CN109824657A - Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application - Google Patents

Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application Download PDF

Info

Publication number
CN109824657A
CN109824657A CN201910230047.XA CN201910230047A CN109824657A CN 109824657 A CN109824657 A CN 109824657A CN 201910230047 A CN201910230047 A CN 201910230047A CN 109824657 A CN109824657 A CN 109824657A
Authority
CN
China
Prior art keywords
afatinib
maleic acid
preparation
crystal form
crystal forms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910230047.XA
Other languages
Chinese (zh)
Inventor
杨占坤
李鹏飞
刘峰
齐珊
苏萌
郑森
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Original Assignee
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd filed Critical CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority to CN201910230047.XA priority Critical patent/CN109824657A/en
Publication of CN109824657A publication Critical patent/CN109824657A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of two maleic acid Afatinib novel crystal forms and its preparation method and application.Novel crystal forms of the invention improve the physicochemical property that two maleic acid Afatinibs have crystal form, there is good pharmaceutical preparation mobility and compressibility, and the tablet that direct tablet compressing technique prepares three specifications can be used, and simple process reduces cost, greatly shortens the production time.

Description

Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application
Technical field
This patent is related to technical field of pharmaceuticals, and in particular to two maleic acid Afatinib novel crystal forms of one kind and preparation method thereof And application.
Background technique
The chemical name of Afatinib is N- [4- [(the chloro- 4- fluorophenyl of 3-) amino] -7- [[(3S)-tetrahydro -3- furans Base] oxygroup] -6- quinazolyl] -4- (dimethylamino) -2- crotonamide, English name Afatinib, also known as BIBW2992, molecular formula C24H25ClFN5O3, chemical structural formula is as follows:
Afatinib is the anticancer kind of Boehringer Ingelheim company research and development, obtains within 2013 U.S.'s food and medicine management respectively Office, European Medicines Agency check and approve listing, and marketed products form is Afatinib 2-maleate, prominent with EGFR for treating The advanced stage of change or Metastatic Nsclc (NSCLC) patient, dosage form are oral tablet.Afatinib is with epidermal growth factor Sub- receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinase are the potent of therapy target and selectivity is double Weight inhibitor can irreversibly play a role in conjunction with corresponding receptor.
Patent document WO200250043A1 discloses Afatinib particular compound, WO2007054550A1 and WO2007054551A1 discloses the indication of Afatinib, and WO2005037824A2 discloses the Afatinib two of crystal state The preparation method of maleate.
Patent document WO2009147238A1 discloses Afatinib 2-maleate described in WO2005037824A2 Crystal is acicular morphology, and physicochemical properties will lead to following problems: the random alignment and length of spicule cause its low heap The large change of product density;Be aligned flow direction spicule resistance increase and caused by bad mobility;Too many air is cut Stay the capping or laminated of tablet during causing directly to compress processing procedure inside final admixture;The problems such as low compressibility.It is unfavorable In the preparation process of later period preparation, it is less useful for the industrialized production of preparation.On the other hand, inventor herein repeats When salifying process in WO2005037824A2, discovery maleic acid solution is easy to get bulk when mix with Afatinib solution and consolidates Body, preparation are difficult.
WO2012121764A1 discloses a kind of B crystal form Afatinib 2-maleate, and the DSC map of the crystal form is shown in 125.9 DEG C have exothermic peak, and 156.8 DEG C have endothermic peak, fusing point at 173.9 DEG C, illustrate crystal form to thermally labile, meeting in heating process Occur to inhale exothermic phenomenon.WO2013052157A1 discloses the Afatinib 2-maleate of C, D, crystal form E.CN105801568A The above-mentioned B, C of middle studies have shown that, D, crystal form E Afatinib 2-maleate have more serious hygroscopicity, cause directly to press Piece is difficult, is unfavorable for the industrialized production of preparation.
The crystal form state of bulk pharmaceutical chemicals is to influence a key factor of preparation process, and the different crystal forms of same bulk pharmaceutical chemicals are outside Sight, mobility, stability, draw the physicochemical properties such as moist in terms of may have larger difference, to be prepared to subsequent tablet Process generates large effect.Therefore, exploitation has two maleic acid Afatinib crystal forms of superior function necessary.
Summary of the invention
It is an object of the invention to overcome the shortcomings of existing two maleic acids Afatinib crystal physicochemical property, in two maleic acids In the crystal form research of salt Afatinib, a kind of two new maleic acid Afatinib salt crystal forms have surprisingly been obtained.The crystal form has good Good mobility and compressibility, slightly draws moist, and the tablet that direct tablet compressing technique prepares three kinds of specifications, technique letter can be used It is single, the production time is substantially reduced, is reduced costs, the industrialized production suitable for preparation.
One aspect of the present invention provides a kind of two maleic acid Afatinib novel crystal forms (referred to as crystal form F), which is characterized in that uses Cu-K α radiation, the powder x-ray diffraction indicated with 2 θ (°) have a characteristic peak in following position: 17.34 ± 0.2 °, 19.94 ± 0.2 °, 21.35 ± 0.2 °, 22.62 ± 0.2 °, 23.18 ± 0.2 °, 23.44 ± 0.2 °, wherein being most strong at 19.94 ± 0.2 ° Peak, the relative intensity of 17.34 ± 0.2 ° and 21.35 ± 0.2 ° of diffraction maximums are 30%~40%, 22.62 ± 0.2 °, 23.18 ± The relative intensity of 0.2 ° and 23.44 ± 0.2 ° of diffraction maximums is 20%-30%.
In this patent, the diffraction maximum position of crystal form and intensity are critically important.In fact, Lv Yang " crystal form drug " (people Defend publishing house, 2009.10) it is pointed out in a book: crystal form powder x-ray diffraction peak position and intensity no less important, the number of diffraction maximum Amount, the position of diffraction maximum and the peak-to-peak relative intensity of each diffraction are react fingerprint feature inside crystal-form substances important Parameter, parameters represent the different meanings in crystal form drug substance, the variation of any parameter, inside expression crystal-form substances It changes.
Further, two maleic acid Afatinib crystal form F of the invention, are radiated using Cu-K α, are indicated with 2 θ angles (°) Powder x-ray diffraction figure it is as shown in Figure 2.
Further, two maleic acid Afatinib crystal form F of the invention, show that differential scanning calorimetry (DSC) curve exists 182.3 DEG C have an endothermic peak.
Further, two maleic acid Afatinib crystal form F of the invention show that DSC figure is as shown in Figure 1.
On the other hand, the invention further relates to the preparation method of above-mentioned two maleic acids Afatinib crystal form F a kind of, this method packets It includes: by Afatinib and methanol mixed dissolution, lower methanol solution of the addition containing maleic acid is stirred at room temperature, cool down crystallization, can obtain Maleic acid Afatinib.
Preferably, in above-mentioned preparation method, the molar ratio of maleic acid and Afatinib is between 2:1~5:1, and preferably 3: 1~4:1.
Preferably, in above-mentioned preparation method, the crystallization temperature is 0 DEG C.
Preferably, in above-mentioned preparation method, volume-weight ratio of the methanol and Afatinib is 10~30ml:1g, excellent It is selected as 15~25ml:1g.
In another aspect, the pharmaceutical composition includes aforementioned form F the present invention also provides a kind of pharmaceutical composition.
Another aspect, the present invention also provides aforementioned form F in preparation for preventing and/or treating EGFR and HER2 tyrosine The purposes of kinases double inhibitor drug.
Detailed description of the invention
Fig. 1: the DSC figure of 1 gained crystal form of embodiment
Fig. 2: the powder X-ray diffractogram of 1 gained crystal form of embodiment
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part or according to the normal condition proposed by manufacturer.
Unless otherwise defined, all professional and scientific terms as used herein and meaning familiar to those skilled in the art Justice is identical.In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.Wen Zhong The preferred implement methods and materials are only done demonstration and are used.
In following instance, the testing conditions that powder x-ray diffraction composes (abbreviation XRD) figure are as follows:
Instrument title and model: Japanese Rigaku D/MAX-2500X x ray diffractometer x.
Condition: Cu-K alpha ray, graphite monochromator, pipe press 40KV, Guan Liu 150mA, 2 0~60 ° of θ scanning ranges.
In following instance, Differential Scanning Calorimetry (abbreviation DSC) figure test condition is as follows:
Instrument title and model: resistance to STA449F3 synchronous solving of speeding.
Determination condition: Al2O3Crucible sample preparation, 10 DEG C/min of heating rate.
The preparation of 1: two maleic acid Afatinib crystal form of embodiment
280g Afatinib and 2.8L methanol are added in a kettle, 20~25 DEG C are added with stirring the methanol containing maleic acid Solution (233g maleic acid is dissolved in 2.8L methanol) is cooled to 0 DEG C, insulated and stirred 0.5h after having solid precipitation, filters, and filter cake 40 ± 5 DEG C of vacuum drying, obtain maleic acid Afatinib 330g, yield 81%, 182.3 DEG C of fusing point, DSC figure is shown in Fig. 1, and XRD diagram is shown in Fig. 2.
The preparation of 2: two maleic acid Afatinib crystal form of embodiment
280g Afatinib and 2.8L methanol are added in a kettle, 20~25 DEG C are added with stirring the methanol containing maleic acid Solution (200g maleic acid is dissolved in 2.8L methanol) is cooled to 0 DEG C, insulated and stirred 0.5h after having solid precipitation, filters, and filter cake 40 ± 5 DEG C of vacuum drying, obtain maleic acid Afatinib 302g, yield 74%, and 182.6 DEG C of fusing point.
The preparation of 3: two maleic acid Afatinib crystal form of embodiment
280g Afatinib and 2.8L methanol are added in a kettle, 20~25 DEG C are added with stirring the methanol containing maleic acid Solution (267g maleic acid is dissolved in 2.8L methanol) is cooled to 0 DEG C, insulated and stirred 0.5h after having solid precipitation, filters, and filter cake 40 ± 5 DEG C of vacuum drying, obtain maleic acid Afatinib 342g, yield 84%, and 182.4 DEG C of fusing point.
The preparation of 4: two maleic acid Afatinib crystal form of embodiment
280g Afatinib and 2.1L methanol are added in a kettle, 20~25 DEG C are added with stirring the methanol containing maleic acid Solution (233g maleic acid is dissolved in 2.1L methanol) is cooled to 0 DEG C, insulated and stirred 0.5h after having solid precipitation, filters, and filter cake 40 ± 5 DEG C of vacuum drying, obtain maleic acid Afatinib 346g, yield 85%, and 182.3 DEG C of fusing point
The preparation of 5: two maleic acid Afatinib crystal form of embodiment
280g Afatinib and 3.5L methanol are added in a kettle, 20~25 DEG C are added with stirring the methanol containing maleic acid Solution (233g maleic acid is dissolved in 3.5L methanol) is cooled to 0 DEG C, insulated and stirred 0.5h after having solid precipitation, filters, and filter cake 40 ± 5 DEG C of vacuum drying, obtain maleic acid Afatinib 310g, yield 76%, and 182.4 DEG C of fusing point.
The two maleic acid Afatinib crystal form samples that embodiment 1-5 is obtained carry out X-ray diffraction analysis, resulting X- Ray diffraction data is as shown in table 1.
1 embodiment 1-5 crystal form samples X-ray diffraction data of table
The measurement of 6: two maleic acid Afatinib crystal form dry jet mixing pile of embodiment
Two maleic acid Afatinib crystal forms are measured using intelligent powder characteristics tester (to be prepared by embodiment 1, made altogether Obtain 4 batches) dry jet mixing pile, it tests the instrument used and method is as follows:
Intelligent powder characteristics tester (model: BT-1001, Baite Instrument Co., Ltd., Dandong)
Angle of repose: under static balance state, acute angle folded by powder accumulation inclined-plane and bottom water plane is called angle of repose.It is By ad hoc fashion make to fall under powder nature and be formed on particular platform.Angle of repose size directly reacts the mobility of powder, Angle of repose is smaller, and the mobility of powder is better.Setup parameter: testing time: 2, calculation method: body fitted coordinate method, charging rate: 4, feed time: 200s carries out charging measurement.
Bulk density: also known as heap density, density of the powder in special container after nature full state.
Non-metal powder apparent density test interface is selected, reads empty cup quality, setup parameter: measurement number 2, charging rate 4, feed time 200s strike off rim of a cup with scraper plate, read cup and powder quality.
Tap density: the powder filling of constant weight (or volume) carries out some strength after special container, to container Vibration, so that the gap between destroying powder granule, makes particle be in compact state.
Tap density test interface is selected, the measurement of solid masses method is clicked, weighs 20g powder, setup parameter: measurement time Number: 2, number of taps: it can measure for 2000 times.
Test result is as follows shown in table 2:
The micromeritis data of the crystal form of the present invention of table 2
Note: Hausner ratio=tap density/heap density, carr index=(tap density-heap density)/tap density * 100%.
Material powder property shows: carr index and Hausner are more as shown in table 3 than with the relationship of mobility, raw material 40 ° of angle of repose <, Hausner ratio is between 1.19-1.25, and mobility and compressibility are good when carr index is between 16-20% It is good.
3 carr index of table and Hausner are than the relationship with mobility
Carr index Hausner ratio Fluidity evaluating
≤ 10% 1.00-1.11 It is very good
11-15% 1.12-1.18 It is good
16-20% 1.19-1.25 It is good or medium
21-25% 1.26-1.34 Still
26-31% 1.35-1.45 Difference
32-37% 1.46-1.59 It is excessively poor
> 38% > 1.60 It is extremely poor
Conclusion: being found out by 2 data of table, and the numeric distribution at angle of repose, carr index and Hausner ratio is uniform, shows this hair Bright crystal form differences between batches are small;Another aspect angle of repose is respectively less than 40 °, carr index be 13~18, Hausner ratio be 1.15~ 1.22, show that crystal form mobility and compressibility of the present invention are good, can satisfy technique of direct powder compression.
The hygroscopicity test of 7: two maleic acid Afatinib crystal form of embodiment
Using 25 DEG C ± 1 DEG C of temperature of thermostatic drier (lower part place ammonium sulfate saturated solution), relative humidity is 80% ± 2%, it is moist to measure drawing for crystal form (embodiment 1 prepares crystal form) of the present invention.
The crystal form hygroscopicity test data of the present invention of table 4
Note: weight gain (%)=(m3-m2)/(m2-m1) × 100%
According to Chinese Pharmacopoeia 2015 editions, draws wet weight gain and be defined as drawing within the scope of 2%-15% moist, draw wet weight gain It is defined as slightly drawing within the scope of 0.2%-2% moist.The results show that this patent crystal form slightly draw it is moist.
8: two maleic acid Afatinib tablet preparation technique of embodiment
Composition (1000)
Ingredient Function 20mg specification 30mg specification 40mg specification Ratio %
API Effective component 29.56g 44.34g 59.12g 16.42
Microcrystalline cellulose Filler 19.94g 29.91g 39.88g 11.08
Lactose Filler 122.40g 183.60g 244.80g 68.00
Crospovidone Disintegrating agent 5.40g 8.10g 10.80g 3.00
Silica Glidant 0.90g 1.35g 1.80g 0.50
Magnesium stearate Lubricant 1.80g 2.70g 3.60g 1.00
Plate core weight / 180g 270g 360g 100
Process description: mixing machine, revolving speed is added in microcrystalline cellulose, API, crospovidone, lactose, silica 10rpm mixes 20min, and magnesium stearate is added, and revolving speed 10rpm mixes 5min.The material mixed is subjected to tabletting, film packet Clothing.
As a result: tableting processes are smooth, unilateral bright and clean, three equal < ± 2% of specification tablet weight variation, are coated unilateral bright and clean complete. Formulation and technology is simple, at low cost, is more suitable for mass production.

Claims (10)

1. a kind of two maleic acid Afatinib novel crystal forms, which is characterized in that radiated using Cu-K α, the powder X-ray-indicated with 2 θ (°) X ray diffraction has a characteristic peak in following position: 17.34 ± 0.2 °, 19.94 ± 0.2 °, 21.35 ± 0.2 °, 22.62 ± 0.2 °, 23.18 ± 0.2 °, 23.44 ± 0.2 °, wherein being highest peak at 19.94 ± 0.2 °, 17.34 ± 0.2 ° are spread out with 21.35 ± 0.2 ° The relative intensity for penetrating peak is 30%~40%, 22.62 ± 0.2 °, 23.18 ± 0.2 ° it is relatively strong with 23.44 ± 0.2 ° of diffraction maximums Degree is 20%-30%.
2. crystal form according to claim 1, which is characterized in that radiated using Cu-K α, penetrated with the powder X-ray-that 2 θ (°) are indicated Ray diffraction diagram is as shown in Figure 2.
3. crystal form according to claim 1, which is characterized in that differential scanning calorimeter (DSC) curve has a suction at 182.3 DEG C Thermal spike.
4. crystal form according to claim 1, it is characterised in that show that DSC figure is as shown in Figure 1.
5. the preparation method of any one of a kind of Claims 1-4 crystal form, this method comprises: Afatinib and methanol are mixed Dissolution is closed, lower methanol solution of the addition containing maleic acid is stirred at room temperature, cool down crystallization, can obtain maleic acid Afatinib.
6. preparation method according to claim 5, which is characterized in that the molar ratio of maleic acid and Afatinib 2:1~ Between 5:1, preferably 3:1~4:1.
7. preparation method according to claim 5, which is characterized in that the crystallization temperature is 0 DEG C.
8. preparation method according to claim 5, which is characterized in that volume-weight ratio of the methanol and Afatinib For 10~30ml:1g, preferably 15~25ml:1g.
9. a kind of pharmaceutical composition, which includes the described in any item crystal forms of Claims 1-4.
10. the described in any item crystal forms of Claims 1-4 are in preparation for preventing and/or treating EGFR and HER2 tyrosine-kinase The purposes of enzyme double inhibitor drug.
CN201910230047.XA 2019-03-26 2019-03-26 Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application Pending CN109824657A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910230047.XA CN109824657A (en) 2019-03-26 2019-03-26 Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910230047.XA CN109824657A (en) 2019-03-26 2019-03-26 Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application

Publications (1)

Publication Number Publication Date
CN109824657A true CN109824657A (en) 2019-05-31

Family

ID=66872174

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910230047.XA Pending CN109824657A (en) 2019-03-26 2019-03-26 Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application

Country Status (1)

Country Link
CN (1) CN109824657A (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1481370A (en) * 2000-12-20 2004-03-10 ���ָ��Ӣ��ķ�������Ϲ�˾ Quinazoline derivatives, medicaments contg. said compounds, their utilization and method for prodn. thereof
CN101402631A (en) * 2003-10-17 2009-04-08 贝林格尔.英格海姆国际有限公司 Amino quinazoline 2-maleate, production method and uses thereof
WO2013052157A1 (en) * 2011-10-06 2013-04-11 Ratiopharm Gmbh Crystalline forms of afatinib di-maleate
CN103476770A (en) * 2010-11-25 2013-12-25 拉蒂欧制药有限责任公司 Novel salts and polymorphic forms of afatinib
CN104744445A (en) * 2013-12-30 2015-07-01 广东东阳光药业有限公司 Crystal form of tyrosine kinase inhibitor
CN104803992A (en) * 2014-01-25 2015-07-29 广东东阳光药业有限公司 Crystal form of Afatinib dimaleate
CN104926800A (en) * 2015-06-26 2015-09-23 河北神威药业有限公司 Crystal form of afatinib di-meleate and method for preparing crystal form
CN106243092A (en) * 2016-07-28 2016-12-21 南京臣功制药股份有限公司 A kind of method that high selectivity prepares maleic acid Afatinib
CN107980041A (en) * 2015-06-12 2018-05-01 费森尤斯卡比肿瘤学有限公司 Polymorphic forms of afatinib free base and its hydrogen maleate salt

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1481370A (en) * 2000-12-20 2004-03-10 ���ָ��Ӣ��ķ�������Ϲ�˾ Quinazoline derivatives, medicaments contg. said compounds, their utilization and method for prodn. thereof
CN101402631A (en) * 2003-10-17 2009-04-08 贝林格尔.英格海姆国际有限公司 Amino quinazoline 2-maleate, production method and uses thereof
CN103476770A (en) * 2010-11-25 2013-12-25 拉蒂欧制药有限责任公司 Novel salts and polymorphic forms of afatinib
WO2013052157A1 (en) * 2011-10-06 2013-04-11 Ratiopharm Gmbh Crystalline forms of afatinib di-maleate
CN104744445A (en) * 2013-12-30 2015-07-01 广东东阳光药业有限公司 Crystal form of tyrosine kinase inhibitor
CN104803992A (en) * 2014-01-25 2015-07-29 广东东阳光药业有限公司 Crystal form of Afatinib dimaleate
CN107980041A (en) * 2015-06-12 2018-05-01 费森尤斯卡比肿瘤学有限公司 Polymorphic forms of afatinib free base and its hydrogen maleate salt
CN104926800A (en) * 2015-06-26 2015-09-23 河北神威药业有限公司 Crystal form of afatinib di-meleate and method for preparing crystal form
CN106243092A (en) * 2016-07-28 2016-12-21 南京臣功制药股份有限公司 A kind of method that high selectivity prepares maleic acid Afatinib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
姚静 主编: "《药用辅料应用指南》", 31 August 2011, 中国医药科技出版社 *

Similar Documents

Publication Publication Date Title
US10039757B2 (en) C-Met modulator pharmaceutical compositions
AU2019226302A1 (en) Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N&#39;-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
JP5757492B2 (en) Pharmaceutical core particles
CN110483486A (en) A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof
CN104800175A (en) Gefitinib tablet preparation method
CN105801568B (en) One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition
CN105061420B (en) A kind of crystal formation of JAK inhibitor and its preparation method and application
CN104829622B (en) A kind of sildenafil citrate compound and pharmaceutical composition thereof
CN109824657A (en) Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application
CN106349192B (en) The eutectic of orlistat and amino acid and include eutectiferous pharmaceutical composition
US20230398108A1 (en) Pharmaceutical Compositions of a Kinase Inhibitor
CN103476743A (en) Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same
CN106748996A (en) A kind of Sorafenib Tosylate crystal-form compound and preparation method thereof
CN106727385A (en) A kind of new amoxicillin tablets
CN106478598B (en) A kind of Vande Thani hydrate crystal and preparation method thereof
WO2022087763A1 (en) Cocrystal containing sorafenib free base and 5-fluorouracil, pharmaceutical composition, and uses thereof
CN109265406A (en) One seed sand library Ba Qu Valsartan sodium novel crystal form and its preparation method and application
CN106822026A (en) A kind of new amoxil capsule
CN106806347A (en) A kind of new amoxicillin granules
CN111035619B (en) Gefitinib tablet and preparation method thereof
CN109988158A (en) X crystal form, doxazosin mesylate containing X crystal form and its preparation method and application
JPH10120408A (en) New production of scaly calcium hydrogen phosphate
JP5637427B2 (en) Calcium hydrogen phosphate fine particles
CN108570003A (en) A kind of water of betrixaban maleate is amorphous and preparation method thereof
CN106146323B (en) Novel desvenlafaxine succinate monohydrate crystal form and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20190531

RJ01 Rejection of invention patent application after publication