CN103319422A - New gefitinib crystal form and preparation method thereof - Google Patents
New gefitinib crystal form and preparation method thereof Download PDFInfo
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- CN103319422A CN103319422A CN2013100915504A CN201310091550A CN103319422A CN 103319422 A CN103319422 A CN 103319422A CN 2013100915504 A CN2013100915504 A CN 2013100915504A CN 201310091550 A CN201310091550 A CN 201310091550A CN 103319422 A CN103319422 A CN 103319422A
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Abstract
The invention relates to a new crystal form alpha crystal form of gefitinib and a preparation method thereof. The crystal form has the strongest characteristic peak at a position where a 2theta angle is 7.12 on an X ray powder diffraction (XRPD) pattern, and has main characteristic peaks at positions where the 2theta angle are respectively 7.12, 24.349 and 26.435, wherein the relative strength of the main characteristic peaks are greater than 60%. The preparation method comprises: (a) adding gefitinib into a strong polarity solvent, and dissolving; (b) adding a smaller polarity anti-solvent into the solution, separating out crystals; (c) filtering, drying, and obtaining an almost white solid. The alpha crystal form is easy to prepare, good in stability and preparation formability, simple in preparation technology and mild in conditions; and the whole preparation process is carried out in 10 hours or less, so that the production efficiency is improved substantially, and the alpha crystal form is more suitable for industrialization production.
Description
Technical field
The present invention relates to new crystal of a kind of cancer therapy drug and preparation method thereof, be specifically related to a kind of Gefitinib new crystal alpha-crystal form and preparation method thereof.
Background technology
Gefitinib, English name Gefitinib, developed by Astrazenca AB, commodity are called Iressa (IRESSA), it is a kind of selectivity EGF-R ELISA (EGFR) tyrosine kinase inhibitor, be applicable to treat local late period or the Metastatic Nsclc (NSCLC) previously accepting chemotherapy or be unsuitable for chemotherapy, structural formula is as follows:
Astrazenca AB has applied for the compound patent CN96193526.X of Gefitinib on April 23rd, 1996, this patent discloses Gefitinib and hydrochloride thereof, but and which kind of crystalline forms is not mentioned Gefitinib can exist, the fusing point of the Gefitinib for preparing in an embodiment is in 119 ℃ ~ 120 ℃ scopes, determine that its crystalline form is different from Form 1 polymorphic form of finding afterwards, be speculated as certain metastable-state crystal form, but do not have to disclose X-ray diffraction method (XRPD) collection of illustrative plates of this crystal formation.
Astrazenca AB applied for CN03809162.3 and division CN200710182400.9 thereof on 02 24th, 2003, in patent, disclose the Gefitinib polymorphic form of called after Form 1, and disclose its XRPD collection of illustrative plates and dsc (DSC) collection of illustrative plates.The fusing point of Form 1 polymorphic form is in 194 ℃ ~ 198 ℃ scopes.This patent also discloses Gefitinib methyl-sulphoxide (DMSO) solvate crystal formation, the Gefitinib methanol solvate compound crystal formation of called after Form 2 and the Gefitinib trihydrate crystal formation of called after Form 5 of called after Form 3.
Summary of the invention
One of purpose of the present invention is to provide a kind of new Gefitinib crystal formation, and the present invention is with its called after alpha-crystal form, and this crystal formation is easy to preparation, has satisfactory stability and preparations shaping, for Gefitinib provides new selection in the application of medicine industry.
Gefitinib alpha-crystal form provided by the invention has new crystal formation feature through X-ray diffraction method (XRPD) conclusive evidence.
Gefitinib new crystal alpha-crystal form provided by the invention, 2 θ angles are that 7.12 position has the strongest characteristic peak on the XRPD collection of illustrative plates, 2 θ angles are that 7.12,24.349,26.435 position has the principal character peak on the XRPD collection of illustrative plates, and described principal character peak relative intensity is greater than 60%.
Further, Gefitinib alpha-crystal form of the present invention, 2 θ angles are that 14.259,15.85,17.716,18.703,19.363 position has the principal character peak on the XRPD collection of illustrative plates, described principal character peak relative intensity is greater than 35%.
Further, Gefitinib alpha-crystal form of the present invention, 2 θ angles are that 16.36,22.429,24.028,26.678 position has the principal character peak on the XRPD collection of illustrative plates, described principal character peak relative intensity is greater than 20%.
Further, Gefitinib alpha-crystal form of the present invention, 2 θ angles are that 11.245,11.593,12.29,14.537,15.207,20.718,21.216,25.23,27.331,28.684,29.138,29.788,30.743,31.972,33.092,34.209,35.86,36.115,39.417,40.653,44.885,46.995,51.376,51.56 position has characteristic peak on the XRPD collection of illustrative plates.
The alleged characteristic peak of the present invention refers to the diffraction peak of relative intensity more than 3%.
Further, Gefitinib alpha-crystal form of the present invention has XRPD collection of illustrative plates as shown in Figure 1.The XRPD data of alpha-crystal form of the present invention see Table 1.
Table 1 Gefitinib alpha-crystal form XRPD diffractogram 2 θ angle and relative intensities
Because the difference of measuring condition, 2 θ angles and the relative intensity at each peak can change to some extent on the XRPD diffractogram, and general 2 θ angles change in ± 0.2, and relative intensity is thought reasonable error ± 0.2% with interior.
Gefitinib alpha-crystal form provided by the invention is analyzed through dsc (DSC), 194 ~ 200 ℃ of melting ranges (seeing accompanying drawing 2), and purity is more than 99.5%, and yield is more than 80%.
Another object of the present invention is to provide the preparation method of described Gefitinib alpha-crystal form, the method can directly obtain Gefitinib alpha-crystal form of the present invention, and technique is simple, and mild condition, whole preparation process have improved production efficiency greatly in 10 hours.
The preparation method of Gefitinib alpha-crystal form provided by the invention comprises the steps:
(a), Gefitinib is added in the intensive polar solvent dissolve;
(b), add in the solution polarity less anti-solvent, crystallization;
(c), filter, drying gets the off-white color solid.
The Gefitinib of mentioning in the above step refers to the Gefitinib crude product that any technique obtains, and comprises the various known or unknown crystal formation of anhydrous form, solvate or hydrate forms of Gefitinib or the industrial crude product of amorphous forms.
For further improving industrial production efficient, reducing solvent load, reduce production costs, the contriver is optimized preparation method's of the present invention condition.
The contriver finds in the research of Gefitinib crystal formation, the rising temperature can reduce the required solvent volume of Gefitinib dissolving in the step (a) greatly, thereby reduce production costs, and the Crystallization Process of step (b) cooling is conducive to rapid crystallization, production efficiency is doubled about.
Therefore, preferably, the solvent temperature of Gefitinib is 40 ~ 150 ℃ among the preparation method of Gefitinib alpha-crystal form of the present invention, step (a), and further preferably, the recrystallization temperature of step (b) is-20 ~ 35 ℃.
The inventor also finds in the research of Gefitinib crystal formation, Gefitinib is only dissolved good in intensive polar solvent, wherein at N, dinethylformamide (DMF), methyl-sulphoxide (DMSO), methyl alcohol, in chloroform or the acetonitrile equal solvent, can realize that solvent volume is lower than 20 times of amount (mass/volume ratios of Gefitinib, g/ml) fully dissolving, but because the product that adopts DMSO or methyl alcohol to obtain as solvent is DMSO solvate or methanol solvate compound, and can not obtain Gefitinib alpha-crystal form of the present invention, therefore, the described intensive polar solvent of preparation method's step provided by the invention (a) refers to DMF, chloroform, the mixed solvent of acetonitrile or two or more described solvents.
Through inventor's verification experimental verification, Gefitinib is equal indissoluble in the less solvent of various polarity, described solvent comprises water, the alcohol except methyl alcohol, ketone, tetrahydrofuran (THF), ester, ether, aliphatic hydrocarbon, aromatic hydrocarbon solvent, and the mixed solvent of two or more described solvents, therefore, in theory, the above solvent or its combination all can be used as preparation method's of the present invention anti-solvent.
But the contriver finds in test, with toluene, the dimethylbenzene anti-solvent as the inventive method, can separate out oily matter, can't obtain described Gefitinib alpha-crystal form; Adopt water to cause separating out Form 5 crystal formations of Gefitinib trihydrate as anti-solvent, thereby can not adopt; In addition, adopt ethanol or Virahol longer as the anti-solvent crystallization time, surpass 8 hours crystallizatioies still incomplete, the products obtained therefrom yield is lower, below 40% and 60%, can not satisfy industrialization production requirements respectively.
Grope through contriver's lot of experiments, the mixed solvent of one or more in the employing trimethyl carbinol, acetone, normal hexane, tetrahydrofuran (THF), ether, methylene dichloride, isopropyl ether, the t-butyl methyl ether can prepare all gratifying Gefitinib alpha-crystal forms of yield and purity as preparation method's of the present invention anti-solvent.Wherein, adopt t-butyl methyl ether: the normal hexane volume ratio be the mixed solvent of 1:0.03 ~ 30 as anti-solvent, crystallization is the rapidest under the similarity condition, yield is high, good product purity is conducive to production efficiency and improves.
In addition, too much for foreign pigment content among the solution Gefitinib alpha-crystal form preparation method, related substance exceeds standard, and affects the problem of crystallization, also can add a small amount of gac in preparation method's step of the present invention (a) and decolour.The crystal formation product that after decolouring, obtains, color and luster is pure, the outward appearance homogeneous, its related substances is starkly lower than the product for preparing without decolouring.
In sum, the invention provides a kind of new Gefitinib crystal formation alpha-crystal form, for Gefitinib provides new selection in the application of medicine industry, the present invention also provides a kind of method for preparing the Gefitinib alpha-crystal form, and the method is easy and simple to handle, mild condition, agents useful for same is cheap and easy to get, is suitable for suitability for industrialized production, and gained alpha-crystal form product purity is high, yield is high, and foreign matter content meets the requirements.
Description of drawings
The XRPD figure of accompanying drawing 1 Gefitinib alpha-crystal form product.
The DSC figure of accompanying drawing 2 Gefitinib alpha-crystal form products.
Embodiment
Following examples are to specify of the present invention, should not be construed as limiting scope of the present invention.
10.0g Gefitinib, 100mlDMF are added in the reactor, normal temperature (approximately 25 ℃) dissolving 30min, the anti-solvent of adding 150ml t-butyl methyl ether, system begins crystallization, normal temperature crystallization 6h, filter, drying gets off-white color solid 8.2g, product is through XRPD and dsc analysis, conclusive evidence is Gefitinib alpha-crystal form, purity 99.5%, yield 82%.
Replace 100mlDMF with the 200ml chloroform, other gets off-white color solid 8.1g according to embodiment 1 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.5%, yield 81%.
Embodiment 3,
Replace 100mlDMF with the 200ml acetonitrile, other gets off-white color solid 8.1g according to embodiment 1 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.5%, yield 81%.
Embodiment 4,
Replace 100mlDMF with the mixed solvent 150ml of DMF and chloroform (1:1), other gets off-white color solid 8.0g according to embodiment 1 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.5%, yield 80%.
Embodiment 5,
Replace 100mlDMF with the mixed solvent 200ml of chloroform and acetonitrile (1:1), other gets off-white color solid 8.0g according to embodiment 1 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.5%, yield 80%.
Embodiment 6,
10.0g Gefitinib, 60mlDMF are added in the reactor, reaction system is warmed up to 60 ℃, insulation dissolving 30min, the lower anti-solvent that adds the 150ml t-butyl methyl ether of normal temperature condition (approximately 25 ℃), system begins crystallization, and normal temperature crystallization 3.5h filters, dry, off-white color solid 8.5g, product is through XRPD and dsc analysis, proves conclusively to be the Gefitinib alpha-crystal form, purity 99.7%, yield 85%.
With the 10.0g Gefitinib, 0.5g gac, 60mlDMF adds in the reactor, reaction system is warmed up to 60 ℃, insulation dissolving decolouring 30min, system is filtered, the lower anti-solvent that adds the 150ml t-butyl methyl ether of normal temperature condition (approximately 25 ℃), system begins crystallization, normal temperature crystallization 3.5h, filter, drying gets off-white color solid 8.5g, product is through XRPD and dsc analysis, conclusive evidence is Gefitinib alpha-crystal form, purity 99.8%, yield 85%, the products obtained therefrom color and luster is pure, the outward appearance homogeneous, its related substances obviously reduces, and product appearance and its related substances control all are better than the product of embodiment 6 preparations.
Embodiment 8,
Solvent temperature is changed to 150 ℃ by 60 ℃, and institute adds the DMF volume and changes 40ml into by 60ml, and other gets off-white color solid 8.7g according to embodiment 6 operations, and product is through XRPD and dsc analysis, proves conclusively to be the Gefitinib alpha-crystal form, purity 99.7%, yield 87%.
Embodiment 9,
Solvent temperature is changed to 40 ℃ by 60 ℃, and the DMF volume changes 80ml into by 60ml, and other gets off-white color solid 8.3g according to embodiment 6 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.6%, yield 83%.
Recrystallization temperature is changed to 35 ℃ by 25 ℃ of normal temperature, and the crystallization time extends to 5h by 3.5h, and other gets off-white color solid 8.3g according to embodiment 6 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.7%, yield 83%.
Recrystallization temperature is changed to-20 ℃ by 25 ℃ of normal temperature, and the crystallization time foreshortens to 2h by 3.5h, and other gets off-white color solid 8.5g according to embodiment 6 operation, and product is through XRPD and dsc analysis, proves conclusively to be Gefitinib alpha-crystal form, purity 99.7%, yield 85%.
Embodiment 12-25,
Adopt the t-butyl methyl ether among the following crystallization solvent replacing embodiment 6, the according to the form below operation of crystallization time, other operation is identical with embodiment 6, and products obtained therefrom is through XRPD and dsc analysis, proves conclusively to be the Gefitinib alpha-crystal form, and product purity and yield are as follows:
The different anti-solvents of table 2 are on the impact of crystallization time and product purity, yield
Can be found out by the present embodiment, adopt t-butyl methyl ether: as anti-solvent, crystallization is fastest for normal hexane (1:0.03 ~ 30), but Effective Raise production efficiency, and products obtained therefrom purity and yield are all better.
Comparative Examples 1,
Adopt the t-butyl methyl ether in the toluene alternative embodiment 1, other operation is identical with embodiment 1, occurs oily matter behind the crystallization, can't make alpha-crystal form.
Comparative Examples 2,
Adopt the t-butyl methyl ether in the dimethylbenzene alternative embodiment 1, other operation is identical with embodiment 1, occurs oily matter behind the crystallization, can't make alpha-crystal form.
Comparative Examples 3,
10.0g Gefitinib, 550ml ethanol are added in the reactor, normal temperature (approximately 25 ℃) is lower can't to be dissolved, be heated to 78 ℃ of settled solutions that reflux to get, slowly be down to the room temperature crystallization, filter, dry, get off-white color solid 3.6g, through XRPD and dsc analysis, prove conclusively 1 crystal formation into Gefitinib Form, purity 96.2%, yield 36%.
Comparative Examples 4,
Replace 550ml ethanol with the 550ml Virahol, other operation is identical with Comparative Examples 3, all can't dissolve fully under normal temperature and 80 ℃ of reflux conditionss.
Comparative Examples 5,
Replace 550ml ethanol with the 550ml propyl carbinol, other operation is identical with Comparative Examples 3, all can't dissolve fully under normal temperature and 80 ℃ of reflux conditionss.
Above simultaneous test explanation, the contriver adopts the method for Comparative Examples 1 ~ 5 all can not prepare the Gefitinib alpha-crystal form.
Comparative Examples 6,
Adopt the t-butyl methyl ether in the ethanol alternative embodiment 6, other operation is identical with embodiment 6, and crystallization 6 hours gets off-white color solid 3.2g, through XRPD and dsc analysis, proves conclusively and is Gefitinib alpha-crystal form, purity 99.2%, yield 32%.
Comparative Examples 7,
The crystallization time changes 10 hours into, and other operation is identical with Comparative Examples 6, gets off-white color solid 3.9g, through XRPD and dsc analysis, proves conclusively and is Gefitinib alpha-crystal form, purity 99.1%, yield 39%.
Comparative Examples 8,
Adopt the t-butyl methyl ether in the Virahol alternative embodiment 6, other operation is identical with embodiment 6, and crystallization 6 hours gets off-white color solid 4.7g, through XRPD and dsc analysis, proves conclusively and is Gefitinib alpha-crystal form, purity 99.3%, yield 47%.
Comparative Examples 9,
The crystallization time changes 10 hours into, and other operation is identical with Comparative Examples 8, gets off-white color solid 5.5g, through XRPD and dsc analysis, proves conclusively and is Gefitinib alpha-crystal form, purity 98.9%, yield 55%.
Above simultaneous test explanation, the contriver adopts the method for Comparative Examples 6 ~ 9 can prepare the Gefitinib alpha-crystal form, but yield is lower, does not meet the industrialized production demand.
Embodiment 26,
According to prior art CN03809162.3 embodiment 4 preparation Gefitinib Form1 crystal formations, according to prior art CN03804616.4 embodiment 2 alpha-crystal form that Gefitinib Form1 crystal formation and the embodiment of the invention 6 of gained makes is made respectively 1000 in tablet, investigate relevant nature in blocks.The result relatively sees Table 3.
Table 3 product relevant nature in blocks relatively
As seen, the tablet of alpha-crystal form preparation of the present invention is compared with the tablet that the disclosed Form1 crystal formation of prior art is made in the same way, alpha-crystal form figure of tablet homogeneous, and appearance luster is all better, and the problems such as sliver are less, and fraction defective is low; The uniformity of dosage units of gained alpha-crystal form tablet obviously is better than the Form1 crystal formation; The alpha-crystal form Dissolution of Tablet obviously is better than Form1 crystal formation tablet, and its related substances also is starkly lower than Form1 crystal formation tablet in the time of 24 months, illustrates that alpha-crystal form has more excellent stability.Above explanation alpha-crystal form provided by the invention has good preparations shaping performance, and good stripping property and stability are arranged, and is suitable for the preparation oral solid formulation.
Claims (10)
1. new Gefitinib alpha-crystal form, it is characterized in that on the XRPD collection of illustrative plates 2 θ angles are that 7.12 position has the strongest characteristic peak, 2 θ angles are that 7.12,24.349,26.435 position has the principal character peak on the XRPD collection of illustrative plates, and described principal character peak relative intensity is greater than 60%.
2. Gefitinib alpha-crystal form as claimed in claim 1, it is characterized in that further on the XRPD collection of illustrative plates 2 θ angles are that 14.259,15.85,17.716,18.703,19.363 position has the principal character peak, described principal character peak relative intensity is greater than 35%.
3. Gefitinib alpha-crystal form as claimed in claim 2 is characterized in that further on the XRPD collection of illustrative plates 2 θ angles are that 16.36,22.429,24.028,26.678 position has the principal character peak, and described principal character peak relative intensity is greater than 20%.
4. Gefitinib alpha-crystal form as claimed in claim 3 is characterized in that further on the XRPD collection of illustrative plates 2 θ angles are that 11.245,11.593,12.29,14.537,15.207,20.718,21.216,25.23,27.331,28.684,29.138,29.788,30.743,31.972,33.092,34.209,35.86,36.115,39.417,40.653,44.885,46.995,51.376,51.56 position has characteristic peak.
5. Gefitinib alpha-crystal form as claimed in claim 4 is characterized in that further having XRPD collection of illustrative plates as shown in Figure 1.
6. method for preparing such as each described Gefitinib alpha-crystal form of claim 1 ~ 5 is characterized in that comprising following steps:
(a), Gefitinib is added in the intensive polar solvent dissolve;
(b), add in the solution polarity less anti-solvent, crystallization;
(c), filter, drying gets the off-white color solid,
Preferably, also in intensive polar solvent, add activated carbon decolorizing and filtration in the step (a).
7. Gefitinib alpha-crystal form preparation method as claimed in claim 6, the temperature that it is characterized in that controlling step (a) is 40 ~ 150 ℃.
8. Gefitinib alpha-crystal form preparation method as claimed in claim 7 is characterized in that the temperature of controlling step (b) is-20 ~ 35 ℃.
9. Gefitinib alpha-crystal form preparation method as claimed in claim 6 is characterized in that intensive polar solvent in the step (a) is selected from one or more in DMF, chloroform and the acetonitrile.
10. Gefitinib alpha-crystal form preparation method as claimed in claim 6, it is characterized in that anti-solvent in the step (b) is selected from one or more in the trimethyl carbinol, acetone, normal hexane, tetrahydrofuran (THF), ether, t-butyl methyl ether, isopropyl ether and the methylene dichloride, preferably, the anti-solvent in the step (b) is that t-butyl methyl ether and normal hexane are with the mixed solvent of the ratio combination of 1:0.03 ~ 30.
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| CN106083739A (en) * | 2016-05-31 | 2016-11-09 | 华南理工大学 | New gefitinib crystal form and preparation method based on super-critical anti-solvent technology thereof |
| US10259805B2 (en) * | 2015-12-30 | 2019-04-16 | Synthon B.V. | Process for making crystalline form a of gefitinib |
| CN110101668A (en) * | 2019-05-29 | 2019-08-09 | 华东理工大学 | A kind of preparation method of Gefitinib composite particles |
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| CN110101668A (en) * | 2019-05-29 | 2019-08-09 | 华东理工大学 | A kind of preparation method of Gefitinib composite particles |
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