CN107573348A - Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof - Google Patents
Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof Download PDFInfo
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- CN107573348A CN107573348A CN201710747417.8A CN201710747417A CN107573348A CN 107573348 A CN107573348 A CN 107573348A CN 201710747417 A CN201710747417 A CN 201710747417A CN 107573348 A CN107573348 A CN 107573348A
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- trifluoroacetate
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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
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
B crystal form the invention provides the Ba Ruike of formula (I) for Buddhist nun's trifluoroacetate,The wherein XRPD collection of illustrative plates of B crystal form is in 2 θ=5.34, and 9.00,10.08,10.70,16.12,17.44,17.80,18.92,19.48,20.22,21.56,22.68,23.42,23.98, there is diffraction maximum at 25.84,27.22,28.76,29.46,32.66, wherein 2 θ values error ranges are ± 0.2.The Ba Ruike of the present invention replaces Buddhist nun's trifluoroacetate semi-crystal for Buddhist nun's trifluoroacetate B crystal form stability better than Ba Ruike, is advantageous to the processing of its medicine and the use in pharmaceutical composition.Ba Ruike for Buddhist nun's trifluoroacetate B crystal form can treatment autoimmune disease, inflammatory disease or cancer medicine in apply, while the qualitative, quantitative information provided, have great importance the effect of to further studying such solid drugs.
Description
The application is the Chinese invention patent application for the Application No. 201610064221.4 submitted on January 29th, 2016
《Ba Ruike is for Buddhist nun's trifluoroacetate A crystal formations and B crystal form and preparation method thereof》Divisional application.
Technical field
The present invention relates to the polymorphic that the Ba Ruike as JAK inhibitor replaces Buddhist nun's trifluoroacetate, in particular it relates to Ba Rui
Gram for Buddhist nun's trifluoroacetate A crystal formations and B crystal form and preparation method thereof.
Background technology
JAK is Janus kinases (Janus Kinase), is a kind of non-receptor type tyrosine protein kinase, and a kind of non-
The EGFR-TK of transmembrane.Because JAK can phosphorylation cytokine receptor combined with it, and can phosphorylation is more
The individual signaling molecule containing specific SH2 domains.JAK protein families include 4 members altogether：JAK1, JAK2, JAK3 and TYK2,
They have 7 JAK homeodomains (JAK homology domain, JH) in structure, wherein JH1 domains be kinases area,
JH2 domains are that "false" kinases area, JH6 and JH7 are receptorbinding regions.
TYK2 is the potential target spot of Immunoinflammatory Disorders, rejects research confirmation (Levy by people's science of heredity and mouse
D. with Loomis C., 1655-1658 pages of New England Journal of Medicine 357 (2007)).
JAK1 is the novel targets in Immunoinflammatory Disorders field., can the transducer cell factor by JAK1 and other JAK heterodimericization
The pro-inflammatory signals conduction of driving.Therefore, it is contemplated that suppress JAK1 and/or other JAK for a series of inflammatory conditions and other by JAK
The disease of the signal transduction driving of mediation has treatment benefit.
Ba Ruike in the present invention for Buddhist nun (Baricitinib) trifluoroacetate be chemistry it is entitled 1- (ethylsulfonyl)-
3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3- bases } acetonitrile trifluoroacetate,
Compound as shown in formula (I),
It is a kind of JAK classes inhibitor compound, available for treatment JAK participate in autoimmune disease, inflammatory disease or
Cancerous disease.In Chinese invention patent CN 102026999 (WO 2009/114512), the compound and its derivative are disclosed
Thing, it is referred to as " Ba Ruike replaces Buddhist nun's trifluoroacetate semi-crystal " in of the invention.
It is well known that same medicine, crystal formation is different, and its bioavilability may also can have difference, and it is stable in addition
Property, mobility, compressibility may also can be different, application of these physicochemical properties to medicine produces certain influence, so as to shadow
The effect of ringing medicine.Therefore it is necessary to have the crystal formation that the Ba Ruike of superior physiochemical properties replaces Buddhist nun's trifluoroacetate, it can
Advantageously used in medicine processing and pharmaceutical composition.The Ba Ruike that the present invention develops replaces the novel crystal forms of Buddhist nun's trifluoroacetate not
Appear in the newspapers.
The content of the invention
Problem to be solved by this invention is that existing bar of Rake has much room for improvement for Buddhist nun's trifluoroacetic acid salt-stable and influence to give birth to
The problem of thing availability, at the same time it is wished that the novel crystal forms that Ba Ruike replaces Buddhist nun's trifluoroacetate can be sought, the effect of being solid drugs
Research provides more qualitative, quantitative information.
In order to solve the above-mentioned technical problem, the first aspect of the invention provides a kind of Ba Ruike and replaces Buddhist nun's trifluoroacetate
New crystal formation, more specifically, being { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrroles
Azoles -1- bases] azetidine -3- bases } (hereinafter referred to as " Ba Ruike replaces Buddhist nun's trifluoroacetate A for the new crystal formation of acetonitrile trifluoroacetate
Crystal formation "), its XRPD collection of illustrative plates is in 2 θ=8.60, and 10.12,10.72,14.02,16.66,17.24,17.84,18.90,19.54,
20.26,21.54,21.94,23.40,23.78,24.66,25.64,25.98,26.32,27.12,28.16,30.34,31.12
There is diffraction maximum at place, wherein 2 θ values error ranges are ± 0.2.
Of the present invention bar of Rake replaces Buddhist nun's trifluoroacetate A crystal formations, has substantially the same with Figure of description Fig. 1
XRPD collection of illustrative plates.
Present invention also offers methods of the Ba Ruike for Buddhist nun's trifluoroacetate A crystal formations is prepared, comprise the following steps：
(1) Ba Ruike will be added for the organic solvent of dissolving replace in Buddhist nun's trifluoroacetate semi-crystal and obtain Ba Ruike and replace Buddhist nun
The solution of trifluoroacetate semi-crystal, and raise the temperature of the solution；
(2) to the Ba Ruike for Buddhist nun's trifluoroacetate semi-crystal solution carry out ultrasound, and be quickly cooled to room temperature or
Less than the temperature of room temperature, suspension is obtained；
(3) gained suspension is filtrated to get Ba Ruike and replaces Buddhist nun's trifluoroacetate A crystal formations.
In certain embodiments, it is described be used for dissolve organic solvent be ketone in any one solvent or two kinds with
Upper solvent is with the mixed solvent of arbitrary proportion.
In some preferred embodiments, the organic solvent for being used to dissolve is acetone.
In certain embodiments, Ba Ruike described in the solution of above-mentioned steps (2) replaces Buddhist nun's trifluoroacetate semi-crystal
Initial proportion with the organic solvent is not less than 80: 1mg/mL.
In certain embodiments, Ba Ruike described in the solution of above-mentioned steps (2) replaces Buddhist nun's trifluoroacetate semi-crystal
Initial proportion with the organic solvent is in the range of 80: 1mg/mL to 120: 1mg/mL.In some preferred embodiments, on
State Ba Ruike described in the solution of step (2) is for the initial proportion of Buddhist nun's trifluoroacetate semi-crystal and the organic solvent
100∶1mg/mL。
In certain embodiments, the temperature of the solution is 40 to 80 DEG C.Actual temp is typically by the boiling point of solvent for use
Determine.For example acetone boiling point is 55 DEG C in a particular embodiment；Solute easily occurs to go bad under high temperature simultaneously.So preferable
In embodiment, the temperature of the solution is 50 DEG C to 54 DEG C.
In certain embodiments, the temperature less than room temperature is 0~20 DEG C.
In addition, the second aspect of the invention provides the new crystal formation that another Ba Ruike replaces Buddhist nun's trifluoroacetate, more
Specifically, it is { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azacyclo-
Butane -3- bases } acetonitrile trifluoroacetate new crystal formation (hereinafter referred to as " Ba Ruike replaces Buddhist nun's trifluoroacetate B crystal form "), its XRPD
Collection of illustrative plates is in 2 θ=5.34, and 9.00,10.08,10.70,16.12,17.44,17.80,18.92,19.48,20.22,21.56,
There is diffraction maximum at 22.68,23.42,23.98,25.84,27.22,28.76,29.46,32.66, wherein 2 θ value error ranges are
±0.2。
Of the present invention bar of Rake replaces Buddhist nun's trifluoroacetate B crystal form, has substantially the same with Figure of description Fig. 8
XRPD collection of illustrative plates.
Present invention also offers methods of the Ba Ruike for Buddhist nun's trifluoroacetate B crystal form is prepared, comprise the following steps：
(1) organic solvent is added into Ba Ruike replaced in Buddhist nun's trifluoroacetate semi-crystal and obtain Ba Ruike and replace Buddhist nun's trifluoroacetate
Suspension, and raise the temperature of the suspension；
(2) organic solvent is added thereto after the suspension suspension certain time that the Ba Ruike is replaced into Buddhist nun's trifluoroacetate
Continue to suspend, then cool down；
(3) Ba Ruike after cooling is filtered and dried for the suspension of Buddhist nun's trifluoroacetate, obtained Ba Ruike and replace
Buddhist nun's trifluoroacetate B crystal form.
In certain embodiments, the organic solvent be ketone in any one solvent or two or more solvents with appoint
The mixed solvent of meaning ratio.
In some preferred embodiments, the organic solvent is acetone.
In certain embodiments, the Ba Ruike is for Buddhist nun's trifluoroacetate semi-crystal and the initial proportion of the organic solvent
For not less than 200: 1mg/mL.The reason is that Ba Ruike is about 100 for the acetone saturated solution concentration of Buddhist nun's trifluoroacetate
: 1mg/mL, in order to be crystallized using suspension rotating crystal method, suspension is obtained using the solvent solute ratio of the present invention, i.e., it is big
In the concentration of acetone saturated solution.
In certain embodiments, the Ba Ruike is for Buddhist nun's trifluoroacetate semi-crystal and the initial proportion of the organic solvent
In the range of 200: 1mg/mL to 300: 1mg/mL.In some preferred embodiments, the Ba Ruike replaces Buddhist nun's trifluoroacetate
The initial proportion of semi-crystal and the organic solvent is 250: 1mg/mL.
In certain embodiments, suspension Ba Ruike is for the temperature of the suspension of Buddhist nun's trifluoroacetate in the step (2)
40 DEG C to 80 DEG C.Actual temp is typically determined by the boiling point of solvent for use.For example acetone boiling point is 55 in a particular embodiment
℃；Solute easily occurs to go bad under high temperature simultaneously.So in a preferred embodiment, the temperature of the suspension is 50 DEG C to 54
℃。
In a preferably a little embodiments, the amount that organic solvent is added in the step (2) has to be added in the step (1)
The 50% of the amount of solvent.
In a preferably a little embodiments, suspension is cooled to room temperature in the step (2).
Those of ordinary skill in the art can be carried out according to its knowledge and experience to the dosage of the inventive method agents useful for same
Adjustment, including scale up or reduce raw material dosage and adjust solvent load, and the temperature of the inventive method can be changed.
The scheme of these adjustment is also contained in the method for the present invention.
Of the present invention bar of Rake replaces Buddhist nun's trifluoroacetate A crystal formations and B crystal form, and its stability all replaces Buddhist nun higher than Ba Ruike
The crystal formation of trifluoroacetate half, be advantageous to the processing of its medicine and the use in pharmaceutical composition.Ba Ruike replaces Buddhist nun's trifluoroacetate A
Crystal formation and B crystal form can be applied in the medicine for the treatment of autoimmune disease, inflammatory disease or cancer, and with higher steady
Qualitative, quantitative information that is qualitative, while providing, has great importance the effect of to further studying such solid drugs.
Brief description of the drawings
Fig. 1 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun's trifluoroacetate A crystal formations.
Fig. 2 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A five days high-temperature stabilities of crystal formation.
Fig. 3 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A ten days high-temperature stabilities of crystal formation.
Fig. 4 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A five days high wet stabilities of crystal formation.
Fig. 5 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A ten days high wet stabilities of crystal formation.
Fig. 6 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A five days light durabilities of crystal formation.
Fig. 7 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun trifluoroacetate A ten days light durabilities of crystal formation.
Fig. 8 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces Buddhist nun's trifluoroacetate B crystal form.
Fig. 9 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces five days high-temperature stabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 10 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces ten days high-temperature stabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 11 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces five days high wet stabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 12 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces ten days high wet stabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 13 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces five days light durabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 14 is the XRPD collection of illustrative plates that provided by the invention bar of Rake replaces ten days light durabilities of Buddhist nun's trifluoroacetate B crystal form.
Figure 15 is the XRPD collection of illustrative plates that existing bar of Rake replaces Buddhist nun's trifluoroacetate semi-crystal.
Figure 16 is the XRPD collection of illustrative plates that existing bar of Rake replaces five days high-temperature stabilities of Buddhist nun's trifluoroacetate semi-crystal.
Figure 17 is the XRPD collection of illustrative plates that existing bar of Rake replaces ten days high-temperature stabilities of Buddhist nun's trifluoroacetate semi-crystal.
Figure 18 is the XRPD collection of illustrative plates that existing bar of Rake replaces five days high wet stabilities of Buddhist nun's trifluoroacetate semi-crystal.
Figure 19 is the XRPD collection of illustrative plates that existing bar of Rake replaces ten days high wet stabilities of Buddhist nun's trifluoroacetate semi-crystal.
Figure 20 is the XRPD collection of illustrative plates that existing bar of Rake replaces five days light durabilities of Buddhist nun's trifluoroacetate semi-crystal.
Figure 21 is the XRPD collection of illustrative plates that existing bar of Rake replaces ten days light durabilities of Buddhist nun's trifluoroacetate semi-crystal.
Embodiment
In from detailed description below, aforementioned aspect of the present invention and other aspects of the present invention will be apparent.
1 bar of Rake of embodiment replaces the preparation of Buddhist nun's trifluoroacetate A crystal formations
Ba Ruike is added in 4mL acetone for Buddhist nun's trifluoroacetate semi-crystal 400mg, the solution being configured at 50 DEG C will
The solution filters after 15 DEG C are quickly cooled under ultrasound condition, is dried to obtain solid, and weighing solid weight is 106mg.
2 bars of Rakes of embodiment replace the preparation of Buddhist nun's trifluoroacetate A crystal formations
Ba Ruike is added in 3.3mL acetone for Buddhist nun's trifluoroacetate semi-crystal 400mg, the solution being configured at 54 DEG C,
Filtered after the solution is quickly cooled into 0 DEG C under ultrasound condition, be dried to obtain solid, weighing solid weight is 113mg.
3 bars of Rakes of embodiment replace the preparation of Buddhist nun's trifluoroacetate A crystal formations
Ba Ruike is added in 5mL acetone for Buddhist nun's trifluoroacetate semi-crystal 400mg, the solution being configured at 52 DEG C will
The solution filters after 20 DEG C are quickly cooled under ultrasound condition, is dried to obtain solid, and weighing solid weight is 97mg.
Embodiment 4 replaces Buddhist nun's trifluoroacetate A crystal formations by XRPD figures to characterize Ba Ruike
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, penetrated using the multifunctional assembled X of Rigaku Ultima IV models
Line diffractometer is carried out, and specific collection information is as follows：Cu anodes (40kV, 40mA), °/minute of sweep speed 20, scanning range (2 θ
Scope) 3~45 °, scanning step 0.02, slit width 0.01.Directly suppressed using slide in test board to sample
Reason.Thereafter XRPD collection of illustrative plates uses similar measuring method.
The Ba Ruike that measure is prepared according to the methods described of embodiment 1 replaces the XRPD collection of illustrative plates of Buddhist nun's trifluoroacetate A crystal formations, in 2 θ
=8.60,10.12,10.72,14.02,16.66,17.24,17.84,18.90,19.54,20.26,21.54,21.94,
There is diffraction maximum at 23.40,23.78,24.66,25.64,25.98,26.32,27.12,28.16,30.34,31.12, such as Fig. 1 institutes
Show.Wherein 2 θ values error ranges are ± 0.2.After testing, 2 θ values error ranges can also be ± 0.15.According to embodiment 2-3's
Ba Ruike prepared by method replaces Buddhist nun's trifluoroacetate B crystal form, and its XRPD result also has an above-mentioned diffraction maximum, XRPD collection of illustrative plates with it is attached
Collection of illustrative plates shown in figure Fig. 8 is essentially identical.
It will be understood by those skilled in the art that these diffraction maximums do not represent Ba Ruike for shown by Buddhist nun's trifluoroacetate A crystal formations
The detailed situation of diffraction maximum.2 θ values of X-ray powder diffraction figure are can be with machine and with the change in sample preparation
Change and slight change between batch, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with
Orientation effect and become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, is not used to definitely relatively.
5 bars of Rakes of embodiment are investigated for the high-temperature stability of Buddhist nun's trifluoroacetate A crystal formations
Take appropriate Ba Ruike to be placed in for Buddhist nun's trifluoroacetate A crystal form samples in 60 DEG C of baking ovens, take sample after 5 days and 10 days
Go out to carry out XPRD tests (as shown in Figures 2 and 3), to investigate stability of crystal form of the sample to temperature.As a result show, Ba Ruike is replaced
Buddhist nun's trifluoroacetate A crystal formations are stablized under the high temperature conditions.
6 bars of Rakes of embodiment replace the high humidity study on the stability of Buddhist nun's trifluoroacetate A crystal formations
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate A crystal form samples under 92.5% damp condition, will after 5 days and 10 days
Sample, which takes out, carries out XPRD tests (as shown in Figure 4 and Figure 5), to investigate stability of crystal form of the sample to humidity.As a result show, bar
Rake is stablized under conditions of high humidity for Buddhist nun's trifluoroacetate A crystal formations.
7 bars of Rakes of embodiment are investigated for the light durability of Buddhist nun's trifluoroacetate A crystal formations
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate A crystal form samples under 4500lux intensities of illumination, after 5 days and 10 days
Sample is taken out and carries out XPRD tests (as shown in Figure 6 and Figure 7), to investigate stability of crystal form of the sample to illumination.As a result show,
Ba Ruike stabilizations under illumination condition for Buddhist nun's trifluoroacetate A crystal formations.
8 bars of Rakes of embodiment replace the preparation of Buddhist nun's trifluoroacetate B crystal form
2g bars of Rake is placed in 10mL acetone for Buddhist nun's trifluoroacetate semi-crystal, Ba Ruike is obtained and replaces Buddhist nun's trifluoroacetate
The suspension of semi-crystal, stirring suspension 8 hours under the conditions of 50 DEG C, 5mL acetone is added again and continues to suspend 0.5 hour, then
Room temperature is cooled to, the suspension after cooling is filtered and is dried in vacuo at room temperature, obtains solid, weighing solid weight is
51mg。
9 bars of Rakes of embodiment replace the preparation of Buddhist nun's trifluoroacetate B crystal form
2.5g bars of Rake is placed in 10mL acetone for Buddhist nun's trifluoroacetate semi-crystal, Ba Ruike is obtained and replaces Buddhist nun's trifluoroacetic acid
The suspension of salt semi-crystal, stirring suspension 8 hours under the conditions of 52 DEG C, 5mL acetone is added again and continues to suspend 0.5 hour, so
After be cooled to room temperature, the suspension after cooling is filtered and is dried in vacuo at room temperature, obtains solid, weighing solid weight is
98mg。
10 bars of Rakes of embodiment replace the preparation of Buddhist nun's trifluoroacetate B crystal form
2.4g bars of Rake is placed in 8mL acetone for Buddhist nun's trifluoroacetate semi-crystal, Ba Ruike is obtained and replaces Buddhist nun's trifluoroacetic acid
The suspension of salt semi-crystal, stirring suspension 8 hours under the conditions of 54 DEG C, 5mL acetone is added again and continues to suspend 0.5 hour, so
After be cooled to room temperature, the suspension after cooling is filtered and is dried in vacuo at room temperature, obtains solid, weighing solid weight is
86mg。
Embodiment 11 replaces Buddhist nun's trifluoroacetate B crystal form by XRPD figures to characterize Ba Ruike
In the same way as in example 2, determine the Ba Ruike prepared according to the methods described of embodiment 8 and replace Buddhist nun's trifluoroacetic acid
The XRPD collection of illustrative plates of salt B crystal form, in 2 θ=5.34,9.00,10.08,10.70,16.12,17.44,17.80,18.92,19.48,
There is diffraction maximum at 20.22,21.56,22.68,23.42,23.98,25.84,27.22,28.76,29.46,32.66, such as Fig. 8 institutes
Show.Wherein 2 θ values error ranges are ± 0.2.After testing, 2 θ values error ranges can also be ± 0.15.According to embodiment 9-10's
Ba Ruike prepared by method replaces Buddhist nun's trifluoroacetate B crystal form, and its XRPD result also has an above-mentioned diffraction maximum, XRPD collection of illustrative plates with it is attached
Collection of illustrative plates shown in figure Fig. 8 is essentially identical.
It will be understood by those skilled in the art that these diffraction maximums do not represent Ba Ruike for shown by Buddhist nun's trifluoroacetate B crystal form
The detailed situation of diffraction maximum.2 θ values of X-ray powder diffraction figure are can be with machine and with the change in sample preparation
Change and slight change between batch, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with
Orientation effect and become, therefore the intensity shown in the XRPD traces contained by the present invention is exemplary, is not used to definitely relatively.
12 bars of Rakes of embodiment are investigated for the high-temperature stability of Buddhist nun's trifluoroacetate B crystal form
Take appropriate Ba Ruike to be placed in for Buddhist nun's trifluoroacetate B crystal form sample in 60 DEG C of baking ovens, take sample after 5 days and 10 days
Go out to carry out XPRD tests (as shown in Figure 9 and Figure 10), to investigate stability of crystal form of the sample to temperature.As a result show, Ba Ruike
Stablize under the high temperature conditions for Buddhist nun's trifluoroacetate B crystal form.
13 bars of Rakes of embodiment replace the high humidity study on the stability of Buddhist nun's trifluoroacetate B crystal form
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate B crystal form sample under 92.5% damp condition, will after 5 days and 10 days
Sample, which takes out, carries out XPRD tests (as is illustrated by figs. 11 and 12), to investigate stability of crystal form of the sample to humidity.As a result show,
Ba Ruike stablizes under conditions of high humidity for Buddhist nun's trifluoroacetate B crystal form.
14 bars of Rakes of embodiment are investigated for the light durability of Buddhist nun's trifluoroacetate B crystal form
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate B crystal form sample under 4500lux intensities of illumination, after 5 days and 10 days
Sample is taken out and carries out XPRD tests (as shown in Figure 13 and Figure 14), to investigate stability of crystal form of the sample to illumination.As a result show
Show, Ba Ruike stabilizations under illumination condition for Buddhist nun's trifluoroacetate B crystal form.
Comparative example 1 replaces Buddhist nun's trifluoroacetate semi-crystal by XRPD figures to characterize Ba Ruike
Method according to disclosed in Chinese invention patent CN 102026999 (WO 2009/114512) prepares Ba Ruike
For Buddhist nun's trifluoroacetate semi-crystal.As shown in figure 15, determined through XRPD, the final product of gained is half crystal formation.
2 bars of Rakes of comparative example are investigated for the high-temperature stability of Buddhist nun's trifluoroacetate semi-crystal
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate semi-crystal sample in 60 DEG C of baking ovens, by sample after 5 days and 10 days
Take out and carry out XPRD tests (as shown in Figure 16 and Figure 17), to investigate stability of crystal form of the sample to temperature.As a result show, Ba Rui
Gram for Buddhist nun's trifluoroacetate semi-crystal it is unstable under the high temperature conditions, at 5 days and 10 days, crystal formation changed.
3 bars of Rakes of comparative example replace the high humidity study on the stability of Buddhist nun's trifluoroacetate semi-crystal
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate semi-crystal sample under 92.5% damp condition, after 5 days and 10 days
Sample is taken out and carries out XPRD tests (as shown in Figure 18 and Figure 19), to investigate stability of crystal form of the sample to humidity.As a result show
Show, Ba Ruike is unstable under conditions of high humidity for Buddhist nun's trifluoroacetate semi-crystal, and at 5 days and 10 days, crystal formation changed.
4 bars of Rakes of comparative example are investigated for the light durability of Buddhist nun's trifluoroacetate semi-crystal
Appropriate Ba Ruike is taken to be placed in for Buddhist nun's trifluoroacetate semi-crystal sample under 4500lux intensities of illumination, after 5 days and 10 days
Sample is taken out and carries out XPRD tests (as shown in Figure 20 and Figure 21), to investigate stability of crystal form of the sample to illumination.As a result show
Show, Ba Ruike is unstable under illumination condition for Buddhist nun's trifluoroacetate semi-crystal, and at 5 days and 10 days, crystal formation changed.
In summary, Ba Ruike can under high temperature, high humidity and illumination condition for Buddhist nun's trifluoroacetate A crystal formations and B crystal form
It is enough to keep stable, better than semi-crystal product.As it is known to the person skilled in the art, compound semi-crystal physicochemical property is unstable,
Therefore stable crystal formation has advantage in the production process of pharmaceutical preparation.Because Ba Ruike replaces Buddhist nun's trifluoroacetate A crystal formations and B
The stability that crystal formation has, it can keep stable in the medicine process of various solid dosages, can determine and finally obtain
The crystal formation of active constituents of medicine in the medicine obtained, it can be ensured that known bioavilability, will not occur because crystal transfer
And the drug effect difference brought.
Those skilled in the art is it should be understood that although for illustrative purposes, this document describes the tool of the present invention
Body embodiment, but various modifications can be carried out to it without departing from the spirit and scope of the present invention.Therefore, it is of the invention specific
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (10)
1. a kind of Ba Ruike of formula (I) replaces Buddhist nun's trifluoroacetate B crystal form, it is characterised in that
Its XRPD collection of illustrative plates is in 2 θ=5.34, and 9.00,10.08,10.70,16.12,17.44,17.80,18.92,19.48,
There is diffraction maximum at 20.22,21.56,22.68,23.42,23.98,25.84,27.22,28.76,29.46,32.66, wherein 2 θ
It is ± 0.2 to be worth error range.
2. Ba Ruike as claimed in claim 1 replaces Buddhist nun's trifluoroacetate B crystal form, it is characterised in that it has attached with specification
XRPD collection of illustrative plates substantially the same figure Fig. 8.
3. prepare the method that Ba Ruike as claimed in claim 1 or 2 replaces Buddhist nun's trifluoroacetate B crystal form, it is characterised in that including
Following steps：
(1) organic solvent is added into Ba Ruike for Ba Ruike is obtained in Buddhist nun's trifluoroacetate semi-crystal for the outstanding of Buddhist nun's trifluoroacetate
Float, and raise the temperature of the suspension；
(2) organic solvent is added thereto after the suspension suspension certain time that the Ba Ruike is replaced into Buddhist nun's trifluoroacetate to continue
Suspend, then cool down；
(3) Ba Ruike after cooling is filtered and dried for the suspension of Buddhist nun's trifluoroacetate, obtained Ba Ruike and replace Buddhist nun three
Fluoroacetate B crystal form.
4. method as claimed in claim 3, it is characterised in that the organic solvent be ketone in any one solvent or
Two or more solvents are with the mixed solvent of arbitrary proportion.
5. method as claimed in claim 3, it is characterised in that the organic solvent is acetone.
6. method as claimed in claim 3, it is characterised in that the Ba Ruike has for Buddhist nun's trifluoroacetate semi-crystal with described
The initial proportion of solvent is not less than 200: 1mg/mL.
7. method as claimed in claim 3, it is characterised in that the Ba Ruike has for Buddhist nun's trifluoroacetate semi-crystal with described
The initial proportion of solvent is in the range of 200: 1mg/mL to 300: 1mg/mL.
8. method as claimed in claim 3, it is characterised in that suspension Ba Ruike replaces Buddhist nun's trifluoroacetate in the step (2)
Suspension temperature be 50 DEG C to 54 DEG C.
9. method as claimed in claim 3, it is characterised in that the amount that organic solvent is added in the step (2) is the step
Suddenly the 50% of the amount of organic solvent is added in (1).
10. method as claimed in claim 3, it is characterised in that suspension is cooled to room temperature in the step (2).
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| CN201610064221.4A CN105566332B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate A crystal formations and B crystal form and preparation method thereof |
| CN201710747417.8A CN107573348B (en) | 2016-01-29 | 2016-01-29 | Ba Ruike is for Buddhist nun's trifluoroacetate B crystal form and preparation method thereof |
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| WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
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| WO2010039939A1 (en) * | 2008-10-02 | 2010-04-08 | Incyte Corporation | Janus kinase inhibitors for treatment of dry eye and other eye related diseases |
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