Summary of the invention
Object of the present invention is exactly to overcome the deficiencies in the prior art, provides a kind of Anastrozole monohydrate and Anastrozole monohydrate crystal form III (hereinafter referred to as crystalline form III);
Wherein, Anastrozole monohydrate can be that other crystalline forms except crystalline form III exist, and the present invention is crystalline form III;
This wherein, the X-ray powder diffraction of crystalline form III is that 9.3,10.5,14.8,15.8,17.9 ± 0.2 ° of places have characteristic absorption peak at the angle of diffraction 2 θ.
This wherein, the X-ray powder diffraction of crystalline form III is that 9.3,10.5,14.8,15.4,15.8,17.9,18.8,19.3,19.7,20.0 and 21.1 ± 0.2 ° of places have characteristic absorption peak at the angle of diffraction 2 θ.
Present invention also offers a kind of method preparing crystalline form III, in following method any one:
A) crystal formation I is formed suspension in the mixed solvent of water and organic solvent, stirring and crystallizing 3 hours ~ 7 days, described suspension formation temperature is the boiling temperature of 0 DEG C ~ dicyandiamide solution, preferably 5 ~ 50 DEG C, then by the crystal separation of precipitation, drying, crystalline form III is obtained; Or
B), under room temperature condition, crystal formation I is formed suspension in the mixed solvent of water and organic solvent, carries out grinding crystallize, then by separate out crystal separation, drying, obtain crystalline form III; Or
C) by crystal formation I in a heated condition in the mixed solvent of water and organic solvent, stir into settled solution, through cooling and stirring and crystallizing, described settled solution formation temperature is the boiling temperature of 20 DEG C ~ dicyandiamide solution, preferably 20 ~ 80 DEG C; Described chilling temperature is-5 ~ 40 DEG C, preferably 0 ~ 30 DEG C, then by the crystal separation of precipitation, drying, obtains crystalline form III.
Wherein, described method a) or method b) in, the mass volume ratio of the mixed solvent of Anastrozole crystalline form I and water and organic solvent is 1:5 ~ 50(mg/ μ L); Described method c) in, the mass volume ratio of the mixed solvent of Anastrozole crystalline form I and water and organic solvent is 1:3 ~ 20(mg/mL);
This wherein, the mixed solvent of water and organic solvent is the mixed solvent that maybe can not dissolve each other that dissolves each other, and when described water and organic solvent dissolve each other, its volume ratio is 2 ~ 100:1; When described water and organic solvent do not dissolve each other, mixed solvent is the saturated solution of organic solvent in water.
Wherein, described organic solvent is alcohols, ketone, amides compound, 5 ~ 6 yuan of Oxygenic heterocyclic compounds, aromatic hydrocarbon, acetonitrile, dimethyl sulfoxine or its any mixed solvents, and described alcohols is C1 ~ C8 alcohol, preferred C1 ~ C4 alcohol, more preferably methanol, ethanol; Described ketone is C3 ~ C6 ketone, preferred acetone, butanone, tetramethyl two pentanone; Described amides compound is DMF; Described 5 ~ 6 yuan of Oxygenic heterocyclic compounds are dioxanes, oxolane; Described aromatic hydrocarbon is toluene.
Described crystalline form III has following beneficial effect:
1., under Aquo System condition, the stability of crystalline form III is better than crystalline form I and crystal form II;
2. under Aquo System condition, relative to crystalline form I and crystal form II, crystalline form III is more suitable for wet granulation, makes oral liquid or suspending agent, has the advantage being easy to store and formulation application is wider.
Present invention also offers a kind of Anastrozole crystalline form IV (hereinafter referred to as " crystalline form IV ")
The X-ray powder diffraction of crystalline form IV is that 9.7,10.7,12.1,14.7,15.6,17.2,17.7,18.8,20.7,21.5 and 23.3 ± 0.2 ° of places have characteristic peak at the angle of diffraction 2 θ.
Wherein, crystalline form IV adopts following method to prepare:
By the suspension agitation 0.5-6h that Anastrozole monohydrate crystal form III (hereinafter referred to as " crystalline form III ") is formed in organic solvent system, then by the crystal separation of precipitation, drying, obtain crystalline form IV.
Wherein, the mass volume ratio of crystalline form III and organic solvent is 1:0.5-1:20(g/mL), preferred 1:2-1:10(g/mL).
This wherein, organic solvent system is selected from normal hexane, cyclohexane extraction or normal heptane;
Present invention also offers a kind of Anastrozole novel crystal forms V (hereinafter referred to as " crystalline form V ").
Wherein, the X-ray powder diffraction of crystalline form V is that 9.9,10.9,11.3,15.9,16.8,17.4,18.8,19.0,19.5,21.9 and 22.7 ± 0.2 ° of places have characteristic absorption peak at the angle of diffraction 2 θ.
Preferably, crystalline form V, the X-ray powder diffraction represented with 2 θ angles has collection of illustrative plates as shown in Figure 8.
Wherein, crystalline form V fusing point is about 76 DEG C.
Crystalline form V preparation method is as follows:
Crystalline form IV is put into DSC(differential scanning calorimetry) crucible tongs 0 DEG C balance, be warming up to 75 DEG C with 5 DEG C/min, then be cooled to 0 DEG C with 10 DEG C/min, dry, obtain crystalline form V;
In the embodiment of the present invention, the crystalline form III of preparation, crystalline form IV and crystal form V are single crystal forms.
Unless stated otherwise, the crystal formation described in the present invention is through drying steps, and this is wherein dry, can constant pressure and dry, also can reduced vacuum dry, preferred vacuum is greater than 0.09MPa, and drying can be dry the temperature of 20 DEG C ~ 45 DEG C, preferably 25 DEG C ~ 35 DEG C.Drying time can be 0.5 ~ 48 hour, preferably 0.5 ~ 5 hour.Drying can be carried out in fume hood, convection oven or vacuum drying oven.
Experimental technique can room temperature or close to the condition of room temperature under operate.Here refer to test is carry out under the condition identical or close with the temperature in room or fume hood.Usually this temperature is from 15 DEG C ~ 25 DEG C, preferably 17 DEG C or 22 DEG C.
Unless stated otherwise, " anhydride " refers to crystalline form IV and crystal form V here, and described crystal formation is measured containing no more than 1.5%(weight ratio through TGA), or no more than 1.0%(weight ratio) water.
Unless stated otherwise, the solvent used in test, without dried, may contain a small amount of water.
Further, the invention provides a kind of pharmaceutical composition, wherein, pharmaceutical composition comprise treat and/or prevent effective dose a kind of Claims 2 or 3 according to any one of crystalline form III and pharmaceutically acceptable carrier;
Wherein, pharmaceutical composition can also comprise the crystalline form IV or crystal form V and pharmaceutically acceptable carrier that treat and/or prevent effective dose;
Wherein, pharmaceutical composition can be solid-state or liquid.If this pharmaceutical composition is liquid, then one or more of above-mentioned crystal formation can remain solid, such as, as suspension in this fluid composition.
In the present invention, Anastrozole monohydrate, crystalline form III, crystalline form IV, crystal form V are treated in preparation or prevent the application in the medicine of advanced breast cancer relevant disease;
The anti-tumor active ingredient of Anastrozole monohydrate, crystalline form III, crystalline form IV, crystal form V is Anastrozole, all has the purposes of the disease suppressing advanced breast cancer to be correlated with;
Wherein, the disease that advanced breast cancer is correlated with refers to the treatment of the advanced breast cancer of postmenopausal women.To the patient of estrogen receptor negative, if it presents positive clinical response to tamoxifen, can consider to use this product.Be applicable to the auxiliary treatment of the breast carcinoma of early stage of postmenopausal women's estrogen receptor positive.
Anastrozole is a kind of potent, selectivity nonsteroidal arimedex.The androstenedione generated in patient adrenal gland after can suppressing menopause is converted into estrone, thus reduces blood plasma estrogen level significantly, produces the effect suppressing breast tumor growth.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.
Detecting instrument and method:
The instrument that X-ray powder diffraction (XPRD) uses is Bruker D8Advance Diffractometer, is configured with θ-2 θ clinometer, Mo monochromator, Lynxeye detector.Acquisition software is Diffrac Plus XRDCommander, and analysis software is MDI Jade5.0.Instrument is before use with standard substance (the being generally corundum) calibration that instrument carries.Testing conditions is: 2 θ scanning angle scopes 3 ~ 40 °, step-length 0.02 °, speed 0.2 second/step.Testing process: employing copper target wavelength is the Ka X-ray of 1.54nm, and under the operating condition of 40kV and 40mA, sample is tested at ambient temperature, is placed on organic slide needing the sample detected.Unless stated otherwise, sample is before detection without grinding.
Micropolariscope (PLM) collection of illustrative plates picks up from XP-500E micropolariscope (the rectangular optical instrument company limited in Shanghai).The powder sample that takes a morsel is placed on microscope slide, and drip a small amount of mineral oil with dispersed powders sample better, covered, is then placed on sample on the object stage of XP-500E micropolariscope, selects the pattern of suitable amplification observing samples and takes pictures.
Differential thermal analysis (DSC) data acquisition is certainly in TA Instruments Q200MDSC, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Usually the sample getting 1 ~ 10 milligram is positioned over does not add a cover in the aluminum crucible of (unless stated otherwise), with the programming rate of 10 DEG C/min at the dry N of 50mL/min
2protection under sample is risen to 150 DEG C from room temperature, the simultaneously thermal change of TA software records sample in temperature-rise period.In this application, fusing point is reported by initial temperature.
Thermogravimetric analysis (TGA) data acquisition is certainly in TA Instruments Q500TGA, and instrument control software is Thermal AdVantage, and analysis software is Universal Analysis.Usually the sample getting 5 ~ 15mg is positioned in platinum crucible, adopts the mode of segmentation high resolution detection, with the programming rate of 10 DEG C/min at the dry N of 50mL/min
2protection under sample is risen to 300 DEG C from room temperature, the simultaneously weight change of TA software records sample in temperature-rise period.
The preparation of Anastrozole compound: with reference to the method preparation of patent documentation WO2007039919.Be specially:
Under nitrogen protection, in 1L there-necked flask, add 54g mono-water 1-Sodium-1,2,4-Triazole and 500mL DMF, stir and be cooled to 25 DEG C; Add 145g2 again, 2 '-(5-bromomethyl-1,3-phenylene) two (2-methyl propionitrile), feed time about 2 hours; Be incubated 25 DEG C to reacting completely.Reactant liquor is poured in 1.6L water, stirs 0.5 hour, and with 600mL toluene extraction secondary, toluene layer 200mL washes once, and activated carbon decolorizing filters, and concentrating under reduced pressure removing toluene, obtains Anastrozole crude product and be about 97g.
Add acetone 400mL by Anastrozole crude product under room temperature, stir 0.5 hour to obtain clear liquor; Add 65g p-methyl benzenesulfonic acid monohydrate again, stir 1 hour, concentrating under reduced pressure removing acetone, then add 400mL acetone, be incubated 25 DEG C and stir 12 hours, filter, filter cake 100mL acetone drip washing, obtains Anastrozole tosilate wet product and is about 140g.
Add 140g Anastrozole tosilate wet product and 500mL acetone in flask, reflux 1 hour, heat to 25 DEG C of insulations 3 hours, filter, the drip washing of filter cake acetone, 50 DEG C of vacuum dryings, obtain Anastrozole tosilate and are about 120g, fusing point about 175 DEG C.
Add 25g Anastrozole tosilate and 200mL water in flask, stirring 0.5 hour, is 8.5-9.0 with ammonia adjust pH; Add 150mL ethyl acetate again, stir 0.5 hour, extraction ethyl acetate layer, water layer uses 150mL extraction into ethyl acetate once again, combined ethyl acetate layer, washes once with 100mL; Ethyl acetate layer anhydrous sodium sulfate drying, concentrating under reduced pressure remove portion ethyl acetate, is cooled to 10 DEG C, large-tonnage product separate out, filter, 50 DEG C of vacuum dryings, obtain Anastrozole, fusing point about 85 DEG C, HPLC purity be 99.5%, H '-NMR,
13c-NMR with Mass (EI-MS) data are consistent with bibliographical information.
The preparation of Anastrozole crystalline form I: with reference to the method preparation in patent documentation WO2007039919 described by embodiment 1.Be specially:
Add 27.5g Anastrozole in flask, 55mL ethyl acetate and 55mL cyclohexane extraction, stir, be heated to backflow, clearly molten, be slowly cooled to 25-30 DEG C, be incubated 1 hour, filtration, 45-50 DEG C of vacuum drying 1 hour, obtains Anastrozole crystalline form I.
X-ray powder diffraction pattern as shown in Figure 5.The X-ray powder diffraction pattern of the crystal formation prepared with embodiment in patent documentation WO2007039919 1 is substantially identical.
Embodiment 1
Get 300mg crystalline form I and be placed in 5mL vial, add 1.2mL water and 0.3mL dimethyl sulfoxine, stirring at room temperature 3 days, after centrifugal, under room temperature in convection oven dry 5 hours, obtain crystalline form III of the present invention.Fig. 1 is shown in by X-ray powder diffraction (XPRD) collection of illustrative plates of described crystalline form III; Fig. 2 is shown in by TGA collection of illustrative plates, display: crystalline form III is weightlessness about 5.6% before 110 DEG C, and decomposition temperature is 263 DEG C; Fig. 3 is shown in by PLM collection of illustrative plates; Fig. 4 is shown in by DSC collection of illustrative plates.
Embodiment 2
Get 30mg crystalline form I and be placed in 5mL vial, add 0.3mL water and 0.1mL ethanol, stirring at room temperature 3 days, after sucking filtration, under room temperature in convection oven dry 3 hours, obtain crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1
Embodiment 3
Get 30mg crystalline form I and be placed in 5mL vial, add 0.9mL water and 0.1mL ethanol, stirring at room temperature 3 hours, after sucking filtration, under room temperature in convection oven dry 2 hours, obtain crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 4
Get 30mg crystalline form I and be placed in 5mL vial, add 0.5mL water and 0.1mL methanol, stirring at room temperature 2 days, after centrifugal, under room temperature in convection oven dry 3 hours, obtain crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 5
Get 30mg crystalline form I and be placed in 5mL vial, add 0.4mL water and 0.05mL acetone, stirring at room temperature 1 day, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 6
Get 30mg crystalline form I and be placed in 5mL vial, add 0.4mL water and 0.1mL diox, stirring at room temperature 5 days, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 7
Get 30mg crystalline form I and be placed in 5mL vial, add 0.4mL water and 0.08 oxolane, stirring at room temperature 4 days, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 8
Get 30mg crystalline form I and be placed in 5mL vial, add 0.4mL water and 0.1mL acetonitrile, stirring at room temperature 5 days, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 9
Get 30mg crystalline form I and be placed in 5mL vial, add 0.5mL water and 0.1mLN, dinethylformamide, stir 7 days under 0 DEG C of condition, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 10
Get 300mg crystalline form I and be placed in 5mL vial, add 8mL water and 0.08mL acetone, stir 6 days under 5 DEG C of conditions, after centrifugal, in ventilating kitchen, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 11
Get 30mg crystalline form I and be placed in 5mL vial, add 1.0mL water and 0.08mL dimethyl sulfoxine, start to stir, be warming up to 30 DEG C, continue stirring 3 days, after centrifugal, in ventilating kitchen, drying at room temperature 4 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 12
Get 300mg crystalline form I and be placed in 5mL vial, add 8mL water and 0.16mL acetonitrile, start to stir, be warming up to 38 DEG C, continue stirring 3 days, after centrifugal, in ventilating kitchen, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 13
Get 30mg crystalline form I and be placed in 5mL vial, add 1.2mL water and 0.3mL oxolane, start to stir, be warming up to 41 DEG C, continue stirring 2 days, after centrifugal, in ventilating kitchen, drying at room temperature 4 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 14
Get 30mg crystalline form I and be placed in 5mL vial, add 0.4mL water and 0.06mL diox, start to stir, be warming up to 50 DEG C, continue stirring 1 day, after centrifugal, in ventilating kitchen, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 15
Get 30mg crystalline form I and be placed in 5mL vial, add 1.0mL water and 0.5mL isopropyl alcohol, start to stir, be warming up to 78 DEG C, continue stirring 4 hours, after centrifugal, in ventilating kitchen, drying at room temperature 3 hours, obtains crystalline form III of the present invention.The X-ray powder diffraction pattern of described crystalline form III is as shown in Figure 9, substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 16
Get 60mg crystalline form I and be placed in 5mL vial, add the aqueous solution that 0.7mL butanone is saturated, stirring at room temperature 3 days, after centrifugal, in ventilating kitchen, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 17
Get 60mg crystalline form I and be placed in 5mL vial, add the aqueous solution that 1.5mL toluene is saturated, stirring at room temperature 3 days, after centrifugal, in ventilating kitchen, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 18
Get 50mg crystalline form I and be placed in mortar, add 0.2mL water and 0.05mL ethanol, grinding 15min, after centrifugal, in ventilating kitchen, drying at room temperature 1 hour, obtains crystalline form III of the present invention.The X-ray powder diffraction pattern of described crystalline form III is as shown in Figure 10, substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 19
Get 50mg crystalline form I and be placed in mortar, add 1mL water and 0.07mL diox, grinding 15min, after centrifugal, in ventilating kitchen, drying at room temperature 3 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 20
Get 50mg crystalline form I and be placed in mortar, add 1mL water and 0.5mL oxolane, grinding 15min, after centrifugal, in convection oven, drying at room temperature 3 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 21
Get 50mg crystalline form I and be placed in mortar, add 2.0mL water and 0.04mL acetonitrile, grinding 15min, after centrifugal, in convection oven, drying at room temperature 4 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 22
Get 50mg crystalline form I and be placed in mortar, add 2.4mL water and 0.1mL acetone, grinding 15min, after centrifugal, in convection oven, drying at room temperature 3 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 23
Get 50mg crystalline form I and be placed in mortar, add 1mL water and 0.07mLN, dinethylformamide, grinding 15min, after centrifugal, in convection oven, drying at room temperature 3 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 24
Get 50mg crystalline form I and be placed in mortar, add 2.0mL water and 0.02mL dimethyl sulfoxine, grinding 15min, after centrifugal, in convection oven, drying at room temperature 2 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 25
Get 50mg crystalline form I and be placed in mortar, add 2.5mL toluene saturated aqueous solution, grinding 15min, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 26
Get 5.0mg crystalline form I and be placed in flask, add 10.5mL water and 4.5mL diox, stir, be warming up to 80 DEG C clearly molten, be cooled to 40 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The X-ray powder diffraction pattern of described crystalline form III is as shown in figure 11, substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 27
Get 50mg crystalline form I and be placed in 5mL vial, add 250mL water and 5mLN, dinethylformamide, stir, be warming up to 80 DEG C clearly molten, be cooled to-5 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 28
Get 20mg crystalline form I and be placed in flask, add 120mL water and 40mL isopropyl alcohol, stir, be warming up to 20 DEG C clearly molten, be cooled to 0 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 29
Get 10mg crystalline form I and be placed in flask, add 120mL water and 1.2mL oxolane, stir, be warming up to 65 DEG C clearly molten, be cooled to 18 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 30
Get 15mg crystalline form I and be placed in flask, add 290mL water and 10mL acetone, stir, be warming up to 50 DEG C clearly molten, be cooled to 30 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 31
Get 15mg crystalline form I and be placed in flask, add 200mL water and 100mL acetonitrile, stir, be warming up to 50 DEG C clearly molten, be cooled to 30 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The XRPD of described crystalline form III detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 32
Get 5.0mg crystalline form I and be placed in flask, add in 15mL toluene saturated aqueous solution, stir, be warming up to 80 DEG C clearly molten, be cooled to 40 DEG C, after centrifugal, in convection oven, drying at room temperature 5 hours, obtains crystalline form III of the present invention.The X-ray powder diffraction pattern of described crystalline form III is as shown in figure 11, substantially identical with Fig. 1, and other spectrograms are consistent with embodiment 1.
Embodiment 33
Get 50mg crystalline form III and be placed in 5mL vial, add 1.0mL normal hexane, stirring at room temperature 1h, after centrifugal, dry 0.5 hour of room temperature in vacuo, obtains crystalline form IV of the present invention.The X-ray powder diffraction pattern of described crystalline form IV as shown in Figure 7.
Embodiment 34
Get 200mg crystalline form III and be placed in 5mL vial, add 2.0mL normal heptane, stirring at room temperature 1h, after centrifugal, dry 1 hour of room temperature in vacuo, obtains crystalline form IV of the present invention.The XRPD of described crystalline form IV detects and obtains the X-ray powder diffraction pattern substantially identical with Fig. 7.
Embodiment 35
Get 1g crystalline form III and be placed in 5mL vial, add 2.0mL normal heptane, stirring at room temperature 1h, after centrifugal, dry 2 hours of room temperature in vacuo, obtains crystalline form IV of the present invention.The XRPD of described crystalline form IV detects and obtains the X-ray powder diffraction figure substantially identical with Fig. 7.
Embodiment 36
Get 2g crystalline form III and be placed in 5mL vial, add 1.0mL cyclohexane extraction, stirring at room temperature 1h, after centrifugal, dry 2 hours of room temperature in vacuo, obtains crystalline form IV of the present invention.The XRPD of described crystalline form IV detects and obtains the X-ray powder diffraction figure substantially identical with Fig. 7.
Embodiment 37
Get 200mg crystalline form III and be placed in 5mL vial, add 1.5mL cyclohexane extraction, stirring at room temperature 1h, after centrifugal, dry 2 hours of room temperature in vacuo, obtains crystalline form IV of the present invention.The XRPD of described crystalline form IV detects and obtains the X-ray powder diffraction figure substantially identical with Fig. 7.
Embodiment 38
Get 2mg crystalline form IV and be placed in DSC specimen disc, 0 DEG C of balance, is warming up to 75 DEG C with 5 DEG C/min, then is cooled to 0 DEG C with 10 DEG C/min, obtain crystal form V of the present invention.The X-ray powder diffraction pattern of described crystal form V as shown in Figure 8.
Embodiment 39
Get 5mg crystalline form IV and be placed in DSC specimen disc, 0 DEG C of balance, is warming up to 75 DEG C with 5 DEG C/min, then is cooled to 0 DEG C with 10 DEG C/min, obtain crystal form V of the present invention.The XRPD of described crystal form V detects and obtains the X-ray powder diffraction figure substantially identical with Fig. 8.
Embodiment 40
Table 1 formula
Concrete steps following (formula is in table 1):
1) crystalline form III is crossed 100 mesh sieves, magnesium stearate crosses 60 mesh sieves, and all the other adjuvants cross 80 mesh sieves respectively.
2) take polyvinylpolypyrrolidone XL-10 mix homogeneously in mixer of crystalline form III, lactose, microcrystalline Cellulose and 1/2 amount, use water as wetting agent and granulate.
3) wet granular is dried to moisture in an oven below 3%, adds polyvinylpolypyrrolidone XL-10 and the magnesium stearate of other 1/2 amount, mix homogeneously in dry granule, measures principal agent composition in granule, determines sheet weight, tabletting.
Embodiment 41
Table 2 formula
Concrete steps following (formula is in table 2):
1) crystalline form III is crossed 100 mesh sieves, magnesium stearate crosses 60 mesh sieves, and all the other adjuvants cross 80 mesh sieves respectively.
2) PVP K30 is dissolved in 40% alcoholic solution, is mixed with 5% PVP K30 alcoholic solution, as binding agent.
3) by crystalline form III, lactose and carboxymethylstach sodium mix homogeneously in mixer, granulate with above-mentioned binding agent.
4) wet granular is dried to moisture in an oven below 3%, adds magnesium stearate, mix homogeneously in dry granule, fill capsule.
Embodiment 42
Table 3 formula
Concrete steps following (formula is in table 3):
1) crystalline form III is crossed 100 mesh sieves, magnesium stearate crosses 60 mesh sieves, and all the other adjuvants cross 80 mesh sieves respectively.
2) starch slurry of 15% is prepared as binding agent with milk cooking process.
3) by API crystalline form III, sucrose, lemon yellow 60 and mannitol mix homogeneously in mixer, granulate with above-mentioned binding agent.
4) wet granular is dried to moisture in an oven below 3%, adds flavoring orange essence, mix homogeneously in dry granule, and screening, makes granule.
Embodiment 43
Table 4 formula
Concrete steps following (formula is in table 4):
1) crystalline form III, cosolvent sodium benzoate, solubilizing agent tween 80, antiseptic sorbic acid are dissolved in 200ml purified water, for subsequent use;
2) be dissolved in 500ml purified water by correctives mannitol, then add the solution of step 1) gained, then add purified water, the mixing of surplus, filter, fill is in 10ml vial, and specification, for often to prop up 10ml, is labelled and is packaged to be crystalline form III oral liquid.
Embodiment 44
Table 5 formula
Concrete steps following (formula is in table 5):
Above-mentioned crystalline form III, thickening agent aluminium-magnesium silicate, antifreeze glycol, defoamer organosilicon to be added in enamel stirred tank after mix homogeneously, pulverize through jet mill, add purified water to 10000ml, fill, in 100ml glass, is labelled and is packaged to be crystalline form III suspension.
Embodiment 45
Table 6 formula
Concrete steps following (formula is in table 6):
1) crystalline form IV or crystal form V are crossed 100 mesh sieves, magnesium stearate crosses 60 mesh sieves, and all the other adjuvants cross 80 mesh sieves respectively.
2) take polyvinylpolypyrrolidone XL-10 mix homogeneously in mixer of crystalline form IV or crystal form V, lactose, microcrystalline Cellulose and 1/2 amount, use water as wetting agent and granulate.
3) wet granular is dried to moisture in an oven below 3%, adds polyvinylpolypyrrolidone XL-10 and the magnesium stearate of other 1/2 amount, mix homogeneously in dry granule, measures principal agent composition in granule, determines sheet weight, tabletting.
Crystalline form III stability test
1, strong illumination, high humidity stable experiment are investigated
Crystalline form III is got the plate being placed in right amount and being numbered A, B, under being placed in illumination (intensity 4500lx), high humidity (relative humidity 92.5) respectively, stability of crystal form is tested, and the results are shown in Table 7.
Table 7, strong illumination, high humidity stable experiment are investigated:
Compared with before on-test, crystal formation does not change, and proves that crystalline form III is stablized, is applicable to long term storage and makes preparation.
2, room temperature shelf-stability
Crystalline form III is placed in cillin bottle seal, ambient temperatare is put, respectively 1 the end of month, 2 the end of month, 3 the end of month, 6 the end of month sample thief, detect its X-ray powder diffraction (XPRD), result is consistent with Fig. 1, and crystal formation is all unchanged, explanation crystalline form III is stablized, and is applicable to long term storage.
Comparative example 1: the present invention prepares crystalline form III and carries out stability with crystalline form I, crystal form II and compare
Crystalline form I is carried out or crystal form II compares with the stability of crystalline form III by competitive assay:
Described competitive assay refers to that the two kinds of crystal formations getting equivalent crystalline form I or crystal form II and crystalline form III are placed in saturated same solvent simultaneously, form suspension, finally see whether it is converted into another kind of crystal formation, for this competitive assay, if crystalline form I or crystal form II change crystalline form III into, illustrate that crystalline form I or crystal form II are relative to unstable in Aquo System crystalline form III.
Specific experiment method is as follows:
(1) 20% ethanol-water mixture, 50% ethanol-water mixture, 80% ethanol-water mixture and 100% ethanol is configured;
(2) crystalline form I and each 500mg of crystalline form III is taken, totally 4 parts; Take crystal form II and each 500mg of crystalline form III again, totally 4 parts, add respectively in the solvent 2mL that step (1) configures, solid sample is clearly insoluble, stirring at room temperature 3-7 days, filters, and detects its X-ray powder diffraction pattern respectively and carries out test front and back and compare, specifically in table 8.
Table 8: crystalline form I or crystal form II and crystalline form III stability test in ethanol-water mixed solvent:
As shown in Table 8, etc. quality crystalline form I or crystal form II and crystalline form III in 100% ethanol, stirring at room temperature 7 days, becomes crystalline form I or crystal form II;
And crystalline form I or crystal form II are in aquiferous ethanol, stirring at room temperature 3 ~ 5 days, is converted into crystalline form III all completely;
In competitive assay, crystalline form I, crystal form II, crystalline form III mutually as crystal seed, can carry out transformation of crystal;
To sum up, in Aquo System, crystal form II I stability is better than crystalline form I or crystal form II.
Crystal form II I is in Aquo System, and stability is better, and based on above-mentioned advantage, crystal form II I can be used for wet granulation, makes oral liquid or suspending agent, can ensure that its formulation application is wider.
It will be understood by those skilled in the art that under the instruction of this description, some amendments or change can be made to the present invention.These modifications and variations also should within the scope of the claims in the present invention.