CN105294649B - A kind of Ceritinib compound and its pharmaceutical composition - Google Patents
A kind of Ceritinib compound and its pharmaceutical composition Download PDFInfo
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- CN105294649B CN105294649B CN201410371118.5A CN201410371118A CN105294649B CN 105294649 B CN105294649 B CN 105294649B CN 201410371118 A CN201410371118 A CN 201410371118A CN 105294649 B CN105294649 B CN 105294649B
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Abstract
The invention belongs to medicinal chemistry arts, and the invention discloses the imperfect crystal formation forms and its pharmaceutical composition of Ceritinib compound.The compound imperfect crystal formation form has the characteristics that stability is high, meets medicinal requirement.The present invention provides stable preparation process, and favorable reproducibility meets the requirement of industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry arts, specifically, being related to a kind of crystal form of Certinib compound, preparation
Method, including pharmaceutical composition and application containing this compound.
Background technique
Ceritinib (LDK 378, and translated name: Ceritinib) is a kind of ALK inhibitor, a plurality of types of for treating
Advanced metastatic non-small cell lung cancer (NSCLC).Ceritinib is a kind of anaplastic lymphoma kinase (ALK) tyrosine kinase suppression
Preparation, exploitation was for previously receiving the ALK+ patient of Crizotinib (gram azoles replaces Buddhist nun) treatment, and gram azoles exists for Buddhist nun
It is only granted ALK kinase inhibitor before Ceritinib.Structural formula is as shown in following formula I:
Ceritinib is developed by Novartis Co., Ltd, and FDA approval listing is obtained on April 29th, 2014, is the second of FDA approval
A ALK inhibitor, as ALK positive non-small cell lung cancer specific drug, for gram azoles for Buddhist nun's drug resistance or the patient not tolerated.In vitro
Test display, ALK inhibitory effect and gram azoles compare for Buddhist nun will be higher by 20 times.One is related to 163 ALK+ metastatic NSCLC and suffers from
The safety and curative effect of Ceritinib of the clinical research confirmation of person, in the patient for receiving Ceritinib treatment, have 1/2 by
Examination person's tumor regression, and the effectiveness can be maintained averagely 7 months.The clinical common adverse reactions of Ceritinib include diarrhea, dislike
The gastrointestinal symptoms such as the heart, vomiting, abdominal pain, laboratory abnormality include that liver drug enzyme, pancreatin and blood glucose level increase.
Polymorphism is that there are more than one crystal forms for substance.The different crystal forms of chemical substance can be to drug
Storage time, dissolubility, preparation nature and working properties exert far reaching influence.Therefore, when developing a kind of novel drugs, understand and
Polymorphism is controlled, selects suitable crystal form to prepare pharmaceutical preparation and has great importance.
Chinese patent application CN200780051064.2 embodiment 7 discloses a kind of preparation side of Ceritinib hydrochloride
Method, preparation process do not obtain the solid form of free alkali, do not provide any crystal information of Certinib.
Chinese patent application CN201180060435.X discloses A, B crystal form of Ceritinib and preparation method thereof.
In addition to this, the other new crystal forms of Ceritinib be there are no and disclose report.
Summary of the invention
The object of the present invention is to provide the substantially pure crystal forms of Ceritinib compound, while the present invention is also public
The preparation method of crystal form, and the pharmaceutical composition containing its crystal form are opened.
Those skilled in the art have unexpectedly obtained the amorphous shape of Ceritinib compound by many experiments
Formula, amorphous form have the characteristics that stability is high.
The present invention provides a kind of Ceritinib compound, structural formula is shown in formula I:
The Ceritinib compound is imperfect crystal formation form.It is characterized by: its powder x-ray diffraction map
In the presence of apparent amorphous characteristic peak, i.e., not sharp absorption peak exists.The imperfect crystal formation is radiated using Cu-Ka, is obtained
To with X- diffraction powder diffracting spectrum as shown in Figure 1.
The present invention also provides a kind of preparation method of Ceritinib imperfect crystal formation form, preparation methods are as follows: will
Ceritinib is dissolved in methylene chloride, then is concentrated to dryness to obtain.
Preferably, Ceritinib imperfect crystal formation form the preparation method comprises the following steps: by Ceritinib be dissolved in 15 times (V/m, i.e.,
15ml:1g) in methylene chloride, it is concentrated to dryness to obtain at 30 DEG C.
It is highly preferred that the preparation method of the Ceritinib imperfect crystal formation form, preparation method are as follows: will
The dihydrochloride of Ceritinib is dissolved in the purified water of 5 times of weight, and the methylene chloride of 15 times of volumes (V/m) is added, and stirs lower drop
Add 50% sodium hydroxide solution, adjusts aqueous solution pH to 7-10, separate organic layer after standing and obtain the methylene chloride of Ceritinib
Solution, 30 DEG C of organic layer are concentrated to dryness to obtain foaming solid.
Two hydrochloric acid of Ceritinib of the present invention can with reference to CN200780051064.2 embodiment 7 or
Method disclosed in CN201180060435.X embodiment 1 is made.
The present invention also provides a kind of pharmaceutical compositions, which is characterized in that the composition includes Ceritinib of the invention
Compound imperfect crystal formation form is made with the imperfect crystal formation form of Ceritinib compound of the invention.Preferably, institute
It states imperfect crystal formation form that pharmaceutical composition includes Ceritinib compound of the invention and at least one is pharmaceutically acceptable
Carrier.
It is further preferred that the dosage form of the composition can be solid pharmaceutical preparation, injection, such as oral tablet, glue
Capsule, freeze drying powder injection etc..
According to the present invention, the composition further includes pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier is usual
It is that those of ordinary skill in the art can be specifically chosen according to specific form of medication.It can use it is well known that technology is such as conventional
Be granulated, mix, dissolving the preparation process such as freeze-drying formation tablet, capsule, freeze-dried powder etc., manufacture obtains pharmaceutical composition of the invention
Object.
Ceritinib compound imperfect crystal formation form provided by the invention can be according to prior art preparation at suitable for medicine
Pharmaceutical composition.Ceritinib capsule (Novartis, trade name: ZYKADIA) of the prior art such as listing.
The pharmaceutical composition for the amorphous form substantially pure containing Ceritinib compound that the present invention provides a kind of
Object.Preferably, the Ceritinib pharmaceutical composition is capsule.It is highly preferred that containing silica, L in described pharmaceutical composition
Hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium carboxymethylstarch, hard gelatin capsule shell.It is further preferred that described
Ceritinib capsule contains the imperfect crystal formation form of 150mg Ceritinib compound.
The present invention has carried out examining for stability etc. to the imperfect crystal formation form of the Ceritinib compound of acquisition
It examines, accelerated stability test shows that the stability of crystal form is good, and active material dramatically increases, stablizes without significant changes, total miscellaneous nothing
Crystal form is not substantially change during investigation.
The present invention also provides the imperfect crystal formation forms of the Ceritinib compound can be used for preparing ALK inhibitor
Drug in application.Preferably, be mainly used for non-small cell lung cancer, gastric cancer, liver cancer, colon and rectum carcinoma, colorectal cancer,
The treatment of breast cancer, melanoma, leukaemia.
The imperfect crystal formation form stable etc. of Ceritinib compound provided by the invention all meets medicinal want
It asks.The preparation process of Ceritinib compound crystal form provided by the invention is simple, favorable reproducibility, and it is big raw to meet industrialization
The requirement of production.
Detailed description of the invention
The X-ray powder diffraction figure (XRD) of Fig. 1: Ceritinib amorphous forms.
The differential scanning calorimetric curve (DSC) of Fig. 2: Ceritinib amorphous forms.
The thermogravimetric curve (TGA) of Fig. 3: Ceritinib amorphous forms.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but following embodiments are not to the scope of the present invention
Limitation, the improvement and polishing that those skilled in the art make on the basis of the present invention should be within protection scope of the present invention.
The preparation of embodiment 1Ceritinib compound imperfect crystal formation form
At room temperature, it takes the dihydrochloride (5g) of Ceritinib to be dissolved in purified water (25g), is added methylene chloride (75ml),
50% sodium hydroxide solution is slowly added dropwise under stirring, adjusts aqueous solution pH to 7-10, separates organic layer after standing, obtain
The dichloromethane solution of Ceritinib, organic layer are concentrated to dryness to obtain foaming solid at 30 DEG C.X-ray powder diffraction
Map shows it as imperfect crystal formation form, and X-ray powder diffraction figure, DSC figure, TGA figure are respectively such as attached drawing 1, Fig. 2, Fig. 3 institute
Show.
The preparation of embodiment 2Ceritinib compound imperfect crystal formation form
At room temperature, it takes Ceritinib (10g), is added methylene chloride (150ml), stirring makes whole dissolutions, filters and 30
It DEG C is concentrated to dryness to obtain foaming solid.The same Fig. 1 of X-ray powder diffraction figure.
Embodiment 3
The imperfect crystal formation form for the Ceritinib compound being prepared according to the method for embodiment 1, sampling, in room
1 month physicochemical property, crystal form are stored under temperature, RH (relative humidity) 45-65%, and cotton thread variation does not occur.At 40 DEG C,
It is lower in the environment of RH75% to carry out accelerated test, stability is investigated, test result is shown in Table 2 respectively.
2 Ceritinib compound imperfect crystal formation form accelerated test (40 DEG C, RH75%) of table
From the point of view of accelerated stability investigates result, present invention imperfect crystal formation form stable excellent effect obtained,
It is suitble to pharmaceutical applications.
Claims (11)
1. a kind of Ceritinib compound, structural formula is shown in formula I,
It is characterized in that, the Ceritinib compound is imperfect crystal formation form；The X-ray of the imperfect crystal formation form
Powder diagram is substantially as shown in Figure 1.
2. Ceritinib compound according to claim 1, which is characterized in that the preparation side of the imperfect crystal formation form
Method are as follows: Ceritinib is dissolved in methylene chloride, then is concentrated to dryness to obtain.
3. Ceritinib compound according to claim 2, which is characterized in that the preparation side of the imperfect crystal formation form
Method are as follows: Ceritinib is dissolved in 15 times of volumes methylene chlorides, is concentrated to dryness to obtain at 30 DEG C.
4. Ceritinib compound according to claim 3, which is characterized in that the preparation side of the imperfect crystal formation form
Method are as follows: the dihydrochloride of Ceritinib is dissolved in the purified water of 5 times of weight, the methylene chloride of 15 times of volumes is added, under stirring
50% sodium hydroxide solution is added dropwise, adjusts aqueous solution pH to 7-10, separates organic layer after standing and obtain the dichloromethane of Ceritinib
Alkane solution, 30 DEG C of organic layer are concentrated to dryness to obtain foaming solid.
5. a kind of pharmaceutical composition containing Ceritinib, including Ceritinib as described in any one of claims 1 to 4
Compound, the Ceritinib compound are imperfect crystal formation form.
6. pharmaceutical composition according to claim 5, which is characterized in that the pharmaceutical composition includes Ceritinib
The imperfect crystal formation form of compound and at least one pharmaceutically acceptable carrier.
7. pharmaceutical composition according to claim 5 or 6, which is characterized in that described pharmaceutical composition is capsule.
8. pharmaceutical composition according to claim 7, which is characterized in that acceptable carrier in the capsule Chinese pharmacology
Including silica, L hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium carboxymethylstarch, hard gelatin capsule shell.
9. pharmaceutical composition according to claim 8, which is characterized in that the capsule contains 150mgCeritinib chemical combination
The imperfect crystal formation form of object.
10. application of the described in any item Ceritinib compounds of claim 1-4 in the drug for preparing ALK inhibitor, institute
Stating Ceritinib compound is imperfect crystal formation form.
11. application described in any one of claim 10, which is characterized in that mainly for the preparation for the treatment of non-small cell lung cancer, gastric cancer, liver
Cancer, colon and rectum carcinoma, colorectal cancer, breast cancer, melanoma, leukaemia drug.
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| CN201410371118.5A CN105294649B (en) | 2014-07-30 | 2014-07-30 | A kind of Ceritinib compound and its pharmaceutical composition |
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| CN201410371118.5A CN105294649B (en) | 2014-07-30 | 2014-07-30 | A kind of Ceritinib compound and its pharmaceutical composition |
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| CN105294649B true CN105294649B (en) | 2019-05-14 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110551102B (en) * | 2018-06-01 | 2021-01-12 | 四川大学 | ALK covalent inhibitors and uses thereof |
| GB201915618D0 (en) * | 2019-10-28 | 2019-12-11 | Univ Oslo | ALK inhibitors for treatment of ALK-negative cancer and antibody-mediated diseases |
| CN114191435B (en) * | 2021-12-08 | 2022-10-04 | 深圳市泰力生物医药有限公司 | Cabotinib, ai Leti and ceritinib pharmaceutical composition as well as preparation method and application thereof |
| CN116370476B (en) * | 2023-04-21 | 2024-01-30 | 遵义医科大学 | Chemotherapy medicine composition and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
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| SG190856A1 (en) * | 2010-12-17 | 2013-07-31 | Novartis Ag | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
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Address after: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road 699, Jiangning District, Nanjing City, Jiangsu Province Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |