CN103755765A - Polycrystalline type for ulipristal acetate and preparation method thereof - Google Patents
Polycrystalline type for ulipristal acetate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a polycrystalline type A1 and a polycrystalline type A2 of ulipristal acetate (shown as a formula I) not containing any solvate, and preparation methods, a medicinal composition and medicinal application thereof. As proved by smelting point, X-ray powder diffraction (XRD), infrared spectrogram (IR), differential thermal analysis spectrogram (DSC) and thermal weight loss spectrogram (TG), the polycrystalline type A1 and the polycrystalline type A2 of ulipristal acetate prepared by using the methods are extremely stable under the conditions of temperature, illumination and moisture, and contribute to long-time storage. A used crystallization solvent is safe and is easy to remove, the prepared polycrystalline type A1 and polycrystalline type A2 can be directly applied to preparation processing, and the preparation methods are easy to operate, and suitable for industrial production.
Description
The application is the divisional application of on 04 17th, 2012 applying date, application number 201210112043.X, denomination of invention " polymorphic of CDB-2914 and preparation method thereof " Chinese patent application.
Technical field
The present invention relates to the polymorphic of CDB-2914, specifically, relate to polymorphic A1, polymorphic A2 of a kind of antiprogestin and Antiglucocorticoid drug CDB-2914 and preparation method thereof.Belong to pharmaceutical chemistry field.
Background technology
As everyone knows, recrystallisation solvent difference or crystallization method difference can produce different polymorphics, and different polymorphics has different stability and solvability, and bioavailability even is in vivo different sometimes.Thereby in drug development, need to find that a kind of to obtain highly purified and stable polymorphic very necessary, and the method is easy to reappear and is applicable to the large-scale preparation of industry.In addition, X-diffraction powder collection of illustrative plates (XRD) is a kind of effective means of determining crystal formation.
CDB-2914 (Ulipristal acetate; Compound I; Chemical name: 17 α-acetoxyl group-11 β-(4-N, N-dimethylamino phenyl)-19-norpregna-4,9-diene-3,20-diketone) be a kind of potent antiprogestin and Antiglucocorticoid drug.Structural formula is as follows:
This medicine is got permission listing in Europe and the U.S., in after unshielded sexual life or known or suspection contraceptive failure 5 days, uses, and be a kind of effective and safe emergency contraception, in Europe, also get permission the treatment for hysteromyoma.But, about particularly not the reporting seldom containing the crystal formation of solvate of good stability of polymorphic of this medicine.
First, U.S. Pat 5929262 discloses successively through dissolving with Virahol, concentrated dry, repeatedly processes three times afterwards then with acetic acid ethyl dissolution, concentrated dryly obtains foam by ether crystallization treatment, to obtain fusing point be again the yellow product of 183-185 ℃;
In addition, world patent WO2004078709 discloses with dissolve with ethanol, diatomite filtration processing, and the crystallization of acetone/normal hexane, then after chromatogram purification, finally by 90% alcohol crystal, obtain white solid product, its purity 99%, fusing point 183-185 ℃;
Whether the above-mentioned document product that all report does not obtain is containing solvent.
In addition, Chinese patent CN200780021915.9 discloses after Virahol crystallization and at 70 ℃, with second alcohol and water heated and stirred 14h, has obtained the not crystal containing solvate, fusing point 184-186 ℃ again.
Above-mentioned document is the unexposed data such as the X powder diffraction collection of illustrative plates (XRD) that product is relevant, infrared (IR), differential thermal analysis curve (DSC) or thermal weight loss collection of illustrative plates (TG) that obtain all, do not report the purity of final product yet, the particularly limitation of relative substance, also reports without product stability data.
Finally, Chinese patent CN100354300C discloses Virahol half solvate that obtains CDB-2914 with Virahol recrystallization, then further through ether or ethanol/water recrystallization, obtain VA-2914, not containing solvate CDB-2914, the document has been reported Virahol half solvate of CDB-2914 and with ether or ethanol/water recrystallization, has been obtained the X diffraction powder collection of illustrative plates (XRD) of VA-2914, infared spectrum (IR), the data such as differential thermal analysis collection of illustrative plates (DSC), but without product Dependent Stability data report and thermal weight loss collection of illustrative plates (TG).The document has also reported that in Virahol half solvate of CDB-2914, isopropanol content is 5.9%.
Above-mentionedly by ethanol/water crystallization treatment, obtain being not in fact helpless to crystallization containing the method for solvate product and remove impurity, even because long-time heat causes new impurity to be produced, thereby be more difficult to obtain the high-purity product of singly mixing below 0.1%.
Summary of the invention
The invention provides not CDB-2914 polymorphic A1, the polymorphic A2 containing solvate, the present invention also provides the simple industrialized method of preparing CDB-2914 crystal form A 1, polymorphic A2 that is applicable to.
Technical solution of the present invention is as follows:
The polymorphic A1 that does not contain the CDB-2914 of solvate of a kind of formula (I),
Its X-ray powder diffraction pattern (XRD) is at the following charateristic avsorption band of 2 θ ± 0.2 tool: 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 and prepares described abovely not containing the method for the polymorphic A1 of the CDB-2914 of solvate, it is characterized in that comprising the step that CDB-2914 or the processing of its solvate anhydrous methanol is made to described CDB-2914 polymorphic A1.
Wherein, as preferably, method described above, it is characterized in that described step is: CDB-2914 solvate is dissolved in methyl alcohol, then be evaporated to doubly (ml/g) of methyl alcohol 0.5-5, then slowly cool to 10-30 ℃, insulated and stirred, filter, dry gained solid, obtain described CDB-2914 polymorphic A1.
Advantageously by methyl alcohol, process crystallization and can obtain high purity 99.8%, single assorted CDB-2914 finished product of 0.1% that is less than.
As another aspect of the present invention, the polymorphic A2 that does not contain the CDB-2914 of solvate of a kind of formula (I) is also provided,
Its X-ray powder diffraction pattern (XRD) is at the following charateristic avsorption band of 2 θ ± 0.2 tool: 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.
It is described above not containing the method for the polymorphic A2 of the CDB-2914 of solvate that the present invention also provides, and it is characterized in that comprising the step that CDB-2914 or the processing of its solvate methanol/water is made to described CDB-2914 polymorphic A2.
Preferably, method described above, is characterized in that described step is:
CDB-2914 solvate is dissolved in methyl alcohol, under 30-60 ℃ of stirring, drips water, after insulated and stirred, cooling, filter, dry gained solid, obtain described CDB-2914 polymorphic A2;
Or, CDB-2914 polymorphic A1 claimed in claim 1 is suspended in methanol/water, after 30-60 ℃ of insulated and stirred, cooling, filter, dry gained solid, obtain described CDB-2914 polymorphic A2.
Preferably, the 0.5-5 that wherein consumption of water is quantity of methyl alcohol doubly.
The polymorphic A1 or the polymorphic A2 that do not contain the CDB-2914 of solvate that the present invention is described above, be the stable form of CDB-2914, and purity is high, for the medicine of antiprogestin or Antiglucocorticoid.Therefore, as content of the present invention, the present invention also provides a kind of pharmaceutical composition, and it comprises active constituents of medicine and pharmaceutically acceptable carrier, and wherein said active constituents of medicine is the described above polymorphic A1 or the polymorphic A2 that do not contain the CDB-2914 of solvate.
CDB-2914 is used for 120 hours emergency contraceptions afterwards, and also can be used for hysteromyoma treatment, for controlling hysteromyoma hemorrhage, reduce myomata volume and improving pain effect etc.Therefore, the polymorphic A1 of the CDB-2914 that does not contain solvate of the present invention or polymorphic A2, as active pharmaceutical ingredients, can be used for emergency contraception in 120 hours afterwards, and dosage is 30mg/ time, oral.In addition, the polymorphic A1 or the polymorphic A2 that do not contain the CDB-2914 of solvate also can be used for hysteromyoma treatment, for controlling hysteromyoma hemorrhage, reducing myomata volume and improve pain effect etc., take 5mg or 10mg dosage day, 3-4 month course for the treatment of.
The activeconstituents that not can be used as emergency contraception or treatment hysteromyoma containing the polymorphic A1 of the CDB-2914 of solvate or polymorphic A2, suitable pharmaceutical dosage form comprises tablet, capsule, dispersible tablet, orally disintegrating tablet etc., auxiliary material is selected from but is not limited to lactose, N.F,USP MANNITOL, polyvinylpolypyrrolidone, micropowder silica gel, Magnesium Stearate, Microcrystalline Cellulose, Xylo-Mucine, hydroxypropylcellulose etc.
In addition, the described above polymorphic A1 that does not contain the CDB-2914 of solvate, can also be as the preparation starting material that does not contain the polymorphic A2 of the CDB-2914 of solvate as above.
The present invention finds unexpectedly, and with the non-water except methyl alcohol, single or mixed solvent crystallization CDB-2914 all easily generates the polymorphic that contains solvate, and the 120 ℃ of bakings under high vacuum of this solvate are all difficult to remove contained solvent for 24 hours.Its solvent is according to the difference of recrystallisation solvent used and variant.Differential thermal analysis (DSC) collection of illustrative plates shows that the polymorphic that contains solvate shows 1-4 endotherm(ic)peak at 160-220 ℃, and thermal weight loss (TG) collection of illustrative plates shows that its fusing point is different, in Table 1 containing 0.2-6% recrystallisation solvent.In addition, these have compared with notable difference containing X-ray powder diffraction pattern (XRD) and infrared (IR) collection of illustrative plates between the polymorphic of solvate.
Table 1, the comparison of different solvents crystallized product
While processing by document CN200780021915.9 with ethanol/water in addition, also obtain the polymorphic containing a small amount of solvate, thermal weight loss (TG) collection of illustrative plates shows containing quantity of solvent approximately 0.36%, differential thermal analysis (DSC) collection of illustrative plates shows two endotherm(ic)peaks, is respectively 167 ℃ and 204 ℃.Again with ethanol/water re-treatment, obtain thermal weight loss (TG) collection of illustrative plates and show the not product containing quantity of solvent, differential thermal analysis (DSC) collection of illustrative plates shows an endotherm(ic)peak, approximately 189 ℃.
Above non-water is single or mixed solvent crystallization CDB-2914 obtains CDB-2914 solvate or polymorphic form except methyl alcohol, even if be repeatedly all difficult to preparation high purity with these solvent crystallizations, particularly single assorted product of 0.1% that is less than.And the above-mentioned polymorphic containing solvate is unfavorable for being directly used in preparation processing.But it is of the present invention not containing the CDB-2914 polymorphic A1 of solvate or the useful intermediates of polymorphic A2 that the solvate of these CDB-2914s or polymorphic form all can be used as preparation.
Research is found, by the CDB-2914 methyl alcohol crystallization according to a conventional method of more than 99% white of purity with additive method (as the purification process of document WO2004078709) acquisition, as get 1g product and add 10-15 times of dissolve with methanol and obtain green solution, be evaporated to and be equivalent to product 2-3 times volume, be cooled to 10 ℃, first separate out yellow thick material, and be difficult to filter.And dry what obtain is a kind of yellow foam material at 60 ℃ of concentrating under reduced pressure, fusing point is lower, approximately 120 ℃.
Further research is found, be evaporated to and be equivalent to product 0.5-5 times methyl alcohol (ml/g), by slowly cooling and maintain 10-30 ℃ grind stir 1-24h or longer time, the loose solid of white can be separated out gradually, cold filtration, 60 ℃ of oven dry obtain the not CDB-2914 polymorphic A1 containing solvate, are white or off-white powder.The fusing point of this polymorphic A1 is 175-180 ℃ after tested.
By using anhydrous methanol processing, not solvent-laden CDB-2914 is constantly separated out, and can effectively remove impurity, particularly yellow substance, improve product purity.And, identical CDB-2914 crude product, by processing with methyl alcohol or the purity of the product that obtains of crystallization significantly improves, impurity number and content are starkly lower than with Virahol, ethanol, ethyl acetate, the product of acetone equal solvent crystallization, and can obtain single assorted highly purified not solvent-laden CDB-2914 polymorphic A1 of 0.1% that is less than.
In addition, CDB-2914 polymorphic A1 also can be used as the useful intermediate of preparing polymorphic A2.
It is the polymorphic A1 containing solvate not that thus obtained polymorphic is analyzed what show to obtain through X-ray powder diffraction (XRD), infrared spectra (IR) (KBr compressing tablet), differential thermal analysis collection of illustrative plates (DSC) and thermal weight loss collection of illustrative plates (TG), the data of its X diffracting spectrum data and bibliographical information ethanol/water crystallized product are different, for a kind of new polymorphic, test result is as follows:
X-ray powder diffraction pattern shows that polymorphic A1 has following notable feature absorption peak in reflection angle 2 θ ± 0.2, and it sees 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 the following notable feature absorption peak of polymorphic A1 tool, 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 endotherm(ic)peak at 160-220 ℃, specifically at 188 ± 2 ℃, show the endotherm(ic)peak of, the 204+2 ℃ of absorption peak of locating can die down gradually or disappear, thermal weight loss (TG) collection of illustrative plates of CDB-2914 polymorphic A1 shows not containing recrystallisation solvent, 250 ℃ of left and right start weightless and decompose, and see accompanying drawing 3.
On the other hand, the invention provides the preparation method who does not contain the CDB-2914 polymorphic A2 of solvate.
Specifically, by above-mentioned CDB-2914 polymorphic, methyl alcohol containing solvate is added to reactor, heating for dissolving, under 30-60 ℃ of stirring, drip water, insulated and stirred 2-8h or longer, cooling, filter, in 60 ℃, dry the CDB-2914 polymorphic A2 that obtains not containing solvate to constant weight.Or directly polymorphic A1 being suspended in methanol/water, in 30-60 ℃ of insulated and stirred 2-8h or longer, filtering, in 60 ℃, dry to constant weight and obtain not the CDB-2914 polymorphic A2 containing solvate, is white or off-white powder.The fusing point of products therefrom is 175-180 ℃.The amount of water is without too many requirement, and doubly or more, the amount that increases water contributes to improve yield to the 0.5-5 that is generally quantity of methyl alcohol.
Advantageously, can be at a lower temperature by use methanol/water, as 30-60 ℃, in short period, as 2-8h, the not CDB-2914 containing solvate is separated out fast, the method has been avoided with ethanol/water long-time (14h), 70 ℃ of heat produce the problems such as new impurity, and the time is short, is easier to industrialization.
It is the polymorphic A2 containing solvate not that the CDB-2914 polymorphic A2 that the present invention obtains analyzes what show to obtain through X-ray powder diffraction (XRD), infrared spectra (IR) (KBr compressing tablet), differential thermal analysis collection of illustrative plates (DSC) and thermal weight loss collection of illustrative plates (TG), for a kind of polymorphic that is different from existing bibliographical information, test result is as follows.
X-ray powder diffraction pattern shows that polymorphic A2 has following notable feature absorption peak in reflection angle 2 θ ± 0.2, sees accompanying drawing 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 absorption 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 endotherm(ic)peak 160-220 ℃ of demonstration, specifically at 189+2 ℃, show unique endotherm(ic)peak, thermal weight loss (TG) collection of illustrative plates shows that CDB-2914 polymorphic A2 is not containing recrystallisation solvent, 251 ℃ of left and right start weightless and decompose, and see accompanying drawing 6.
Polymorphic A1 and polymorphic A2 difference:
Polymorphic A1 and polymorphic A2 are embodied in the former in the difference of X-ray powder diffraction pattern (XRD) and in reflection angle 2 θ ± 0.2, have more following notable feature absorption peak than the latter: 4.75,6.29,8.25,9.53,12.63,13.32,18.53.From infared spectrum (IR), the infared spectrum of polymorphic A1 and polymorphic A2 is basically identical.
Differential thermal analysis collection of illustrative plates (DSC) shows, polymorphic A2 only has a strong endotherm(ic)peak between 150-210 ℃, specifically 189 ± 2 ℃ of left and right, and polymorphic A1 at least has a strong endotherm(ic)peak 189 ± 2 ℃ of left and right, sometimes 205 ± 2 ℃ of left and right, also have a weak endotherm(ic)peak.
Both are concrete relatively in Table 2.Both fusing points are different from the fusing point of bibliographical information ethanol/water crystallized product.
Table 2, polymorphic A1 and the comparison of polymorphic A2 difference
The comparison of all kinds of SOLVENTS crystallization effect and stability study:
By ethanol/water crystallized product, CDB-2914 polymorphic A1 and crystal form A 2 are carried out to Study on influencing factors, show that CDB-2914 polymorphic A1 and crystal form A 2 have better stability.Relatively showing of influence factor experiment, CDB-2914 polymorphic A1, polymorphic A2 are stable under super-humid conditions, and illumination experiment shows that its stability is better, and concrete data see the following form 3.
Table 3: the stability experiment result of study of polycrystal A1 and polymorphic A2
Accompanying drawing explanation
The accompanying drawing that the application comprises is a part that forms specification sheets, and accompanying drawing and specification sheets and claim one are used from explanation flesh and blood of the present invention, for understanding better the present invention.
Accompanying drawing 1: the X-ray powder diffraction pattern (XRD) of polymorphic A1
Accompanying drawing 2: the infared spectrum (IR) of polymorphic A1
Accompanying drawing 3: the differential thermal analysis (DSC) of polymorphic A1 and thermal weight loss (TG) collection of illustrative plates
Accompanying drawing 4: the X-ray powder diffraction pattern (XRD) of polymorphic A2
Accompanying drawing 5: the infared spectrum (IR) of polymorphic A2
Accompanying drawing 6: the differential thermal analysis (DSC) of polymorphic A2 and thermal weight loss (TG) collection of illustrative plates
The X-ray powder diffraction pattern spectrum data of the polymorphic A1 of accompanying drawing 1 is as follows:
The X-ray powder diffraction pattern spectrum data of the polymorphic A2 of accompanying drawing 4 is as follows:
Testing tool and testing method:
X-ray powder diffraction (XPD):
Instrument model: Bruker D8ADVANCE powder x-ray diffraction
Experiment condition: light source: CuK α 40kV40mA; Divergent slit: 1mm; Rope draws slit: 0.4mm; Scan mode: continuous sweep; Sweep limit: 3 °～45 °; Sampling interval: 0.02 °; Sweep velocity: 8 °/min.
Infrared:
Instrument model: NICOLET670-FTIR experiment condition: KBr compressing tablet
DSC?parmeters：
Instrument model: NETZSCH DSC204F1
Crucible type: aluminium crucible (acupuncture perforation)
Sweep gas: High Purity Nitrogen, 20mL/min
Protection gas: High Purity Nitrogen, 60mL/min
Heat-up rate: 10 ℃/min
TG?parmeters
Instrument model: NETZSCH TG209F1
Crucible type: alumina crucible
Sweep gas: High Purity Nitrogen, 20mL/min
Protection gas: High Purity Nitrogen, 10mL/min
Heat-up rate: 10 ℃/min
Fusing point: b shape pipe, thermometer is not proofreaied and correct.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiment do not form any restriction to the present invention.
Preparation example 1: the polymorphous general preparation method of CDB-2914 solvate:
By CDB-2914 crude product 1g, add in 10-13 times of ethanol (ml/g), reflux is dissolved, and adds gac 0.1g decolouring, filters, and is evaporated to 3-5 times of volume, under then stirring, is chilled to 10 ℃, stirs after 30 minutes-1 hour, filters.60 ℃ of oven dry.Obtain 0.88 gram of CDB-2914 ethylate, mp:150-170 ℃.
Use equally acetone instead, Virahol, ethyl acetate, crystallization obtains different CDB-2914 solvate polymorphics.
Preparation example 2: CDB-2914 Virahol/alcohol solvent compound preparation method:
By CDB-2914 crude product 1g, add in 10 times of Virahol/ethanol (9: 1), reflux is dissolved, and adds gac 0.1g decolouring, filters, and under then stirring, is chilled to 10 ℃, stirs after 30 minutes-1h, filters.60 ℃ of oven dry obtain 0.85 gram of CDB-2914 Virahol/alcohol solvent compound, mp:164-170 ℃.
Preparation example 3: CDB-2914 ethyl acetate/petroleum ether solvate preparation method:
By CDB-2914 crude product 1g, add 5 times of methylene dichloride to dissolve, add gac 0.1g decolouring, filter, be evaporated to substantially solvent-freely, add ethyl acetate/petroleum ether (1: 5), be chilled to 20 ℃ and stir after 30 minutes-1h, filter.60 ℃ of oven dry obtain 0.85 gram of CDB-2914 ethyl acetate/petroleum ether solvate, mp:160-210 ℃.
Embodiment 1: CDB-2914 polymorphic A1
By CDB-2914 ethylate polymorphic (10.0g), add in methyl alcohol 120ml, heating for dissolving, adds gac 0.1g decolorization filtering, be evaporated to about 20-30ml, Slow cooling, successively in 40 ℃, 30 ℃, 20 ℃ are stirred 1h, in 10 ℃, stir 5-6h, filtration.60 ℃ of oven dry, obtain approximately 8.6 grams of CDB-2914 polymorphic A1, mp:176-178 ℃.
Take CDB-2914 ethyl acetate solvent compound, acetone solvate or isopropanol solvate as raw material, obtain similar results equally.
Embodiment 2: CDB-2914 polymorphic A2
By CDB-2914 ethylate polymorphic (12.0g), add in methyl alcohol 150ml, heating for dissolving, in 50-60 ℃ of dropping distilled water 150ml, 50-60 ℃ of insulated and stirred 5-6h, is cooled to 10 ℃ of filtrations.60 ℃ of oven dry, obtain approximately 10.5 grams of CDB-2914 polymorphic A2, mp:177-179 ℃.
Take CDB-2914 ethyl acetate solvent compound, acetone solvate or isopropanol solvate as raw material, obtain similar results equally.
Embodiment 3: CDB-2914 polymorphic A2
CDB-2914 polymorphic A1 (10.0g) is suspended in and is added in methyl alcohol (50ml) and water (150ml), in 50-60 ℃ of insulated and stirred 5-6h, be cooled to 10 ℃ of filtrations.60 ℃ of oven dry, obtain approximately 9.2 grams of CDB-2914 polymorphic A2, mp:177-179 ℃.
Embodiment 4:
Main ingredient is crossed 200 mesh sieves, and weighting agent, disintegrating agent are crossed 80 mesh sieves, and the weighting agent, the disintegrating agent that take recipe quantity mix, then the main ingredient of recipe quantity is mixed according to the equivalent method of progressively increasing with it, add glidant and the lubricant of recipe quantity, after mixing, compressing tablet and get final product.
Embodiment 5:
Preparation technology
Main ingredient is crossed 200 mesh sieves, and weighting agent, disintegrating agent are crossed 80 mesh sieves, and the weighting agent, the disintegrating agent that take recipe quantity mix, then the main ingredient of recipe quantity is mixed according to the equivalent method of progressively increasing with it, add glidant and the lubricant of recipe quantity, after mixing, compressing tablet and get final product.
Embodiment 6:
Preparation technology
Main ingredient is crossed 200 mesh sieves, and weighting agent, disintegrating agent are crossed 80 mesh sieves, and the main ingredient of recipe quantity is mixed according to the equivalent method of progressively increasing with weighting agent, adds suitable amount of adhesive to granulate, dry after, add disintegrating agent and the lubricant of recipe quantity, after mixing, compressing tablet and get final product.
Embodiment 7:
Preparation technology
Main ingredient is crossed 200 mesh sieves, and weighting agent, disintegrating agent are crossed 80 mesh sieves, and the main ingredient of recipe quantity is mixed according to the equivalent method of progressively increasing with weighting agent, adds suitable amount of adhesive to granulate, dry after, add disintegrating agent and the lubricant of recipe quantity, after mixing, compressing tablet and get final product.
Claims (6)
1. a polymorphic A2 who does not contain the CDB-2914 of solvate for formula (I),
Its X-ray powder diffraction pattern (XRD) is at the following charateristic avsorption band of 2 θ ± 0.2 tool: 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. prepare claimed in claim 1ly not containing a method of the polymorphic A2 of the CDB-2914 of solvate, it is characterized in that comprising the step that CDB-2914 or the processing of its solvate methanol/water is made to described CDB-2914 polymorphic A2.
3. method according to claim 2, is characterized in that described step is:
CDB-2914 solvate is dissolved in methyl alcohol, under 30-60 ℃ of stirring, drips water, after insulated and stirred, cooling, filter, dry gained solid, obtain described CDB-2914 polymorphic A2;
Or, CDB-2914 polymorphic A1 is suspended in methanol/water, after 30-60 ℃ of insulated and stirred, cooling, filter, dry gained solid, obtain described CDB-2914 polymorphic A2;
Wherein, described CDB-2914 polymorphic A1, its X-ray powder diffraction pattern (XRD) is at the following charateristic avsorption band of 2 θ ± 0.2 tool: 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.
4. the 0.5-5 that according to the method in claim 2 or 3, wherein the water yield is quantity of methyl alcohol doubly.
5. a pharmaceutical composition, it contains active constituents of medicine and pharmaceutically acceptable carrier, and wherein said active constituents of medicine is the polymorphic A2 that does not contain the CDB-2914 of solvate claimed in claim 1.
6. the purposes of the polymorphic A2 of the CDB-2914 that does not contain solvate claimed in claim 1 in the medicine for the preparation of antiprogestin or Antiglucocorticoid.
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