CN105924444B - The crystal form and preparation method thereof of JAK inhibitor - Google Patents
The crystal form and preparation method thereof of JAK inhibitor Download PDFInfo
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- CN105924444B CN105924444B CN201610136379.8A CN201610136379A CN105924444B CN 105924444 B CN105924444 B CN 105924444B CN 201610136379 A CN201610136379 A CN 201610136379A CN 105924444 B CN105924444 B CN 105924444B
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- C07—ORGANIC CHEMISTRY
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- 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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Abstract
The present invention relates to novel crystal forms of JAK inhibitor and preparation method thereof.Novel crystal forms provided by the invention can be used for treating autoimmune disease, especially rheumatoid arthritis.Novel crystal forms stability provided by the invention is good, and technique refining effect is significant, and solubility, draws and moist meet medicinal requirements.The preparation method of novel crystal forms is simple, low in cost, has important value to the optimization and exploitation of the following drug.
Description
Technical field
The present invention relates to chemical medicines, more particularly to { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-
D] pyrimidine-4-yl) -1H- pyrazol-1-yl] azetidine -3- base acetonitrile crystal form and preparation method thereof.
Background technique
JAK (Janus kinase) kinases is an intracellular nonreceptor tyrosine kinase family, and mediating cytokine produces
Raw signal, and handed on by JAK-STAT signal path.There are four types of known JAK family members at present: jak kinase 1
(JAK1), jak kinase 2 (JAK2), jak kinase 3 (JAK3) and tyrosine kinase 2 (Tyrosine Kinase, TYK2).JAK-
The dependent cell factor participates in the pathogenic process of inflammation and autoimmune disease, JAK inhibitor or can be widely used for controlling
Treat various inflammatory diseases.
Baricitinib is a kind of selection researched and developed jointly by gift Lai (Lilly) pharmacy and Yin Saite (Incyte) company
Property JAK1 and JAK2 inhibitor, in kinase assay, the inhibition strength that Baricitinib is shown for JAK1 and JAK2 is wanted
Than 100 times of JAK3 high.Baricitinib is in clinical test in the U.S. at present, the treatment for rheumatoid arthritis.The medicine
The chemical name of object are as follows: { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl]
Azetidine -3- base } acetonitrile, shown in structural formula such as formula (I).
Specific medical active is that pharmaceutically active substance goes through to list the basic prerequisite that must meet.However, having
Various other requirements is also the condition that pharmaceutically active substance must comply with.These requirements are with various active materials with itself
Based on the related parameter of property.In the absence of constraints, the examples of these parameters be active constituent under various environmental conditions
Chemistry and solid-state stability and stable storing, the stability during pharmaceutical composition manufacture and active constituent are in final medicine
The stability etc. of compositions.
The pharmaceutically active substance for being used to prepare pharmaceutical composition should be as pure as possible and must assure that under various ambient conditions
Stability with long-term preservation.It avoids using containing in addition to containing also containing such as its decomposition product outside certain active material
Pharmaceutical composition be it is most basic, in these cases, the activity substance content in drug is possibly less than the content of mark.This
Outside, pharmaceutically active substances be non-hygroscopic, to degradation and then its solid form variation it is stable be important, if pharmacy
Active material its absorb water (slowly or at any time) in the sense that be it is hygroscopic, then it is almost impossible reliably by pharmacy
Drug is made in active material, the reason is that be added can be significantlyd change with the amount for providing the substance of same dose according to hydration levels,
In addition, hydration or the change of solid form can cause the variation of physicochemical property (such as solubility or rate of dissolution), physics and chemistry
The variation of matter can cause the inconsistent absorption of patient in turn.It is preferred that pharmaceutically active substance should only have slight inhale
It is moist.
Therefore, pharmaceutically active substances chemical stability, solid-state stability, " storage life " and material processing property (such as
The easness for dissolving compound) it is very important factor.In ideal conditions, pharmaceutically active substances and appointing comprising it
What pharmaceutical composition can should effectively store quite long period, without show active material physicochemical property (such as its
Activity, moisture content, solubility properties, solid form etc.) significant changes.In addition, drug will usually require processing to reach
Suitable for sucking partial size and any crystal type handle herein during must stablize so that the property of final products is predictable and reliable.
In short, no matter which kind of is possible, when producing viable commercial and pharmaceutically acceptable Pharmaceutical composition with a kind of abundant
It is all ideal that crystallization and stable form, which provide drug,.
The different crystal forms of same drug appearance, solubility, fusing point, dissolution rate, in terms of might have
It is dramatically different, also can stability, bioavilability and curative effect to drug generate different influences.Therefore, it researches and develops new more suitable
The crystal form for closing application has very important significance for drug development.
As it is known by the man skilled in the art, the presence of the new solid polymorph form of known chemical substance is unpredictable
's.The presence of multi-crystalline compounds or the quantity of polymorphic forms are unpredictable.In addition, crystallization occurs simultaneously under what conditions
Obtain specific form and the polymorphic forms characteristic how, be also all uncertain.Due to multi-crystalline compounds
Every kind of polymorphous characteristic (such as solubility, stability) and therefore caused by application it is different from the applicability of storage, because
All solid-state forms of this research drug substance have improved stable storing for providing including all polymorphic forms
The drug of property or predictable dissolubility property is necessary.
Solid chemical crystal form is different, its solubility and stability can be caused different, thus influence drug absorption and
Bioavilability, and will lead to the difference of clinical drug effect.However, there is no the related report of the crystal form of formula (I) compound at present,
Therefore, it is necessary to carry out comprehensive and systematic screening polymorph to formula (I) compound, the crystal form for being most suitable for exploitation is selected.
The present inventor has had surprisingly found that two kinds of crystal forms and three kinds of phosphoric acid of formula (I) compound in the course of the research
Salt crystal form.And stability of crystal form of the invention is good, solubility, draw it is moist meet medicinal requirements, and preparation method is simple, cost
It is cheap, there is important value to the optimization and exploitation of the following drug.
Summary of the invention
The present invention provides the novel crystal forms of formula (I) compound, novel crystal forms of salt and its preparation method and application.
It is an object of the present invention to provide a kind of crystal forms of formula (I) compound, are named as crystal form I.
Crystal form I provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 15.33 ° ±
There is characteristic peak at 0.20 °, 16.66 ° ± 0.20 °, 19.06 ° ± 0.20 °.
Further, crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 14.91 ° ± 0.20 °, 16.25 ° ± 0.20 °, 15.74 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 14.91 ° in 2theta value
There is characteristic peak at ± 0.20 °, 16.25 ° ± 0.20 °, 15.74 ° ± 0.20 °.
Further, crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 25.51 ° ± 0.20 °, 12.40 ° ± 0.20 °, 17.39 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 25.51 ° in 2theta value
There is characteristic peak at ± 0.20 °, 12.40 ° ± 0.20 °, 17.39 ° ± 0.20 °.
Preferably, crystal form I provided by the invention, X-ray powder diffraction figure be included in 2theta value be 15.33 ° ±
0.20°、16.66°±0.20°、19.06°±0.20°、14.91°±0.20°、16.25°±0.20°、15.74°±0.20°、
25.51 ° ± 0.20 °, 12.40 ° ± 0.20 °, the characteristic peak of one or more in 17.39 ° ± 0.20 ° of position.
Further, crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Fig. 1
It is shown.
Crystal form I provided by the invention, which is characterized in that when carrying out differential scanning calorimetric analysis, be heated near 212 DEG C
Start endothermic peak occur, differential scanning calorimetric thermogram is substantially as shown in Figure 2.
Crystal form I provided by the invention, which is characterized in that when carrying out thermogravimetric analysis, when being heated to 200 DEG C, have about
0.8% weight loss gradient, thermogravimetric analysis figure are substantially as shown in Figure 3.
It is a further object to provide the preparation methods of crystal form I, which is characterized in that formula (I) compound is added
Into one or more dicyandiamide solutions selected from the following: water, alcohols, ketone, esters, aromatic hydrocarbon, halogenated hydrocarbons, nitrile, nitroparaffin
Hydrocarbon, cyclic ethers or fat hydrocarbon single or their mixed system pass through anti-solvent addition, the stirring that suspends, heating decrease temperature crystalline
Or volatilization crystallization is made.
Further, the preferred methanol of the alcohols solvent；The preferred acetone of ketones solvent；The halogenated hydrocarbons preferably two
Chloromethanes.
It is a further object to provide a kind of crystal forms of formula (I) compound, are named as crystal form II.
Crystal form II provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 18.00 ° ±
There is characteristic peak at 0.20 °, 10.80 ° ± 0.20 °, 7.26 ° ± 0.20 °.
Further, crystal form II provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 14.60 ° ± 0.20 °, 12.14 ° ± 0.20 °, 11.21 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form II provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta value
There is characteristic peak at 14.60 ° ± 0.20 °, 12.14 ° ± 0.20 °, 11.21 ° ± 0.20 °.
Further, crystal form II provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta
It is worth to have characteristic peak at one in 22.59 ° ± 0.20 °, 22.03 ° ± 0.20 °, 19.64 ° ± 0.20 ° or at two or at three；
Preferred crystal form II provided by the invention, it is further characterized in that, X-ray powder diffraction figure 2theta value be 22.59 ° ±
There is characteristic peak at 0.20 °, 22.03 ° ± 0.20 °, 19.64 ° ± 0.20 °.
Preferably, crystal form II provided by the invention, X-ray powder diffraction figure be included in 2theta value be 18.00 ° ±
0.20°、10.80°±0.20°、7.26°±0.20°、14.60°±0.20°、12.14°±0.20°、11.21°±0.20°、
22.59 ° ± 0.20 °, 22.03 ° ± 0.20 °, the characteristic peak of one or more in 19.64 ° ± 0.20 ° of position.
Further, crystal form II provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Fig. 5
It is shown.
Crystal form II provided by the invention, which is characterized in that when carrying out differential scanning calorimetric analysis, be heated to 144 DEG C it is attached
Closely start first endothermic peak occur, continues to be heated to starting near 213 DEG C second endothermic peak, differential scanning calorimetry occur
Analysis chart is substantially as shown in Figure 6.
Crystal form II provided by the invention, which is characterized in that when carrying out thermogravimetric analysis, when being heated to 200 DEG C, have about
16.5% weight loss gradient, thermogravimetric analysis figure are substantially as shown in Figure 7.
It is a further object to provide the preparation methods of crystal form II, including the solid of (I) compound to be added to
In the mixed system of glacial acetic acid or glacial acetic acid and other solvents, pass through anti-solvent addition, volatilization, heating cooling or the stirring system that suspends
?.
Further, other described organic solvents include but is not limited to water, alcohols, ketone, esters, and aromatic hydrocarbon is halogenated
Hydrocarbon, nitrile, nitroparaffins, cyclic ethers, fat hydrocarbon solvent.
It is a further object to provide a kind of Pharmaceutical compositions, crystal form I or crystal form II comprising effective therapeutic dose
Or both mixture and pharmaceutically acceptable carrier, diluent or excipient.Usually by the crystal form I of therapeutically effective amount
Or the mixture of crystal form II or both is mixed or is contacted with one or more pharmaceutic adjuvants and Pharmaceutical composition or preparation is made, the medicine
It with composition or preparation is prepared in a manner of well known in pharmaceutical field.
The mixture of the crystal form I or crystal form II or both of formula (I) compound provided by the invention, which can be used for treating, itself exempts from
The preparation of the drug of epidemic disease, especially for treating the purposes of medicine for treating rheumatoid arthritis preparation.
It is a further object to provide a kind of phosphate crystal forms of formula (I) compound, are named as crystal form A.
Crystal form A provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 17.22 ° ±
There is characteristic peak at 0.20 °, 8.37 ° ± 0.20 °, 3.59 ° ± 0.20 °.
Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 23.96 ° ± 0.20 °, 19.40 ° ± 0.20 °, 18.55 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 23.96 ° in 2theta value
There is characteristic peak at ± 0.20 °, 19.40 ° ± 0.20 °, 18.55 ° ± 0.20 °.
Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 7.78 ° ± 0.20 °, 18.00 ° ± 0.20 °, 25.40 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 7.78 ° in 2theta value
There is characteristic peak at ± 0.20 °, 18.00 ° ± 0.20 °, 25.40 ° ± 0.20 °.
Preferably, the crystal form A that the present invention supplies, X-ray powder diffraction figure be included in 2theta value be 17.22 ° ±
0.20°、8.37°±0.20°、3.59°±0.20°、23.96°±0.20°、19.40°±0.20°、18.55°±0.20°、
7.78 ° ± 0.20 °, 18.00 ° ± 0.20 °, the characteristic peak of one or more in 25.40 ° ± 0.20 ° of position.
Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Figure 14
It is shown.
Crystal form A provided by the invention, which is characterized in that when carrying out differential scanning calorimetric analysis, be heated near 187 DEG C
Start endothermic peak occur, differential scanning calorimetric thermogram is substantially as shown in figure 15.
Crystal form A provided by the invention, which is characterized in that when carrying out thermogravimetric analysis, when being heated to 175 DEG C, have about
1.3% weight loss gradient, thermogravimetric analysis figure are substantially as shown in figure 16.
It is a further object to provide the preparation methods of phosphate crystal form A, which is characterized in that by formula (I) chemical combination
Object is added to that multi-solvents are appropriate to be mixed in crystallization solvent with phosphoric acid, is made by stirring.
Further, the mixing crystallization solvent appropriate includes but is not limited to alcohols, ketone, nitrile, cyclic ethers, fat
The mixed system of hydrocarbon solvent.
Further, the preferred acetonitrile of the mixed solvent system and ethyl alcohol mixing, the preferred body of the acetonitrile and ethyl alcohol
For product than being about 4:1 to 2:1, more preferable volume ratio is about 3:1.
It is a further object to provide a kind of phosphate crystal forms of formula (I) compound, are named as crystal form B.
Crystal form B provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 19.62 ° ±
There is characteristic peak at 0.20 °, 16.73 ° ± 0.20 °, 3.20 ° ± 0.20 °.
Further, crystal form B provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 16.21 ° ± 0.20 °, 22.67 ° ± 0.20 °, 25.85 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form B provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 16.21 ° in 2theta value
There is characteristic peak at ± 0.20 °, 22.67 ° ± 0.20 °, 25.85 ° ± 0.20 °.
Further, crystal form B provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 20.90 ° ± 0.20 °, 17.53 ° ± 0.20 °, 26.67 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form B provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 20.90 ° in 2theta value
There is characteristic peak at ± 0.20 °, 17.53 ° ± 0.20 °, 26.67 ° ± 0.20 °.
Preferably, the crystal form B that the present invention supplies, X-ray powder diffraction figure be included in 2theta value be 19.62 ° ±
0.20°、16.73°±0.20°、3.20°±0.20°、16.21°±0.20°、22.67°±0.20°、25.85°±0.20°、
20.90 ° ± 0.20 °, 17.53 ° ± 0.20 °, the characteristic peak of one or more in 26.67 ° ± 0.20 ° of position.
Further, crystal form B provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Figure 17
It is shown.
Crystal form B provided by the invention, which is characterized in that when carrying out differential scanning calorimetric analysis, be heated near 169 DEG C
Start endothermic peak occur, differential scanning calorimetric thermogram is substantially as shown in figure 18.
Crystal form B provided by the invention, which is characterized in that when carrying out thermogravimetric analysis, when being heated to 160 DEG C, have about
1.2% weight loss gradient, thermogravimetric analysis figure are substantially as shown in figure 19.
It is a further object to provide the preparation methods of phosphate crystal form B, which is characterized in that by formula (I) chemical combination
Object and phosphoric acid are added in crystallization solvent appropriate, are made by stirring.
Further, the crystallization solvent appropriate includes but is not limited to anhydrous alcohols, ketone, esters, aromatic hydrocarbon, halogen
For hydrocarbon, nitrile, nitroparaffins, cyclic ether solvents system.
Further, the preferred methylisobutylketone of ketone crystallization solvent；The preferred acetic acid of esters crystallization solvent is different
Propyl ester.
It is a further object to provide a kind of phosphate crystal forms of formula (I) compound, are named as crystal form C.
Crystal form C provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 20.90 ° ±
There is characteristic peak at 0.20 °, 18.01 ° ± 0.20 °, 24.10 ° ± 0.20 °.
Further, crystal form C provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value is special to have at one in 15.30 ° ± 0.20 °, 21.46 ° ± 0.20 °, 14.62 ° ± 0.20 ° or at two or at three
Levy peak；Preferred crystal form C provided by the invention, it is further characterized in that, X-ray powder diffraction figure is 15.30 ° in 2theta value
There is characteristic peak at ± 0.20 °, 21.46 ° ± 0.20 °, 14.62 ° ± 0.20 °.
Further, crystal form C provided by the invention, it is further characterized in that, X-ray powder diffraction figure further include
2theta value be 4.46 ° ± 0.20 °, 22.83 ° ± 0.20 °, 18.94 ± 0.20 ° in one at or two at or three at have feature
Peak；Preferred crystal form C provided by the invention, it is further characterized in that, X-ray powder diffraction figure 2theta value be 4.46 ° ±
There is characteristic peak at 0.20 °, 22.83 ° ± 0.20 °, 18.94 ± 0.20 °.
Preferably, crystal form C provided by the invention, X-ray powder diffraction figure be included in 2theta value be 20.90 ° ±
0.20°、18.01°±0.20°、24.10°±0.20°、15.30°±0.20°、21.46°±0.20°、14.62°±0.20°、
4.46 ° ± 0.20 °, 22.83 ° ± 0.20 °, the characteristic peak of one or more in 18.94 ± 0.20 ° of position.
Further, crystal form C provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Figure 20
It is shown.
Crystal form C provided by the invention, which is characterized in that when carrying out differential scanning calorimetric analysis, be heated near 157 DEG C
Start a small endothermic peak occur, and nearby there is a sharp endothermic peak, differential scanning amount at 178 DEG C (peak temperatures)
Thermogram is substantially as shown in figure 21.
Crystal form C provided by the invention, which is characterized in that when carrying out thermogravimetric analysis, when being heated to 162 DEG C, have about
2.4% weight loss gradient, thermogravimetric analysis figure are substantially as shown in figure 22.
It is a further object to provide the preparation methods of phosphate crystal form C, which is characterized in that by formula (I) chemical combination
The phosphate powder of object is added to stirring in the mixed system of single solvent or multi-solvents and can be obtained.
Further, the solvent includes but is not limited to nitrile, water, alcohols, ketone, esters, and arene is halogenated
Hydro carbons, nitroparaffin hydro carbons, the single or mixed system of cyclic ether solvents.
Further, the mixed solvent of the preferred water of the solvent or water and nitrile solvents.
Further, the mixed solvent of the water and the mixed solvent of nitrile solvents preferred water and acetonitrile.
Further, the phosphate powder includes the phosphate crystal form B.
Wherein the phosphate crystal form B of formula (I) compound be by by formula (I) compound and phosphoric acid be added to alcohols,
Ketone, cyclic ethers class, stirs to get in fat hydrocarbon solvent system nitrile.
Wherein the X-ray powder diffraction figure of the phosphate crystal form B of formula (I) compound be included in 2theta value be 19.62 ° ±
0.20°、16.73°±0.20°、3.20°±0.20°、16.21°±0.20°、22.67°±0.20°、25.85°±0.20°、
20.90 ° ± 0.20 °, 17.53 ° ± 0.20 °, the characteristic peak of one or more in 26.67 ° ± 0.20 ° of position.
It is a further object to provide the preparation methods of phosphate crystal form C, which is characterized in that by formula (I) chemical combination
Object is added to stirring in aqueous solvent with concentrated phosphoric acid (14.6mol/L) and can be obtained.
Further, the aqueous solvent include water and nitrile, alcohols, ketone, esters, arene, halogenated hydrocarbon,
The mixed solvent of nitroparaffin hydro carbons or cyclic ether solvents.
It is a further object to provide a kind of Pharmaceutical compositions, include a effective amount of phosphate crystal form A, phosphate
Mixture and pharmaceutically acceptable carrier, the diluent or figuration of crystal form B, phosphate crystal form C or in which the two or three
Agent.Usually by the phosphate crystal form A of therapeutically effective amount, phosphate crystal form B, phosphate crystal form C or in which the two or three
Mixture, which is mixed or contacted with one or more pharmaceutic adjuvants, is made Pharmaceutical composition or preparation, and the Pharmaceutical composition or preparation are
It is prepared in a manner of well known in pharmaceutical field.
Further, in Pharmaceutical composition of the present invention, the phosphate crystal form A, phosphate of formula (I) compound are brilliant
The mixture of type B, phosphate crystal form C or in which the two or three can be used for preparing the drug for the treatment of autoimmune disease, especially
It is the purposes in rheumatoid arthritis pharmaceutical preparation.
Aforementioned pharmaceutical compositions can be made into certain dosage form, is administered by suitable approach.Such as oral, parenteral (packet
Include subcutaneous, muscle, vein or intradermal), rectum, transdermal, intranasal, the approach such as vagina.Be suitble to oral administration dosage form include tablet,
Capsule, granule, powder, pill, pulvis, pastille, solution, syrup or suspension may be adapted to pharmaceutical activity as needed
Quick release, sustained release or the adjusting release of ingredient；It includes aqueous or non-aqueous sterile for being suitble to the dosage form of parenteral administration
Inject solution, lotion or suspension；The dosage form for being suitble to rectally includes suppository or enema；It is suitble to the dosage form packet of cutaneous penetration
Include ointment, creme, patch；The dosage form for being suitble to nose administration includes aerosol, spray, nasal drop；It is suitble to the dosage form of vagina administration
Including suppository, suppository, gel, paste or spray.Preferably, crystal form of the invention is especially suitable for being prepared into tablet, suspension, glue
Wafer disintegrated tablet, is released, is sustained and Dospan；Further preferably tablet, suspension and capsule.
Acceptable excipient in aforementioned pharmaceutical compositions Chinese pharmacology, in the case where solid oral dosage form, including but not
Be limited to: diluent, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate,
Mannitol, sorbierite, sugar etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxy propyl cellulose
Element, hydroxypropyl methyl cellulose, polyethylene glycol etc.；Disintegrating agent, such as starch, sodium starch glycollate, pregelatinized starch, crosslinking
Povidone, croscarmellose sodium, colloidal silicon dioxide etc.；Lubricant, for example, stearic acid, magnesium stearate, zinc stearate,
Sodium benzoate, sodium acetate etc.；Glidant, such as colloidal silicon dioxide etc.；Complex forming agents, such as the cyclodextrin of various ranks
And resin；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose
Element, methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable excipient include but is not limited to
Film forming agent, plasticizer, colorant, flavoring agent, viscosity modifier, preservative, antioxidant etc..Optionally, tablet is coated and is wrapped
Clothing layer, such as shellac isolation coat, sugar-coat or polymer coating are provided, the polymer such as hydroxypropyl methyl fiber in coatings
Element, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose or starch can also include antisticking
Agent such as silica, talcum powder, opacifiers such as titanium dioxide, colorant such as iron oxides colorant.In liquid oral dosage form
In the case of, suitable excipient includes water, oils, alcohols, glycols, flavoring agent, preservative, stabilizer, colorant etc.；Water or
Non-aqueous sterile suspensions can contain suspending agent and thickener；Excipient suitable for aqueous suspension includes rubber polymer or natural
Glue such as gum arabic, Siberian cocklebur natural gum, alginates, glucan, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrole
Alkanone or gelatin.In the case where parenteral dosage forms, the excipient of water or non-aqueous aseptic injectable solution is usually sterile
Water, physiological saline or glucose solution containing buffer, antioxidant, bacteriostatic agent and can make the pharmaceutical composition
The isotonic solute with blood.Each excipient must be acceptable, can it is compatible with the other compositions in formula and for
Patient is harmless.
Described pharmaceutical composition can be used that well known to a person skilled in the art methods in the prior art to prepare.Prepare medicine
When compositions, crystal form of the invention and one or more pharmaceutically acceptable excipient are mixed, optionally with one kind
Or various other active pharmaceutical ingredients mixes.For example, tablet, capsule, granule can pass through mixing, granulation, tabletting
Or the techniques such as capsule are filled to prepare；Pulvis is made by mixing the finely ground active pharmaceutical ingredient to suitable size and excipient
It is standby；Solution and syrup can be prepared by the way that active pharmaceutical ingredient to be dissolved in suitably seasoned water or aqueous solution；It is suspended
Agent can be prepared by dispersing active pharmaceutical ingredient in pharmaceutically acceptable carrier.
Formula (I) compound crystal form provided by the invention and its phosphate crystal form may be used as the inhibition of one or more JAK
Agent, crystal form of the invention can adjust the activity of JAK by dosage.Formula (I) compound crystal form and its phosphate crystal form are adjustable
The JAK of section includes any member of JAK family, and JAK can be JAK1, JAK2, JAK3 or TYK2, it is preferred that JAK be JAK1 or
JAK2。
Formula (I) compound crystal form provided by the invention and its phosphate crystal form can be used for treating individual (such as patient's)
JAK is diseases related or illness, by by the compound of the present invention crystal form of therapeutically effective amount or treatment effective dose or its
Phosphate crystal form or its pharmaceutical composition deliver medicine to the individual for needing this treatment and carry out.JAK is diseases related to may include
Expression or activity with JAK including be overexpressed and/or the horizontal directly or indirectly associated any disease of abnormal activity, obstacle or
Illness.JAK diseases related can also include any disease that can prevent, improve or cure by adjusting JAK activity, barrier
Hinder or illness.JAK diseases related includes autoimmunity disease such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, ox
Psoriasis arthritis, type-1 diabetes mellitus, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, severe flesh without
Power, immunoglobulin nephrosis, autoimmune thyroid disease etc..
In other embodiments, it is cancer that the JAK is diseases related, including the cancer (example characterized by solid tumour
Such as prostate cancer, kidney, liver cancer, cancer of pancreas, gastric cancer, breast cancer, lung cancer, head-neck carcinoma, thyroid cancer, glioblastoma, card
Wave Ji sarcoma, castleman disease (Castleman ' s disease), melanoma etc.), hematological cancer (example
Such as, lymthoma, leukaemia such as acute lymphoblastic leukemia, acute myeloid leukaemia (AML) or Huppert's disease),
And cutaneum carcinoma such as skin T cell lymphoma (CTCL) and cutaneous B-cell lymphoma.The example of skin T cell lymphoma includes
Sezary syndrome and mycosis fungoides.Other JAK diseases related include inflammation and inflammatory disease.Exemplary inflammatory disease
Inflammatory disease (for example, iritis, uveitis, sclerotitis, conjunctivitis or related disease) including eyes, the inflammation of respiratory tract
Property disease (the upper respiratory tract for example including nose and nasal sinus, such as rhinitis or nasosinusitis or lower respiratory tract, including bronchitis, slow
Property obstructive lung disease etc.), inflammatory myositis such as myocarditis and other inflammatory diseases.
Phrase " effective therapeutic dose " used herein or " therapeutically effective amount ", which refer to, to be caused by researcher, animal doctor, doctor
The raw or biological respinse to be sought in tissue, system, animal, individual or people of other clinicians or the activity of drug response
The amount of compound or medicament.
Term as used herein " treatment " refers to one of the following or a variety of: (1) preventing disease；Such as it may incline
To in disease, illness or obstacle, but without by or show in the lesion of the disease or the individual of symptom and prevent the disease
Disease, illness or obstacle；(2) inhibit the disease；Such as just by or show the lesion or symptom of the disease, illness or obstacle
Inhibit the disease, illness or obstacle in individual；And (3) improve the disease；For example, by or show the disease, illness or
Improve the disease, illness or obstacle (i.e. reverse lesion and/or symptom) in the lesion of obstacle or the individual of symptom, such as lowers disease
The severity of disease.
Term as used herein " multi-crystalline compounds " refers to the different crystal forms of the same compound and includes but is not limited to
Other solid state molecular forms of hydrate and solvate comprising the same compound.Same drug molecule forms a variety of crystal forms
The phenomenon that referred to as polymorph in pharmaceuticals, polymorph in pharmaceuticals be phenomenon generally existing in solid drugs.
Term as used herein " X-ray powder diffraction figure " refers to the diffraction pattern that experimental observation arrives or the ginseng from it
Number.X-ray powder diffraction figure is characterized by peak position and peak intensity.
The invention has the benefit that
It there is no the crystal form of patent or reported in literature formula (I) compound at present, the present inventor after study, breaches
This problem has found several novel crystal forms for being suitble to exploitation.
Stability of crystal form provided by the invention is good, and technique refining effect is significant.Drug can be avoided to store and open well
Occur to turn crystalline substance during hair, to avoid the change of bioavilability and drug effect.
Crystal form provided by the invention draw it is moist lower, meet bioavilability and drug effect requirement, be not necessarily in preparation process
Special drying condition simplifies the preparation process and aftertreatment technology of drug, and does not influence vulnerable to humidity, wants to condition of storage
It asks not harsh, convenient for long-term storage, greatly reduces the cost of material storing and quality control aspect, there is very strong economy
Value.
Detailed description of the invention
The XRPD that Fig. 1 is crystal form I schemes
The DSC that Fig. 2 is crystal form I schemes
The TGA that Fig. 3 is crystal form I schemes
The DVS that Fig. 4 is crystal form I schemes
The XRPD that Fig. 5 is crystal form II schemes
The DSC that Fig. 6 is crystal form II schemes
The TGA that Fig. 7 is crystal form II schemes
Fig. 8 is crystal form II's1H NMR figure
Fig. 9 be under the conditions of crystal form I is placed on 5 DEG C 90 days front and back XRPD comparison diagram (upper figure be placement before XRPD scheme, under
Figure is the XRPD figure after placing)
Figure 10 is that crystal form I is placed on the XRPD comparison diagrams of 90 days front and backs under the conditions of 25 DEG C/60% (relative humidity) (upper figure is
XRPD figure before placement, the following figure are the XRPD figure after placing)
Figure 11 is that crystal form I is placed on the XRPD comparison diagrams of 90 days front and backs under the conditions of 40 DEG C/75% (relative humidity) (upper figure is
XRPD figure before placement, the following figure are the XRPD figure after placing)
Figure 12 be under the conditions of crystal form II is placed on 5 DEG C 90 days front and back XRPD comparison diagram (upper figure be placement before XRPD scheme,
The following figure is the XRPD figure after placing)
Figure 13 is XRPD comparison diagram (the upper figure that crystal form II is placed on 30 days front and backs under the conditions of 25 DEG C/60% (relative humidity)
Scheme for the XRPD before placing, the following figure is the XRPD figure after placing)
The XRPD that Figure 14 is phosphate crystal form A schemes
The DSC that Figure 15 is phosphate crystal form A schemes
The TGA that Figure 16 is phosphate crystal form A schemes
The XRPD that Figure 17 is phosphate crystal form B schemes
The DSC that Figure 18 is phosphate crystal form B schemes
The TGA that Figure 19 is phosphate crystal form B schemes
The XRPD that Figure 20 is phosphate crystal form C schemes
The DSC that Figure 21 is phosphate crystal form C schemes
The TGA that Figure 22 is phosphate crystal form C schemes
The DVS that Figure 23 is phosphate crystal form A schemes
The DVS that Figure 24 is phosphate crystal form C schemes
Figure 25 be phosphate crystal form C is placed under 25 DEG C/60% relative humidities before and after 30 days XRPD comparison diagram (on
The XRPD figure that figure is phosphate crystal form C before placing, the XRPD figure that the following figure is phosphate crystal form C after placing)
Figure 26 be phosphate crystal form C is placed under 40 DEG C/75% relative humidities before and after 30 days XRPD comparison diagram (on
The XRPD figure that figure is phosphate crystal form C before placing, the XRPD figure that the following figure is phosphate crystal form C after placing)
Specific embodiment
Below will by specific embodiment, the present invention is further explained, but the protection scope being not intended to restrict the invention.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as
Protection scope of the present invention.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
In following embodiments, the test method is usually according to normal condition or the condition of manufacturer's suggestion is implemented.
Used abbreviation is explained as follows in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
DVS: dynamic water absorption
1H NMR: liquid nucleus magnetic hydrogen spectrum
X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instrument
Collection.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
Kα11.540598；Kα21.544426
1 intensity of K α 2/K α: 0.50
Voltage: 45 volt (kV)
Electric current: 40 milliamperes (mA)
Scanning range: from 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention acquires on TA Q2000.Differential of the present invention
The method parameter for scanning thermometric analysis (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Thermogravimetric analysis (TGA) figure of the present invention acquires on TA Q5000.Thermogravimetric analysis (TGA) of the present invention
Method parameter it is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Embodiment 1
The preparation method of formula (I) compound crystal form I:
39.5mg formula (I) compound is added in 1.5mL acetone and obtains suspension, which is placed in 50 DEG C of constant temperature incubations
It is stirred 100 minutes in case, filters to obtain clear solution while hot, with 0.1 DEG C of speed slow cooling per minute to 5 DEG C, there is solid analysis
Out, centrifuging and taking lower layer solid is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, and through detecting, obtained solid is crystal form I.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 1.Its XRPD figure such as Fig. 1, DSC figure
Such as Fig. 2, TGA figure such as Fig. 3.
Table 1
Embodiment 2
The preparation method of formula (I) compound crystal form I:
Formula (I) compound of 5.16mg is dissolved in 1.80mL methylene chloride, is volatilized at room temperature, obtained solid is through detecting
For crystal form I.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 2.
Table 2
Embodiment 3
The preparation method of formula (I) compound crystal form II:
Formula (I) compound of 106.3mg is dissolved in 1.0mL glacial acetic acid, at room temperature slowly volatilization, obtained solid is through examining
Surveying is crystal form II.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 3.Its XRPD figure such as Fig. 5, DSC figure
If Fig. 6, TGA scheme such as Fig. 7,1H-NMR figure such as Fig. 8,1H-NMR data are as follows:
1H-NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.92(s,1H),8.71(s,1H),8.47(s,1H),
7.62(dd,J1=2.4Hz, J2=3.2Hz, 1H), 7.08 (dd, J1=1.2Hz, J2=3.2Hz, 1H), 4.60 (d, J=
9.2Hz, 2H), 4.24 (d, J=9.2Hz, 2H), 3.69 (s, 2H), 3.23 (q, J=7.2Hz, 2H), 1.90 (s, 3H), 1.25
(t, J=7.2Hz, 3H).
Table 3
Embodiment 4
The preparation method of formula (I) compound crystal form II:
The solid of 5.22mg formula (I) compound is dissolved in 0.1mL glacial acetic acid, is volatilized at room temperature, obtained solid is through examining
Surveying is crystal form II.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 4.
Table 4
Embodiment 5
The hygroscopicity test of formula (I) compound crystal form I:
Take formula of the invention (I) compound crystal form I about 10mg using dynamic water absorption (DVS) instrument test its draw it is moist.
Experimental result is as shown in table 5.The DVS figure of the hygroscopicity test of crystal form I is as shown in Figure 4.
Table 5
Define that (Chinese Pharmacopoeia version annex XIX J drug in 2010 draws with draw moist weight gain about the description of moist feature is drawn
Moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
It deliquesces: absorbing enough moisture and form liquid
It is great draw it is moist: draw wet weight gain not less than 15%
Have draw it is moist: draw wet weight gain less than 15% but not less than 2%
Slightly draw moist: drawing wet weight gain less than 2% but not less than 0.2%
Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%
The result shows that formula (I) compound crystal form I of the invention increases weight 0.44% after balancing under 80% humidity, according to drawing
The defining standard of moist weight gain, belong to slightly draw it is moist.
Embodiment 6
The stability experiment of formula (I) compound crystal form I:
The crystal form I that the present invention is prepared is respectively in 5 DEG C, 25 DEG C/60% relative humidity, 40 DEG C/75% relative humidity
Under conditions of place 90 days, measure its XRPD.Experimental result is shown in Table 6.Crystal form I was placed under the conditions of above three before and after 90 days
(the upper figure of Fig. 9, the upper figure of Figure 10, the upper figure of Figure 11 are XRPD of the crystal form I before placement to XRPD as shown in Fig. 9, Figure 10, Figure 11 respectively
Figure).
Table 6
The result shows that formula (I) compound crystal form I is in 5 DEG C, 25 DEG C/60% relative humidity and 40 DEG C/75% relative humidity item
It under part, places 90 days crystal forms and remains unchanged, formula (I) compound crystal form I provided by the invention is with good stability.
Embodiment 7
The stability experiment of formula (I) compound crystal form II:
The crystal form II that the present invention is prepared is placed under conditions of 5 DEG C, 25 DEG C/60% relative humidity respectively, is measured
Its XRPD.Experimental result is shown in Table 7.Crystal form II places XRPD difference (Figure 12 as shown in Figure 12 and Figure 13 of front and back under the above conditions
The upper figure of upper figure, Figure 13 is XRPD figure of the crystal form II before placement).
Table 7
The result shows that formula (I) compound crystal form II is placed 90 days at 5 DEG C, 25 DEG C/60% relative humidity places 30 days crystal forms
It remains unchanged, formula (I) compound crystal form II provided by the invention is with good stability.
Embodiment 8
The preparation method of formula (I) compound phosphate crystal form A:
502.6mg formula (I) compound is suspended in the in the mixed solvent of 12.5mL acetonitrile and 4.0mL ethyl alcohol, 90 μ L are dense
Phosphoric acid (14.6mol/L) is added drop-wise in the suspension after being dissolved in 1mL ethyl alcohol, is placed in 70 DEG C of baking ovens and is stirred 24 hours, centrifugation
Lower layer's solid is taken, 25 DEG C of freeze-day with constant temperature is placed in and stays overnight, obtained solid is detected as phosphate crystal form A.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 8.Its XRPD figure such as Figure 14, DSC figure
Such as Figure 15, TGA figure such as Figure 16.
Table 8
Embodiment 9
The preparation method of formula (I) compound phosphate crystal form A:
100.4mg formula (I) compound is suspended in the in the mixed solvent of 2.5mL acetonitrile and 0.79mL ethyl alcohol, by 17.7 μ L
Concentrated phosphoric acid (14.6mol/L) is added drop-wise in the suspension after being dissolved in 390 μ L ethyl alcohol, is placed in 70 DEG C of baking ovens and is stirred 24 hours,
Centrifuging and taking lower layer solid is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, and obtained solid is detected as phosphate crystal form A.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 9.
Table 9
| 2theta | The interval d | Intensity % |
| 3.56 | 24.79 | 77.29 |
| 7.78 | 11.36 | 73.30 |
| 8.37 | 10.57 | 61.12 |
| 11.52 | 7.68 | 4.20 |
| 14.77 | 6.00 | 5.34 |
| 15.72 | 5.64 | 23.84 |
| 17.20 | 5.15 | 100.00 |
| 18.00 | 4.93 | 48.24 |
| 18.55 | 4.78 | 45.75 |
| 19.42 | 4.57 | 49.05 |
| 20.56 | 4.32 | 6.53 |
| 21.63 | 4.11 | 8.99 |
| 23.96 | 3.71 | 37.14 |
| 25.38 | 3.51 | 52.10 |
| 26.24 | 3.40 | 21.72 |
| 27.67 | 3.22 | 9.74 |
| 29.36 | 3.04 | 5.10 |
| 31.74 | 2.82 | 4.01 |
| 35.18 | 2.55 | 2.21 |
| 36.89 | 2.44 | 1.16 |
Embodiment 10
The preparation method of formula (I) compound phosphate crystal form B:
503.4mg formula (I) compound is suspended in 15.0mL methylisobutylketone, 0.14mL concentrated phosphoric acid is added
It is stirred at room temperature after (14.6mol/L) 24 hours, centrifuging and taking lower layer solid, is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, obtained solid is through examining
Surveying is phosphate crystal form B.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 10.Its XRPD figure such as Figure 17, DSC
Figure such as Figure 18, TGA figure such as Figure 19.
Table 10
Embodiment 11
The preparation method of formula (I) compound phosphate crystal form B:
10.6mg formula (I) compound is suspended in 0.8mL isopropyl acetate, 17mL phosphoric acid ethanol solution (2mol/ is added
L it) is placed in 50 DEG C of constant incubators and stirs 24 hours, centrifuging and taking lower layer solid is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, and gained is solid
Body is detected as phosphate crystal form B.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 11.
Table 11
Embodiment 12
The preparation method of formula (I) compound phosphate crystal form C:
The phosphate crystal form B of 10.2mg formula (I) compound is suspended in the mixed solvent of 0.97mL acetonitrile and 0.03mL water
In, which is placed in 25 DEG C and is stirred 12 hours, centrifuging and taking lower layer solid is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, obtained solid
For phosphate crystal form C.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 12.Its XRPD figure such as Figure 20, DSC
Figure such as Figure 21, TGA figure such as Figure 22.
Table 12
Embodiment 13
The preparation method of formula (I) compound phosphate crystal form C:
The phosphate crystal form B of 9.6mg formula (I) compound is suspended in the mixed solvent of 0.95mL acetonitrile and 0.05mL water
In, which is placed in 25 DEG C and is stirred 12 hours, centrifuging and taking lower layer solid is placed in 25 DEG C of oven dried overnights, obtained solid
For phosphate crystal form C.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 13.
Table 13
Embodiment 14
The preparation method of formula (I) compound phosphate crystal form C:
The phosphate crystal form B of 8.0mg formula (I) compound is suspended in the mixed solvent of 0.97mL acetonitrile and 0.03mL water
In, which is placed in 40 DEG C and is stirred 12 hours, centrifuging and taking lower layer solid is placed in 25 DEG C of freeze-day with constant temperature and stays overnight, obtained solid
For phosphate crystal form C.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 14.
Table 14
Embodiment 15
The draws moist test of formula (I) compound phosphate crystal form A and crystal form C:
Take formula of the invention (I) compound crystal form A and formula (I) compound phosphate crystal form C about 10mg using dynamic respectively
Water adsorption (DVS) instrument test it is respective draw it is moist.Experimental result is as shown in Table 15.The DVS figure of the hygroscopicity test of crystal form A is such as
Shown in Figure 23, the DVS figure of the hygroscopicity test of crystal form C is as shown in figure 24.
Table 15
Define that (Chinese Pharmacopoeia version annex XIX J drug in 2010 draws with draw moist weight gain about the description of moist feature is drawn
Moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
It deliquesces: absorbing enough moisture and form liquid
It is great draw it is moist: draw wet weight gain not less than 15%
Have draw it is moist: draw wet weight gain less than 15% but not less than 2%
Slightly draw moist: drawing wet weight gain less than 2% but not less than 0.2%
Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%
The result shows that formula (I) compound phosphate crystal form A and crystal form C of the invention distinguishes after balancing under 80% humidity
Weight gain 0.99% and 2.85%.
Embodiment 16
The stability experiment of formula (I) compound phosphate crystal form A:
The phosphate crystal form A that the present invention is prepared is respectively in 5 DEG C, 25 DEG C/60% relative humidity, 40 DEG C/75% phase
It is placed 90 days under conditions of humidity, measures its XRPD.Experimental result is shown in Table 16.
Table 16
The result shows that formula (I) compound phosphate crystal form A is opposite in 5 DEG C, 25 DEG C/60% relative humidity and 40 DEG C/75%
It under damp condition, places 90 days crystal forms and remains unchanged, formula (I) compound phosphate crystal form A provided by the invention has good
Stability.
Embodiment 17
The stability test of formula (I) compound phosphate crystal form C:
Taking 2 parts of phosphate crystal form C, respectively opening is placed in 25 DEG C/60% relative humidity and 40 DEG C/75% phase to about 10mg respectively
Crystal form XRPD variation and purity to test sample is distinguished after in the climatic chamber of humidity, placing 30 days.As a result such as 17 institute of table
Show, XRPD comparison diagram is respectively such as Figure 25 and Figure 26 (Figure 25: upper figure is phosphate crystal form C before placing before and after stability test
XRPD figure, the following figure are the XRPD figure for being placed on 25 DEG C/60% relative humidities phosphate crystal form C after 30 days；Figure 26: upper figure is
The XRPD figure of phosphate crystal form C before placing, the following figure are to be placed on 40 DEG C/75% relative humidities phosphate crystal form C after 30 days
XRPD figure).
Table 17
Claims (8)
1. a kind of crystal form I of formula (I) compound,
It is characterized in that, its X-ray powder diffraction figure 2theta value be 15.33 ° ± 0.20 °, 16.66 ° ± 0.20 °,
19.06°±0.20°、14.91°±0.20°、16.25°±0.20°、15.74°±0.20°、25.51°±0.20°、12.40°
There is characteristic peak at ± 0.20 °, 17.39 ° ± 0.20 °.
2. crystal form I according to claim 1, which is characterized in that its X-ray powder diffraction figure is substantially consistent with Fig. 1.
3. a kind of preparation method of crystal form I of any of claims 1-2, which is characterized in that add formula (I) compound
Enter into one or more dicyandiamide solutions selected from the following: ketone, halogenated hydrocarbons single or their mixed system pass through suspension
Stirring, heating decrease temperature crystalline or volatilization crystallization are made.
4. preparation method according to claim 3, the ketones solvent is acetone；The halogenated hydrocarbon solvent is dichloromethane
Alkane.
5. a kind of Pharmaceutical composition, the Pharmaceutical composition includes the of any of claims 1-2 of effective therapeutic dose
Crystal form I and pharmaceutically acceptable carrier, diluent or excipient.
6. purposes of the crystal form I of any one of claim 1-2 in the drug that production is used for jak kinase inhibitor.
7. the crystal form I of any one of claim 1-2 is producing the purposes in the drug for treating autoimmune disease.
8. the crystal form I of any one of claim 1-2 is producing the purposes for treating medicine for treating rheumatoid arthritis preparation.
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Address after: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Applicant after: Suzhou crystal cloud medicine Polytron Technologies Inc Address before: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Applicant before: Crystal Pharmatech Co., Ltd. |
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Effective date of registration: 20210803 Address after: indiana Patentee after: Lilai Co. Address before: 215123 Biological Park B4-101, No. 218 Xing Hu Street, Suzhou Industrial Park, Jiangsu Patentee before: CRYSTAL PHARMATECH Co.,Ltd. |