was cooled to 10 C. crystals precipitated from the solution, and the system was stirred for 3 hours at this temperature, so that a large amount of crystals precipitated. 100 ml of ethyl acetate were slowly added, and crystal A was obtained by filtration. The obtained crystals were placed into a vacuum-dryer, and a plate of ice-water mixture was put on the bottom of the vacuum-dryer. The content of water was controlled at 22%, and crystal B was obtained by vacuum-drying. The total amount of residual solvent in crystal A was determined as 0.6% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 13
[0134] Preparation of Crystal B of the Compound of Formula I
[0135] The crystals obtained in Example 2 were placed into a vacuum-dryer, and a plate of tap water was put on the bottom of the vacuum-dryer. The content of water was controlled at 12.1%, and crystal B was obtained by vacuum-drying. The XRPD pattern of crystal B are shown in
EXAMPLE 14
[0136] Preparation of Crystal B of the Compound of Formula I
[0137] The crystals obtained in Example 6 were placed into a vacuum-dryer, and a plate of crushed ice was put on the bottom of the vacuum-dryer. The content of water was controlled at 4%, and crystal B was obtained by vacuum-drying. The total amount of residual solvent in crystal A was determined as 0.8% (mass percentage) by GC (Gas Chromatoaraphy).
EXAMPLE 15
[0138] Preparation of Crystal C of the Compound of Formula I
[0139] At 27 C., 2 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 100 ml of an aqueous methanol/isobutanol solution (isobutanol:water:methanol=8:2:1), the resultant solution was slowly cooled to 0 C., crystals precipitated from the solution, and the system was stirred for 4 hours at this temperature, so that a large amount of crystals precipitated. 150 mi of ethyl acetate were slowly added, and crystal A was obtained by filtration. The obtained crystals were placed into a vacuum-dryer, and a plate of tap water was put on the bottom of the vacuum-dryer. The content of water was controlled at 17.7%, and crystal B was obtained by vacuum-drying. The plate of tap water was then removed, and the sample was further dried. When the content of water was determined as 2.1%, crystal C of the compound of formula I was obtained. The XRPD pattern of crystal C is shown in
EXAMPLE 16
[0140] Preparation of Crystal C of the Compound of Formula I
[0141] At 20 C., 3.3 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 120 ml of an aqueous methanolisopropanol solution (isopropanol:water:methanol=3:1:3), the resultant solution was cooled to 5 C., crystals precipitated from the solution, and the system was stirred for 1.5 hours at this temperature, so that a large amount of crystals precipitated. 200 ml of n-propyl acetate was slowly added, and crystal A was obtained by filtration. The obtained crystals were placed into a vacuum-dryer, and a plate of pure water was put on the bottom of the vacuum-dryer. The content of water was controlled at 7.6%, and crystal B of the compound of formula I was obtained by vacuum-drying. The plate of pure water was then removed, and the sample was further vacuum-dried. When the content of water was determined as 3.7%, crystal C of the compound of formula I was obtained. The total amount of residual solvent in crystal A was determined as 0.5% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 17
[0142] Preparation of Crystal C of the Compound of Formula I
[0143] Crystal B obtained in Example 13 was vacuum-dried. When the content of water was determined as 2.9%, crystal C was obtained. The total amount of residual solvent in crystal A was determined as 0.4% (mass percentage) by GC (Gas Chromatography).
EXAMPLE 18
[0144] Preparation of Crystal C of the Compound of Formula I
[0145] Crystal B obtained in Example 14 was vacuum-dried. When the content of water was determined as 0.8%, crystal C was obtained. The total amount of residual solvent in crystal A was determined as 0.4% (mass percentage) by GC (Gas Chromatography).
COMPARATIVE EXAMPLE 2
[0146] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0147] At 25 C., 0.8 g of the compound of formula I in amorphous form prepared in Example I were dissolved into 5 ml of an, aqueous methanol solution (methanol:water=3:2). The resultant solution was slowly cooled to 0 C., crystals precipitated from the solution, and the system was stirred for 3 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 3
[0148] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0149] At 32 C. 2.1 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 50 ml of an aqueous ethanol solution (ethanol:water=5:1). The resultant solution was slowly cooled to 10 C., crystals precipitated from the solution, and the system was stirred for 5 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 4
[0150] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0151] At 20 C., 3 g of the compound of formula I in amorphous form prepared in Example I were dissolved into 55 ml of an aqueous n-propanol solution (n-propanol:water=1:1). The resultant solution was slowly cooled to 0 C., crystals precipitated from the solution, and the system was stirred for 5 hours at this temperature. A solid amorphous powder was obtained by filtration,
COMPARATIVE EXAMPLE 5
[0152] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0153] At 45 C., 2.5 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 32 ml of an aqueous isopropanol solution (isopropanol:water=2:3). The resultant solution was slowly cooled to 15 C., crystals precipitated from the solution, and the system was stirred for 1 hour at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 6
[0154] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0155] At 32 C., 1.7 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 90 ml of an aqueous isopropanol solution (isopropanol:water=4:1). The resultant solution was slowly cooled to 10 C., crystals precipitated from the solution, and the system was stirred for 2 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 7
[0156] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0157] At 28 C., 1 g of the compound of formula I in amorphous form prepared in Example 1 was dissolved into 50 ml of an aqueous n-butanol solution (n-butanol:water=9:1). The resultant solution was slowly cooled to 0 C., 50 ml of methyl acetate were slowly added, and A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 8
[0158] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0159] At 17 C., 1.2 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 45 ml of an aqueous acetone solution (acetone:water=4:1). The resultant solution was slowly cooled to 5 C., crystals precipitated from the solution, and the system was stirred for 3.5 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 9
[0160] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0161] At 25 C., 5 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 150 ml of an aqueous acetonitrile solution (acetonitrile:water 3:1). The resultant solution was slowly cooled to 8 C., crystals precipitated from the solution, and the system was stirred for 2 hours at this temperature. 200 ml of isopropyl acetate were slowly added, and a solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 10
[0162] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0163] At 30 C., 1.7 g of the compound of formula I in amorphous Fenn prepared in Example I were dissolved into 100 ml of an aqueous methanol/ethanol solution (methanol:ethanol:water=8:2:1.). The resultant solution was slowly cooled to 11 C., crystals precipitated from the solution, and the system was stirred for 6 hours at this temperature, 100 ml of ethyl acetate were slowly added, and a solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 11
[0164] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0165] At 23 C., 1.7 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 100 ml of an aqueous propanol butanol solution (propanol:butanol:water=6:5:3). The resultant solution was slowly cooled to 5 C. crystals precipitated from the solution, and the system was stirred for 7 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 12
[0166] Effects of Different Solvents on the Crystal Forms of the Compound of Formula 1
[0167] At 45 C., 4 g of the compound of formula 1 in amorphous form prepared in Example 1 were dissolved into 28 ml of an aqueous methanolln-butanol solution (methanol:n-butanol:water=1:7:2). The resultant solution was slowly cooled to 11 C., crystals precipitated from the solution, and the system was stirred for 6 hours at this temperature. A solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 13
[0168] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0169] At 20 C., 1 g of the compound of formula I in amorphous form prepared in Example 1 was dissolved into 70 ml of an aqueous ethanollbutanol solution (ethanol:butanol:water=2:2:5). 100 ml of ethyl acetate were slowly added, and a solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 14
[0170] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0171] At 50 C., 3 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 20 ml of an aqueous methanol/acetonitrile solution (methanol:acetonitrile:water=4:1:2). The resultant solution was cooled to 25 C., crystals precipitated from the solution, and the system was stirred for 2 hours at this temperature. 70 ml of ethyl acetate were slowly added, and a solid amorphous powder was obtained by filtration.
COMPARATIVE EXAMPLE 15
[0172] Effects of Different Solvents on the Crystal Forms of the Compound of Formula I
[0173] At 30 C., 2 g of the compound of formula I in amorphous form prepared in Example 1 were dissolved into 10 ml of an aqueous methanol/acetone solution (methanol:acetone:water=9:2:2). The resultant solution was cooled to 5 C., crystals precipitated from the solution, and the system was stirred for 4 hours at this temperature. 50 ml of ethyl acetate were slowly added, and A solid amorphous powder was obtained by filtration.
EXAMPLE 19
[0174] Purity and Stability Test
[0175] In this Example, the purity and stability of the samples obtained in Comparative Examples and Examples were compared. The method used is as follows:
[0176] Crystals A-C of the compound of formula I prepared in Examples 2, 11 and 15, the crystal of B82 type obtained in Comparative Example 1 and the amorphous solid obtained in Example 1 were taken respectively and sealed at 25 C. for 30 days. And then the content of impurities in the sample was analyzed. Results of comparing the stability of crystals A-C of the compound of formula I according to the present invention, the crystal of B82 type and the amorphous solid are shown in the followam table:
TABLE-US-00005 Purity of sample after Sample Purity of initial sample stored at 25 C. for 30 days Crystal A 99.68% 99.65% Crystal B 99.55% 99.50% Crystal C 99.64% 99.43% B82-type Crystal 99.50% 96.98% Amorphous solid 99.38% 89.27%
[0177] From the data in the table, it is clear that the stability of crystals A-C of the compound of formula I is obviously superior to that of the B82-type crystal, and is far superior to that of the amorphous solid.
EXAMPLE 20
[0178] Preparation of Pharmaceutical Compositions
[0179] The preparation process was: a stabilizer was dissolved in 200 ml of water, the crystal of the compound of formula I was added and dissolved, the pH was adjusted, and the resulting mixture was added into 100 vials of 10 ml volume and lyophilized, so as to obtain pharmaceutical compositions. The formulations of the composition before lyophilization are listed in the following table:
TABLE-US-00006 Added crystal of the compound pH adjusting Number of formula I Stabilizer agent 1 Crystal A of the Lactose, 20 g Anhydrous citric compound of acid-sodium formula I obtained hydroxide, pH 5.5 according to the method of Example 2, 2.5 g 2 Crystal B of the Trehalose, 25 g Phosphate, pH 6.0 compound of formula I obtained according to the method of Example 11, 2.5 g 3 Crystal C of the Sucrose, 15 g Acetate, pH 5.5 compound of formula I obtained according to the method of Example 15, 2.5 g
EXAMPLE 21
[0180] Preparation of Pharmaceutical Compositions
[0181] 0.2 g of crystal A of the compound of formula I obtained by the method in Example 2, 0.2 g of crystal B of the compound of formula I obtained by the method in Example 11, and 0.2 g of crystal C of the compound of formula I obtained by the method in Example 14 were prepared into eye drops respectively according to the method in Example 2 of US2007249546A1.
[0182] Characterization of Crystal A of the Compound of Formula I
[0183] Crystal A of the compound of formula I obtained in Example 2 was characterized by an X-ray powder diffractometer. There are characteristic peaks at the following 2 angles in the X-ray diffraction pattern; 3.6, 6.4, 6.8, 7.5, 9.4, 10.8, 12.4, 13.6, 20.4, and the X-ray power diffraction pattern is shown in
[0184] Under an optical microscope, crystal A of the compound of formula I is a column-like crystal and its shape before filtration is shown in
[0185] Upon examination, the structure and shape of the crystals of Examples 3-10 are identical with those of the crystal of Example 2. Therefore, the reproducibility of the method of the present invention is excellent, and the stable crystal A of the compound of formula I can be obtained.
[0186] Characterization of Crystal B of the Compound of Formula I
[0187] Crystal B of the compound of formula I obtained in Example 11 was characterized by an X-ray powder diffractometer. There are characteristic peaks at the following 2 angles in the X-ray diffraction pattern: 4.4, 5.2, 7.5, 8.5, 8.8, 9.6, 12.6, 13.7, 14.9, 15.7, 16.7, 22.5, 25.1, and the X-ray power diffraction pattern is shown in
[0188] Crystal B of the compound of formula I obtained in Example 13 was characterized by an X-ray powder diffractometer. There are characteristic peaks at the following 2 angles in the X-ray diffraction pattern: 4.4, 5.1, 7.4, 8.4, 8.7, 9.5, 12.6, 13.6, 14.8, 15.5, 16.6, 22.4, 25.0, and the X-ray power diffraction pattern is shown in
[0189] The IR pattern of crystal B of the compound of formula I is shown in
[0190] Upon examination, the structure of the crystals of Examples 12-14 is identical with that of the crystal of Example 11. Therefore, the reproducibility of the method of the present invention is excellent, and the stable crystal B of the compound of formula I can be obtained.
[0191] Characterization of Crystal C of the Compound of Formula I
[0192] Crystal C of the compound of formula I obtained in Example 15 was characterized by an X-ray powder diffractometer. There are characteristic peaks at the following 2 angles in the X-ray diffraction pattern: 4.5, 5.2, 8.5, 9.6, and the X-ray power diffraction pattern is shown in
[0193] Upon examination, the structure of the crystals of Examples 16-18 is identical with that of the crystal of Example 15. Therefore, the reproducibility of the method of the present invention is excellent, and the stable crystal C of the compound of formula I can be obtained.
[0194] The embodiments described above are merely preferred embodiments of the present invention, and not provided to limit the scope of the substantial technical contents of the present invention, which are broadly defined in the claims of the present application. If any technical entity or method completed by other people is identical with that defined by the claims of the present application, or is an equivalent modification, all of them will be deemed as falling within the scope of the claims.