CN103755765B - Polymorphic of CDB-2914 and preparation method thereof - Google Patents
Polymorphic of CDB-2914 and preparation method thereof Download PDFInfo
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Abstract
The invention discloses the polymorphic A1 without solvate CDB-2914 (Formulas I), polymorphic A2 and preparation method thereof, pharmaceutical composition and medical usage.Pass through fusing point, X diffraction powders collection of illustrative plates (XRD), infared spectrum (IR), differential thermal analysis collection of illustrative plates (DSC) and thermal weight loss collection of illustrative plates (TG) confirmation.The CDB-2914 polymorphic A1 and polymorphic A2 being prepared using the inventive method, it is extremely stable to temperature, illumination and humidity, beneficial to long-term storage, recrystallisation solvent safety used simultaneously is easy to remove, gained polymorphic A1 and polymorphic A2 can be directly used for preparation processing, and preparation method is simple to operate to be suitable for industrialized production.
Description
The application is the applying date 2012 year 04 month 17, application number 201210112043.X, denomination of invention " acetic acid Wu Lisi
The divisional application of his polymorphic and preparation method thereof " Chinese patent application.
Technical field
The present invention relates to the polymorphic of CDB-2914, specifically, is related to a kind of antiprogestin and anti-sugared cortical hormone
Polymorphic A1, polymorphic A2 of plain medicine CDB-2914 and preparation method thereof.Belong to medicinal chemistry art.
Background technology
It is well known that recrystallisation solvent is different or method for crystallising difference can produce different polymorphics, and different polymorphics
It is different with different stability and dissolubility, bioavilability sometimes or even in vivo.Thus needed in drug development
It is very necessary to find a kind of polymorphic obtaining high-purity and stable, and this method is easy to reappear and is adapted to the big rule of industry
The preparation of mould.In addition, X- diffraction powders collection of illustrative plates (XRD) is to determine a kind of effective means of crystal formation.
CDB-2914 (Ulipristal acetate；Compound I；Chemical name：17 α-the β of acetoxyl group-11-(4-N,
N- dimethylamino phenyls) -19- norpregna -4,9- diene -3,20- diketone) it is a kind of potent antiprogestin and anti-sugared cortex
Hormonal medicaments.Structural formula is as follows：
The medicine is approved to list in Europe and the U.S., for after unshielded sexual life or known or suspection contraceptive failure 5
Used in it, be a kind of effective and safe emergency contraception, be also approved the treatment for fibroid in Europe.However, close
It is few in the good report of the crystal formation without solvate of the polymorphic particularly stability of the medicine.
First, United States Patent (USP) US5929262 is disclosed successively through being dissolved with isopropanol, and concentration is dry, after handling three times repeatedly
Then dissolved with ethyl acetate, the dry foam that obtains of concentration is handled to obtain the yellow production that fusing point is 183-185 DEG C again with crystallizing from ether
Thing；
In addition, world patent WO2004078709 is disclosed and dissolved with ethanol, and diatomite filtration treatment, acetone/n-hexane
Crystallization, then after chromatogram purification, white solid product most is obtained through 90% alcohol crystal afterwards, its purity 99%, fusing point 183-185
℃；
Whether the product that above-mentioned document is not reported to obtain contains solvent.
In addition, Chinese patent CN200780021915.9 discloses uses second alcohol and water at 70 DEG C again after isopropanol crystallizes
Heating stirring 14h obtains the crystal without solvate, 184-186 DEG C of fusing point.
Above-mentioned document not publicly obtains the related X powder diffraction collection of illustrative plates (XRD) of product, infrared (IR), differential thermal analysis curve
(DSC) or the data such as thermal weight loss collection of illustrative plates (TG), also without the purity of report final product, more particularly to the limitation of impurity,
Without product stability data report.
Finally, Chinese patent CN100354300C discloses obtains the isopropanol of CDB-2914 with recrystallisation from isopropanol
Half solvate, VA-2914 further then is recrystallized to give through ether or ethanol/water, i.e., without solvate acetic acid crow profit
Him is taken charge of, the document reports the solvate of isopropanol half of CDB-2914 and is recrystallized to give VA- with ether or ethanol/water
The data such as 2914 X diffraction powders collection of illustrative plates (XRD), infared spectrum (IR), differential thermal analysis collection of illustrative plates (DSC), but it is related without product
Stability number is it is reported that and thermal weight loss collection of illustrative plates (TG).The document also reported in the solvate of isopropanol half of CDB-2914
Isopropanol content is 5.9%.
It is above-mentioned with ethanol/water crystallization treatment obtain the method without solvate product be actually helpless to crystallization remove it is miscellaneous
Matter, or even because high-temperature heating causes new impurity to produce for a long time, thus it is single miscellaneous high-purity below 0.1% to be more difficult to acquisition
Spend product.
The content of the invention
The invention provides CDB-2914 polymorphic A1, the polymorphic A2 without solvate, the present invention also provides
Simply it is adapted to industrialized prepare CDB-2914 crystal formation A1, polymorphic A2 method.
Technical solution of the present invention is as follows：
A kind of polymorphic A1 of the CDB-2914 without solvate of formula (I),
Its X-ray powder diffraction figure (XRD) has following characteristic absorption peak in 2 θ ± 0.2：4.75,6.29,8.25,9.07,
9.51,11.32,11.62,11.88,12.63,13.28,14.38,15.12,15.78,16.42,16.87,17.29,17.94,
18.51,18.93,19.64,20.31,20.90,21.35,21.99,22.44,22.77,23.51,23.76,24.21,
24.63 25.42
The present invention also provides a kind of polymorphic A1's for preparing the CDB-2914 without solvate described above
Method, it is characterised in that including CDB-2914 or its solvate are handled into the acetic acid for being made described crow profit with absolute methanol
The step of taking charge of his polymorphic A1.
Wherein, preferably, method described above, it is characterised in that described step is：CDB-2914 is molten
Agent compound is dissolved in methanol, is then concentrated under reduced pressure into 0.5-5 times of methanol (ml/g), then slowly cools to 10-30 DEG C, insulation
Stirring, filtering, drying gained solid, produces described CDB-2914 polymorphic A1.
High-purity 99.8% advantageously can be obtained by methyl alcohol process crystallization, it is single it is miscellaneous be less than 0.1% acetic acid crow profit
Take charge of his finished product.
As another aspect of the present invention, also provide a kind of formula (I) the CDB-2914 without solvate it is more
Crystal formation A2,
Its X-ray powder diffraction figure (XRD) has following characteristic absorption peak in 2 θ ± 0.2：9.06,11.30,11.58,
11.88 14.42,15.13,15.79,16.42,16.89,17.29,17.94,18.25,18.96,20.33,20.98,
21.47,21.94,22.79,23.54,23.80,24.21,24.63.
The method that the present invention also provides the polymorphic A2 of the CDB-2914 without solvate described above, it is special
Sign is to include CDB-2914 or the processing of its solvate methanol/water described CDB-2914 polymorphic is made
The step of A2.
Preferably, method described above, it is characterised in that described step is：
CDB-2914 solvate is dissolved in methanol, under 30-60 DEG C of stirring, water is added dropwise, after insulated and stirred,
Cooling, filtering, drying gained solid, produces described CDB-2914 polymorphic A2；
Or the CDB-2914 polymorphic A1 described in claim 1 is suspended in methanol/water, in 30-60 DEG C of guarantor
After temperature stirring, cooling, filtering, drying gained solid, described CDB-2914 polymorphic A2 is produced.
Preferably, the dosage of its reclaimed water is 0.5-5 times of quantity of methyl alcohol.
The polymorphic A1 or polymorphic A2 of the present invention CDB-2914 without solvate described above, are acetic acid
The stable form of Ulipristal, purity is high, for antiprogestin or the medicine of Antiglucocorticoid.Therefore, as in the present invention
Hold, the present invention also provides a kind of pharmaceutical composition, and it includes active constituents of medicine and pharmaceutically acceptable carrier, wherein described
Active constituents of medicine be the CDB-2914 without solvate described above polymorphic A1 or polymorphic A2.
CDB-2914 is used for 120 hours emergency contraceptions afterwards, and can be additionally used in fibroid treatment, for controlling
Hysteromyoma hemorrhage, reduce myomata volume and improve pain effect etc..Therefore, the vinegar of the present invention without solvate
The polymorphic A1 or polymorphic A2 of sour Ulipristal are as medicinal active ingredient, available for emergency contraception in 120 hours afterwards, dosage
For 30mg/ times, orally.In addition, the polymorphic A1 or polymorphic A2 of the CDB-2914 without solvate can also be used for son
The treatment of palace myomata, for controlling hysteromyoma hemorrhage, reducing myomata volume and improving pain effect etc., take dosage day 5mg or
10mg, course for the treatment of 3-4 months.
The polymorphic A1 or polymorphic A2 of CDB-2914 without solvate can be used as emergency contraception or treatment
The active component of fibroid, suitable pharmaceutical dosage form include tablet, capsule, dispersible tablet, oral disintegrating tablet etc., and auxiliary material is selected from but unlimited
It is fine in lactose, mannitol, PVPP, superfine silica gel powder, magnesium stearate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl
Tie up element etc..
In addition, the polymorphic A1 of the CDB-2914 without solvate described above, is also used as preparing such as
The polymorphic A2 of the upper described CDB-2914 without solvate starting material.
Present invention surprisingly has found that with the non-aqueous single or mixed solvent crystallization CDB-2914 in addition to methanol
All easy polymorphic of the generation containing solvate, the solvate under a high vacuum 120 DEG C dry all be difficult within 24 hours to remove it is contained
Solvent.Its solvent used in recrystallisation solvent it is different and variant.Differential thermal analysis (DSC) collection of illustrative plates, which is shown, contains solvate
Polymorphic 160-220 DEG C show 1-4 endothermic peak, thermal weight loss (TG) collection of illustrative plates display display recrystallisation solvent containing 0.2-6%, its
Fusing point is different, is shown in Table 1.In addition, X-ray powder diffraction figure (XRD) between these polymorphics containing solvate and red
(IR) collection of illustrative plates has more apparent difference outside.
Table 1, different solvents crystallized product compare
The polycrystalline containing a small amount of solvate is also obtained when being handled in addition with ethanol/water by document CN200780021915.9
Type, thermal weight loss (TG) collection of illustrative plates, which is shown, contains quantity of solvent about 0.36%, and differential thermal analysis (DSC) collection of illustrative plates shows two endothermic peaks, is respectively
167 DEG C and 204 DEG C.Reprocess to obtain thermal weight loss (TG) collection of illustrative plates with ethanol/water again and show the product without quantity of solvent, differential thermal
Analysis (DSC) collection of illustrative plates shows an endothermic peak, about 189 DEG C.
Acetic acid crow profit obtained by the non-aqueous single or mixed solvent crystallization CDB-2914 in addition to methanol above
His solvate or polymorph are taken charge of, it is particularly single miscellaneous to be less than even if being all difficult repeatedly to prepare high-purity with these solvent crystallizations
0.1% product.And the above-mentioned polymorphic containing solvate is unfavorable for being directly used in preparation processing.But these acetic acid are black
Li Sita solvate or polymorph can be as preparing the CDB-2914 of the present invention without solvate
Polymorphic A1 or polymorphic A2 useful intermediates.
Research finds, the purity 99% obtained by using other method (such as document WO2004078709 purification process) with
Upper white CDB-2914 is crystallized according to a conventional method with methanol, such as takes 1g products to add 10-15 times of methanol to dissolve to obtain green
Solution, it is concentrated under reduced pressure into equivalent to 2-3 times of volume of product, is cooled to 10 DEG C, separates out yellow, viscous material, Er Qienan first
With filtering.And be concentrated under reduced pressure at 60 DEG C it is dry obtain is a kind of yellow colored foam material, fusing point is relatively low, about 120 DEG C.
Further study show that it is concentrated under reduced pressure into equivalent to 0.5-5 times of methanol of product (ml/g), by slowly cooling down simultaneously
Maintaining 10-30 DEG C of grinding or stirring 1-24h or longer time, the solid of white fluffy can gradually separate out, cold filtration, 60 DEG C
Drying obtains the CDB-2914 polymorphic A1 without solvate, for white or off-white powder.The polymorphic after tested
A1 fusing point is 175-180 DEG C.
Handled by using absolute methanol, not solvent-laden CDB-2914 is constantly separated out, and can be effectively
Remove impurity, particularly yellow substance, improve product purity.Also, identical CDB-2914 crude product, by using methyl alcohol process
Or the purity of product that crystallization obtains significantly improves, impurity number and content are significantly lower than using isopropanol, ethanol, ethyl acetate, third
The product of ketone equal solvent crystallization, and the not solvent-laden CDB-2914 of single miscellaneous high-purity for being less than 0.1% can be obtained
Polymorphic A1.
In addition, CDB-2914 polymorphic A1 can also be as the useful intermediate for preparing polymorphic A2.
Thus obtained polymorphic is through X-ray powder diffraction collection (XRD), infrared spectrum (IR) (KBr tablettings), differential thermal
Analysis collection of illustrative plates (DSC) and thermal weight loss collection of illustrative plates (TG) carry out the polymorphic A1 for being free from solvate, its X that analysis shows obtain
Diffracting spectrum data and the data of document report ethanol/water crystallized product are different, are a kind of new polymorphic, test result is such as
Under：
X-ray powder diffraction figure shows that polymorphic A1 has following notable feature absworption peak in θ ± 0.2 of angle of reflection 2, and it is seen
Accompanying drawing 1：
4.75,6.29,8.25,9.07,9.51,11.32,11.62,11.88,12.63,13.28,14.38,15.12,
15.78,16.42,16.87,17.29,17.94,18.51,18.93,19.64,20.31,20.90,21.35,21.99,
22.44,22.77,23.51,23.76,24.21,24.63,25.42
Infrared (IR) spectrum shows that polymorphic A1 has following notable feature absworption peak, sees accompanying drawing 2：
1731,1714,1660,1611,1596,1517,1438,1383,1365,1350,1303,1254,1235,
1201,1168,1147,1091,1063,1023,964,921,862,832,809,768,735,699,670,615,575,
540,495,420cm-1
Differential thermal analysis (DSC) collection of illustrative plates shows that polymorphic A1 shows at least one endothermic peak at 160-220 DEG C, specifically 188
± 2 DEG C of displays endothermic peaks of one, the absworption peak at 204+2 DEG C gradually can die down or disappear, CDB-2914 polymorphic A1
Thermal weight loss (TG) collection of illustrative plates show and be free of recrystallisation solvent, 250 DEG C or so start it is weightless simultaneously decompose, see accompanying drawing 3.
On the other hand, the invention provides the preparation method of the CDB-2914 polymorphic A2 without solvate.
Specifically, by the way that the above-mentioned CDB-2914 polymorphic containing solvate, methanol are added into reactor, heating
Dissolving, under 30-60 DEG C of stirring, water is added dropwise, insulated and stirred 2-8h or longer, cools down, filtering, is dried to constant weight in 60 DEG C and obtains
CDB-2914 polymorphic A2 without solvate.Or directly polymorphic A1 is suspended in methanol/water, in 30-60
DEG C insulated and stirred 2-8h or longer, filtering, constant weight is dried in 60 DEG C and obtains the CDB-2914 polycrystalline without solvate
Type A2, for white or off-white powder.The fusing point of products therefrom is 175-180 DEG C.The amount of water is without too many requirement, generally methanol
0.5-5 times or more of amount, the amount for increasing water are favorably improved yield.
Advantageously, in the short period, such as 2-8h, can make not at a lower temperature, such as 30-60 DEG C by using methanol/water
CDB-2914 containing solvate quickly separates out, and this method avoid with ethanol/water, for a long time (14h), 70 DEG C of high temperature add
Heat produces the problems such as new impurity, and the time is short, it is easier to industrialization.
The CDB-2914 polymorphic A2 that the present invention is obtained is through X-ray powder diffraction collection (XRD), infrared spectrum
(IR) what (KBr tablettings), differential thermal analysis collection of illustrative plates (DSC) and thermal weight loss collection of illustrative plates (TG) progress analysis shows obtained is free from solvent
The polymorphic A2 of compound, it is as follows for a kind of polymorphic different from existing literature report, test result.
X-ray powder diffraction figure shows that polymorphic A2 has following notable feature absworption peak in θ ± 0.2 of angle of reflection 2, sees attached
Fig. 4：
9.06,11.30,11.58,11.88,14.42,15.13,15.79,16.42,16.89,17.29,17.94,
18.25,18.96,20.33,20.98,21.47,21.94,22.79,23.54,23.80,24.21,24.63
Infrared (IR) spectrum shows that polymorphic A2 has following notable feature absworption peak, sees accompanying drawing 5：
1730,1716,1659,1612,1596,1517,1438,1383,1365,1350,1304,1253,1236,
1202,1167,1147,1091,1078,1064,1046,1024,966,953,921,867,833,809,767,734,699,
670,615,575,540,496,419cm-1
Differential thermal analysis (DSC) collection of illustrative plates shows that polymorphic A2 only has an endothermic peak in 160-220 DEG C of display, specifically in 189+
2 DEG C of unique endothermic peaks of display, the display of thermal weight loss (TG) collection of illustrative plates show that CDB-2914 polymorphic A2 is free of recrystallisation solvent,
251 DEG C or so start weightless and decompose, and see accompanying drawing 6.
Polymorphic A1 and polymorphic A2 difference：
Polymorphic A1 and polymorphic A2 is embodied in the former in the difference of X-ray powder diffraction figure (XRD) and reflected than the latter
θ ± 0.2 of angle 2 has more following notable feature absworption peak：4.75,6.29,8.25,9.53,12.63,13.32,18.53.From infrared
Collection of illustrative plates (IR) sees that polymorphic A1 and polymorphic A2 infared spectrum are basically identical.
Differential thermal analysis collection of illustrative plates (DSC) shows that polymorphic A2 only has a highly endothermic peak between 150-210 DEG C, specifically exists
189 ± 2 DEG C or so, and polymorphic A1 at least has a highly endothermic peak at 189 ± 2 DEG C or so, sometimes at 205 ± 2 DEG C or so
Have a weak endothermic peak.
Both are specifically relatively shown in Table 2.Both fusing points are different from the fusing point of document report ethanol/water crystallized product.
Table 2, polymorphic A1 and polymorphic A2 difference compare
Various solvent crystallization effects compare and stability study：
By carrying out Study on influencing factors to ethanol/water crystallized product, CDB-2914 polymorphic A1 and crystal formation A2,
Show that CDB-2914 polymorphic A1 and crystal formation A2 have more preferable stability.Influence factor experiment comparison show, acetic acid
Ulipristal polymorphic A1, polymorphic A2 stablize under conditions of high humidity, and illumination experiment shows that its stability is more preferable, and specific data are shown in
Table 3 below.
Table 3：Polycrystal A1 and polymorphic A2 stability experiment result of study
Brief description of the drawings
The accompanying drawing that the application includes is a part for constitution instruction, and accompanying drawing is reinstated with description and claims item one
In the substantive content of the explanation present invention, for more fully understanding the present invention.
Accompanying drawing 1：Polymorphic A1 X-ray powder diffraction figure (XRD)
Accompanying drawing 2：Polymorphic A1 infared spectrum (IR)
Accompanying drawing 3：Polymorphic A1 differential thermal analysis (DSC) and thermal weight loss (TG) collection of illustrative plates
Accompanying drawing 4：Polymorphic A2 X-ray powder diffraction figure (XRD)
Accompanying drawing 5：Polymorphic A2 infared spectrum (IR)
Accompanying drawing 6：Polymorphic A2 differential thermal analysis (DSC) and thermal weight loss (TG) collection of illustrative plates
The polymorphic A1 of accompanying drawing 1 X-ray powder diffraction figure spectrum data is as follows：
The polymorphic A2 of accompanying drawing 4 X-ray powder diffraction figure spectrum data is as follows：
Tester and method of testing：
X-ray powder diffraction (XPD)：
INSTRUMENT MODEL：Bruker D8ADVANCE powder x-ray diffractions
Experiment condition：Light source：CuKα40kV40mA；Divergent slit：1mm；Rope draws slit：0.4mm；Scan mode：Continuously
Scanning；Scanning range：3 °~45 °；Sampling interval：0.02°；Sweep speed：8 °/min.
It is infrared：
INSTRUMENT MODEL：NICOLET670-FTIR experiment conditions：KBr tablettings
DSC parmeters：
INSTRUMENT MODEL：NETZSCH DSC204F1
Crucible type：Aluminium crucible (acupuncture perforation)
Purge gass：High Purity Nitrogen, 20mL/min
Protect gas：High Purity Nitrogen, 60mL/min
Programming rate：10 DEG C/min
TG parmeters
INSTRUMENT MODEL：NETZSCH TG209F1
Crucible type：Alumina crucible
Purge gass：High Purity Nitrogen, 20mL/min
Protect gas：High Purity Nitrogen, 10mL/min
Programming rate：10 DEG C/min
Fusing point：B shape pipes, thermometer do not correct.
Embodiment
With reference to embodiment, the present invention is further elaborated, but these embodiments do not form any limit to the present invention
System.
Preparation example 1：CDB-2914 solvate is polymorphous to be typically prepared method：
By CDB-2914 crude product 1g, add in 10-13 times of ethanol (ml/g), be heated to reflux dissolving, add activated carbon
0.1g is decolourized, and filtering, is concentrated under reduced pressure into 3-5 times of volume, and 10 DEG C are cooled under then stirring, after stirring -1 hour 30 minutes, mistake
Filter.60 DEG C of drying.Obtain 0.88 gram of CDB-2914 alcoholate, mp：150-170℃.
Equally use acetone instead, isopropanol, ethyl acetate, crystallize and obtain different CDB-2914 solvate polycrystalline
Type.
Preparation example 2：CDB-2914 isopropanol/alcohol solvent compound preparation method：
By CDB-2914 crude product 1g, add in 10 times of isopropanol/ethanol (9: 1), be heated to reflux dissolving, add activated carbon
0.1g decolourizes, and filtering, 10 DEG C is cooled under then stirring, after stirring 30 minutes -1h, filtering.60 DEG C of drying obtain acetic acid Wu Lisi
His 0.85 gram of isopropanol/alcohol solvent compound, mp：164-170℃.
Preparation example 3：CDB-2914 ethyl acetate/petroleum ether solvate preparation method：
By CDB-2914 crude product 1g, 5 times of dichloromethane dissolvings are added, adds activated carbon 0.1g to decolourize, filtering, depressurizes dense
Substantially solvent-free, addition ethyl acetate/petroleum ether (1: 5) is reduced to, after being cooled to 20 DEG C of stirrings, 30 minutes -1h, filtering.60 DEG C of drying
Obtain 0.85 gram of CDB-2914 ethyl acetate/petroleum ether solvate, mp：160-210℃.
Embodiment 1：CDB-2914 polymorphic A1
CDB-2914 alcoholate polymorphic (10.0g) is added in methanol 120ml, dissolve by heating, add activated carbon
0.1g decolorization filterings, about 20-30ml is concentrated under reduced pressure into, Slow cooling, successively in 40 DEG C, 30 DEG C, 20 DEG C of stirring 1h, is stirred in 10 DEG C
5-6h is mixed, is filtered.60 DEG C of drying, obtain about 8.6 grams of CDB-2914 polymorphic A1, mp：176-178℃.
Equally using CDB-2914 ethyl acetate solvate, acetone solvate or isopropanol solvate as original
Material, obtains similar results.
Embodiment 2：CDB-2914 polymorphic A2
CDB-2914 alcoholate polymorphic (12.0g) is added in methanol 150ml, dissolved by heating, in 50-60
DEG C be added dropwise distilled water 150ml, 50-60 DEG C of insulated and stirred 5-6h, be cooled to 10 DEG C of filterings.60 DEG C of drying, obtain acetic acid Wu Lisi
He is about 10.5 grams of polymorphic A2, mp：177-179℃.
Equally using CDB-2914 ethyl acetate solvate, acetone solvate or isopropanol solvate as original
Material, obtains similar results.
Embodiment 3：CDB-2914 polymorphic A2
CDB-2914 polymorphic A1 (10.0g) is suspended in and added in methanol (50ml) and water (150ml), in 50-
60 DEG C of insulated and stirred 5-6h, it is cooled to 10 DEG C of filterings.60 DEG C of drying, obtain about 9.2 grams of CDB-2914 polymorphic A2, mp：
177-179℃。
Embodiment 4：
Main ingredient crosses 200 mesh sieves, and filler, disintegrant cross 80 mesh sieves, and filler, the disintegrant mixing for weighing recipe quantity are equal
It is even, then the main ingredient of recipe quantity is well mixed with it according to the equivalent method of progressively increasing, adds the glidant and lubricant of recipe quantity, is mixed
After closing uniformly, tabletting produces.
Embodiment 5：
Preparation technology
Main ingredient crosses 200 mesh sieves, and filler, disintegrant cross 80 mesh sieves, and filler, the disintegrant mixing for weighing recipe quantity are equal
It is even, then the main ingredient of recipe quantity is well mixed with it according to the equivalent method of progressively increasing, adds the glidant and lubricant of recipe quantity, is mixed
After closing uniformly, tabletting produces.
Embodiment 6：
Preparation technology
Main ingredient crosses 200 mesh sieves, and filler, disintegrant cross 80 mesh sieves, and the main ingredient of recipe quantity is passed with filler according to equivalent
Addition is well mixed, and adds suitable amount of adhesive granulation, after drying, adds the disintegrant and lubricant of recipe quantity, after being well mixed,
Tabletting produces.
Embodiment 7：
Preparation technology
Main ingredient crosses 200 mesh sieves, and filler, disintegrant cross 80 mesh sieves, and the main ingredient of recipe quantity is passed with filler according to equivalent
Addition is well mixed, and adds suitable amount of adhesive granulation, after drying, adds the disintegrant and lubricant of recipe quantity, after being well mixed,
Tabletting produces.
Claims (5)
1. a kind of polymorphic A2 of the CDB-2914 without solvate of formula (I),
Its X-ray powder diffraction figure (XRD) has following characteristic absorption peak in 2 θ ± 0.2：9.06,11.30,11.58,11.88,
14.42,15.13,15.79,16.42,16.89,17.29,17.94,18.25,18.96,20.33,20.98,21.47,
21.94,22.79,23.54,23.80,24.21,24.63.
2. a kind of method for the polymorphic A2 for preparing the CDB-2914 without solvate described in claim 1, it is special
Sign is to include CDB-2914 or the processing of its solvate methanol/water described CDB-2914 polymorphic is made
The step of A2, and described step is：
CDB-2914 solvate is dissolved in methanol, under 50-60 DEG C of stirring, water is added dropwise, it is cold after insulated and stirred
But, filter, dry gained solid, produce described CDB-2914 polymorphic A2；
Or CDB-2914 polymorphic A1 is suspended in methanol/water, after 50-60 DEG C of insulated and stirred, cooling, filtering,
Drying gained solid, produces described CDB-2914 polymorphic A2；
Wherein, described CDB-2914 polymorphic A1, its X-ray powder diffraction figure (XRD) have following special in 2 θ ± 0.2
Levy absworption peak：4.75,6.29,8.25,9.07,9.51,11.32,11.62,11.88,12.63,13.28,14.38,15.12,
15.78,16.42,16.87,17.29,17.94,18.51,18.93,19.64,20.31,20.90,21.35,21.99,
22.44,22.77,23.51,23.76,24.21,24.63,25.42.
3. the method according to claim 11, wherein water are 0.5-5 times of quantity of methyl alcohol.
4. a kind of pharmaceutical composition, it contains active constituents of medicine and pharmaceutically acceptable carrier, wherein described medicine is lived
Property composition be claim 1 described in the CDB-2914 without solvate polymorphic A2.
5. the polymorphic A2 of the CDB-2914 without solvate described in claim 1 preparing for antiprogestin or
Purposes in the medicine of Antiglucocorticoid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410022440.7A CN103755765B (en) | 2012-04-17 | 2012-04-17 | Polymorphic of CDB-2914 and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410022440.7A CN103755765B (en) | 2012-04-17 | 2012-04-17 | Polymorphic of CDB-2914 and preparation method thereof |
| CN201210112043.XA CN102675395B (en) | 2012-04-17 | 2012-04-17 | Polycrystal forms of ulipristal acetate and preparation method thereof |
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