CN105085529A - Novel crystal form of ibrutinib and preparation method thereof - Google Patents
Novel crystal form of ibrutinib and preparation method thereof Download PDFInfo
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- CN105085529A CN105085529A CN201510246220.7A CN201510246220A CN105085529A CN 105085529 A CN105085529 A CN 105085529A CN 201510246220 A CN201510246220 A CN 201510246220A CN 105085529 A CN105085529 A CN 105085529A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention relates to a novel crystal form of ibrutinib and a preparation method thereof, and belongs to the technical field of pharmacy. The differential scanning calorimetry curve of the novel crystal form has endothermic peak at 194-204 DEG C; and the novel crystal form has good physical and chemical properties, is conducive to the production operation, and can be used in the preparation of pharmaceutical preparations.
Description
Technical field
The present invention relates to new crystal replacing Buddhist nun according to Shandong and preparation method thereof, belong to medicinal chemistry art.
Background technology
According to Shandong for Buddhist nun (English name Ibrutinib), chemistry 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 by name, 4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, a kind of irreversible bruton's tyrosine kinase (BTK, Bruton'styrosinekinase) inhibitor, the propagation of malignant B cell, existence can be suppressed, can be used for the diseases such as treatment chronic lymphocytic leukemia (CLL) and minicell lymphocytic lympboma; Its structure is such as formula shown in (1):
PCT application WO2013184572 discloses its multiple crystal formation.But because of the common phenomenon that polymorph in pharmaceuticals is in drug research and development, be the important factor affecting drug quality.The different crystal forms of same medicine may have remarkable difference in the physico-chemical properties such as outward appearance, mobility, solubleness, stability in storage, bioavailability, may huge difference be there is, can shift the storage of medicine, apply, stability, curative effect etc. produce different impacts; In order to obtain effective crystal formation, need comprehensively to investigate according to the crystallization behavior of Shandong for Buddhist nun, to be met the crystal formation of production requirement.
Summary of the invention
Summary of the invention
First aspect present invention provides the crystal form A 2 and the A3 that replace Buddhist nun according to Shandong.
Second aspect present invention provides according to Shandong for the crystal form A 2 of Buddhist nun and the preparation method of A3.
Third aspect present invention provides replaces the crystal form A 2 of Buddhist nun and/or the application of A3 in the medicine for the treatment of potential treatment chronic lymphocytic leukemia (CLL) and minicell lymphocytic lympboma according to Shandong.
Fourth aspect present invention provides and comprises according to the pharmaceutical composition of Shandong for the crystal form A 2 of Buddhist nun.
Term definition
The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.In combined document, patent and one or more different from the application or conflicting situations of analogous material (including but not limited to defined term, term application, described technology etc.), be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS version are consistent with 1994 the 75th edition " chemistry and physics handbook ".In addition, organic chemistry General Principle can with reference to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to herein by reference.
Term " comprises " or " comprising " is open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
Term " crystal formation " is used for describing the existence of solid chemical compound, describes the different kinds of parameters aggregate of the ion of crystals, atom or molecular composition, symmetric property and periodic arrangement rule.
For the various parametric descriptions of " crystal formation " of the present invention are obtained clearer, the present invention is by testing various parameter to containing sample time substantially pure certain " crystal formation " and characterize described crystal formation and differentiate.Term " substantially pure " refers in sample substantially by the main crystal formation composition of one, be substantially devoid of another kind or multiple other crystal formation or amorphous in addition, its main crystal form purity at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%.Term " is substantially devoid of one or more other crystal formations or amorphous " and refers to that other crystal formation or unbodied content per-cent in sample gross weight is less than 20%, or be less than 10%, or be less than 5%, or be less than 3%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
Term " substantially as shown in the figure " to refer in substantially pure certain " crystal formation " its X-ray powder diffraction pattern at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or the peak of at least 99% appears in given X-ray powder diffraction pattern.When in sample, the content of certain crystal formation reduces gradually, the diffraction peak that some in its X-ray powder diffraction pattern belong to this crystal formation may tail off due to the factor of the detection sensitivity of instrument.
Term " relative intensity " refers to the strength definition at the last the first peak belonged in one group of diffraction peak of a certain crystal formation when being 100%, the ratio of the intensity at the intensity at other peak and the last the first peak.
In the context of the present invention, 2 θ (also known as the 2theta) value in X-ray powder diffraction pattern (XRPD) is all to spend (°) for unit.
When mentioning data in collection of illustrative plates and/or figure, term " diffraction peak " refers to that those skilled in the art can not belong to a feature of background noise.
The differential scanning calorimetric curve (DSC) of described crystal formation has experimental error, between a machine and another machine and between a sample and another sample, the position of endotherm(ic)peak and peak value may slightly difference, the numerical value of experimental error or difference may be less than or equal to 5 DEG C, or be less than or equal to 4 DEG C, or be less than or equal to 3 DEG C, or be less than or equal to 2 DEG C, or be less than or equal to 1 DEG C, therefore the peak position of described DSC endotherm(ic)peak or the numerical value of peak value can not be considered as absolute.
The X-ray powder diffraction peak of described crystal formation, 2 θ of its X-ray powder diffraction or diffraction peak measured experimental error, between a machine and another machine and between a sample and another sample, measuring of 2 θ of X-ray powder diffraction or diffraction peak may slightly difference, the numerical value of described experimental error or difference may be +/-0.2 unit or +/-0.1 unit or +/-0.05 unit, and therefore the numerical value of described 2 θ or diffraction peak can not be considered as absolute.
In the context of the present invention, when using the wording such as " approximately " or " about ", the numerical value of each numeral likely there will be 1%, 2%, or the difference such as 5%.
" envrionment temperature " refers to the natural temperature around things present position, and described envrionment temperature can be different according to their location, residing season, residing time, generally approximately between-20 DEG C-45 DEG C.
" room temperature " refers to that temperature is at about 18 DEG C-30 DEG C, or about 20 DEG C-25 DEG C or about 22 DEG C.
Term " dissolution solvent " can be single solvent or mixed solvent, refer to be greater than 1g/L according to Shandong for the solubleness of Buddhist nun in this single solvent or mixed solvent, or be greater than 2g/L, or be greater than 3g/L, or be greater than 4g/L, or be greater than 5g/L, or be greater than 6g/L, or be greater than 7g/L, or be greater than 8g/L, or be greater than 9g/L, or be greater than 10g/L, or be greater than 15g/L, or be greater than 20g/L, or be greater than 30g/L, or be greater than 40g/L, or be greater than 50g/L, or be greater than 60g/L, or be greater than 70g/L, or be greater than 80g/L, or be greater than 100g/L.In certain embodiments, replace the solubleness of Buddhist nun in dissolution solvent than dissolution solvent is not large according to Shandong; In certain embodiments, dissolution solvent and not dissolution solvent be approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% to according to Shandong for the difference of solubleness of Buddhist nun; In certain embodiments, dissolution solvent, to replacing the solubleness of Buddhist nun than dissolution solvent is not large according to Shandong, is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
Term " not dissolution solvent " refers to and can promote that solution reaches the solvent of supersaturation state or crystallization.In certain embodiments, be less than 0.001g/L according to Shandong for the solubleness of Buddhist nun in not dissolution solvent, or be less than 0.01g/L, or be less than 0.1g/L, or be less than 0.2g/L, or be less than 0.3g/L, or be less than 0.4g/L, or be less than 0.5g/L, or be less than 0.6g/L, or be less than 0.8g/L, or be less than 1g/L, or be less than 2g/L, or be less than 3g/L, or be less than 4g/L, or be less than 5g/L, or be less than 6g/L, or be less than 7g/L, or be less than 8g/L, or be less than 9g/L, or be less than 10g/L.
Detailed Description Of The Invention
First aspect, contriver, by having researched and developed according to the crystal formation of Shandong for Buddhist nun, is called crystal form A 2.
According to the crystal form A 2 of Shandong for Buddhist nun, there is following characteristic: its differential scanning calorimetric curve curve (DSC) has endotherm(ic)peak at 185 DEG C of-210 DEG C of places.
In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 2 of Buddhist nun is replaced to have endotherm(ic)peak at 190 DEG C of-205 DEG C of places according to Shandong.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 2 of Buddhist nun is replaced to have endotherm(ic)peak at 194 DEG C of-204 DEG C of places according to Shandong.In some embodiments, replace the endotherm(ic)peak summit value of the differential scanning calorimetric curve (DSC) of the crystal form A 2 of Buddhist nun greatly about 201.3 DEG C according to Shandong.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 2 of Buddhist nun is replaced according to Shandong as shown in Figure 1.
Above-mentioned according to the crystal form A 2 of Shandong for Buddhist nun, also there is following characteristic: in its X-ray powder diffraction pattern (XRPD), have peak in the position that 2 θ are 22.71 degree.
In some embodiments, according to being 15.97,18.65 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, there is peak the position of 22.71 degree.
In some embodiments, according to being 7.65,15.97 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, there is peak the position of 18.65,20.07,22.71,24.16 degree.
In some embodiments, according to being 7.65,15.97 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 18.65,19.06,20.07,22.71, there is peak the position of 24.16 degree.
In some embodiments, according to being 7.65,15.97 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, there is peak a place or the many places of the position of 18.65,19.06,20.07,22.71,24.16,26.15,29.52,31.74 degree.
In some embodiments, according to being 7.65,12.07 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 12.53,15.97,18.65,19.06,20.07,22.71,24.16,25.13,26.15,29.52, there is peak a place or the many places of the position of 31.74 degree.
In some embodiments, according to being 7.65,9.96,12.07,12.53,15.97 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 18.65,19.06,20.07,22.71,23.66,24.16,25.13,26.15,29.52,30.04, there is peak a place or the many places of the position of 31.74 degree.
In some embodiments, according to being 7.65,7.98,9.96 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 12.07,12.53,13.10,15.97,18.65,19.06,20.07,20.78,22.71,23.66,24.16,25.13,26.15,29.52,30.04, there is peak a place or the many places of the position of 31.74 degree.
In some embodiments, according to being 7.65,7.98,9.96 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 10.83,12.07,12.53,13.10,15.97,18.65,19.06,20.07,20.78,21.47,22.71,23.66,24.16,25.13,25.55,26.15, there is peak one place or the many places of the position of 29.52,30.04,31.74,32.54 degree.
In some embodiments, according to being 7.65,7.98,9.96,10.83,12.07 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 2 of Buddhist nun, 12.53,13.10,13.66,15.97,18.65,19.06,20.07,20.78,21.47,22.19,22.71,23.66,24.16,24.96,25.13,25.55,26.15,27.93,29.52,30.04,30.78,31.06,31.74,32.54,34.95,37.76, there is peak a place or the many places of the position of 38.73 degree.
In some embodiments, replace diffraction angle 2 θ in the X-ray powder diffraction pattern of the crystal form A 2 of Buddhist nun to be that 24.16 degree of positions have peak according to Shandong, its relative intensity is greater than 50%.
In some embodiments, be less than 25% according to Shandong for the relative intensity that diffraction angle 2 θ in the X-ray powder diffraction pattern of the crystal form A 2 of Buddhist nun is the peak of the position of 12.53 degree.
In some embodiments, have peak according to Shandong for the position that diffraction angle 2 θ in the X-ray powder diffraction pattern of the crystal form A 2 of Buddhist nun is 24.16 degree, and its relative intensity is greater than 50%, and the relative intensity that 2 θ are the peak of the position of 12.53 degree is less than 25%.
In some embodiments, the X-ray powder diffraction pattern of the crystal form A 2 of Buddhist nun is replaced substantially as shown in Figure 2 according to Shandong, wherein diffraction angle 2 θ is that the relative intensity at the peak of 22.71 degree is greater than 50%, or be greater than 60%, or be greater than 70%, or be greater than 80%, or be greater than 90%, or be greater than 99%, or be 100%.
In some embodiments, according to Shandong for the crystal form A 2 of Buddhist nun X-ray powder diffraction pattern substantially as shown in Figure 2, wherein diffraction angle 2 θ is that the relative intensity at the peak of 24.16 degree is greater than 50%.
In some embodiments, according to Shandong for the crystal form A 2 of Buddhist nun X-ray powder diffraction pattern substantially as shown in Figure 2, wherein diffraction angle 2 θ is that the relative intensity at the peak of the position of 12.53 degree is less than 25%.
Second aspect, this provides according to the crystal formation of Shandong for Buddhist nun, is called crystal form A 3.
According to the crystal form A 3 of Shandong for Buddhist nun, there is following characteristic: its differential scanning calorimetric curve (DSC) has endotherm(ic)peak at 135 DEG C of-150 DEG C of places.
In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 3 of Buddhist nun is replaced to have endotherm(ic)peak at 138 DEG C of-145 DEG C of places according to Shandong.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 3 of Buddhist nun is replaced to have endotherm(ic)peak at 138.8 DEG C of-144.7 DEG C of places according to Shandong.In some embodiments, replace the summit value of differential scanning calorimetric curve (DSC) endotherm(ic)peak of the crystal form A 3 of Buddhist nun greatly about 144.7 DEG C according to Shandong.In some embodiments, the differential scanning calorimetric curve (DSC) of the crystal form A 3 of Buddhist nun is replaced according to Shandong as shown in Figure 3.
Above-mentioned according to Shandong for the crystal form A 3 of Buddhist nun, also there is following characteristic: be 14.02,17.76 at 2 θ in its X-ray powder diffraction pattern (XRPD), 21.27,21.66, the position of 33.92 degree have peak.
In some embodiments, according to being 10.88,12.48 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 16.00,18.75,22.68,23.99, there is peak the position of 25.04 degree.
In some embodiments, according to being 10.88,12.48,16.00,18.75 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 22.68,23.99, there is peak the position of 25.04 degree, and 14.02, there is peak one place or the many places of the position of 17.76,21.27,21.66,33.92 degree.
In some embodiments, according to being 7.73,10.88 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 12.48,13.31,16.00,18.75,20.21,22.68,23.99,25.04, there is peak a place or the many places of the position of 27.95 degree.
In some embodiments, according to being 7.73,10.88 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 12.48,13.31,16.00,18.75,20.21,22.68,23.99,25.04, there is peak the position of 27.95 degree, and 14.02,17.76,21.27, there is peak one place or the many places of the position of 21.66,33.92 degree.
In some embodiments, according to being 7.73,10.88,12.48,13.31 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 16.00,18.75,20.21,22.10,22.68,23.99,25.04,27.95,29.64, there is peak a place or the many places of the position of 31.77 degree.
In some embodiments, according to being 7.73,10.88,12.48 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 13.31,16.00,18.75,20.21,22.10,22.68,23.99,25.04,27.95,29.64, there is peak the position of 31.77 degree, and 14.02,17.76,21.27,21.66, there is peak a place or the many places of the position of 33.92 degree.
In some embodiments, according to being 7.73,10.88 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 12.48,13.31,16.00,18.75,19.08,20.21,22.10,22.68,23.99,25.04,25.64,26.18,27.95,29.64, there is peak a place or the many places of the position of 31.77 degree.
In some embodiments, according to being 7.73,10.88,12.48 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 13.31,16.00,18.75,19.08,20.21,22.10,22.68,23.99,25.04,25.64,26.18,27.95, there is peak the position of 29.64,31.77 degree, and 14.02,17.76,21.27,21.66, there is peak a place or the many places of the position of 33.92 degree.
In some embodiments, according to being 7.73,10.88,12.48 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 13.31,14.02,16.00,18.75,19.08,20.21,21.27,22.10,22.68,23.99,25.04,25.64,26.18,27.95,29.64,30.00,31.77, there is peak a place or the many places of the position of 33.92 degree.
In some embodiments, according to being 7.73,10.88,12.48 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 13.31,14.02,16.00,18.75,19.08,20.21,21.27,22.10,22.68,23.99,25.04,25.64,26.18,27.95,29.64,30.00, there is peak the position of 31.77,33.92 degree, and has peak the position of 17.76 or 21.66 degree.
In some embodiments, according to being 7.73,8.04,10.01,10.88 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 12.14,12.48,13.31,14.02,16.00,17.76,18.75,19.08,20.21,21.27,21.66,22.10,22.68,23.99,25.04,25.64,26.18,27.95,29.52,29.64, there is peak one place or the many places of the position of 30.00,31.77,32.35,33.92 degree.
In some embodiments, according to being 7.73,8.04,10.01,10.88 at 2 θ in the X-ray powder diffraction pattern of Shandong for the crystal form A 3 of Buddhist nun, 12.14,12.48,13.31,14.02,16.00,17.76,18.75,19.08,20.21,21.27,21.66,22.10,22.68,23.99,25.04,25.64,26.18,27.95,29.52,29.64, there is peak the position of 30.00,31.77,32.35,33.92 degree.
In some embodiments, the X-ray powder diffraction pattern of the crystal form A 3 of Buddhist nun is replaced substantially as shown in Figure 4 according to Shandong, wherein diffraction angle 2 θ is that the relative intensity at the peak of 22.68 degree is greater than 50%, or be greater than 60%, or be greater than 70%, or be greater than 80%, or be greater than 90%, or be greater than 99%, or be 100%.
In some embodiments, according to Shandong for the crystal form A 3 of Buddhist nun X-ray powder diffraction pattern substantially as shown in Figure 4, wherein diffraction angle 2 θ is that the relative intensity at the peak of the position of 12.48 degree is greater than 25%.
Crystal form A 2 is comparatively similar with the X-ray powder diffraction of crystal form A 3, but according to detected result, can find out the not identical of these two kinds of crystal formations.By the sample mix of these two kinds of crystal formations, then detect the DSC of biased sample, clearly can distinguish two kinds of crystal formations, see Fig. 5.
Of the present invention non-hygroscopic for the crystal form A 2 of Buddhist nun according to Shandong, there is good performance in stability, mobility etc., be conducive to operating in storage, production technique, may be used in pharmaceutical preparation.
The third aspect, replaces Buddhist nun's crystal form A 2 according to Shandong described in present invention also offers, the preparation method of crystal form A 3.
A kind of preparation comprises for the method for Buddhist nun's crystal form A 2 according to Shandong: will be dissolved in dissolution solvent for Buddhist nun according to Shandong, and then add not dissolution solvent and/or lowered the temperature by crystallization solution, crystallize out, collects crystal, except desolventizing, obtain product.
In some embodiments, be dissolved in dissolution solvent described in and comprise heating for dissolving in dissolution solvent; Described Heating temperature is the arbitrary value of room temperature to the reflux temperature of solvent.In some embodiments, reflux will be dissolved in dissolution solvent for Buddhist nun according to Shandong.
Described dissolution solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, acetone, butanone, methyl iso-butyl ketone (MIBK), or its combination.
Described not dissolution solvent is selected from water, acetone, butanone, or its combination etc.
Preparing in crystal form A 2 process, when dissolution solvent is ethanol, dissolution solvent is not water.
Described cooling refers in Crystallization Process, and the temperature of crystallization solution is comparatively low to moderate crystallize out, temperature can be reduced to 40 DEG C-subzero 15 DEG C.In some embodiments, the temperature of crystallization solution is reduced to 35 DEG C-0 DEG C.In some embodiments, the temperature of crystallization solution is reduced to 35 DEG C-15 DEG C.In some embodiments, the temperature of crystallization solution is reduced to 30 DEG C-20 DEG C.In some embodiments, the temperature of crystallization solution is reduced to 25 DEG C-15 DEG C.In some embodiments, the temperature of crystallization solution is reduced to 10 DEG C-0 DEG C.In some embodiments, the temperature of crystallization solution is reduced to subzero 15 DEG C-5 DEG C.In some embodiments, the temperature of crystallization solution is comparatively low to moderate subzero 10 DEG C-0 DEG C.
In some embodiments, methyl alcohol will be dissolved according to Shandong for Buddhist nun, then gained methyl alcohol crystallization solution be cooled to 15 DEG C-20 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, ethanol will be dissolved according to Shandong for Buddhist nun, then gained ethanol crystallization solution be cooled to 15 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, propyl carbinol will be dissolved according to Shandong for Buddhist nun, then gained propyl carbinol crystallization solution be cooled to 20 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, sec-butyl alcohol will be dissolved according to Shandong for Buddhist nun, then gained sec-butyl alcohol crystallization solution be cooled to 25 DEG C-30 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, methyl alcohol and ethanol will be dissolved according to Shandong for Buddhist nun, then gained methyl alcohol and ethanol crystallization solution be cooled to 15 DEG C-20 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, n-propyl alcohol will be dissolved according to Shandong for Buddhist nun, and add water, then gained n-propyl alcohol crystallization solution is cooled to 20 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, isopropylcarbinol will be dissolved according to Shandong for Buddhist nun, and add water, then gained isopropylcarbinol crystallization solution is cooled to 20 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, acetone will be dissolved according to Shandong under Buddhist nun's heated reflux condition, then gained acetone crystallization solution be cooled to 20 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, methyl alcohol will be dissolved according to Shandong for Buddhist nun, and add acetone, then gained mixing crystallization solution is cooled to 15 DEG C-20 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, methyl alcohol will be dissolved according to Shandong for Buddhist nun, and add butanone, then gained methyl alcohol crystallization solution is cooled to 25 DEG C-30 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
In some embodiments, ethanol will be dissolved according to Shandong for Buddhist nun, and add acetone, then gained mixing crystallization solution is cooled to 20 DEG C-25 DEG C, crystallize out, and filter, except desolventizing, obtain crystal form A 2.
A kind of preparation comprises according to the method for Shandong for Buddhist nun's crystal form A 3: will be dissolved in ethanol for Buddhist nun according to Shandong, and be then added to the water by gained ethanolic soln, crystallize out, and collect crystal, except desolventizing, obtain product.
In some embodiments, a kind of preparation comprises according to the method for Shandong for Buddhist nun's crystal form A 3: will be dissolved in ethanol for Buddhist nun's heating according to Shandong, and then be added dropwise in water by gained ethanolic soln, crystallization solution is cooled to 20 DEG C-25 DEG C, crystallize out, collects crystal, except desolventizing, obtain product.
Fourth aspect, this provides according to crystal form A 2 application in the medicine for the treatment of potential treatment chronic lymphocytic leukemia (CLL) and minicell lymphocytic lympboma of Shandong for Buddhist nun.
5th aspect provides and comprises according to the pharmaceutical composition of Shandong for the crystal form A 2 of Buddhist nun.
Of the present inventionly can to mix with the pharmaceutically acceptable inert excipient of at least one or carrier for Buddhist nun's crystal form A 2 according to Shandong, to be prepared into the various solid dosages of oral medicine, to comprise capsule, tablet etc.; Solid dispersion etc. can also be prepared into various vehicle or carrier, then be prepared into various solid preparation.
In some embodiments, described inert excipient or carrier comprise Microcrystalline Cellulose; In some embodiments, described inert excipient or carrier comprise croscarmellose sodium.
In some embodiments, the pharmaceutical composition of the crystal form A 2 of Buddhist nun is replaced to contain Magnesium Stearate according to Shandong.
In some embodiments, the pharmaceutical composition of the crystal form A 2 of Buddhist nun is replaced to contain sodium lauryl sulphate according to Shandong.
In some embodiments, crystal form A 2 and Microcrystalline Cellulose, croscarmellose sodium, Magnesium Stearate, sodium lauryl sulphate mixes, and then loads in applicable capsule and is prepared into capsule.
The treatment significant quantity weight percent of Buddhist nun's crystal form A 2 is replaced to account for about 0.1% to 99.5% at whole mixture according to Shandong, in certain embodiments for the weight percent of about 0.5% to 95% weight is present in said medicine preparation.
Accompanying drawing explanation
Fig. 1 shows according to the differential scanning calorimetric curve (DSC) of Shandong for Buddhist nun's crystal form A 2.
Fig. 2 shows according to the X-ray powder diffraction pattern (XRPD) of Shandong for Buddhist nun's crystal form A 2.
Fig. 3 shows according to the differential scanning calorimetric curve (DSC) of Shandong for Buddhist nun's crystal form A 3.
Fig. 4 shows according to the X-ray powder diffraction pattern (XRPD) of Shandong for Buddhist nun's crystal form A 3.
Fig. 5 shows the differential scanning calorimetric curve (DSC) of the biased sample replacing Buddhist nun's crystal form A 2 and crystal form A 3 according to Shandong.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, g represents gram, and mL represents milliliter.
Instrument parameter
Make separate stipulations except in distribution free, all analyses are carried out all at ambient temperature.
X-ray powder diffraction (XRPD)
The x'celerator detector being furnished with the 2 θ scopes with 120 ° is used to carry out X-ray powder diffraction (XRPD) analysis.Use Cu-K α radiation to be 3 ° at 2 θ to start to collect real time data with 0.01672 θ resolving power.Tube voltage and amperage are set as 45kV and 40mA respectively.Antiscatter slits is set as 6.6mm, and divergent slit is 1 degree.Show 2 θ at the pattern of 3 °-40 °.Get and appropriate be placed in zero Background Samples frame circular groove place according to Shandong for Buddhist nun's crystal form samples, gently press with clean slide glass, obtain a smooth plane, and zero Background Samples frame is fixed, to obtain final product, sample to be placed on automatic sampling apparatus, sample introduction successively, sample analysis 99 seconds.Silicon is used to carry out instrument calibration with reference to standard specimen.Collect experiment XRPD figure, in X-ray powder diffraction pattern, ordinate zou is the diffracted intensity represented with counting (counts), and X-coordinate is diffraction angle 2 θ that expenditure (°) represents.
Differential scanning calorimetric curve (DSC) detects
Use TAInstruments differential scanning calorimeter 2000 to carry out means of differential scanning calorimetry (DSC) to detect.Sample put into aluminium DSC dish and accurately record weight.This dish lid covers, and then crimping or maintenance do not crimp.Sample pool is balanced at 40 DEG C or 25 DEG C the outlet temperature being also heated to 300 DEG C under nitrogen purge with the speed of 10 DEG C/min.Use indium metal as calibration sample.In DSC figure, X-coordinate represents temperature (Temperature, DEG C), the heat flux (HeatFlow, W/g) that the material of ordinate zou representation unit quality is released.
The detected temperatures scope of the differential scanning calorimetric curve (DSC) of the blend sample of crystal form A 2 sample and crystal form A 2 and A3 is 25 DEG C-300 DEG C.
The detected temperatures scope of the differential scanning calorimetric curve (DSC) of crystal form A 3 sample is 40 DEG C-300 DEG C.
Embodiment 1
Add according to Shandong for Buddhist nun 0.20g, methyl iso-butyl ketone (MIBK) 10mL in reaction flask, stir, reaction flask is moved to room temperature (25 DEG C) after being heated to 70 DEG C of dissolvings and is stirred to precipitation solid, then stirring at room temperature 1 hour by oil bath, filters.Products obtained therefrom 35 DEG C of dryings 5 hours under vacuo, obtain product 0.17g; Detecting DSC and XRPD, is crystal form A 2, see Fig. 1 and Fig. 2.
Embodiment 2
Add according to Shandong for Buddhist nun 0.20g, ethanol 10mL in reaction flask, stir, be heated to 60 DEG C, stop heating after dissolving, stir, Temperature fall, to room temperature (25 DEG C), stirs 1 hour at 20 DEG C-25 DEG C after separating out solid.Filter, products obtained therefrom 35 DEG C of dryings 5 hours under vacuo, obtain product 0.16g; DSC and XRPD detects, and is crystal form A 2.
Embodiment 3
Add according to Shandong for Buddhist nun 0.20g, methyl alcohol 10mL in reactor, stir, be heated to 50 DEG C, after dissolving, reaction is moved to room temperature (25 DEG C) to stir, slowly add acetone 5mL, separate out solid, filter, products obtained therefrom 35 DEG C of dryings 6 hours under vacuo, obtain product 0.16g; DSC and XRPD detects, and is crystal form A 2.
Embodiment 4
Add according to Shandong for Buddhist nun 0.20g, n-propyl alcohol 10mL in reactor, stir, be heated to 90 DEG C, after dissolving, reaction is moved to room temperature (25 DEG C) to stir, slowly add water 6mL, separate out solid, filter, products obtained therefrom 35 DEG C of dryings 6 hours under vacuo, obtain product 0.17g; DSC and XRPD detects, and is crystal form A 2.
Embodiment 5
Add according to Shandong for Buddhist nun 0.20g in reactor, ethanol and each 5mL of methyl alcohol, stir, be heated to 50 DEG C, after dissolving, reaction moved to room temperature (25 DEG C-20 DEG C) and be stirred to precipitation solid, then stir 1 hour, filter, products obtained therefrom 35 DEG C of dryings 5 hours under vacuo, obtain product 0.16g; DSC and XRPD detects, and is crystal form A 2.
Embodiment 6
Add in reactor according to Shandong for Buddhist nun 0.20g, add ethanol 10mL, stir, be warming up to 70 DEG C of dissolvings, then solution is dropped in the water of the 20mL under room temperature (25 DEG C-20 DEG C), stir 0.5 hour after separating out solid, filter, products therefrom 35 DEG C of dryings 5 hours under vacuo, obtain product 0.15g; Detecting DSC and XRPD, is crystal form A 3, see Fig. 3, Fig. 4.
Embodiment 7 draws moist investigation
According to the regulation of existing Chinese Pharmacopoeia, contrived experiment, investigates drawing of crystal form A 2 and crystal form A 3 moist; Result shows that drawing of crystal form A 2 and crystal form A 3 is moist extremely low, as shown in table 1 below:
Table 1: crystal form A 2 and crystal form A 3 draw moist investigation result
Embodiment 8: study on the stability
According to bulk drug and the pharmaceutical preparation stability test governing principle of Chinese Pharmacopoeia version annex XIXC in 2010, carry out Acceleration study after using double-deck PE bag to seal packaging to crystal form A 2, place condition: 40 DEG C ± 2 DEG C, relative humidity: 75% ± 5% climatic chamber; 30 DEG C ± 2 DEG C, relative humidity: 65% ± 5% climatic chamber; Storage period: 1 month; DSC and X-ray powder diffraction is detected respectively the 3rd, 15,30 day time.
Detected result: DSC and X-ray powder diffraction detected result display placement is after 1 month, and the crystal formation of sample is unchanged, is still crystal form A 2.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1., according to the crystal form A 2 of Shandong for Buddhist nun, the differential scanning calorimetric curve of described crystal form A 2 has endotherm(ic)peak at 194 DEG C of-204 DEG C of places.
2. crystal form A 2 according to claim 1, its X-ray powder diffraction is 7.65,15.97 at 2 θ, 18.65,19.06,20.07,22.71, there is peak the position of 24.16 degree.
3. the arbitrary described crystal form A 2 of claim 1-2, its X-ray powder diffraction is 7.65,15.97 at 2 θ, and there is peak the position of 18.65,19.06,20.07,22.71,24.16,26.15,29.52,31.74 degree.
4. the arbitrary described crystal form A 2 of claim 1-3, its X-ray powder diffraction is 7.65,12.07 at 2 θ, 12.53,15.97,18.65,19.06,20.07,22.71,24.16,25.13,26.15,29.52, there is peak the position of 31.74 degree.
5. the arbitrary described crystal form A 2 of claim 1-4, its X-ray powder diffraction is 7.65,9.96,12.07,12.53,15.97 at 2 θ, 18.65,19.06,20.07,22.71,23.66,24.16,25.13,26.15,29.52,30.04, there is peak the position of 31.74 degree.
6. the arbitrary described crystal form A 2 of claim 1-5, substantially as shown in Figure 2, its diffraction angle 2 θ is that the relative intensity at the peak of 24.16 degree is greater than 50% to its X-ray powder diffraction pattern.
7. prepare claim 1-6 arbitrary described according to the method for Shandong for the crystal form A 2 of Buddhist nun, comprising: will be dissolved in dissolution solvent for Buddhist nun according to Shandong, then add poor solvent and/or lowered the temperature by crystallization solution, crystallize out, collects crystal, except desolventizing, obtains product; Described dissolution solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, acetone, butanone, methyl iso-butyl ketone (MIBK), or its combination.
8. method according to claim 7, described poor solvent is selected from water, acetone, butanone, or its combination.
9. method according to claim 8, described cooling comprises temperature is reduced to-15 DEG C-40 DEG C.
10. method according to claim 7, will replace Buddhist nun's heating for dissolving in ethanol according to Shandong, and then crystallization system will be cooled to 15 DEG C-25 DEG C, crystallize out, collect crystal, except desolventizing, obtain crystal form A 2.
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