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 PDFInfo
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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
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.
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