CN108218872A - A kind of Ai Dailalisi crystal forms C and preparation method thereof - Google Patents
A kind of Ai Dailalisi crystal forms C and preparation method thereof Download PDFInfo
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- CN108218872A CN108218872A CN201810214985.6A CN201810214985A CN108218872A CN 108218872 A CN108218872 A CN 108218872A CN 201810214985 A CN201810214985 A CN 201810214985A CN 108218872 A CN108218872 A CN 108218872A
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- dailalisi
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of Ai Dailalisi crystal forms C and preparation method thereof.Specifically, crystal form C purity of the present invention is high, relative to 4 molecule hydrates and the hydrate of 0.7 molecule, has better thermal stability, high wet stability and pressure stability, and electrostatic interaction is small, suitable for preparation preparation of industrialization and meet the various performance requirements of preparation.In addition, the preparation process of the crystal form C of the present invention is simple, operability is strong, and process conditions are mild, and yield is high, and stable quality is of low cost, with short production cycle, it is easy to accomplish large-scale production.
Description
Technical field
The present invention relates to medicinal chemistry art, more particularly to a kind of Ai Dailalisi crystal forms C and preparation method thereof.
Background technology
Ai Dailalisi, English name Idelalisib, chemistry are entitled：(S) -2- (1- (9H- purine -6- bases amino) third
Base) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-, trade name：Zydelig, molecular formula are：C22H18FN7O, molecular weight are：
415.42 No. CAS is：870281-82-6, chemical structural formula are：
The medicine is a kind of phosphatidyl-inositol 3-kinase delta inhibitor (abbreviation PI3K δ inhibitor) developed by Gilead companies,
For chronic lymphocytic leukemia, inertia non-Hodgkin lymphoma, lymphoma mantle cell, diffusivity large B cell lymphoid tumor,
The treatment of Hodgkin lymphoma, Huppert's disease, acute myelocytic leukemia and Malignancy, in 2014 7
Obtained the approval listing of FDA on the moon 23.
WO2005113556 discloses Ai Dailalisi and preparation method thereof, later research shows that：Using the preparation side
What method obtained is that solvates of the Ai Dailalisi containing 0.4 molecules of ethanol (is known as in WO2015014315 international patent applications
Crystal form I), WO2015014315 states it, and there are following defects：Weight change is about in 20-80% RH ranges
0.95%, there is certain hygroscopicity, and stability is poor.
WO2013134288 discloses Ai Dailalisi polymorphics I, polymorphs, polymorphic III, polymorphic IV, polycrystalline
Type V, polymorphic VI, polymorphic VII and preparation method thereof, wherein：Polymorphic I and polymorphs are anhydrides, and polymorphic III is
Isopropanol/water solvate, polymorphic IV are n,N-Dimethylformamide solvates, and polymorphic V is dimethylsulfoxide solvent
Object, polymorphic VI are dichloromethane solvates, and polymorphic VII is ethanol/water solvate；And research shows that：Polymorphic I
It is poor with the solubility of polymorphs, it is unfavorable for absorption of human body.Other crystal forms are solvate, and for the crystalline substance of solvate
Type since common solvent has volatility, keeps stablizing for crystal form difficult in follow-up preparation process.
WO2015014315 discloses Ai Dailalisi crystal forms I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form
VIth, crystal form VII, crystal form VIII, crystal form Ⅸ, crystal form Ⅹ and preparation method thereof, wherein：Crystal form I is 0.4 molecules of ethanol solvate, brilliant
Type V is 1 molecule tetrahydrofuran solvate, and crystal form VII is 0.5 molecule methyl tert-butyl ether solvent compound, and crystal form Ⅹ is 0.8 point
Sub- dioxanes solvate, crystal form VI are 4 molecule hydrates, and crystal form Ⅸ is 0.7 molecule hydrate, crystal form II, crystal form III, crystalline substance
Type IV and crystal form VIII are anhydrides.And research shows that：Crystal form I, crystal form IV, crystal form V, crystal form VI, the crystal form of Ai Dailalisi
VIIth, it is crystal form II that crystal form VIII, crystal form Ⅸ and crystal form Ⅹ, which easily turn brilliant,；Crystal form I and other crystal forms described in the invention are (including crystalline substance
Type VI and crystal form Ⅸ) it is transformed into crystal form III in competitive reaction；And crystal form II and crystal form III are anhydride, solubility compared with
Difference is unfavorable for absorption of human body.
WO 2017093773 discloses Ai Dailalisi acetonitriles compound Form E-S and desolventizing compound Form E.Crystal form
E preparation processes are cumbersome, are not suitable for industrialized production.
CN 106632337A disclose Ai Dailalisi crystal forms R.Solubility is poor in the water of crystal form R, is unfavorable for human body suction
It receives and utilizes.
WO 2016188506A1 Ai Dailalisi crystal forms Form 1 (1 water object) and 2 (DMF solvent compounds).It is prepared by Form1
Method is dissolved in the organic solvent of boiling for Ai Dailalisi crude products, filters while hot, filtrate is placed in cooling crystallization in ice-water bath and obtains
Form1, technological operation difficulty is big, is not suitable for industrialized production.
CN106565716A discloses Ai Dailalisi crystal forms A (a water object).Although crystal form A has preferable thermostabilization
Property, high wet stability and pressure stability, but crystal form A electrostatic is larger, is easily coalesced in production process.
In conclusion Ai Dailalisi is there are a variety of crystal forms, but crystal form or there are stability it is poor or there are dissolubility it is poor,
Or it is larger or there is the problems such as being not suitable for industrialized production there are electrostatic, so needing to find a kind of both has good solubility
And stability, and the crystal form with smaller electrostatic interaction, it is suitable for the preparation of industrialization of preparation and meets the various property of preparation
It can requirement.
Invention content
Not only there is good solubility and stability, but also there is smaller electrostatic interaction the object of the present invention is to provide a kind of
Ai Dailalisi crystal forms C of suitable formulations production and preparation method thereof.
The first aspect of the present invention, provides a kind of crystal of Ai Dailalisi, and the crystal is mono- water of Ai Dailalisi
Object is closed, the crystal form of the crystal is selected from down for the X-ray powder diffraction pattern of crystal form C, the crystal form C including 3 or 3 or more
2 θ values of group：9.8±0.2°、12.7±0.2°、18.3±0.2°、19.0±0.2°、22.8±0.2°、 23.1±0.2°、
25.6±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form C is selected from the group below including 5 or 5 or more
2 θ values：9.8±0.2°、12.7±0.2°、18.3±0.2°、19.0±0.2°、22.8±0.2°、23.1±0.2°、 25.6±
0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form C includes 2 θ values of the following group： 9.8±0.2°、
12.7±0.2°、18.3±0.2°、19.0±0.2°、22.8±0.2°、23.1±0.2°、25.6±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form C is in the characteristic peak phase of 2 θ values selected from the group below
50% is more than to intensity：9.8±0.2°、12.7±0.2°、18.3±0.2°、19.0±0.2°、22.8±0.2°、 23.1±
0.2 °, 25.6 ± 0.2 °, or combination.
In another preferred example, the relative intensity refers to relative to the characteristic peak of maximum intensity in the crystal form C
The relative intensity of the characteristic peak (2 θ values are 18.95 ± 0.2) of intensity, i.e. maximum intensity is 100%.
In another preferred example, the X-ray powder diffraction pattern of the crystal form C further includes 1 or 1 or more and is selected from the group
2 θ values：11.7±0.2°、13.7±0.2°、15.3±0.2°、16.3±0.2°、19.5±0.2°、29.8 ±0.2°.
In another preferred example, the X-ray powder diffraction pattern of the crystal form C further includes 1 or 1 or more and is selected from the group
2 θ values：11.7±0.2°、13.7±0.2°、15.3±0.2°、16.3±0.2°.
In another preferred example, the X-ray powder diffraction pattern of the crystal form C further includes 1 or 1 or more and is selected from the group
2 θ values：19.5±0.2°、29.8±0.2°.
In another preferred example, the crystal form C has selected from 2 θ (°) values shown in table 1.
Table 1
In another preferred example, the crystal form C has feature selected from the group below：
(1) X-ray powder diffraction pattern of the crystal form C is basic as Fig. 1 is characterized；And/or
(2) the thermogravimetric analysis collection of illustrative plates of the crystal form C is basic as Fig. 2 is characterized.
The second aspect of the present invention provides a kind of method for preparing the crystal described in first aspect present invention, the side
Method includes step：
(a) provide Ai Dailalisi the first solution in organic solvent and
(b) anti-solvent is added in into the first solution, forms the second solution, and crystallization processing is carried out to the second solution, so as to
Form the crystal described in first aspect present invention.
In another preferred example, the organic solvent, which is included at 15~120 DEG C, can be completely dissolved having for Ai Dailalisi
Solvent.
In another preferred example, the organic solvent is selected from the group：Methanol, ethyl alcohol, acetonitrile, acetone, tetrahydrofuran, N, N-
Dimethylformamide, N-Methyl pyrrolidone, thionyl chloride, or combination.
In another preferred example, the organic solvent is selected from the group：Tetrahydrofuran, methanol, acetonitrile, acetone, N, N- diformazans
Base formamide, or combination.
In another preferred example, in first solution Ai Dailalisi a concentration of 0.005~1.0g/mL, preferably
0.01~0.1g/mL.
In another preferred example, the anti-solvent is water.
In another preferred example, the step (a) by Ai Dailalisi dissolvings including in organic solvent, it is molten to obtain first
Liquid, preferably, described be dissolved at 15-120 DEG C carries out, more preferably 20-80 DEG C.
In another preferred example, first solution is clear.
In another preferred example, after the step (a), before step (b), the method further includes；It is molten to concentrate first
Liquid is (a small amount of) muddy to occurring.
In another preferred example, described be concentrated at a temperature of t1 carries out, wherein the t1 is 20-40 DEG C.
In another preferred example, the step (b) carries out at a temperature of t2, wherein the t2 is 0-60 DEG C, preferably 0-
50℃。
In another preferred example, crystallization processing includes being stirred the second solution, preferably at 0-50 DEG C into
Row stirring.
In another preferred example, after step (b), the method further includes：(c) it is detached from the solution of previous step
The crystal form C.
In another preferred example, after step (c), the method further includes：(d) the crystal form C of the separation is carried out
It is dry.
The third aspect of the present invention, provides a kind of pharmaceutical composition, and described pharmaceutical composition includes：
(a) as described in the first aspect of the invention the pharmaceutically acceptable auxiliary material of crystal and (b) or carrier.
The fourth aspect of the present invention provides the purposes of crystal in medicine preparation as described in the first aspect of the invention.
In another preferred example, the drug is phosphatidyl-inositol 3-kinase delta inhibitor.
In another preferred example, the drug is used to treat tumour or cancer.
In another preferred example, the drug for treat chronic lymphocytic leukemia, inertia non-Hodgkin lymphoma,
Lymphoma mantle cell, diffusivity large B cell lymphoid tumor, Hodgkin lymphoma, Huppert's disease, acute myelocytic leukemia,
Malignancy, or combination.
The fifth aspect of the present invention provides the use of pharmaceutical composition in medicine preparation described in fourth aspect present invention
On the way.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Description of the drawings
Fig. 1 shows the XRD spectra of Ai Dailalisi crystal forms C of the present invention.
Fig. 2 shows the TGA spectrograms of Ai Dailalisi crystal forms C of the present invention.
Fig. 3 shows the XRD spectra of 1 gained Ai Dailalisi crystal forms VI of comparative example.
Fig. 4 shows the DSC spectrograms of 1 gained Ai Dailalisi crystal forms VI of comparative example.
Fig. 5 shows the TGA spectrograms of 1 gained Ai Dailalisi crystal forms VI of comparative example.
Fig. 6 shows the XRD spectra of 2 gained Ai Dailalisi crystal forms Ⅸ of comparative example.
Fig. 7 shows the DSC spectrograms of 2 gained Ai Dailalisi crystal forms Ⅸ of comparative example.
Fig. 8 shows the TGA spectrograms of 2 gained Ai Dailalisi crystal forms Ⅸ of comparative example.
Fig. 9 shows the XRD spectra of 3 gained Ai Dailalisi crystal forms A of comparative example.
Figure 10 shows the DSC spectrograms of 3 gained Ai Dailalisi crystal forms A of comparative example.
Figure 11 shows the TGA spectrograms of 3 gained Ai Dailalisi crystal forms A of comparative example.
Specific embodiment
The present inventor and in-depth study, is developed study carefully for the first time, be surprised to find that Ai Dailalisi's for the first time by extensive
Crystal form C, its application and preparation method.The crystal form C purity is high, relative to 4 molecule hydrates and the hydrate of 0.7 molecule, tool
Have better thermal stability, high wet stability and pressure stability, and electrostatic interaction is small, suitable for preparation preparation of industrialization and
Meet the various performance requirements of preparation.In addition, the preparation process of the crystal form C of the present invention is simple, operability is strong, process conditions temperature
High with, yield, stable quality is of low cost, with short production cycle, it is easy to accomplish large-scale production.On this basis, inventor is complete
Into the present invention.
Term explanation
Unless otherwise defined, otherwise whole technologies used herein are respectively provided with scientific terminology such as fields of the present invention
The normally understood identical meanings of those of ordinary skill.
As used herein, in use, term " about " means that the value can be from enumerating in the numerical value specifically enumerated is mentioned
Value changes not more than 1%.For example, as used herein, statement " about 100 " including 99 and 101 and between whole values (for example,
99.1st, 99.2,99.3,99.4 etc.).
As used herein, term " containing " or can be open, semi-enclosed and enclosed " including (including) ".It changes
Yan Zhi, the term also include " substantially by ... form " or " by ... form ".
As used herein, term " n or n or more 2 θ values selected from the group below " refers to including n and arbitrary just whole more than n
Number (such as n, n+1 ...), wherein upper limit Nup is the number of all 2 θ peak values in the group.Such as " 1 or 1 or more " is not only
Including 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 ... upper limit Nup is each just whole
Number, further includes " 2 or 2 or more ", " 3 or 3 or more ", " 4 or 4 or more ", " 5 or 5 or more ", " 6 or 6
More than a ", " 7 or 7 or more ", " 8 or 8 or more ", " 9 or 9 or more ", " 10 or 10 or more ", etc. models
It encloses.Such as " 3 or 3 or more " not only include 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,
21st ... each positive integers of upper limit Nup further include " 4 or 4 or more ", " 5 or 5 or more ", " 6 or 6 or more ", " 7
It is a or 7 or more ", " 8 or 8 or more ", " 9 or 9 or more ", " 10 or 10 or more ", etc. ranges.
Ai Dailalisi
Ai Dailalisi, English name Idelalisib, chemistry are entitled：(S) -2- (1- (9H- purine -6- bases amino) third
Base) fluoro- 3- phenylquinazolines -4 (3H) -one of -5-, trade name：Zydelig, molecular formula are：C22H18FN7O, molecular weight are：
415.42 No. CAS is：870281-82-6, chemical structural formula are：
The medicine is a kind of phosphatidyl-inositol 3-kinase delta inhibitor (abbreviation PI3K δ inhibitor) developed by Gilead companies,
For chronic lymphocytic leukemia, inertia non-Hodgkin lymphoma, lymphoma mantle cell, diffusivity large B cell lymphoid tumor,
The treatment of Hodgkin lymphoma, Huppert's disease, acute myelocytic leukemia and Malignancy, in 2014 7
Obtained the approval listing of FDA on the moon 23.
Polymorph
It is exactly to exist in the form of crystallization in the form of unbodied that solid, which is not,.In the case of crystal form, molecule is fixed
In three-dimensional lattice case.When compound is crystallized out from solution or slurries, the space lattice that it can be different arranges
Crystallization (this property is referred to as " polymorphism "), forms the crystal with different crystal forms, this various crystal form
Referred to as " polymorph ".The different polymorphs of given substance can in terms of one or more physical attributes (such as solubility and
Rate of dissolution, true specific gravity, crystalline form, accumulation mode, mobility and/or solid-state stability) it is different from each other.
The polymorphic forms of compound can show different fusing points, hygroscopicity, stability, solubility, biological utilisation
Degree, bioactivity and mobility etc., and these are an important factor for influencing druggability.
WO2005113556 discloses Ai Dailalisi and preparation method thereof, later research shows that：Using the preparation side
What method obtained is that solvates of the Ai Dailalisi containing 0.4 molecules of ethanol (is known as in WO2015014315 international patent applications
Crystal form I), WO2015014315 states it, and there are following defects：Weight change is about in 20-80% RH ranges
0.95%, there is certain hygroscopicity, and stability is poor.
WO2013134288 discloses Ai Dailalisi polymorphics I, polymorphs, polymorphic III, polymorphic IV, polycrystalline
Type V, polymorphic VI, polymorphic VII and preparation method thereof, wherein：Polymorphic I and polymorphs are anhydrides, and polymorphic III is
Isopropanol/water solvate, polymorphic IV are n,N-Dimethylformamide solvates, and polymorphic V is dimethylsulfoxide solvent
Object, polymorphic VI are dichloromethane solvates, and polymorphic VII is ethanol/water solvate；And research shows that：Polymorphic I
It is poor with the solubility of polymorphs, it is unfavorable for absorption of human body.Other crystal forms are solvate, and for the crystalline substance of solvate
Type since common solvent has volatility, keeps stablizing for crystal form difficult in follow-up preparation process.
WO2015014315 discloses Ai Dailalisi crystal forms I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form
VIth, crystal form VII, crystal form VIII, crystal form Ⅸ, crystal form Ⅹ and preparation method thereof, wherein：Crystal form I is 0.4 molecules of ethanol solvate, brilliant
Type V is 1 molecule tetrahydrofuran solvate, and crystal form VII is 0.5 molecule methyl tert-butyl ether solvent compound, and crystal form Ⅹ is 0.8 point
Sub- dioxanes solvate, crystal form VI are 4 molecule hydrates, and crystal form Ⅸ is 0.7 molecule hydrate, crystal form II, crystal form III, crystalline substance
Type IV and crystal form VIII are anhydrides.And research shows that：Crystal form I, crystal form IV, crystal form V, crystal form VI, the crystal form of Ai Dailalisi
VIIth, it is crystal form II that crystal form VIII, crystal form Ⅸ and crystal form Ⅹ, which easily turn brilliant,；Crystal form I and other crystal forms described in the invention are (including crystalline substance
Type VI and crystal form Ⅸ) it is transformed into crystal form III in competitive reaction；And crystal form II and crystal form III are anhydride, solubility compared with
Difference is unfavorable for absorption of human body.
WO 2017093773 discloses Ai Dailalisi acetonitriles compound Form E-S and desolventizing compound Form E.Crystal form
E preparation processes are cumbersome, are not suitable for industrialized production.
CN 106632337A disclose Ai Dailalisi crystal forms R.Solubility is poor in the water of crystal form R, is unfavorable for human body suction
It receives and utilizes.
WO 2016188506A1 Ai Dailalisi crystal forms Form 1 (1 water object) and 2 (DMF solvent compounds).It is prepared by Form1
Method is dissolved in the organic solvent of boiling for Ai Dailalisi crude products, filters while hot, filtrate is placed in cooling crystallization in ice-water bath and obtains
Form1, technological operation difficulty is big, is not suitable for industrialized production.
CN106565716A discloses Ai Dailalisi crystal forms A (a water object).Although crystal form A has preferable thermostabilization
Property, high wet stability and pressure stability, but crystal form A electrostatic is larger, is easily coalesced in production process.
As used herein, " crystal ", " crystal of the present invention ", " crystal form C " are used interchangeably, and are referred to described in first aspect present invention
Crystal, crystal form is crystal form C, and (molar ratio of Ai Dailalisi and water is 1 for monohydrate that crystal form C be Ai Dailalisi:
1)。
Ai Dailalisi crystal forms C of the present invention is the 1 molecule hydrate of Ai Dailalisi, spreads out in powder X-ray ray
Penetrate down, 2 θ for 9.8 ± 0.2 °, 12.7 ± 0.2 °, 18.3 ± 0.2 °, 19.0 ± 0.2 °, 22.8 ± 0.2 °, 23.1 ± 0.2 °,
There is characteristic peak at 25.6 ± 0.2 °.
Furtherly, under powder x-ray diffraction, 2 θ for 9.8 ± 0.2 °, 11.7 ± 0.2 °, 12.7 ± 0.2 °,
There is characteristic peak at 15.3 ± 0.2 °, 18.3 ± 0.2 °, 19.0 ± 0.2 °, 23.1 ± 0.2 °, 25.6 ± 0.2 °.
Furtherly, Ai Dailalisi crystal forms C of the present invention, under powder x-ray diffraction, 2 θ for 9.8 ±
0.2°、11.7±0.2°、12.7±0.2°、13.7±0.2°、16.3±0.2°、22.8±0.2°、15.3±0.2°、 18.3
There is characteristic peak at ± 0.2 °, 19.0 ± 0.2 °, 23.1 ± 0.2 °, 25.6 ± 0.2 °.
Furtherly, Ai Dailalisi crystal forms C of the present invention has as shown in table 1 under powder x-ray diffraction
Characteristic peak and its relative intensity.
Crystallization
Working solution can be passed through so that the solubility limit of compound of interest is exceeded, so as to complete production scale
Crystallization.This can be completed by a variety of methods, for example, dissolved compound at relatively high temperature, then cools down solution
To saturation limit.Or by boiling, atmospheric evaporation, vacuum drying or by some other methods reduce liquid bulk
Product.Can have the solvent of low solubility or the mixture of such solvent wherein by adding in anti-solvent or compound, come
Reduce the solubility of compound of interest.Another optional method is to adjust pH value to reduce solubility.In terms of related crystallization
It is described in detail and refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd.,
1993,ISBN0750611294。
If the formation and crystallization of it is expected salt occur simultaneously, if salt is smaller than dissolution of raw material degree in reaction medium, then
The direct crystallization of required salt can be led to by adding in appropriate acid or alkali.Equally, it is smaller than reactant solubility in finally desired form
Medium in, the completion of synthetic reaction can make final product direct crystallization.
The optimization of crystallization may include that the crystal by the use of required form is inoculated in as crystal seed in crystallization medium.In addition, many knots
Crystal method uses the combination of above-mentioned strategy.One embodiment be at high temperature by interested compound dissolving in a solvent, with
The anti-solvent of proper volume is added in by controlled way afterwards, so that system is just under saturated level.At this point, needed for can adding in
System is cooled down to complete to crystallize by the crystal seed (and keeping the integrality of crystal seed) of form.
Solvate
In compound or drug molecule and solvent molecule contact process, external condition causes solvent point with interior condition factor
The situation that son forms eutectic with compound molecule and remains in solid matter is difficult to avoid that.It is formed after compound and solvent crystallization
Substance be referred to as solvate (solvate).Easily with organic compound formed solvate solvent type for water, methanol,
Benzene, ethyl alcohol, ether, aromatic hydrocarbons, heterocyclic arene etc..
Hydrate is a kind of special solvate.In pharmaceuticals industry, no matter the synthesis of bulk pharmaceutical chemicals, pharmaceutical preparation,
In medicine storage and pharmaceutical activity evaluation, hydrate all has the value individually discussed because of its particularity.
Differential scanning calorimetry
Also known as " differential scanning calorimetry " (DSC) is in heating process, measures between measured matter and reference substance
A kind of technology of relationship between energy difference and temperature.Peak position, shape and the property of peak number mesh and substance on DSC collection of illustrative plates have
It closes, therefore can qualitatively be used for identifying substance.This method commonly used in the art detects the phase transition temperature of substance, glass transition temperature
The many kinds of parameters such as degree, reaction heat.
Preparation method
The present invention prepares crystal form C of the present invention using method as described in respect of the second aspect of the invention.Specifically include reversely molten
Analyse crystallisation.Method is simple by the present invention, and operability is strong, and process conditions are mild, and yield is high, and stable quality is at low cost
It is honest and clean, it is with short production cycle, it is easy to accomplish large-scale production.
In the preference of the present invention, the preparation method includes the following steps：
A) by Ai Dailalisi dissolution of raw material in organic solvent, solution temperature is for 15~120 DEG C (with 20 DEG C~80 DEG C
Preferably), clear solution is obtained；
B) above-mentioned 20-40 DEG C of solution is carried out being concentrated into a small amount of muddiness of appearance；
C) under 0~60 DEG C (preferably 0~50 DEG C), it is brilliant that anti-solvent elutriation is added dropwise into step a) acquired solutions；
D) insulated and stirred；
E) room temperature is cooled to, is filtered, it is dry to get the Ai Dailalisi crystal forms C.
The crystal form of the Ai Dailalisi raw materials is unlimited, can be any one unformed or known crystal form or they
Mixture.
The solvent refers to, at 15~120 DEG C, Ai Dailalisi raw materials can be made to be dissolved completely in solvent therein, including
But methanol is not limited to, ethyl alcohol, acetone, acetonitrile, tetrahydrofuran, n,N-Dimethylformamide, N-Methyl pyrrolidone or dichloro are sub-
The organic solvents such as sulfone or the mixed solvent formed by several organic solvents.
Preferably, the suitable solvent is selected from tetrahydrofuran, methanol, acetonitrile, acetone or N, N- dimethyl methyl
Amide or by several mixed solvents formed in them.
The concentration of step a) acquired solutions can be 0.005~1.0g/mL, preferably 0.01~0.1g/mL.
Main advantages of the present invention are：
(1) the crystal form C described in is relative to known various solvates, and there is no solvent toxicity problems；
(2) crystal form C described in relative to 4 molecule hydrates and the hydrate of 0.7 molecule, have better thermal stability,
High wet stability and pressure stability are of great significance to the preparation and storage of follow-up preparation；
(3) the crystal form C described in has electrostatic interaction small referring now to existing 1 molecule hydrate, and suitable formulations produce excellent
Gesture；
(4) preparation process of the crystal form C described in is simple, and operability is strong, and process conditions are mild, and yield is high, stable quality,
It is of low cost, it is with short production cycle, it is easy to accomplish large-scale production.
With reference to specific embodiment, the present invention is further explained.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.Test method without specific conditions in the following example, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.Following reality
Applying experiment material used in example and reagent can obtain unless otherwise instructed from commercially available channel.Room temperature or room temperature refer to 20 DEG C -28
℃。
Raw material and universal method
1) determination condition of XRD diagram is as follows obtained by following embodiment and comparative examples：
With 1.5460 angstromsWavelength α1, 1.54439 angstromsWavelength α2Radiation source, intensity compares α1/α2For
It is measured in the equipment of 0.5,40kV voltage and Dedye~Scherrer INEL CPS of 30mA current strength~120.
2) determination condition of DSC figures is as follows obtained by following embodiment and comparative examples：
In closed container, be passed through 50mL/min nitrogen streams, in the range of 20~450 DEG C, the rate of heat addition for 10 DEG C/
Min is measured in DSC Q 2000 (TA companies of the U.S.) equipment.
3) determination condition of TGA figures is as follows obtained by following embodiment and comparative examples：
In the range of 20~450 DEG C, the rate of heat addition is 10 DEG C/min, nitrogen flow rate 50mL/min, in TA companies of the U.S.
SDT Q600 type equipment in measure.
4) determination condition of HPLC purity is as follows obtained by following embodiment and comparative examples：
Chromatographic column：YMC-Pack Pro C18 4.6*150mm, 3 μm；Wavelength：270nm；Column temperature：35℃；Flow velocity：
1.0mL/min；Diluent：50% acetonitrile；Sample size：10μL；
Mobile phase A：The water of the trifluoroacetic acid containing 0.1wt% and acetonitrile (volume ratio 95:5)
Mobile phase B：Acetonitrile
Gradient is as shown in the table：
Embodiment 1：The preparation of Ai Dailalisi crystal forms C
Embodiment 1.1
It is at 40 DEG C, 1g Ai Dailalisi raw materials (so-called crystal form I in WO2015014315 international patent applications) is molten
Solution obtains clear solution in 30mL tetrahydrofurans；Solution is carried out at 25 DEG C to be concentrated into appearance muddiness；At 40 DEG C,
Anti-solvent water is slowly added dropwise into more than solution, insulated and stirred makes crystallization 2 hours after solid is precipitated, and is cooled to room temperature；Filtering,
It is dry, obtain 0.90g crystal；Yield is that 90%, HPLC purity is 99.2%.
Fig. 1 is the XRD spectra of gained crystal, as seen from Figure 1：The crystal under powder x-ray diffraction, 2 θ 9.8 ±
0.2°、11.7±0.2°、12.7±0.2°、15.3±0.2°、18.3±0.2°、19.0±0.2°、23.1±0.2°、 25.6
There is characteristic peak at ± 0.2 °.
Furtherly, Ai Dailalisi crystal forms C of the present invention, under powder x-ray diffraction, 2 θ for 9.8 ±
0.2°、11.7±0.2°、12.7±0.2°、13.7±0.2°、16.3±0.2°、22.8±0.2°、15.3±0.2°、18.3±
There is characteristic peak at 0.2 °, 19.0 ± 0.2 °, 23.1 ± 0.2 °, 25.6 ± 0.2 °.
Specifically, Ai Dailalisi crystal forms C has the characteristic peak and relatively strong shown in the following table 1 under powder x-ray diffraction
Degree：
Table 1
Fig. 2 is the TGA spectrograms of gained crystal, as seen from Figure 2：The crystal illustrates institute in 80~130 DEG C of weightlessness 3.977%
Obtain the 1 molecule hydrate that crystal is Ai Dailalisi.
It to sum up analyzes visible：Crystal obtained by the embodiment is the Ai Dailalisi crystal forms C of the present invention.
Embodiment 1.2
At 55 DEG C, 1g Ai Dailalisi raw materials (no matter which kind of kenel) are dissolved in 40mL methanol/acetonitrile, and (volume ratio is
1:1) in the mixed solvent obtains clear solution；Above-mentioned solution at 30 DEG C be concentrated into and muddiness occurs；At 30 DEG C, to
Anti-solvent water is slowly added dropwise in more than solution, insulated and stirred makes crystallization 2 hours after solid is precipitated, and is cooled to room temperature；Filtering is done
It is dry, obtain 0.85g crystal；Yield is that 85%, HPLC purity is 99.3%.
It analyzes after measured, gained crystal has XRD spectra feature shown in FIG. 1 and TGA chromatogram characteristics shown in Fig. 2, says
Crystal obtained by bright the present embodiment is also Ai Dailalisi crystal forms C of the invention.
Comparative example 1
Ai Dailalisi crystal forms VI are prepared with reference to embodiment 15 in WO2015014315A1 (i.e.：4 molecules of Ai Dailalisi
Hydrate crystal)：
22mL is added in into 1g Ai Dailalisi raw materials (so-called crystal form I in WO2015014315 international patent applications)
Water and 22mL isopropanols, ultrasonic 5min obtain suspension；Then 8 angel's crystallizations are stirred at room temperature, filter, it is dry, it obtains
0.76g crystal, yield 76%, HPLC purity are 99.53%.
Fig. 3 is the XRD spectra of gained crystal.As seen from Figure 3, the XRD spectra of the crystal and institute in WO 2015014315A1
The XRD spectra of crystal form VI shown has the consistency in error range.
Fig. 4 is the DSC spectrograms of gained crystal.From fig. 4, it can be seen that the crystal has a solvent peak at 60~126 DEG C, 187
There is a heat release to turn brilliant peak at~221 DEG C, the melting range after heat release turns brilliant is 241~248 DEG C, shown in WO2015014315A1
Crystal form VI DSC spectrograms it is with uniformity.
Fig. 5 is the TGA spectrograms of gained crystal.As seen from Figure 5, crystal weightlessness about 15% before 127.5 DEG C, illustrates institute
Obtain the 4 molecule hydrates that crystal is Ai Dailalisi.
Comparative example 2
Ai Dailalisi crystal forms Ⅸ are prepared with reference to embodiment 21 in WO2015014315A1 (i.e.：0.7 point of Ai Dailalisi
Sub- hydrate crystal)：
32mL is added in into 1g Ai Dailalisi raw materials (so-called crystal form I in WO2015014315 international patent applications)
Water and 8mL ethyl alcohol, ultrasonic 5min obtain suspension；Then 8 angel's crystallizations are stirred at room temperature, filter, it is dry, obtain 0.65g
Crystal, yield 65%, HPLC purity are 99.64%.
Fig. 6 is the XRD spectra of gained crystal.As seen from Figure 6, the XRD spectra of the crystal and institute in WO 2015014315A1
The XRD spectra of crystal form Ⅸ shown has the consistency in error range.
Fig. 7 is the DSC spectrograms of gained crystal.As seen from Figure 7, which has one at 37~96 DEG C and 96~128 DEG C
Solvent peak has a heat release to turn brilliant peak at 184~210 DEG C, and the melting range after heat release turns brilliant is 241~247 DEG C, with
The DSC spectrograms of crystal form Ⅸ shown in WO2015014315A1 are with uniformity.
Fig. 8 is the TGA spectrograms of gained crystal.As seen from Figure 8, crystal weightlessness about 3.3% before 100 DEG C, illustrates institute
Obtain the 0.7 molecule hydrate that crystal is Ai Dailalisi.
Comparative example 3
Ai Dailalisi crystal forms A is prepared with reference to embodiment 1.1 in CN106565716 (i.e.：1 molecular water of Ai Dailalisi
Solvate crystal)：
At 30 DEG C, 1g Ai Dailalisi raw materials (no matter which kind of kenel) are dissolved in 30mL acetone, are obtained clear
Solution；At 30 DEG C, anti-solvent water is slowly added dropwise into more than solution to muddy (about 100ml), insulated and stirred is begun to show makes crystallization 2
Hour, it is cooled to room temperature；Filtering, it is dry, obtain 0.85g crystal；Yield is that 85%, HPLC purity is 99.58%.
Fig. 9 is the XRD spectra of gained crystal.As seen from Figure 9, Fig. 1 institutes in the XRD spectra and CN106565716 of the crystal
The XRD spectra of crystal form A shown has the consistency in error range.
Figure 10 is the DSC spectrograms of gained crystal.As seen from Figure 10, which has at 50~75 DEG C and 80~100 DEG C
One solvent peak turns crystalline substance in 197 DEG C or so place's heat releases, is melted at 253 DEG C, with crystal form A's shown in Fig. 2 in CN106565716
DSC spectrograms are with uniformity.
Figure 11 is the TGA spectrograms of gained crystal.As seen from Figure 11, crystal weightlessness about 4% before 100 DEG C, illustrates institute
Obtain the 1 molecule hydrate that crystal is Ai Dailalisi.
Embodiment 2：Stability experiment
Take Ai Dailalisi crystal forms C made from above-described embodiment 1.1 and 1.2 (1 molecule hydrate crystal) and comparative example 1
(0.7 point of Ai Dailalisi crystal forms Ⅸ made from Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) obtained and comparative example 1
Sub- hydrate crystal) sample, it is handled as follows respectively：
1. it is placed 3 months under 60 DEG C of humidity；
2. it is placed 3 months under 25 DEG C, 65% humidity；
3. it is strongly ground in mortar 30 minutes；
Progress XRD and HPLC separately sampled to 0 month, 1 month, 3 months and 6 months of above-mentioned sample during processing is surveyed
Setting analysis, analysis result is as shown in Table 1 and Table 2.
Table 1
Table 2
Remarks：The name of above comparison crystal form, with reference to being named in WO2015014315.
By above-mentioned the experimental results showed that：Although the Chinese mugwort generation in the Ai Dailalisi crystal forms C and WO2015014315 of the present invention
La Lisi crystal forms VI and Ai Dailalisi crystal forms Ⅸ are all the hydrate crystal of Ai Dailalisi.But the Ai Dailalisi of the present invention
Crystal form C (1 molecule hydrate crystal) is relative to the Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) in WO2015014315
It is steady that apparent thermal stability, high wet stability and pressure are respectively provided with Ai Dailalisi crystal forms Ⅸ (0.7 molecule hydrate crystal)
It is qualitative.Known Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) and (the 0.7 molecule hydrate of Ai Dailalisi crystal forms Ⅸ
Crystal) at 60 DEG C and 25 DEG C, the monthly part that has occurred of storage 1 turns brilliant behavior under 65% humidity, complete after storage 2 months
Switch to Ai Dailalisi crystal form II entirely, and Ai Dailalisi crystal forms II is anhydride, solubility is poor, is unfavorable for absorption of human body,
It can influence the result of extraction of preparation.
Embodiment 3：Solubility experiment
Take Ai Dailalisi crystal forms C made from above-described embodiment 1.1 and 1.2 (1 molecule hydrate crystal) and comparative example 1
(0.7 point of Ai Dailalisi crystal forms Ⅸ made from Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) obtained and comparative example 2
Sub- hydrate crystal) sample, carry out solubility experiment：
The above-mentioned samples of 0.2g are weighed respectively to be put into test tube, under 25 DEG C of water-baths, are slowly added dropwise into test tube in concussion
The aqueous hydrochloric acid solution of pH1.2, until solid is completely dissolved, the solubility results of each sample are shown in Table 3.
Table 3
| Sample | Solubility (g/mL) |
| Embodiment 1.1 | 0.060 |
| Embodiment 1.2 | 0.057 |
| Comparative example 1 | 0.048 |
| Comparative example 2 | 0.039 |
From table 3：Although the Ai Dailalisi crystal forms in the Ai Dailalisi crystal forms C and WO2015014315 of the present invention
VI and Ai Dailalisi crystal forms Ⅸ are all the hydrate crystal of Ai Dailalisi, but (1 point of the Ai Dailalisi crystal forms C of the present invention
Sub- hydrate crystal) relative to the Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) and Ai Daila in WO2015014315
Profit department's crystal form Ⅸ (0.7 molecule hydrate crystal) has in the aqueous hydrochloric acid solution of pH1.2 (relative to the gastric juice environment of human body)
Excellent dissolubility, solubility are 1.25 times and 1.54 times of crystal form VI and crystal form Ⅸ respectively, are very beneficial for oral preparation
Dissolution absorb.
Embodiment 4
Respectively with crystal form C, Ai Dailalisi crystal form VI and Ai Dailalisi crystal forms Ⅸ, Ai Dailalisi of Ai Dailalisi
For crystal form A as medicine activity component, the formula as shown in table 4 prepares tablet.
The tablet formulation of 4 Ai Dailalisi of table
The preparation method of tablet is as follows：Medicine activity component is mixed with microcrystalline cellulose, croscarmellose sodium
Uniformly, mixed powder is obtained；Hydroxypropyl cellulose is soluble in water, it is added in above-mentioned mixed powder after 8% aqueous solution is made, system is soft
Material；24 mesh sieve series grains are crossed, it is dry under 50~70 DEG C of ＆ relative humidity 20-30%, obtain dry particl；Again by sodium carboxymethyl starch with
Magnesium stearate is added in dry particl, tabletting after mixing.
Gained tablet at 60 DEG C is placed 3 months simultaneously, 1 month, 2 months and 3 months during processing is taken respectively
Sample carries out XRD analysis, and analysis result is as shown in table 5.
Table
From table 5：With the Ai Dailalisi crystal forms C (1 molecule hydrate crystal) of the present invention and crystal form A, (1 molecule is hydrated
Object crystal) as tablet made from medicine activity component, it is placed at 60 DEG C and crystal form variation occurs within 3 months yet, and with
Ai Dailalisi crystal forms VI (4 molecule hydrate crystal) or (0.7 molecular water of Ai Dailalisi crystal forms Ⅸ in WO2015014315
Solvate crystal) as tablet made from medicine activity component, 1 monthly part that has occurred is placed at 60 DEG C and turns brilliant behavior,
Storage switchs to Ai Dailalisi crystal form II completely after 2 months, and Ai Dailalisi crystal forms II is anhydride, and solubility is poor,
It is unfavorable for absorption of human body, the dissolution that can influence preparation absorbs；
But it is found in tablet manufacture：Electrostatic force of crystal form A itself is slightly larger, there is easily adherency in tablet manufacture
Container and the first-class phenomenon of tablet machine drift, are not easy to prepare, and cause drug loss, low yield, and machine not easy cleaning.It is and brilliant
Type C electrostatic force is smaller, it is easier to tablet be made, be very suitable for the preparation of industrialization of preparation, and the various performances for meeting preparation will
It asks.
Therefore, illustrate that the Ai Dailalisi crystal forms C (1 molecule hydrate crystal) of the present invention is more suitable for relative to the prior art
As the medicine activity component of preparation, there is apparent industrial application value, relative to the prior art, have conspicuousness progress and
Unexpected effect.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To be made various changes or modifications to the present invention, such equivalent forms equally fall within the model that the application the appended claims are limited
It encloses.
Claims (10)
1. a kind of crystal of Ai Dailalisi, which is characterized in that the crystal is Ai Dailalisi monohydrates, the crystal
Crystal form is that the X-ray powder diffraction pattern of crystal form C, the crystal form C include 3 or 3 or more 2 θ values selected from the group below：9.8±
0.2°、12.7±0.2°、18.3±0.2°、19.0±0.2°、22.8±0.2°、23.1±0.2°、25.6±0.2°。
2. crystal as described in claim 1, which is characterized in that the X-ray powder diffraction pattern of the crystal form C further includes 1
Or 1 or more 2 θ value selected from the group below：11.7±0.2°、13.7±0.2°、15.3±0.2°、16.3±0.2°、19.5±
0.2°、29.8±0.2°。
3. crystal as described in claim 1, which is characterized in that the crystal form C has feature selected from the group below：
(1) X-ray powder diffraction pattern of the crystal form C is basic as Fig. 1 is characterized；And/or
(2) the thermogravimetric analysis collection of illustrative plates of the crystal form C is basic as Fig. 2 is characterized.
A kind of 4. method for preparing any crystal in claim 1-3, which is characterized in that the method includes the steps：
(a) provide Ai Dailalisi the first solution in organic solvent and
(b) anti-solvent is added in into the first solution, the second solution is formed, and crystallization processing is carried out to the second solution, so as to be formed
Any crystal in claim 1-3.
5. method as claimed in claim 4, which is characterized in that the organic solvent is selected from the group：Methanol, ethyl alcohol, acetonitrile, third
Ketone, tetrahydrofuran, N,N-dimethylformamide, N-Methyl pyrrolidone, thionyl chloride, or combination.
6. method as claimed in claim 4, which is characterized in that a concentration of the 0.005 of Ai Dailalisi in first solution
~1.0g/mL, preferably 0.01~0.1g/mL.
7. method as claimed in claim 4, which is characterized in that the anti-solvent is water.
8. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes：
(a) crystal as described in any one of claim 1-3 and (b) pharmaceutically acceptable auxiliary material or carrier.
9. the purposes of crystal in medicine preparation as described in any described in claim 1-3.
10. the purposes of pharmaceutical composition as claimed in claim 8 in medicine preparation.
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|---|---|---|---|---|
| US11358966B2 (en) | 2018-03-16 | 2022-06-14 | Johnson Matthey Public Limited Company | Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565716A (en) * | 2015-10-10 | 2017-04-19 | 上海创诺制药有限公司 | Idelalisib crystal form A and preparation method thereof |
| CN106632337A (en) * | 2016-10-18 | 2017-05-10 | 湖北生物医药产业技术研究院有限公司 | Idelalisib crystal, pharmaceutical composition comprising idelalisib crystal, and preparation method and application of idelalisib crystal |
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2018
- 2018-03-15 CN CN201810214985.6A patent/CN108218872A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106565716A (en) * | 2015-10-10 | 2017-04-19 | 上海创诺制药有限公司 | Idelalisib crystal form A and preparation method thereof |
| CN106632337A (en) * | 2016-10-18 | 2017-05-10 | 湖北生物医药产业技术研究院有限公司 | Idelalisib crystal, pharmaceutical composition comprising idelalisib crystal, and preparation method and application of idelalisib crystal |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11358966B2 (en) | 2018-03-16 | 2022-06-14 | Johnson Matthey Public Limited Company | Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
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