CN108558856A - A kind of crystal form of triazines hydrobromate compound - Google Patents
A kind of crystal form of triazines hydrobromate compound Download PDFInfo
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- CN108558856A CN108558856A CN201810417738.6A CN201810417738A CN108558856A CN 108558856 A CN108558856 A CN 108558856A CN 201810417738 A CN201810417738 A CN 201810417738A CN 108558856 A CN108558856 A CN 108558856A
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- crystal form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of crystal form A of triazines hydrobromic acid compound and preparation method thereof, and provide the pharmaceutical composition prepared using this crystalline compounds, and the purposes in preparing for antitumor drug especially treats lung cancer, liver cancer and prostate cancer.The crystal form preparation process of the present invention is simple, and with good stability and dissolubility meets medicinal demand.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of crystal form of triazines hydrobromate compound, preparation side
The application of method and its pharmaceutical composition in anticancer therapy.
Background technology
The chemical stability of drug substance, solid-state stability and " shelf life " are especially important in the preparation of drug
Factor.Differentiate that the form for the drug that can easily prepare, prepare and be applied to patient just seems important.Ideal drug substance
Can effectively be stored within the assessment phase with the composition containing it, without show active constituent physical and chemical character (such as chemistry
Composition, density, wettability, solubility and dissolution rate etc.) significant change.
Known amorphous drug substance not can be well solved problem above.Such as amorphous drug substance is generally difficult to
Processing and preparation provide insecure solubility, and are generally found amorphous state physics and unstable chemcial property.
There are mainly two types of results of the above problems, one is by making drug molecule at salt, especially makes nitrogenous original
The drug molecule of son can make hydrogen cation provide unoccupied orbital and the lone pair electrons bonding on nitrogen at salt, such as hydrobromate, to
Make nitrogen-atoms be not easy to be aoxidized, increases the stability of drug molecule；The second is finding stable crystal form, many above problems can
To be resolved.
Patent CN105175410B is to the free state of Formulas I, i.e. triaizine compounds, preparation method and purposes application shown in I '
Corresponding protection, but the relevant report that so far there are no about its hydrobromate crystal form.
Invention content
The present invention provides novel crystal forms, preparation method and its drug of triazines hydrobromate compound shown in a kind of Formulas I
Composition, crystal form preparation process is simple, with good stability, of low cost, to the following compound patent medicine into one
Step research and development are of great significance.
Specifically, it is an object of the present invention to provide a kind of novel crystal forms of compound of formula I, it is named as crystal form A.
The characteristics of crystal form A provided by the invention, is as follows：
The powder of compound of formula I crystal form A in X ray diffracting spectrum, 2 angles θ be 11.16 ° ± 0.2 °, 12.37 ° ±
0.2 °, 13.49 ° ± 0.2 °, 14.58 ° ± 0.2 °, 16.25 ° ± 0.2 °, 17.86 ° ± 0.2 °, 21.54 ° ± 0.2 °, 24.22 °
There is characteristic peak at ± 0.2 °, 26.37 ° ± 0.2 °, 28.39 ° ± 0.2 °, 31.52 ° ± 0.2 °.
Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure is substantially such as Fig. 1
It is shown.
Crystal form A provided by the invention, which is characterized in that start endothermic peak occur being heated to 162 DEG C, the fusing point of crystal form A
It it is 166 DEG C, the DSC heating rates are 10 DEG C/min.Its differential scanning calorimetry (DSC) curve is as shown in Figure 2.
Another object of the present invention is to provide the preparation methods of compound of formula I crystal form A, which is characterized in that by chemical combination
Object I powder is added to heating for dissolving in the mixed system of one or more of solvents and crystallisation by cooling obtains.The solvent is selected from
Water, methanol, ethyl alcohol, acetone, ethyl acetate, toluene, n-hexane.The heating temperature is solvent reflux temperature.The solvent
Mass ratio with compound of formula I is 8:1~20:1.
Further, by Formulas I ' compound is added in dichloromethane, is passed through hydrogen bromide, filters, and solid is added in methanol,
Heating makes solid be completely dissolved, and stirs 2h, is cooled to room temperature, and continues to stir 1h.Drying is filtered, crystal form A is obtained.
It is a further object to provide a kind of crystal form A of the compound of formula I comprising effective therapeutic dose and its pharmacy
The Pharmaceutical composition of upper acceptable carrier composition.Pharmaceutically acceptable carrier includes excipient, diluent, dispersant, hangs
Floating agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, colorant, releasing agent, sweetener,
Coating agents, corrigent, antioxidant or lubricant etc..
The pharmaceutical composition of the present invention can be any acceptable peroral dosage form comprising but it is not limited to capsule, piece
Agent, pill, pulvis, granula, water suspension or solution.
The pharmaceutical composition of the present invention can be injection comprising but it is not limited to aseptic injection or oil suspension
Liquid or lotion.
It includes ointment, paste, breast that the pharmaceutical composition of the present invention, which can be by part or the dosage form through percutaneous drug delivery,
Agent, lotion, gelling agent, pulvis, solution, spray, inhalant or patch.
The specific effective dose of pharmaceutical composition of the present invention.Specific effective dose level is special for any one
Patient or organism by include depending on many factors treated illness and illness seriousness, the activity of particular compound,
Concrete composition used, age, weight, health status, gender and the eating habit of patient, administration time, administration route and
The discharge rate of particular compound used, the duration for the treatment of, medicinal application in drug combination or with specific compound
Combination and some other factor well-known in the field of pharmacy.
Further, in Pharmaceutical composition of the present invention, the crystal form A of compound of formula I can be used for preparing treatment liver
The purposes of cancer, lung cancer and prostate cancer pharmaceutical preparation.
Crystal form A obtained by preparation method provided by the invention is sampled in different time and is examined through high performance liquid chromatography
Content is surveyed to be held essentially constant；Secondly X-ray powder diffraction detection of the detection after grinding, tabletting shows the angle of diffraction of 2 θ
It does not change, shows that crystal form will not change in production process.
Description of the drawings
Fig. 1：X-ray powder diffraction (XRPD) figure of compound of formula I crystal form A.The longitudinal axis indicates that peak intensity, horizontal axis indicate diffraction
Angle (2 θ).
Fig. 2：Differential scanning calorimetry (DSC) curve of compound of formula I crystal form A.The longitudinal axis indicates that W/g, horizontal axis indicate temperature
℃。
Specific implementation mode
Formulas I ' compound is prepared according to the patent CN105175410B methods reported.
Embodiment 1:The preparation of crystal form A
2g Formulas I ' compound is added in 35g dichloromethane, stirring is opened, is passed through bromination hydrogen, it is small persistently to lead to 3
When, filtering is added to solid in 15g methanol, stirs 2h under heated reflux condition, stops heating, and stirring is cooled to room temperature
Afterwards, continue to stir 1h.Gained suspension is filtered, filter cake is washed with a small amount of cold methanol, collects filter cake, and vacuum is dry at 45 DEG C
It is dry, obtain the crystal of 1.5g compound of formula I crystal forms A.DSC tests fusing point：166℃.
It is tested by X-ray powder diffraction, is radiated using Cu-K α, there is the characteristic peak indicated below with 2 θ of angle：
11.16 ° ± 0.2 °, 12.37 ° ± 0.2 °, 13.49 ° ± 0.2 °, 14.58 ° ± 0.2 °, 16.25 ° ± 0.2 °, 17.86 ° ±
0.2 °, 21.54 ° ± 0.2 °, 24.22 ° ± 0.2 °, 26.37 ° ± 0.2 °, 28.39 ° ± 0.2 °, 31.52 ° ± 0.2 °.
Embodiment 2:Stable content is tested
Stable content Journal of Sex Research has been carried out to compound of formula I crystal form A crystal；：[high temperature (60 DEG C), high humidity (90% ±
5%), illumination (4500lx)], accelerated test (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%) and long term test (temperature 25
DEG C ± 2 DEG C, relative humidity 60% ± 10%) high performance liquid chromatography detection level is carried out to sample, test result is as follows：
Test result shows：The stable content of compound I prepared by the present invention is higher than its free state I '.
Embodiment 3:Stability of crystal form is tested
Stability study has been carried out to compound of formula I crystal form A crystal；：[high temperature (60 DEG C), high humidity (90% ± 5%), light
According to (4500lx)], accelerated test (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%) and long term test (25 DEG C ± 2 of temperature
DEG C, relative humidity 60% ± 10%) and ground, tabletting after X-ray powder diffraction test is carried out to sample, test result is as follows
It is shown：
Test result shows：This product is ground, significant changes do not occur for the angles XRPD main 2 θ after tabletting, illustrates that this product exists
Stability of crystal form is preferable in production process.Another this product accelerated test 6 months and it is long-term keep sample 12 months after, crystal form is not also sent out
Raw significant changes, illustrate this product crystal form stable crystal form in storing process, meet medicinal demand.
Embodiment 4：Dissolubility test
350mg samples are taken, are added in 1ml water, sonic oscillation at a temperature of 25 ± 5 DEG C, observation dissolving situation.Such as without mesh
Depending on visible particles of solute, that is, it is considered as and is completely dissolved；If there is visual visible particles of solute, it is considered as precipitation.Record dissolving feelings
Condition, result are：350mg/ml sample preparations are completely dissolved, and 2 hours without precipitation.The result shows that the favorable solubility of crystal form A.
Claims (7)
1. a kind of triaizine compounds hydrobromic acid crystal form A that Formulas I indicates：
2. crystal form A as described in claim 1, which is characterized in that its X-ray powder diffraction figure 2 angles θ be 11.16 ° ±
0.2 °, 12.37 ° ± 0.2 °, 13.49 ° ± 0.2 °, 14.58 ° ± 0.2 °, 16.25 ° ± 0.2 °, 17.86 ° ± 0.2 °, 21.54 °
± 0.2 °, 24.22 ° ± 0.2 °, 26.37 ° ± 0.2 °, 28.39 ° ± 0.2 °, 31.52 ° ± 0.2 ° of main peak.
3. the preparation method of crystal form A as described in claim 1, which is characterized in that be added to compound I powder a kind of or several
In the mixed system of kind solvent dissolve by heating and crystallisation by cooling obtains.
4. the preparation method of crystal form A as claimed in claim 3, which is characterized in that the compound I powder is by I
Free state dissolves in methylene chloride, and logical hydrogen bromide is precipitated to obtain.
5. the preparation method of crystal form A as claimed in claim 3, the solvent includes water, alcohols, ketone, esters, aromatic hydrocarbon,
One or more solvent mixed systems of fat hydrocarbon solvent.
6. a kind of pharmaceutical composition, including the crystal form described in claim 1-2 and its pharmaceutically acceptable carrier, excipient,
Diluent, adjuvant, medium or combination thereof.
7. a kind of pharmaceutical composition using described in claim 1-2 or claim 6 is controlled in lung cancer, liver cancer and prostate cancer
Purposes in treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810417738.6A CN108558856A (en) | 2018-05-04 | 2018-05-04 | A kind of crystal form of triazines hydrobromate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810417738.6A CN108558856A (en) | 2018-05-04 | 2018-05-04 | A kind of crystal form of triazines hydrobromate compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108558856A true CN108558856A (en) | 2018-09-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810417738.6A Withdrawn CN108558856A (en) | 2018-05-04 | 2018-05-04 | A kind of crystal form of triazines hydrobromate compound |
Country Status (1)
| Country | Link |
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| CN (1) | CN108558856A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175410A (en) * | 2015-10-14 | 2015-12-23 | 湖南华腾制药有限公司 | Triazine compound and preparing method and antineoplastic application thereof |
-
2018
- 2018-05-04 CN CN201810417738.6A patent/CN108558856A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175410A (en) * | 2015-10-14 | 2015-12-23 | 湖南华腾制药有限公司 | Triazine compound and preparing method and antineoplastic application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 方亮: "《药剂学》", 31 March 2016, 中国医药科技出版社 * |
| 赵桂森，史国生: "《新药设计与开发基础》", 30 November 2015, 山东大学出版社 * |
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Application publication date: 20180921 |