CN104650034A - Stable axitinib compound - Google Patents
Stable axitinib compound Download PDFInfo
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- CN104650034A CN104650034A CN201310591197.6A CN201310591197A CN104650034A CN 104650034 A CN104650034 A CN 104650034A CN 201310591197 A CN201310591197 A CN 201310591197A CN 104650034 A CN104650034 A CN 104650034A
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- axitinib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The present invention belongs to the technical field of medicine, and particularly relates to an axitinib crystal and a preparation method thereof. The obtained axitinib crystal of the present invention has advantages of high purity and good stability, wherein the moisture absorption weight increase of the axitinib crystal is not significant even under the high humidity condition. The present invention further relates to applications of a composition using the axitinib crystal in treatment of advanced renal cell carcinoma.
Description
Technical field
The invention belongs to medical art, be specifically related to Axitinib crystal and preparation method thereof, the invention still further relates to the application of the composition treatment chronic renal cell carcinoma using this hydrate.
Background technology
Renal cell carcinoma (renal cell carcinoma, RCC) is a kind of modal cancer kidney.The whole world has every year and is diagnosed as RCC more than 210,000 people, causes people more than 100,000 nearly dead.Half a century in the past, the incidence of RCC constantly rises, and only in the U.S., since nineteen fifty, its incidence and lethality rate just add 126% and 36.5% respectively.The Natural history of treated of RCC is difficult to expect, its clinical manifestation is intricate again, except local symptom (pain, blood urine and kidney lump), more commonly general (heating, anaemia, hepatopathy and neuromuscular disease) and incretion symptom (polycythemia, hypertension and hypercalcemia).Therefore, although diagnostic method achieves progress in recent years, nearly 30%RCC shifts when going to a doctor, and most likely shifts after locality cancer (I ~ III phase) row radical nephrectomy, and the effective treatment seeking advanced renal cell carcinoma (ARCC) is very urgent.
ARCC often tolerates chemotherapy and cytokine such as interleukin II (interleukin-2, IL-2) or interferon-' alpha ' (interferon-α, INF α).Xi Peier in ARCC-forest-road (vonHippel-Lindau, VHL) disappearance of gene function causes vascular endothelial growth factor (vascular endothelial growthfactor, VEGF) approach imbalance, vegf protein overexpression and tumor vessel hyperplasia.The antiangiogenic drugs of target VEGF pathway comprises vegf receptor (VEGFreceptor, VEGFR) clinical application of inhibitor (Sutent Xarelto and pazopanib) and Avastin, so far, Axitinib has been the 7th medicine of FDA approval treatment ARCC, significantly improves the result for the treatment of of patient.
Axitinib (axitinib, trade(brand)name Inlyta
?), researched and developed by Pfizer, in approval listing in Huo U.S. food Drug Administration January 27 in 2012 (FDA), be used for the treatment of the ARCC that other drug is failed to respond to any medical treatment, specification is 1mg, 5mg.This product is a kind of 2nd generation VEGFR inhibitor of oral medication, and selectively acting, in VEGFR1, VEGFR2 and VEGFR3, by suppressing endothelial cell proliferation and the survival of VEGF mediation, plays the effect suppressing tumor growth and cancer progression.Multinomial clinical experimental study shows, Axitinib shows clinical activity to the ARCC patient accepting too much to plant pharmacological agent invalid.
The chemistry of Axitinib is called: N-methyl-2-((3-((1E)-2-(pyridine-2-base) ethene)-1H-indazole-6-base) sulphur) benzene, and its structural formula is:
Because Axitinib can have multiple different crystalline forms, and the stability of compound can change along with the change of often kind of crystal formation.So for same Axitinib compound, its different crystal formation, polymorphic form are all different in stability, physical properties, solvability and preparation method.
Therefore specific polymorphic takes advantage in stability, in drug production process, find have high solubility, stability strong, be beneficial to long storage periods under certain environment, keep the polymorphic of its specific physics, stable chemical nature significant in other words.
Axitinib has great advantage in validity and security, but in actual production process, applicant finds, there is purification difficult, foreign matter content is higher and have the problems such as certain moisture absorption weightening finish in Axitinib preparation technology.
The Axitinib crystal that the present inventor obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Summary of the invention
One object of the present invention, discloses a kind of Axitinib.
Another object of the present invention, discloses the preparation method of Axitinib.
Another object of the present invention, discloses the pharmaceutical composition comprising Axitinib.
The invention also discloses the application of Axitinib in the medicine of preparation treatment advanced renal cell carcinoma.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of Axitinib (shown in formula I),
SHAPE * MERGEFORMAT (formula I)
This Axitinib crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows:
| No. | d（?） | 2θ | I/I 0 |
| 1 | 15.221 | 9.13 | 11 |
| 2 | 14.362 | 10.01 | 35 |
| 3 | 13.921 | 10.96 | 24 |
| 4 | 13.012 | 11.88 | 67 |
| 5 | 12.214 | 12.43 | 82 |
| 6 | 11.541 | 12.97 | 69 |
| 7 | 10.689 | 13.65 | 54 |
| 8 | 9.978 | 14.23 | 35 |
| 9 | 9.158 | 15.11 | 95 |
| 10 | 8.574 | 15.94 | 41 |
| 11 | 7.632 | 16.51 | 84 |
| 12 | 6.588 | 16.97 | 61 |
| 13 | 6.102 | 18.32 | 71 |
| 14 | 5.543 | 19.64 | 39 |
| 15 | 4.832 | 20.77 | 42 |
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention, discloses the preparation method of Axitinib crystal, by being dissolved at isopropylcarbinol-tetrahydrofuran (THF)-heated in water solution by Axitinib, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that Axitinib adds in the mixed solution of 7-10 times of (weigh-volume ratio) isopropylcarbinol-tetrahydrofuran (THF)-water=3-6:0.1-0.4:3-6.5, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 4-6 hour again, crystallization, filter, drying obtains.A large amount of experiments proves: the adding of piperidines, the proportioning of mixed solution, standing temperature and time are most important to obtaining Axitinib crystal of the present invention.
In order to verify the stability of Axitinib crystal formation provided by the present invention further, the present invention has carried out stability test to it, and utilizes high performance liquid chromatography (Chinese Pharmacopoeia 2010 editions two annex VD) to measure.
Chromatographic column: Lichrospher100-5 RP8(250 × 4mm);
Moving phase: A:0.05M Sodium phosphate dibasic-phosphoric acid solution, B: acetonitrile (7:3, volume ratio);
Flow velocity: 0.5ml/min;
Column temperature: 30 DEG C;
Sample size: 10 μ L;
Determined wavelength: 450nm.
Axitinib meets the requirements with being separated of other impurities peak.
Method of masurement: measure sample, add moving phase and dissolve and make the solution containing 0.3mg sample in 1mL, measure 50 μ L, respectively injection liquid chromatography, record color atlas is to 6 times of principal constituent retention time.
Stability
1, exposure experiments to light
Evenly shared by Axitinib crystal in uncovered culture dish, thickness≤5mm, adjustable range, make intensity of illumination be 4500 ± 500Lx, sampling in 5,10 days detects respectively, and contrasts with the result of 0 day.Result is as follows:
Note: temperature variation 22 ~ 26 DEG C, relative humidity variations 56 ~ 62%
2, high temperature test
Be positioned in sealing clean vial by Axitinib crystal, be placed in 60 DEG C of thermostatic drying chambers, respectively with 5, sampling in 10 days detects, and contrasts with the result of 0 day.Result is as follows:
3, high wet test
Evenly spread out by Axitinib crystal in uncovered culture dish, thickness≤5mm, be placed in room temperature (about 25 DEG C), relative humidity is in the constant incubator of 75 ± 5%, and respectively at 5, sampling in 10 days detects, and contrasts with the result of 0 day.Result is as follows:
4, accelerated test
Packed by Axitinib crystal polyethylene film plastic bag sealing, be placed in 40 ± 2 DEG C, relative humidity is in the constant incubator of 75 ± 5%, places 6 months, detects, and contrast in the result of 0 day respectively at sampling at the the the 1st, 2,3,6 the end of month.Result is as follows:
Experimental result shows, the Axitinib crystal that the present invention obtains outward appearance and related substance in illumination condition, high temperature (60 DEG C), high humidity experiment have no significant change; Acceleration study result shows that its physico-chemical property is relatively stable, it can be used to prepare the preparation such as tablet, capsule, be used for the treatment of advanced renal cell carcinoma.
Another object of the present invention, provides the composition comprising the Axitinib that Axitinib crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
Present invention also offers the application of Axitinib in the medicine manufacturing treatment advanced renal cell carcinoma.
Newborn mice M24met people is transplanted to the impact of melanoma cell
Test medicine: Axitinib; Physiological saline.
Animal subject: M24met people transplants melanoma tumor model nude mouse 20, male and female half and half, is divided into 1. blank group (physiological saline) at random; 2. Axitinib; Often organize 10 animal subjects, male and female half and half.
Experimental technique: give test mice Axitinib 30mg/kg and physiological saline respectively by grouping peroral route (stomach oesophagus), gavage solution is 3ml/kg, continuous 5 days.
Experimental result: under test conditions, the M24met people in all test mice bodies of Axitinib group transplants melanoma cell and eliminates completely, be significantly better than blank group (
p< 0.001).
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 10L reactor that stirring, thermometer, condenser are housed, add 250 grams of Axitinibs and 488ml isopropylcarbinol, 61ml tetrahydrofuran (THF), 1951ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 20 DEG C-35 DEG C, leave standstill insulation 3 hours again, crystallization, filter, through indoor seasoning, obtain Axitinib white crystals 234.6 grams, content 99.95%, single contaminant is less than 0.06%.
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing Axitinib
Prescription: Axitinib 100 grams, Microcrystalline Cellulose 10g, pregelatinized Starch 15.4g, carboxymethylstach sodium 4.4g, lactose 150 grams, 20 grams of PEG-4000, Magnesium Stearate 4 grams, 29 grams of PVP K30s, croscarmellose sodium 30 grams, distilled water is appropriate, makes 1000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of 16 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200 m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Claims (6)
1. Axitinib (Compound I),
（Ⅰ）
The crystal of described Axitinib, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of Axitinib described in claim 1, by being dissolved at isopropylcarbinol-tetrahydrofuran (THF)-heated in water solution by Axitinib, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that Axitinib adds in the mixed solution of 7-10 times of (weigh-volume ratio) isopropylcarbinol-tetrahydrofuran (THF)-water=3-6:0.1-0.4:3-6.5, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 4-6 hour again, crystallization, filter, drying obtains.
4. one kind forms the composition of Axitinib containing Axitinib crystal according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of Axitinib according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of Axitinib crystal described in claim 1 in the medicine manufacturing treatment chronic renal cell carcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310591197.6A CN104650034A (en) | 2013-11-22 | 2013-11-22 | Stable axitinib compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310591197.6A CN104650034A (en) | 2013-11-22 | 2013-11-22 | Stable axitinib compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104650034A true CN104650034A (en) | 2015-05-27 |
Family
ID=53241733
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310591197.6A Pending CN104650034A (en) | 2013-11-22 | 2013-11-22 | Stable axitinib compound |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106918658A (en) * | 2017-01-22 | 2017-07-04 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of pazopanib raw material and its preparation |
| CN110974828A (en) * | 2019-12-24 | 2020-04-10 | 苏州大学 | Application of compound Axitinib in preparation of medicine for treating cerebrovascular diseases and pharmaceutical composition of compound Axitinib |
| CN111187253A (en) * | 2020-01-09 | 2020-05-22 | 鲁南制药集团股份有限公司 | Novel crystalline form of axitinib |
| CN113943271A (en) * | 2020-07-15 | 2022-01-18 | 鲁南制药集团股份有限公司 | Acixtinib crystal form and preparation method thereof |
| CN113943270A (en) * | 2020-07-15 | 2022-01-18 | 鲁南制药集团股份有限公司 | Crystalline form of axitinib |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122858A2 (en) * | 2007-04-05 | 2008-10-16 | Pfizer Products Inc. | Crystalline forms of 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-e- [2- (pyridin-2-yl) ethenyl] indazole suitable for the treatment of abnormal cell growth in mammals |
| US20090062347A1 (en) * | 2007-08-29 | 2009-03-05 | Protia, Llc | Deuterium-enriched axitinib |
| CN103387565A (en) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | Preparation method of Axitinib |
-
2013
- 2013-11-22 CN CN201310591197.6A patent/CN104650034A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008122858A2 (en) * | 2007-04-05 | 2008-10-16 | Pfizer Products Inc. | Crystalline forms of 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-e- [2- (pyridin-2-yl) ethenyl] indazole suitable for the treatment of abnormal cell growth in mammals |
| US20090062347A1 (en) * | 2007-08-29 | 2009-03-05 | Protia, Llc | Deuterium-enriched axitinib |
| CN103387565A (en) * | 2013-07-29 | 2013-11-13 | 苏州明锐医药科技有限公司 | Preparation method of Axitinib |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106918658A (en) * | 2017-01-22 | 2017-07-04 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of pazopanib raw material and its preparation |
| CN110974828A (en) * | 2019-12-24 | 2020-04-10 | 苏州大学 | Application of compound Axitinib in preparation of medicine for treating cerebrovascular diseases and pharmaceutical composition of compound Axitinib |
| CN110974828B (en) * | 2019-12-24 | 2023-03-31 | 苏州大学 | Application of compound Axitinib in preparation of medicine for treating cerebrovascular diseases and pharmaceutical composition of compound Axitinib |
| CN111187253A (en) * | 2020-01-09 | 2020-05-22 | 鲁南制药集团股份有限公司 | Novel crystalline form of axitinib |
| CN111187253B (en) * | 2020-01-09 | 2023-05-09 | 鲁南制药集团股份有限公司 | Novel crystal form of acitinib |
| CN113943271A (en) * | 2020-07-15 | 2022-01-18 | 鲁南制药集团股份有限公司 | Acixtinib crystal form and preparation method thereof |
| CN113943270A (en) * | 2020-07-15 | 2022-01-18 | 鲁南制药集团股份有限公司 | Crystalline form of axitinib |
| CN113943270B (en) * | 2020-07-15 | 2023-05-09 | 鲁南制药集团股份有限公司 | Acetinib crystal form |
| CN113943271B (en) * | 2020-07-15 | 2023-11-14 | 鲁南制药集团股份有限公司 | Acetinib crystal form and preparation method thereof |
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