CN104628662A - Anastrozole and novel crystal form, preparation method and application of monohydrate of anastrozole - Google Patents
Anastrozole and novel crystal form, preparation method and application of monohydrate of anastrozole Download PDFInfo
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- CN104628662A CN104628662A CN201510047680.7A CN201510047680A CN104628662A CN 104628662 A CN104628662 A CN 104628662A CN 201510047680 A CN201510047680 A CN 201510047680A CN 104628662 A CN104628662 A CN 104628662A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention belongs to the technical field of pharmaceutical chemical crystallization and particularly relates to novel monohydrate of anastrozole and a crystal form III of the monohydrate. According to the crystal form III, an X-ray powder diffraction pattern has characteristic peaks at diffraction angles (2theta) of 9.3 degrees, 10.5 degrees, 14.8 degrees, 15.8 degrees and 17.9+/-0.2 degrees. The invention further provides three preparation methods of the crystal form III, a pharmaceutical composition of the crystal form III and an application of the crystal form III in the treatment or prevention of related diseases of advanced breast cancers. The crystal form III is relatively stable in a water-containing system or a high-humidity environment, so that compared with a crystal form I or a crystal form II of anastrozole, the crystal form III has the advantages that the storage is easy, and the application range of a preparation is relatively wide, and the like.
Description
The divisional application that the present invention is the applying date is on September 6th, 2013, application number is 201310403006.9, denomination of invention is the patent application of " new crystal of Anastrozole and monohydrate thereof, preparation and purposes ".
Technical field
The invention belongs to medicine crystal technical field, be specifically related to a kind of Anastrozole monohydrate and crystalline form III, Anastrozole crystalline form IV and crystal form V, their preparation method, the pharmaceutical composition containing crystal formation and be used for the treatment of or the purposes of the disease of preventing advanced breast cancer relevant.
Background technology
Anastrozole tablets is used for the treatment of the treatment of the advanced breast cancer of postmenopausal women in nineteen ninety-five through U.S. food and drug administration (FDA) approval.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 assisting therapy of the breast carcinoma of early stage of postmenopausal women's estrogen receptor positive in addition.This product tablet formally went on the market in 1999 at home through China National Drug Surveillance Authority (CFDA) approval, and the formulation of going on the market at present is only tablet, dispersible tablet and capsule is domestic declares clinical study, but domesticly not yet had listing; Domestic oral liquid and suspension preparation not yet have producer to declare clinical study.
Anastrozole is a kind of potent nonsteroidal arimedex, can reduce plasma estrogens water body, and produce the effect suppressing breast tumor growth, the advanced breast cancer clinically for postmenopausal women is treated.The chemical name of Anastrozole is: α, α, α ' α '-tetramethyl--5-(1H-1,2,4-triazol-1-yl methyl)-1,3-benzene diacetonitrile; Chemical formula is: C17H19N5; Molecular weight is: 293.37; Chemical structural formula is as follows:
Disclose Anastrozole crystalline form I (hereinafter referred to as crystalline form I) and II crystal formation (hereinafter referred to as crystal form II) in world patent WO2007039919, wherein the X-ray powder diffraction of crystalline form I is that 9.83,16.77,18.45,18.81,22.95,29.38,29.86,33.83 and 43.94 places have charateristic avsorption band at diffraction angle 2 θ; The X-ray powder diffraction of crystal form II is that 9.64,10.92,12.48,16.58,17.07,18.58,19.56,21.19,21.51,22.12,22.74,25.59,26.10,28.90,29.27,29.78,30.09,30.64,31.67,33.64 and 35.25 places have charateristic avsorption band at diffraction angle 2 θ; Also disclose the preparation method of Anastrozole and crystalline form I and crystal form II.
World patent WO2005089511 embodiment 5 discloses Anastrozole Crystal form of oxalate, its oblique system parameter
α=γ=90 °, β=101.652 (4) °,
z=4, fusing point is 164-166 DEG C.
The present inventor finds column defects in the presence of Anastrozole crystalline form I and crystal form II are all in research process: two kinds of crystal formations are anhydride, all unstable in Aquo System or high humidity environment, thus can not maintain original crystal habit.
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 charateristic avsorption band at diffraction angle 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 charateristic avsorption band at diffraction angle 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 ~ solvent system, 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 crystallization, 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 ~ solvent system, preferably 20 ~ 80 DEG C; Described cooling 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, 5 ~ 6 yuan of Oxygenic heterocyclic compounds, aromatic hydrocarbon, acetonitrile, methyl-sulphoxide or its any mixed solvents, and described alcohols is C1 ~ C8 alcohol, preferred C1 ~ C4 alcohol, more preferably methyl alcohol, ethanol; Described ketone is C3 ~ C6 ketone, preferred acetone, butanone, tetramethyl-two pentanone; Described amides is DMF; Described 5 ~ 6 yuan of Oxygenic heterocyclic compounds are dioxan, tetrahydrofuran (THF); 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 suspension 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 diffraction angle 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, hexanaphthene or normal heptane;
Present invention also offers a kind of Anastrozole new crystal 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 charateristic avsorption band at diffraction angle 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 (dsc) 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 step, and this is wherein dry, can constant pressure and dry, also can reduced vacuum dry, preferred vacuum tightness 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.Time of drying can be 0.5 ~ 48 hour, preferably 0.5 ~ 5 hour.Drying can be carried out in stink cupboard, 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 stink cupboard.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 the water of no more than 1.0% (weight ratio).
Unless stated otherwise, the solvent used in test, without drying treatment, may contain a small amount of water.
Further, the invention provides a kind of pharmaceutical composition, wherein, pharmaceutical composition comprise treat and/or prevent significant quantity 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 significant quantity;
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 liquid 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 relative disease;
The antitumor activity component 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 assisting therapy 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's suprarenal gland after can suppressing climacteric is converted into oestrone, thus reduces blood plasma estrogen level significantly, produces the effect suppressing breast tumor growth.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of crystalline form III of the present invention.
Fig. 2 is thermogravimetric analysis (TGA) collection of illustrative plates of crystalline form III of the present invention.
Fig. 3 is polarization microscope (PLM) collection of illustrative plates of crystalline form III of the present invention.
Fig. 4 is dsc (DSC) collection of illustrative plates of crystalline form III of the present invention.
Fig. 5 is the X-ray powder diffraction pattern of Anastrozole crystalline form I.
Fig. 6 is the X-ray powder diffraction comparison diagram of Anastrozole crystalline form I and crystalline form III of the present invention.
Fig. 7 is the X-ray powder diffraction pattern of crystalline form IV of the present invention.
Fig. 8 is the X-ray powder diffraction pattern of crystal form V of the present invention.
Fig. 9 is the X-ray powder diffraction pattern that the embodiment of the present invention 15 prepares crystalline form III.
Figure 10 is the X-ray powder diffraction pattern that the embodiment of the present invention 18 prepares crystalline form III.
Figure 11 is the X-ray powder diffraction pattern that the embodiment of the present invention 26 prepares crystalline form III.
Use Cu-K α radiation, the experimental error of X-ray powder diffraction pattern depends on the preparation of the condition of instrument, sample and the purity of sample.Particularly, as well known to those skilled in the art, X-ray diffractogram can change along with the condition of instrument usually to some extent.Special needs to be pointed out is, the relative intensity of X-ray diffractogram also may change along with the change of experiment condition, so the order of peak intensity can not as unique or deciding factor.In addition, the experimental error of peak angle is usually 5% or less, and the error of these angles also should be considered into, and usual diffraction angle 2 θ allows ± error of 0.2 °.In addition, due to the impact of the empirical factors such as height of specimen, the overall offset of peak angle can be caused, usually allow certain skew.Thus, it will be understood by those skilled in the art that, crystal form X-x ray diffration pattern x that the different preparation method of the present invention obtains need not be identical with spectrogram shown in corresponding diagram 1, Fig. 7, Fig. 8, as long as its diffraction angle 2 θ allow ± limit of error of 0.2 ° in, be substantially identical X-ray powder diffraction.Any have crystal formation that is identical with the characteristic peak in these collection of illustrative plates or characteristic peak in limit of error and all belong within category of the present invention.
Embodiment
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 goniometer, Mo monochromator, Lynxeye detector.Acquisition software is Diffrac Plus XRDCommander, and analysis software is MDI Jade 5.0.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 operational 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.
Polarization microscope (PLM) collection of illustrative plates picks up from XP-500E polarization microscope (the rectangular opticinstrument company limited in Shanghai).The powdered sample that takes a morsel is placed on slide glass, and drip a small amount of mineral oil with dispersed powders sample better, covered, is then placed on sample on the Stage microscope of XP-500E polarization microscope, selects the pattern of suitable magnification 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 aluminium crucible of (unless stated otherwise), with the heat-up 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 starting 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 heat-up 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 changes in weight 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 145g 2 again, 2 '-(5-brooethyl-1,3-phenylene) two (2-methyl propionitrile), feed time about 2 hours; Be incubated 25 DEG C to reacting completely.Reaction solution 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 tosic 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 ammoniacal liquor 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 hexanaphthene, 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 methyl-sulphoxide, 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 suction 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 suction 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 methyl alcohol, 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 tetrahydrofuran (THF), 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 methyl-sulphoxide, 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 tetrahydrofuran (THF), 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 Virahol, 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 tetrahydrofuran (THF), 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 methyl-sulphoxide, 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 Virahol, 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 tetrahydrofuran (THF), 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 hexanaphthene, 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 hexanaphthene, 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 sample 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 sample 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 is filled a prescription
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 auxiliary materials cross 80 mesh sieves respectively.
2) the polyvinylpolypyrrolidone XL-10 taking crystalline form III, lactose, Microcrystalline Cellulose and 1/2 amount mixes in mixing machine, uses water as wetting agent and granulates.
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 in dry particle, measures main ingredient composition in particle, determines sheet weight, compressing tablet.
Embodiment 41
Table 2 is filled a prescription
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 auxiliary materials cross 80 mesh sieves respectively.
2) PVP K30 is dissolved in 40% ethanolic soln, is mixed with 5% PVP K30 alcoholic solution, as tackiness agent.
3) crystalline form III, lactose and carboxymethylstach sodium are mixed in mixing machine, granulate with above-mentioned tackiness agent.
4) wet granular is dried to moisture in an oven below 3%, adds Magnesium Stearate, mix in dry particle, filling capsule.
Embodiment 42
Table 3 is filled a prescription
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 auxiliary materials cross 80 mesh sieves respectively.
2) starch slurry of 15% is prepared as tackiness agent with milk cooking process.
3) API crystalline form III, sucrose, lemon yellow 60 and N.F,USP MANNITOL are mixed in mixing machine, granulate with above-mentioned tackiness agent.
4) wet granular is dried to moisture in an oven below 3%, adds flavoring orange essence, mix in dry particle, and screening, makes granule.
Embodiment 43
Table 4 is filled a prescription
Concrete steps following (formula is in table 4):
1) crystalline form III, solubility promoter Sodium Benzoate, solubilizing agent tween-80, sanitas Sorbic Acid are dissolved in 200ml purified water, for subsequent use;
2) correctives N.F,USP MANNITOL is dissolved in 500ml purified water, then adds step 1) solution of gained, then add purified water, the mixing of surplus, filter, filling in 10ml vial, specification, for often to prop up 10ml, is labelled and is packaged to be crystalline form III oral liquid.
Embodiment 44
Table 5 is filled a prescription
Concrete steps following (formula is in table 5):
Above-mentioned crystalline form III, thickening material neusilin, antifreeze glycol, defoamer organosilicon are added after mixing in enamel stirring tank, pulverize through micronizer mill, add purified water to 10000ml, filling in 100ml glass, label and be packaged to be crystalline form III suspension.
Embodiment 45
Table 6 is filled a prescription
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 auxiliary materials cross 80 mesh sieves respectively.
2) the polyvinylpolypyrrolidone XL-10 taking crystalline form IV or crystal form V, lactose, Microcrystalline Cellulose and 1/2 amount mixes in mixing machine, uses water as wetting agent and granulates.
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 in dry particle, measures main ingredient composition in particle, determines sheet weight, compressing tablet.
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 standing 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 standing 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 liquid, 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 in the solvent 2mL that step (1) configures respectively, solid sample is clearly insoluble, stirring at room temperature 3-7 days, filters, detect its X-ray powder diffraction pattern respectively to carry out comparing, specifically in table 8 before and after test.
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 aqueous 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 suspension 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 specification sheets, 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.
Claims (5)
1. an Anastrozole crystalline form V, is characterized in that, the X-ray powder diffraction of described 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 charateristic avsorption band at diffraction angle 2 θ.
2. Anastrozole crystalline form V described in claim 1, is characterized in that, described crystalline form V has collection of illustrative plates as shown in Figure 8 with the X-ray powder diffraction that 2 θ angles represent.
3. the preparation method of Anastrozole crystalline form V described in claim 1 or 2, comprises the steps:
Anastrozole crystalline form IV is put into 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.
4. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprise treat and/or prevent significant quantity claim 1 or 2 described in Anastrozole crystalline form V and its pharmaceutically acceptable carrier.
5. Anastrozole crystalline form V described in claim 1 or 2 is treated in preparation or is prevented the application in the medicine of advanced breast cancer relative disease.
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| WO2005089511A2 (en) * | 2004-03-19 | 2005-09-29 | Transform Pharmaceuticals, Inc. | Novel pharmaceutical forms, and methods of making and using the same |
| WO2007039919A1 (en) * | 2005-10-06 | 2007-04-12 | Natco Pharma Limited | Crystalline forms of anastrozole |
| CN101568526A (en) * | 2006-05-19 | 2009-10-28 | 斯索恩有限公司 | Process for purification of anastrozole |
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- 2013-09-06 CN CN201510047680.7A patent/CN104628662A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005089511A2 (en) * | 2004-03-19 | 2005-09-29 | Transform Pharmaceuticals, Inc. | Novel pharmaceutical forms, and methods of making and using the same |
| WO2007039919A1 (en) * | 2005-10-06 | 2007-04-12 | Natco Pharma Limited | Crystalline forms of anastrozole |
| CN101568526A (en) * | 2006-05-19 | 2009-10-28 | 斯索恩有限公司 | Process for purification of anastrozole |
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| 崔中立,等.: "芳香化酶抑制剂的研究进展", 《中国药物化学杂志》 * |
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