CN106432042A - New medicine crystal form of nintedanib ethanesulfonate hydrate - Google Patents
New medicine crystal form of nintedanib ethanesulfonate hydrate Download PDFInfo
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- CN106432042A CN106432042A CN201510498211.7A CN201510498211A CN106432042A CN 106432042 A CN106432042 A CN 106432042A CN 201510498211 A CN201510498211 A CN 201510498211A CN 106432042 A CN106432042 A CN 106432042A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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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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Abstract
Diffraction peaks with the diffraction angles 2theta of 11.554 DEG, 17.423 DEG, 18.800 DEG, 19.683 DEG and 19.986 DEG exist in an X-ray diffraction pattern obtained by detecting nintedanib ethanesulfonate monohydrate crystal form A by a Rigaku Smartlab-3 type X-ray diffractometer under CuK-beta, 40 KV and 30 mA detection conditions, and the 2theta error is 0.2 DEG. The crystal form of nintedanib ethanesulfonate monohydrate has the advantages of simple preparation technology, high purity and good stability.
Description
Technical field
The invention belongs to pharmaceutical technology field, new more particularly to a kind of medicine for Nintedanib ethyl sulfonic acid hydrate
Crystal formation and preparation method thereof.
Background technology
Nintedanib, Chinese name synonym：Buddhist nun replaces Buddhist nun's cloth.English name：INTEDANIB, entitled (3Z) -2,3- dihydro of chemistry
- 3- [[[4- [methyl [2- (4- methyl isophthalic acid-piperazinyl) acetyl] amino] phenyl] amino] benzylidene] -2- oxo -1H- indole -6-
Methyl formate, is researched and developed by Boehringer Ingelheim, and in October, 2014 is ratified through FDA(Nintedanib) is used for treating spy
The property sent out pulmonary fibrosiss (IPF), becomes only one and is approved the tyrosine kinase inhibitor (TKI) for treating IPF.2014 6
Announce that the listing license application acquisition of Nintedanib treatment idiopathic pulmonary fibrosises (IPF) confirms and included by EMA to add moon EMA
Speed examination ＆ approval list.It is adenocarcinoma that September European Union announces that Nintedanib joint docetaxel is applied to histodiagnosis after First-line chemotherapy
, the supportive suggestion of Locally Advanced or transitivity or local recurrence nonsmall-cell lung cancer (NSCLC) adult patients.
Nintedanib chemical structural formula is as follows：
Patent of invention WO 2004/013099 discloses Nintedanib list esilate and its hemi-hydrate crystalline and preparation method thereof,
Its hemihydrate crystalline water can lose its half water of crystallization at a temperature of 130 DEG C.
Patent of invention CN 101466675 discloses crystal formation of the different types of salt of Nintedanib or hydrate and preparation method thereof.
The dosage form that Nintedanib esilate lists product is soft capsule, this area need badly find different from the former purity grinding kind high,
The Nintedanib esilate novel crystal forms that stability is good, solubility property is excellent.
The present inventor studies to the crystal formation of Nintedanib esilate, there is provided a kind of preparation process is simple, purity higher and
Stability preferable Nintedanib esilate novel crystal forms.
Content of the invention
It is an object of the invention to provide a kind of Nintedanib esilate monohydrate crystal preparation method；
It is a further object to provide a kind of Nintedanib esilate hydrate novel crystal form.
In the application, the Nintedanib esilate monohydrate crystal form A of preparation adopts Rigaku Smartlab-3 type X-ray diffraction
Instrument, the x-ray diffraction pattern recording under CuK-beta, 40KV, 30mA condition determination has including in the angle of diffraction 2 θ：11.554
Degree, 17.423 degree, 18.800 degree, 19.683 degree, 19.986 degree of diffraction maximum, 2 θ errors are 0.2 degree.
Further, the Nintedanib esilate monohydrate crystal form A of preparation includes following characteristic diffraction angles (2 θ)：
9.810 degree, 11.554 degree, 13.639 degree, 14.139 degree, 16.282 degree, 16.666 degree, 17.423 degree, 18.800 degree,
The diffraction maximum of 18.985 degree, 19.297 degree, 19.683 degree, 19.986 degree, 22.033 degree, 22.951 degree and 23.271 degree, 2
θ error is 0.2 degree.
In a kind of scheme, the Nintedanib esilate monohydrate crystal form A of preparation have following characteristic diffraction angles (2 θ),
Interplanar distance (d) and relative intensity (%),
Table 1
In the DSC thermal analysis curue of Nintedanib esilate monohydrate crystal form A, start to melt at 304.94 DEG C, 306.97 DEG C
There is a sharp endothermic peak, fusing point is 304.94 DEG C about, described 10 DEG C/min of DSC heating rate, and water of crystallization is at 129.38 DEG C
Start to overflow.
The invention provides for the preparation method preparing the polymorphous crude drug crude product of Nintedanib esilate monohydrate, but
It is not limited only to the method：
Nintedanib intermediate compound IV is added in the methylene chloride of about 15 times of weight, adds ethyl sulfonic acid, stir anti-under room temperature
Should, 3～6h, collects the yellow solid separating out, post processing obtains final product the crude product of Nintedanib esilate monohydrate；
Further, ethyl sulfonic acid and the mol ratio of Nintedanib intermediate compound IV are (1.05～1.3)：1.
Present invention also offers the preparation method of Nintedanib esilate monohydrate A type crystal, comprise the steps of：
(1) by Nintedanib esilate dissolving crude product in alcohol solvent, add water, stir to reflux temperature so as to
All dissolve；
(2) activated carbon reflux decolour 0.5～1h；
(3) hot sucking filtration, 15～30 DEG C of stirring and crystallizing 8～12h of filtrate；
(4) solid obtaining, drying under reduced pressure are collected；
Wherein, the mass ratio of wherein ethanol, water and Nintedanib esilate crude product is (11.8～16)：(0.18～0.62)：
1.
In a kind of scheme, the mass ratio of ethanol, water and Nintedanib esilate crude product is 11.8：0.62：1.
The Nintedanib esilate that this method prepares through the water content that karl Fischer moisture measurement method and TG record is
2.6%～2.8%, containing about 1 water of crystallization.
Measuring purity through efficient liquid-phase chromatography method (HPLC) is more than 99.8%, and maximum single contaminant is less than 1 ‰, shows this
The Nintedanib esilate monohydrate crystal form A purity of method preparation is high, is conducive to the preparation of high purity chemical.
The Nintedanib esilate monohydrate crystal form A using accelerated test being prepared by the present invention carries out stability study, finds
This crystal formation has excellent chemical stability, and crystal formation is keeping constant through hot and humid environment accelerated test, has preferable storage
Deposit and processing stability.
For the crystal formation of the same race of same compound, its X-ray diffractogram has similarity on the whole, characterizes the d value of peak position
, typically within ± 2%, not over ± 2%, relative intensity error may be larger, but variation tendency is consistent for most of error for error.
In addition, in the identification of mixture, because the factors such as content decline can cause part diffracted ray to lack, now, height need not be relied on
The whole bands of a spectrum observed in pure sample, or even bands of a spectrum are likely to given crystallization be distinctive.Determine the present invention's
During the angle of diffraction 2 θ of the powder x-ray diffraction collection of illustrative plates in specification and claims, the value of gained is interpreted as in this value
In the range of ± 1.0 degree, preferably in the range of ± 0.2 degree of this value；Fusing point in DSC thermal analysis curue, the value of gained should be managed
Solution is in the range of ± 3.0 DEG C of degree of this value, preferably in the range of ± 1 DEG C of this value.
Term " multi-crystalline compounds " refers to the different crystal forms of identical compound and including but not limited to comprises the hydration of identical compound
Thing is (for example：There is the combination water in crystalline texture) and solvate is (for example：Other than water combines solvent) its
Its solid state molecular forms.The phenomenon that same drug molecule forms multiple crystal formations is referred to as polymorph in pharmaceuticals, and polymorph in pharmaceuticals is solid
The phenomenon of generally existing in medicine.
Term " powder x-ray diffraction collection of illustrative plates " refers to diffraction pattern that experimental observation arrives or is derived from its parameter.By peak position and peak
Intensity characterizes powder x-ray diffraction collection of illustrative plates.
In XRD spectrum, " intensity, CPS " is writing a Chinese character in simplified form of " intensity integration counts per second ", represents
Diffraction peak intensity.
Brief description
Fig. 1 show the powder x-ray diffraction figure of Nintedanib esilate monohydrate crystal form A of the present invention.The longitudinal axis represents
Peak intensity, transverse axis represents the angle of diffraction (2 θ).
Fig. 2 show the DSC thermal analysis curue of Nintedanib esilate monohydrate crystal form A of the present invention.Longitudinal axis table
Show mW/mg, transverse axis represents temperature DEG C, the fusing point of this product is 304.9 ± 2 DEG C.
Fig. 3 is thermogravimetric analysiss (TGA) figure of Nintedanib esilate monohydrate A crystal formation, wherein Range of measuring temp：
20-600℃
Heating rate：10℃/min.This product this product when temperature is higher than 310 DEG C starts fusion and decomposition as seen from the figure, and this product is about
Containing 2.699% moisture.
Specific embodiment
Following examples further describe the present invention, but, these embodiments are only for the present invention is described, rather than to this
The restriction of bright scope.
The preparation of embodiment 1 Nintedanib esilate crude product
Table 2 spent material counts
| Title | Specification | Molecular weight | Inventory | Mass ratio | The amount of material |
| Intermediate compound IV | 98.5% | 539.62 | 5.92kg | 1 | 1 |
| Ethylsulfonic acid | Analysis is pure | 110.13 | 1.27kg | 0.21 | 1.05 |
| Dichloromethane | Analysis is pure | — | 90.0kg | 15.0 | — |
Intermediate IV 5.92kg is added, with 88.8kg dichloromethane stirring and dissolving, reaction can not be molten clear, slowly in 100L reactor
Add ethylsulfonic acid 1.27kg, (10 DEG C) stirring reaction under room temperature.Carry out with reaction, solution gradually becomes cloudy, separate out yellow
Color solid, continues stirring 5h.Separate out a large amount of solids, sucking filtration, a small amount of eluent methylene chloride of filter cake, 30 DEG C of reduced vacuum are dried
12h, obtains yellow solid 5.7kg, molar yield 79.9%.
HPLC detects purity=99.1%.MASS:[M+H]+=540.4.For Nintedanib esilate in following embodiment
The preparation of monohydrate A crystal formation.
The preparation of embodiment 2 Nintedanib esilate monohydrate crystal form A
Table 3
| Title | Specification | Inventory | Mass ratio |
| Ethylsulfonic acid Nintedanib crude product | 99.1% | 5.5kg | 1 |
| Activated carbon | Analysis is pure | 0.6kg | — |
| Water | Analysis is pure | 3.42kg | 0.62 |
| Ethanol | Analysis is pure | 65.0kg | —11.8 |
Add 5.5kg ethyl sulfonic acid Nintedanib crude product in 100L reactor, add 65.0kg ethanol stirring and dissolving, add
3.42kg water, stirs molten clear to making it all be dissolved to backflow, adds activated carbon 0.6kg reflux decolour 1h, hot sucking filtration, filter
25 DEG C of stirring and crystallizing 12h of liquid, filter, 45 DEG C of drying under reduced pressure 24.0h, obtain yellow solid 4.12kg, molar yield 74.9%
HPLC detects purity：99.98%.
MASS:[M+H]+=540.4
Nuclear magnetic data：1H NMR(DMSO-d6),δ(ppm):1.14～1.11 (3H, t, J=7.40Hz), 2.53～2.49 (2H, m, J
=7.40Hz), 2.76 (7H, m), 3.09 (9H, m), 3.78 (3H, s), 5.86～5.85 (1H, d, J=8.25Hz), 6.90～6.89 (2H, d, J
=8.45Hz), 7.16～7.14 (2H, d, J=8.45Hz), 7.21～7.19 (1H, m, J=8.2Hz), 7.47 (1H, s), 7.51～7.50 (2H, d,
J=7.1Hz), 7.60～7.57 (2H, m, J=7.1Hz), 7.65～7.62 (1H, m, J=7.3,7.25), 9.52 (1H, s), 10.92 (1H, m),
12.26(1H,s).
Water content testing result：Through the detection of karl Fischer moisture titration, moisture is 2.79%.
The preparation of embodiment 3 Nintedanib esilate monohydrate crystal form A
Table 4
| Title | Specification | Inventory | Mass ratio |
| Ethylsulfonic acid Nintedanib crude product | 99.1% | 5.5kg | 1 |
| Activated carbon | Analysis is pure | 0.6kg | — |
| Water | Analysis is pure | 0.99kg | 0.18 |
| Ethanol | Analysis is pure | 65.0kg | 11.8 |
Add 5.5kg ethyl sulfonic acid Nintedanib crude product in 100L reactor, add 65.0kg ethanol stirring and dissolving, add
3.42kg water, stirs molten clear to making it all be dissolved to backflow, adds activated carbon 0.6kg reflux decolour 1h, hot sucking filtration, filter
30 DEG C of stirring and crystallizing 12h of liquid, filter, 45 DEG C of drying under reduced pressure 24.0h, obtain yellow solid 4.32kg,
HPLC detects purity：99.89%.MASS:[M+H]+=540.4.
The preparation of embodiment 4 Nintedanib esilate monohydrate crystal form A
Table 5
| Title | Specification | Inventory | Mass ratio |
| Ethylsulfonic acid Nintedanib crude product | 99.1% | 5.5kg | 1 |
| Activated carbon | Analysis is pure | 0.6kg | — |
| Water | Analysis is pure | 0.99kg | 0.18 |
| Ethanol | Analysis is pure | 88kg | 16 |
Add 5.5kg ethyl sulfonic acid Nintedanib crude product in 100L reactor, add 88.0kg ethanol stirring and dissolving, add
0.99kg water, stirs molten clear to making it all be dissolved to backflow, adds activated carbon 0.6kg reflux decolour 1h, hot sucking filtration, filter
25 DEG C of stirring and crystallizing 12h of liquid, filter, 45 DEG C of drying under reduced pressure 24.0h, obtain yellow solid 4.67kg.
HPLC detects purity：99.89%.MASS:[M+H]+=540.4.
Tests prove that, when for prepare the material purity of Nintedanib esilate monohydrate crystal form A more than 97.5% when,
Can draw and meet the Nintedanib esilate monohydrate crystal form A that purity is more than 99.8%.In preparation process, such as need
The higher Nintedanib esilate monohydrate crystal form A of prepared purity is it is also possible to repeat the recrystallization method of above-described embodiment.
Embodiment 3 Nintedanib esilate monohydrate crystal form A stability study
Press《Chinese Pharmacopoeia》(two annex of version in 2010) relevant study on the stability project demand, by Nintedanib esilate one
Hydrate crystal forms A (sample 1, sample 2, sample 3) is placed in relative humidity in 75% ± 5% exsiccator with commercially available back, then puts
In 40 DEG C of ± 2 DEG C of thermostatic drying chambers, respectively at 1,2,3, June sampling, test fusing point, single impurity and always miscellaneous knot respectively
Fruit such as following table：
Table 6 accelerated test result
Respectively by accelerated test six months after Nintedanib esilate monohydrate crystal form A be ground and tabletting after to sample
Carry out X-ray powder diffraction test, result of the test is as follows：
0 day XRD test result of table 7 sample 1
XRD test result after 6 months accelerated tests of table 8 sample 1
Result of the test shows：After the accelerated test of this product, X-ray powder diffraction is tested, and main 2 θ angles all do not occur significantly to become
Change, this product stability of crystal form is described preferably, we check the relevant material of this product using high performance liquid chromatography, and checked for impurities contains
Amount is not apparent from increasing, and chemical stability is excellent, meets medicinal demand.
Embodiment 6, the stability study of Nintedanib esilate monohydrate A crystal formation
Experimental technique：Certainly the soft capsule that grinds of Nintedanib esilate monohydrate A crystal formation (is ground, prescription grinds product with reference to former certainly
Prescription) place 10 days under the conditions of 60 DEG C, 4500lx ± 500 and RH92.5% with former product (100mg, the outsourcing) sample that grinds,
It is respectively adopted the situation of change about material when efficient liquid phase detects 0 day and 10 days, result is as shown in the table.
Table 9
| Testing conditions | From grinding sample always miscellaneous % | Former grind sample always miscellaneous % |
| 100mg soft capsule, 0 day | 0.12 | 0.17 |
| 100mg soft capsule, 60 DEG C, 10 days | 0.14 | 0.28 |
| 100mg soft capsule, RH92.5%, 10 days | 0.14 | 0.25 |
| 100mg soft capsule, 4500lx ± 500,10 days | 0.15 | 0.38 |
As can be seen from the above table, the impurity growth pattern of the soft capsule of Nintedanib esilate monohydrate A crystal formation is better than former grinding
Product, has excellent stability.
Claims (5)
1. a kind of Nintedanib esilate monohydrate crystal form A is it is characterised in that have bag in its powder x-ray diffraction collection of illustrative plates
Include in the angle of diffraction 2 θ：11.554th, 17.423 degree, 18.800 degree, 19.683 degree, 19.986 degree of diffraction maximum, 2 θ errors are
0.2 degree, described powder x-ray diffraction figure is the collection of illustrative plates being obtained with CuK alpha ray.
2. Nintedanib esilate monohydrate crystal form A as claimed in claim 1 is it is characterised in that its powder x-ray diffraction
In collection of illustrative plates, have including in the angle of diffraction 2 θ：9.810 degree, 11.554 degree, 13.639 degree, 14.139 degree, 16.282 degree, 16.666
Degree, 17.423 degree, 18.800 degree, 18.985 degree, 19.297 degree, 19.683 degree, 19.986 degree, 22.033 degree, 22.951 degree and
23.271 degree of diffraction maximum, 2 θ errors are 0.2 degree, and described powder x-ray diffraction figure is the collection of illustrative plates being obtained with CuK alpha ray.
3. a kind of preparation method of Nintedanib esilate monohydrate crystal form A is it is characterised in that comprise the steps of：
(1) by Nintedanib esilate dissolving crude product in alcohol solvent, add water, stir to reflux temperature so as to
All dissolve；
(2) activated carbon reflux decolour 0.5～1h；
(3) hot sucking filtration, 15～30 DEG C of stirring and crystallizing of filtrate；
(4) solid obtaining, drying under reduced pressure are collected.
4. Nintedanib esilate monohydrate crystal form A as claimed in claim 3 preparation method it is characterised in that ethanol,
The mass ratio of water and Nintedanib esilate crude product is (11.8～16)：(0.18～0.62)：1.
5. Nintedanib esilate monohydrate crystal form A as claimed in claim 3 preparation method it is characterised in that ethanol,
The mass ratio of water and Nintedanib esilate crude product is 11.8：0.62：1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
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| US7259181B2 (en) * | 2000-07-06 | 2007-08-21 | Les Laboratoires Servier | β crystalline form of perindopril tert-butylamine salt |
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| WO2012068441A2 (en) * | 2010-11-19 | 2012-05-24 | Ratiopharm Gmbh | Intedanib salts and solid state forms thereof |
| CN104844499A (en) * | 2015-06-05 | 2015-08-19 | 北京康立生医药技术开发有限公司 | Synthetic method for preparing Nintedanib through one-pot process |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7259181B2 (en) * | 2000-07-06 | 2007-08-21 | Les Laboratoires Servier | β crystalline form of perindopril tert-butylamine salt |
| CN1671660A (en) * | 2002-07-24 | 2005-09-21 | 贝林格尔英格海姆法玛两合公司 | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composi |
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| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
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