CN109776543A - Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application are replaced according to Shandong - Google Patents
Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application are replaced according to Shandong Download PDFInfo
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Abstract
The invention discloses replace Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application according to Shandong.Described has the structure as shown in formula (I) according to Shandong for the crystal of Buddhist nun's salt, and wherein X is HCl, HBr or benzoic acid.The preparation method for Buddhist nun according to Shandong with X the following steps are included: in organic solvent, will mix, and be heated at a temperature of 40-130 DEG C, be completely dissolved, cooling crystallization.The crystal disclosed in this invention that three kinds of salt of Buddhist nun are replaced according to Shandong is novel crystal forms, with excellent dissolubility, thermal stability, and hygroscopicity is greatly improved, significantly improve the dissolubility and bioavilability that Buddhist nun is replaced according to Shandong, and the preparation method of the crystal is simple, it is suitble to large-scale industrial production, there is preferable prospects for commercial application.
Description
Technical field
The present invention relates to replace Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application according to Shandong.
Background technique
Replacing Buddhist nun (Ibrutinib) according to Shandong is that the BTK inhibitor class researched and developed by Pharmacyclics company and Johson & Johnson resists
Tumour medicine, entitled 1- [(3R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3, the 4-d] pyrimidine -1- of chemistry
Base] -1- piperidyl] -2- propylene -1- ketone, molecular formula C25H24N6O2, indication is lymphoma mantle cell, chronic lymphocytic
Property leukaemia, hair property macroglobulinemia and marginal zone lymphoma.Its structural formula is as follows:
Crystal form, solvate and the pharmaceutical composition that Buddhist nun is replaced according to Shandong, including listing are disclosed in patent WO2013184572
Medicinal crystal-form A, but crystal form A's is still poor for Buddhist nun's dissolubility according to Shandong, and solubility only has 0.013mg/ in pH=8.0 aqueous solution
Ml, BCS are classified as II class (indissoluble Thief zone).The specification of FDA is mentioned: Ibrutinib empty stomach oral administration absolute bioavailability
It is poor, only 2.9%, it can be improved one times with meal is oral.
Therefore, how to improve and be still a problem according to Shandong for the solubility and bioavilability of Buddhist nun.
Summary of the invention
The present invention be purpose be solve this field lack it is a kind of have higher solubility and bioavilability according to Shandong for Buddhist nun
The problem of pharmaceutical salts, and then provide according to Shandong for Buddhist nun's salt, its crystal, preparation method, pharmaceutical composition and application.It is of the invention according to
Shandong has preferable dissolubility, stability for the new crystal of Buddhist nun's salt, and hygroscopicity obtains larger improvement, and preparation process is simple, fits
Close large-scale industrial production.
The present invention is to solve technical problem by the following technical programs.
The present invention provides one kind as shown in formula (I) replaces the crystal of Buddhist nun's salt according to Shandong,
X is HCl, HBr or benzoic acid；
Wherein, when X is HCl, in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, in 2 θ of the angle of diffraction
For 8.2 °, 9.8 °, 10.7 °, 11.3 °, 13.6 °, 14.1 °, 15.3 °, 15.6 °, 16.5 °, 17.1 °, 17.3 °, 18.4 °,
There is characteristic peak at 19.9 °, 20.6 °, 21.1 °, 22.6 °, 23.7 °, 24.3 °, 25.5 °, 28.9 °, 29.4 °, 32.1 ° and 32.7 °,
2 θ value error ranges are ± 0.2；
When X is HBr, in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, it is in 2 θ of the angle of diffraction
5.5°、10.5°、11.1°、12.3°、12.7°、14.8°、15.6°、15.9°、16.6°、18.1°、18.3°、20.2°、21.6°、
22.2°、22.9°、24.4°、24.8°、25.3°、25.6°、26.8°、27.4°、28.5°、29.6°、30.8°、31.3°、
Have at 31.8 °, 32.3 °, 33.7 °, 36.0 °, 36.4 °, 37.0 °, 37.8 °, 38.7 °, 39.5 °, 39.9 °, 41.2 ° and 44.1 °
Characteristic peak, 2 θ value error ranges are ± 0.2；
When X is benzoic acid, in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, it is in 2 θ of the angle of diffraction
8.9°、12.0°、13.4°、13.8°、15.0°、15.9°、16.1°、17.1°、18.2°、18.9°、19.3°、19.9°、21.0°、
There is characteristic peak at 21.9 °, 22.8 °, 23.7 °, 24.4 °, 25.7 °, 27.8 °, 28.5 °, 30.1 °, 31.2 °, 35.7 ° and 36.6 °,
2 θ value error ranges are ± 0.2.
The crystal that Buddhist nun's salt is replaced according to Shandong, wherein
When X is HCl, the crystal is to preferably have about 212-216 DEG C for Buddhist nun's hydrochloric acid salt crystal according to Shandong
Fusing point；
And/or when X is HBr, the crystal is to replace Buddhist nun's hydrobromic acid salt according to Shandong, is preferably had about
209-212 DEG C of fusing point；
And/or when X is benzoic acid, the crystal is to replace Buddhist nun's benzoate crystal according to Shandong, is preferably had about
168-170 DEG C of fusing point.
The present invention also provides described as shown in formula (I) according to Shandong for the preparation method of the crystal of Buddhist nun's salt comprising with
Lower step: in organic solvent, will mix with X for Buddhist nun according to Shandong, and be heated at a temperature of 40-130 DEG C, be completely dissolved, cooling crystallization,
?；Wherein, X HCl, HBr or benzoic acid.
In preparation method of the present invention, the organic solvent can be this field conventional organic solvent, preferably select
From one of alcohol solvent, ketone solvent and esters solvent or a variety of；Wherein, the preferred methanol of the alcohols solvent, ethyl alcohol and
One of isopropanol is a variety of；The preferred acetone of the ketones solvent and methyl iso-butyl ketone (MIBK)；The preferred acetic acid of esters solvent
Ethyl ester.
It is described to be preferably 1:0.3- respectively according to Shandong for the molar ratio of Buddhist nun and X in preparation method of the present invention
1:3 is more preferably 1:0.4-1:2, for example, 1:1,1:1.2 and 1:1.5.
In preparation method of the present invention, the heating temperature is preferably 50-120 DEG C, is more preferably 60 DEG C, 70
DEG C, 80 DEG C or 118 DEG C.
In preparation method of the present invention, the volume (ml) of the organic solvent is compared with replacing Buddhist nun's mass (g) according to Shandong
It is goodly 2-40ml/g, is more preferably 4ml/g, 5ml/g, 6ml/g or 40ml/g.
In preparation method of the present invention, the cooling is preferably natural cooling, and the temperature of the cooling can be this
Field conventional chilling temperature, preferably 40 DEG C are hereinafter, be more preferably 0-30 DEG C.
The present invention also provides one kind to replace Buddhist nun's salt according to Shandong as shown in formula (I), and wherein X is HCl, HBr or benzoic acid.
The present invention also provides a kind of pharmaceutical compositions comprising the of the present invention of therapeutically effective amount replaces Buddhist nun's salt according to Shandong
Or its crystal and pharmaceutically acceptable carrier.
In the present invention, the pharmaceutically acceptable carrier can be this field routine carrier, be preferably comprised lubricant, glue
One of mixture, filler and disintegrating agent are a variety of.The lubricant be selected from magnesium stearate, superfine silica gel powder, silica and
One of talcum powder is a variety of；The disintegrating agent is selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxylic first
One of base sodium starch, starch and crospovidone are a variety of；Described adhesive is selected from hydroxypropyl cellulose, polyvinyl pyrrole
One of alkanone and methylcellulose are a variety of；The filler is in lactose, pregelatinized starch and microcrystalline cellulose
It is one or more.
In the present invention, the dosage of the pharmaceutically acceptable carrier is not specially limited, as long as this field can be reached
The requirement of conventional preparation.
In the present invention, the pharmaceutical composition can be made into various dosage forms, as tablet, capsule, pill, pulvis, emulsion,
Granule, suppository and injection etc..In a preferred embodiment, the dosage form of described pharmaceutical composition is tablet or capsule
Agent.
In a preferred embodiment, the raw material for preparing of the tablet includes following components: replacing Buddhist nun's hydrochloride according to Shandong
1 part of crystal, 0.5-1.5 parts of microcrystalline cellulose, 12-18 parts of starch, 4-6 parts of mannitol, 0.2-0.8 parts of magnesium stearate.
In a preferred embodiment, the raw material for preparing of the capsule includes following components: replacing Buddhist nun's hydrogen bromine according to Shandong
1 part of hydrochlorate crystal, 0.5-1.5 parts of microcrystalline cellulose, 4-6 parts of starch, 4-6 parts of lactose, 0.2-0.8 parts of magnesium stearate.
It is anti-in preparation BTK inhibitor class for the crystal of Buddhist nun's salt according to Shandong as shown in formula (I) that the present invention also provides described
Application in tumour medicine.
In the present invention, the preparation method of the raw material according to Shandong for Buddhist nun can refer to United States Patent (USP) US20080108636.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
It is disclosed in this invention according to Shandong for three kinds of salt of Buddhist nun crystal --- hydrochloride, hydrobromate and benzoate are
Novel crystal forms have excellent dissolubility, thermal stability, and hygroscopicity is greatly improved, and significantly improve according to Shandong for the molten of Buddhist nun
Solution property and bioavilability, and the preparation method of the crystal is simple, is suitble to large-scale industrial production, has preferable industry
Application prospect.
Detailed description of the invention
Fig. 1 is X-ray powder diffraction (XRD) figure that Buddhist nun's hydrochloric acid salt crystal is replaced according to Shandong prepared by present invention preparation embodiment 1
Spectrum.
Fig. 2 is differential scanning calorimetery (DSC) figure that Buddhist nun's hydrochloric acid salt crystal is replaced according to Shandong prepared by present invention preparation embodiment 1
Spectrum.
Fig. 3 present invention prepares X-ray powder diffraction (XRD) figure that Buddhist nun's hydrobromic acid salt is replaced according to Shandong prepared by embodiment 4
Spectrum.
Fig. 4 present invention prepares X-ray powder diffraction (XRD) figure that Buddhist nun's benzoate crystal is replaced according to Shandong prepared by embodiment 5
Spectrum.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In the embodiment of the present invention, HPLC purity is detected and is calculated using normalization method, and wherein HPLC is Agilent
1000, chromatographic column: Agilent Eclipse XDB C18 chromatographic column (4.6mm × 250mm, 5 μm)；Mobile phase: acetonitrile-water (body
Product is than 40:60)；Flow velocity: 0.8mL/min；Detection wavelength: 260nm；Column temperature: 30 DEG C.
The preparation method of A type Ibrutinib can be found in United States Patent (USP) US20080108636.
Prepare the preparation that embodiment 1 replaces Buddhist nun's hydrochloric acid salt crystal according to Shandong
It into 100ml reaction flask, is added and replaces Buddhist nun (2.0g, 4.5mmol) and methanol 4ml according to Shandong, stir the lower first that HCl is added dropwise
Alcoholic solution (2.25ml, 2.0M), is heated to 50 DEG C or so after dripping off, make reaction solution dissolved clarification, is cooled to 20 DEG C of stirring 4h.Filtering,
A small amount of methanol washing, 60 DEG C of vacuum drying 6h obtain white crystalline powder according to Shandong for Buddhist nun's hydrochloric acid salt crystal, amount to 1.4g, yield
65%, M.P.:214-216 DEG C, HPLC content 99.5%.C25H24N6O2.HCl elemental analysis experiment value: C:62.37, H:5.38,
N:17.39；Theoretical value C:62.95, H:5.28, N:17.62, through X-ray powder diffraction (XRD) and differential scanning calorimetery
(DSC) characterization identification, as a result as shown in Figs. 1-2.
Prepare the preparation that embodiment 2 replaces Buddhist nun's hydrochloric acid salt crystal according to Shandong
It into 100ml reaction flask, is added and replaces Buddhist nun (2.0g, 4.5mmol) and ethyl alcohol 10ml according to Shandong, stir lower dropwise addition HCl's
Ethanol solution (2.75ml, 2.0M), is heated to 80 DEG C or so after dripping off, make reaction solution dissolved clarification, is cooled to 0 DEG C of stirring 4h.Filtering,
A small amount of ethanol washing, 60 DEG C of vacuum drying 6h obtain white crystalline powder according to Shandong for Buddhist nun's hydrochloric acid salt crystal, amount to 1.6g, yield
74%, M.P.:214-216 DEG C, HPLC content 99.6%.XRD and DSC characterization result is the same as embodiment 1.
Prepare the preparation that embodiment 3 replaces Buddhist nun's hydrochloric acid salt crystal according to Shandong
It into 100ml reaction flask, is added and replaces Buddhist nun (2.0g, 4.5mmol) and isopropanol 8ml according to Shandong, stir lower dropwise addition HCl's
Aqueous isopropanol (3.4ml, 2.0M), is heated to 60 DEG C or so after dripping off, make reaction solution dissolved clarification, is cooled to 0 DEG C of stirring 4h.It crosses
Filter, a small amount of isopropanol washing, 60 DEG C of vacuum drying 6h obtain white crystalline powder according to Shandong for Buddhist nun's hydrochloric acid salt crystal, amount to 1.5g, receive
Rate 69%, M.P.:214-216 DEG C, HPLC content 99.5%.XRD and DSC characterization result is the same as embodiment 1.
Prepare the preparation that embodiment 4 replaces Buddhist nun's hydrobromic acid salt according to Shandong
It into 100ml reaction flask, is added and replaces Buddhist nun (2.0g, 4.5mmol) and isopropanol 12ml according to Shandong, stir lower dropwise addition 48%
Hydrogen bromide solution (1.5g), is heated to 70 DEG C or so after dripping off, make reaction solution dissolved clarification, is cooled to 0 DEG C of stirring 4h.Filtering, on a small quantity
Isopropanol washing, 60 DEG C of vacuum drying 6h obtain white crystalline powder according to Shandong for Buddhist nun's hydrobromic acid salt, amount to 1.9g, yield
82%, M.P.:209-212 DEG C, HPLC content 99.5%.C25H24N6O2.HBr elemental analysis experiment value: C:57.25, H:4.92,
N:16.34；Theoretical value C:57.58, H:4.80, N:16.12, crystal form are characterized through X-ray powder diffraction (XRD) and are identified, as a result see
Fig. 3.
Prepare the preparation that embodiment 5 replaces Buddhist nun's hydrogen benzoate crystal according to Shandong
It into 100ml reaction flask, is added and replaces Buddhist nun (2.0g, 4.5mmol) and methyl iso-butyl ketone (MIBK) 80ml according to Shandong, stirring is lower to be added
Enter benzoic acid (0.83g, 6.75mmol), 118 DEG C or so are heated to after dripping off, make reaction solution dissolved clarification, is cooled to 50 DEG C of stirring 4h.
Filtering, a small amount of methyl iso-butyl ketone (MIBK) washing, 60 DEG C of vacuum drying 6h obtain white crystalline powder according to Shandong for Buddhist nun's benzoate, amount to
1.8g, yield 70%, M.P.:168-170 DEG C, HPLC content 99.6%.C25H24N6O2.C6H5COOH elemental analysis experiment value: C:
68.22,H:5.45,N:14.68；Theoretical value C:68.33, H:5.34, N:14.95, crystal form is through X-ray powder diffraction (XRD) table
Sign identification, is as a result shown in Fig. 4.
Application Example 1 replaces the preparation of Buddhist nun's HCl tablets according to Shandong
In this application embodiment, the number of each component is parts by weight.
The preparation method comprises the following steps: replacing 1 part of Buddhist nun's hydrochloric acid salt crystal according to Shandong by preparation embodiment 3 is resulting, 1 part of microcrystalline cellulose, form sediment
15 parts of powder, 5 parts of mannitol, 0.5 part of magnesium stearate, tablet is made according to conventional methods in the art, 100 tablets of medicines are made altogether
Piece.
Application Example 2 replaces the preparation of Buddhist nun's hydrobromate capsule according to Shandong
In this application embodiment, the number of each component is parts by weight
The preparation method comprises the following steps: by preparation embodiment 4 it is resulting according to Shandong replace 1 part of Buddhist nun's hydrobromic acid salt, 1 part of microcrystalline cellulose,
5 parts of starch, 5 parts of lactose, 0.5 part of magnesium stearate, it is prepared into capsule according to conventional methods in the art, 100 glue are made altogether
Capsule.
Comparison preparation embodiment 1 replaces the preparation of Buddhist nun's vitriol according to Shandong
In the present invention, inventor is also prepared for according to Shandong for Buddhist nun's vitriol, and preparation method is real referring to present invention preparation
It applies described in example 1, the difference is that with the methanol solution of sulfuric acid substitution hydrochloric acid, remaining condition is all the same.
Comparison preparation embodiment 2 replaces the preparation of Buddhist nun's nitric acid salt crystal according to Shandong
In the present invention, inventor also tests preparation according to Shandong for Buddhist nun's nitric acid salt crystal, and preparation method is referring to present invention preparation
Described in embodiment 1, the difference is that remaining condition is all the same with the methanol solution of Nitric Acid Instead of Hydrochloric Acid, but fail to obtain nitre
Hydrochlorate crystal allows methanol to evaporate into dry, and what is obtained is the paste that can not be filtered.
The measurement of 1 dissolubility of effect example
In this effect example, the deliquescent method of test substance is investigated are as follows: precision weighs test substance, is slowly added to molten
Agent becomes suspension；The suspension is balanced into 2h at 25 DEG C, then pH value determination；It is filtered through glass fibre funnel, and will be clear
Clear filtrate dilutes 10 times, is quantitative determined by HPLC method, HPLC condition is same as above.
Ni Benjia is replaced for Buddhist nun's hydrobromic acid salt and Yi Lu for Buddhist nun's hydrochloric acid salt crystal, according to Shandong according to Shandong described in this effect example
Hydrochlorate crystal is prepared by preparation embodiment 1,4 and 5 respectively；It is prepared for Buddhist nun's vitriol by comparison preparation embodiment 1 according to Shandong.
Solvent described in this effect example is distilled water (pH=8).
The dissolubility measurement the results are shown in Table 1.
Table 1
| Test substance | Solubility |
| Buddhist nun's hydrochloric acid salt crystal is replaced according to Shandong | 5.2×10-5g/ml |
| Buddhist nun's hydrobromic acid salt is replaced according to Shandong | 4.8×10-5g/ml |
| Buddhist nun's benzoate crystal is replaced according to Shandong | 4.3×10-5g/ml |
| Buddhist nun's vitriol is replaced according to Shandong | 1.9×10-5g/ml |
| A type Ibrutinib | 1.5×10-5g/ml |
As it can be seen from table 1 A type Ibrutinib is compared, it is of the invention brilliant for Buddhist nun's hydrochloric acid salt crystal, hydrobromate according to Shandong
The solubility of body and benzoate crystal is more than doubled；And essence is had no for the dissolubility of Buddhist nun's vitriol according to Shandong
Property improve.
2 thermal stability determination of effect example
In this effect example, the method for investigation test substance thermal stability are as follows: test substance is placed in culture dish, and
It is placed 10 days in 60 DEG C of thermostatic drying chambers, samples, measure its fusing point.
Buddhist nun's benzene is replaced for Buddhist nun's hydrobromic acid salt and Yi Lu for Buddhist nun's hydrochloric acid salt crystal, according to Shandong according to Shandong described in this effect example
Formic acid salt crystal is prepared by preparation embodiment 1,4 and 5 respectively.
The thermal stability determination the results are shown in Table 2.
Table 2
From table 2 it can be seen that A type Ibrutinib is compared, it is of the invention brilliant for Buddhist nun's hydrochloric acid salt crystal, hydrobromate according to Shandong
Content and fusing point do not change substantially after 10 days for body and benzoate crystal；In addition, three kinds of salt crystals are in 60 DEG C of perseverances
After placing 10 days in warm drying box, X-ray powder diffraction collection is consistent with primary sample.
The measurement of 3 hygroscopicity of effect example
In this effect example, the hygroscopic method of test substance is investigated are as follows: precision weighs test substance, in temperature T=
It stores two weeks, is measured by sampling under the conditions of 40 DEG C and relative humidity RH=75%；The measurement micro-analytical balance that water content changes
It completes.
Ni Benjia is replaced for Buddhist nun's hydrobromic acid salt and Yi Lu for Buddhist nun's hydrochloric acid salt crystal, according to Shandong according to Shandong described in this effect example
Hydrochlorate crystal is prepared by preparation embodiment 1,4 and 5 respectively；It is prepared for Buddhist nun's vitriol by comparison preparation embodiment 1 according to Shandong.
Hygroscopicity measurement result is shown in Table 3, and changing (%) in table to measure sample quality indicates moisture varying situation.
Table 3
| Test substance | T/RH | After 1 week | After 2 weeks |
| Buddhist nun's hydrochloric acid salt crystal is replaced according to Shandong | 40 DEG C/75% | +0.06 | +0.22 |
| Buddhist nun's hydrobromic acid salt is replaced according to Shandong | 40 DEG C/75% | +0.08 | +0.20 |
| Buddhist nun's benzoate crystal is replaced according to Shandong | 40 DEG C/75% | +0.05 | +0.12 |
| Buddhist nun's vitriol is replaced according to Shandong | 40 DEG C/75% | +1.34 | +3.26 |
From table 3 it can be seen that of the invention exist according to Shandong for Buddhist nun's hydrochloric acid salt crystal, hydrobromic acid salt and benzoate crystal
Under the conditions of surveying, moisture content increases 0.12%-0.22% after 2 weeks, and increases 3.26% according to Shandong for Buddhist nun's vitriol,
The latter's moisture absorption, weight gain are obvious, illustrate it is of the invention according to Shandong for Buddhist nun's hydrochloric acid salt crystal, hydrobromic acid salt and benzoate crystal
Hygroscopicity has larger improvement compared to vitriol.
In addition, the appearance character and X- for replacing Buddhist nun's hydrochloric acid salt crystal, hydrobromic acid salt and benzoate crystal according to Shandong
Ray powder diffraction is consistent with primary sample.
Claims (10)
1. a kind of crystal for replacing Buddhist nun's salt according to Shandong as shown in formula (I), which is characterized in that
X is HCl, HBr or benzoic acid；
Wherein, when X is HCl, in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, it is in 2 θ of the angle of diffraction
8.2°、9.8°、10.7°、11.3°、13.6°、14.1°、15.3°、15.6°、16.5°、17.1°、17.3°、18.4°、19.9°、
There is characteristic peak at 20.6 °, 21.1 °, 22.6 °, 23.7 °, 24.3 °, 25.5 °, 28.9 °, 29.4 °, 32.1 ° and 32.7 °, 2 θ values are missed
Poor range is ± 0.2；
When X be HBr when, using radiation source be Cu-K α powder x-ray diffraction spectrum in, 2 θ of the angle of diffraction be 5.5 °,
10.5°、11.1°、12.3°、12.7°、14.8°、15.6°、15.9°、16.6°、18.1°、18.3°、20.2°、21.6°、
22.2°、22.9°、24.4°、24.8°、25.3°、25.6°、26.8°、27.4°、28.5°、29.6°、30.8°、31.3°、
Have at 31.8 °, 32.3 °, 33.7 °, 36.0 °, 36.4 °, 37.0 °, 37.8 °, 38.7 °, 39.5 °, 39.9 °, 41.2 ° and 44.1 °
Characteristic peak, 2 θ value error ranges are ± 0.2；
When X is benzoic acid, in the powder x-ray diffraction spectrum for the use of radiation source being Cu-K α, it is in 2 θ of the angle of diffraction
8.9°、12.0°、13.4°、13.8°、15.0°、15.9°、16.1°、17.1°、18.2°、18.9°、19.3°、19.9°、21.0°、
There is characteristic peak at 21.9 °, 22.8 °, 23.7 °, 24.4 °, 25.7 °, 27.8 °, 28.5 °, 30.1 °, 31.2 °, 35.7 ° and 36.6 °,
2 θ value error ranges are ± 0.2.
2. replacing the crystal of Buddhist nun's salt according to Shandong as shown in formula (I) as described in claim 1, which is characterized in that
When X is HCl, the crystal is that Buddhist nun's hydrochloric acid salt crystal is replaced according to Shandong, and fusing point is 212-216 DEG C；
And/or when X is HBr, the crystal is that Buddhist nun's hydrobromic acid salt is replaced according to Shandong, and fusing point is 209-212 DEG C；
And/or when X is benzoic acid, the crystal is that Buddhist nun's benzoate crystal is replaced according to Shandong, and fusing point is 168-170 DEG C.
3. a kind of preparation method of the crystal as shown in formula (I) according to Shandong for Buddhist nun's salt as described in claim 1, feature exist
In comprising following steps: in organic solvent, will mix with X for Buddhist nun according to Shandong, be heated at a temperature of 40-130 DEG C, completely molten
Solution, cooling crystallization；Wherein, X HCl, HBr or benzoic acid.
4. preparation method as claimed in claim 3, which is characterized in that it is molten that the organic solvent is selected from alcohols solvent, ketone
One of agent and esters solvent are a variety of；Wherein, the alcohols solvent is selected from one of methanol, ethyl alcohol and isopropanol or more
Kind；The ketones solvent is acetone or methyl iso-butyl ketone (MIBK)；The esters solvent is ethyl acetate.
5. preparation method as claimed in claim 3, which is characterized in that the molar ratio according to Shandong for Buddhist nun and X respectively divides
Not Wei 1:0.3-1:3, preferably 1:0.4-1:2, be more preferably 1:1,1:1.2 and 1:1.5.
6. preparation method as claimed in claim 3, which is characterized in that the heating temperature be 50-120 DEG C, preferably 60
DEG C, 70 DEG C, 80 DEG C or 118 DEG C.
7. preparation method as claimed in claim 3, which is characterized in that the volume of the organic solvent with according to Shandong for Buddhist nun's mass it
Than for 2-40ml/g, preferably 4ml/g, 5ml/g, 6ml/g or 40ml/g.
8. a kind of pharmaceutical composition comprising the as described in claim 1 of therapeutically effective amount replaces Buddhist nun according to Shandong as shown in formula (I)
The crystal and pharmaceutically acceptable carrier of salt.
9. pharmaceutical composition as claimed in claim 8, which is characterized in that the dosage form of described pharmaceutical composition includes tablet, glue
Wafer, pill, pulvis, emulsion, granule, suppository and injection；Preferably tablet or capsule.
10. antitumor in preparation BTK inhibitor class for the crystal of Buddhist nun's salt according to Shandong as shown in formula (I) as described in claim 1
Application in drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106995445A (en) * | 2016-01-22 | 2017-08-01 | 山东新时代药业有限公司 | A kind of bruton's tyrosine kinase inhibitor crystal formation and preparation method thereof |
| CN110317203A (en) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of carboxylic acid and preparation method thereof according to Shandong |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106995445A (en) * | 2016-01-22 | 2017-08-01 | 山东新时代药业有限公司 | A kind of bruton's tyrosine kinase inhibitor crystal formation and preparation method thereof |
| CN106995445B (en) * | 2016-01-22 | 2021-08-03 | 山东新时代药业有限公司 | Bruton's tyrosine kinase inhibitor crystal form and preparation method thereof |
| CN110317203A (en) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of carboxylic acid and preparation method thereof according to Shandong |
| CN110317203B (en) * | 2019-07-08 | 2022-05-13 | 浙江工业大学 | Co-amorphous substance of ibrutinib and carboxylic acid and preparation method thereof |
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