CN103319422B - A kind of Gefitinib crystal formation and preparation method thereof - Google Patents
A kind of Gefitinib crystal formation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to novel crystal forms alpha-crystal form of a kind of Gefitinib and preparation method thereof, there is the strongest characteristic peak this crystal formation position that 2 θ angles are 7.12 on XRPD collection of illustrative plates, on XRPD collection of illustrative plates, 2 θ angles are to have principal character peak on 7.12,24.349,26.435 position, and described principal character peak relative intensity is greater than 60%. The invention still further relates to the preparation method of described alpha-crystal form: (a), Gefitinib is added in intensive polar solvent and dissolved; (b), in solution, add the anti-solvent that polarity is less, crystallization; (c), filter, dry, obtain off-white color solid. Alpha-crystal form of the present invention is easy to preparation, has good stability and preparations shaping, and preparation method's technique is simple, mild condition, and whole preparation process, in 10 hours, has improved production efficiency greatly, is more applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to novel crystal forms of a kind of cancer therapy drug and preparation method thereof, be specifically related to a kind of Gefitinib novel crystal forms 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 selective EGF-R ELISA (EGFR) tyrosine kinase inhibitor, be applicable to local late period or Metastatic Nsclc (NSCLC) that treatment was previously accepted chemotherapy or was 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 not mentioned Gefitinib can exist, the fusing point of the Gefitinib preparing is in an embodiment within the scope of 119 DEG C～120 DEG C, determine that its crystal form is different from the Form1 polymorph of finding afterwards, be speculated as certain metastable-state crystal form, but there is no to disclose X-ray diffraction method (XRPD) collection of illustrative plates of this crystal formation.
Astrazenca AB has applied for CN03809162.3 and division CN200710182400.9 thereof on 02 24th, 2003, in patent, disclose the Gefitinib polymorph of called after Form1, and disclose its XRPD collection of illustrative plates and differential scanning calorimetry (DSC) collection of illustrative plates. The fusing point of Form1 polymorph is within the scope of 194 DEG C～198 DEG C. This patent also discloses Gefitinib methyl-sulfoxide (DMSO) solvate crystal formation, the Gefitinib methanol solvate compound crystal formation of called after Form2 and the Gefitinib trihydrate crystal formation of called after Form5 of called after Form3.
Summary of the invention
One of object of the present invention is to provide a kind of new Gefitinib crystal formation, and the present invention is by its called after alpha-crystal form, and this crystal formation is easy to preparation, has good stability and preparations shaping, for Gefitinib provides new selection in the application of medical industry.
Gefitinib alpha-crystal form provided by the invention, has new crystal formation feature through X-ray diffraction method (XRPD) confirmation.
Gefitinib novel crystal forms alpha-crystal form provided by the invention, there is the strongest characteristic peak the position that 2 θ angles are 7.12 on XRPD collection of illustrative plates, on XRPD collection of illustrative plates, 2 θ angles are to have principal character peak on 7.12,24.349,26.435 position, and described principal character peak relative intensity is greater than 60%.
Further, Gefitinib alpha-crystal form of the present invention, on XRPD collection of illustrative plates, 2 θ angles are to have principal character peak on 14.259,15.85,17.716,18.703,19.363 position, described principal character peak relative intensity is greater than 35%.
Further, Gefitinib alpha-crystal form of the present invention, on XRPD collection of illustrative plates, 2 θ angles are to have principal character peak on 16.36,22.429,24.028,26.678 position, described principal character peak relative intensity is greater than 20%.
Further, Gefitinib alpha-crystal form of the present invention, on XRPD collection of illustrative plates, 2 θ angles are to have characteristic peak on 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.
The alleged characteristic peak of the present invention refers to more than 3% diffraction maximum of relative intensity.
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 are in table 1.
Table 1 Gefitinib alpha-crystal form XRPD diffraction pattern 2 θ angle and relative intensities
Due to the difference of measuring condition, on XRPD diffraction pattern, 2 θ angles and the relative intensity at each peak can change to some extent, and general 2 θ angles change in ± 0.2, and relative intensity is thought reasonable error in ± 0.2%.
Gefitinib alpha-crystal form provided by the invention, analyzes through differential scanning calorimetry (DSC), 194 ~ 200 DEG C 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, mild condition, and whole preparation process, in 10 hours, has improved production efficiency greatly.
The preparation method of Gefitinib alpha-crystal form provided by the invention comprises the steps:
(a), Gefitinib is added in intensive polar solvent and dissolved;
(b), to add in solution polarity less anti-solvent, crystallization;
(c), filter, dry, obtain off-white color solid.
The Gefitinib of mentioning in 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 efficiency, reducing solvent load, reduce production costs, inventor is optimized preparation method's of the present invention condition.
Inventor finds in the research of Gefitinib crystal formation, rising temperature can greatly reduce Gefitinib in step (a) and dissolve required solvent volume, thereby reduce production costs, and the Crystallization Process of step (b) cooling is conducive to rapid crystallization, makes production efficiency double left and right.
Therefore, preferably, the preparation method of Gefitinib alpha-crystal form of the present invention, in step (a), the solution temperature of Gefitinib is 40 ~ 150 DEG C, further preferably, the recrystallization temperature of step (b) is-20 ~ 35 DEG C.
The inventor also finds in the research of Gefitinib crystal formation, Gefitinib only dissolves good in intensive polar solvent, wherein at N, dinethylformamide (DMF), methyl-sulfoxide (DMSO), methyl alcohol, in chloroform or acetonitrile equal solvent, can realize solvent volume lower than 20 times of amount (mass/volume ratios of Gefitinib, g/ml) dissolve completely, 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, oxolane, 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 inventor finds in test, the anti-solvent using toluene, dimethylbenzene as the inventive method, can separate out grease, cannot obtain described Gefitinib alpha-crystal form; Adopt water to cause separating out the Form5 crystal formation of Gefitinib trihydrate as anti-solvent, thereby can not adopt; In addition, adopt ethanol or isopropyl alcohol longer as the anti-solvent crystallization time, exceed 8 hours crystallizatioies still incomplete, products obtained therefrom yield is lower, below 40% and 60%, can not meet industrialization production requirements respectively.
Grope through inventor's lot of experiments, the mixed solvent of one or more in the employing tert-butyl alcohol, acetone, n-hexane, oxolane, ether, carrene, isopropyl ether, t-butyl methyl ether, as preparation method's of the present invention anti-solvent, can prepare all gratifying Gefitinib alpha-crystal forms of yield and purity. Wherein, adopt t-butyl methyl ether: the mixed solvent that n-hexane volume ratio is 1:0.03 ~ 30 is as anti-solvent, and under similarity condition, crystallization is the rapidest, and yield is high, good product purity, is conducive to production efficiency and improves.
In addition, too much for foreign pigment content in solution Gefitinib alpha-crystal form preparation method, related substance exceeds standard, and affects the problem of crystallization, also can add a small amount of active carbon to decolour in preparation method's step of the present invention (a). The crystal formation product obtaining after decolouring, color and luster is pure, outward appearance homogeneous, its related substances is starkly lower than the product 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 medical industry, the present invention also provides a kind of method of preparing 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 impurity content meets the requirements.
Brief description of the 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.
Detailed description of the invention
Following examples are to illustrate of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1,
10.0g Gefitinib, 100mlDMF are added in reactor, normal temperature (approximately 25 DEG C) dissolves 30min, adds the anti-solvent of 150ml t-butyl methyl ether, and system starts crystallization, normal temperature crystallization 6h, filter, dry, obtain off-white color solid 8.2g, product is through XRPD and dsc analysis, confirmation is Gefitinib alpha-crystal form, purity 99.5%, yield 82%.
Embodiment 2,
Replace 100mlDMF with 200ml chloroform, other operates according to embodiment 1, obtains off-white color solid 8.1g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.5%, yield 81%.
Embodiment 3,
Replace 100mlDMF with 200ml acetonitrile, other operates according to embodiment 1, obtains off-white color solid 8.1g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.5%, yield 81%.
Embodiment 4,
Mixed solvent 150ml with DMF and chloroform (1:1) replaces 100mlDMF, and other operates according to embodiment 1, obtains off-white color solid 8.0g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.5%, yield 80%.
Embodiment 5,
Mixed solvent 200ml with chloroform and acetonitrile (1:1) replaces 100mlDMF, and other operates according to embodiment 1, obtains off-white color solid 8.0g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.5%, yield 80%.
Embodiment 6,
10.0g Gefitinib, 60mlDMF are added in reactor, reaction system is warmed up to 60 DEG C, 30min is dissolved in insulation, under normal temperature condition (approximately 25 DEG C), add the anti-solvent of 150ml t-butyl methyl ether, system starts crystallization, and normal temperature crystallization 3.5h filters, dry, obtain off-white color solid 8.5g, product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form, purity 99.7%, yield 85%.
Embodiment 7,
By 10.0g Gefitinib, 0.5g active carbon, 60mlDMF adds in reactor, reaction system is warmed up to 60 DEG C, decolouring 30min is dissolved in insulation, system is filtered, under normal temperature condition (approximately 25 DEG C), add the anti-solvent of 150ml t-butyl methyl ether, system starts crystallization, normal temperature crystallization 3.5h, filter, dry, obtain off-white color solid 8.5g, product is through XRPD and dsc analysis, confirmation is Gefitinib alpha-crystal form, purity 99.8%, yield 85%, products obtained therefrom color and luster is pure, outward appearance homogeneous, its related substances obviously reduces, product appearance and its related substances control are all better than product prepared by embodiment 6.
Embodiment 8,
Solution temperature is changed to 150 DEG C by 60 DEG C, and institute adds DMF volume and changes 40ml into by 60ml, and other operates according to embodiment 6, obtains off-white color solid 8.7g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form, purity 99.7%, yield 87%.
Embodiment 9,
Solution temperature is changed to 40 DEG C by 60 DEG C, and DMF volume changes 80ml into by 60ml, and other operates according to embodiment 6, obtains off-white color solid 8.3g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.6%, yield 83%.
Embodiment 10,
Recrystallization temperature is changed to 35 DEG C by 25 DEG C of normal temperature, and the crystallization time extends to 5h by 3.5h, and other operates according to embodiment 6, obtains off-white color solid 8.3g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.7%, yield 83%.
Embodiment 11,
Recrystallization temperature is changed to-20 DEG C by 25 DEG C of normal temperature, and the crystallization time foreshortens to 2h by 3.5h, and other operates according to embodiment 6, obtains off-white color solid 8.5g, and product, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form purity 99.7%, yield 85%.
Embodiment 12-25,
Adopt the t-butyl methyl ether in following crystallization solvent alternative embodiment 6, the according to the form below operation of crystallization time, other operation is identical with embodiment 6, and products obtained therefrom, through XRPD and dsc analysis, is confirmed as Gefitinib alpha-crystal form, and product purity and yield are as follows:
The impact of the different anti-solvents of table 2 on crystallization time and product purity, yield
Can be found out by the present embodiment, adopt t-butyl methyl ether: n-hexane (1:0.03 ~ 30) is as anti-solvent, and crystallization is fastest, can effectively enhance productivity, and products obtained therefrom purity and yield are all better.
Comparative example 1,
Adopt the t-butyl methyl ether in toluene alternative embodiment 1, other operation is identical with embodiment 1, occurs grease after crystallization, cannot make alpha-crystal form.
Comparative example 2,
Adopt the t-butyl methyl ether in dimethylbenzene alternative embodiment 1, other operation is identical with embodiment 1, occurs grease after crystallization, cannot make alpha-crystal form.
Comparative example 3,
10.0g Gefitinib, 550ml ethanol are added in reactor, normal temperature (approximately 25 DEG C) is lower cannot be dissolved, be heated to 78 DEG C of settled solutions that reflux to obtain, be slowly down to room temperature crystallization, filter, dry, obtain off-white color solid 3.6g, through XRPD and dsc analysis, confirm the crystal formation into Gefitinib Form1, purity 96.2%, yield 36%.
Comparative example 4,
Replace 550ml ethanol with 550ml isopropyl alcohol, other operation is identical with comparative example 3, under normal temperature and 80 DEG C of counterflow conditions, all cannot dissolve completely.
Comparative example 5,
Replace 550ml ethanol with 550ml n-butanol, other operation is identical with comparative example 3, under normal temperature and 80 DEG C of counterflow conditions, all cannot dissolve completely.
Above contrast test explanation, inventor adopts the method for comparative example 1 ~ 5 all can not prepare Gefitinib alpha-crystal form.
Comparative example 6,
Adopt the t-butyl methyl ether in ethanol alternative embodiment 6, other operation is identical with embodiment 6, and crystallization 6 hours, obtains off-white color solid 3.2g, through XRPD and dsc analysis, confirms as Gefitinib alpha-crystal form purity 99.2%, yield 32%.
Comparative example 7,
The crystallization time changes 10 hours into, and other operation is identical with comparative example 6, obtains off-white color solid 3.9g, through XRPD and dsc analysis, confirms as Gefitinib alpha-crystal form purity 99.1%, yield 39%.
Comparative example 8,
Adopt the t-butyl methyl ether in isopropyl alcohol alternative embodiment 6, other operation is identical with embodiment 6, and crystallization 6 hours, obtains off-white color solid 4.7g, through XRPD and dsc analysis, confirms as Gefitinib alpha-crystal form purity 99.3%, yield 47%.
Comparative example 9,
The crystallization time changes 10 hours into, and other operation is identical with comparative example 8, obtains off-white color solid 5.5g, through XRPD and dsc analysis, confirms as Gefitinib alpha-crystal form purity 98.9%, yield 55%.
Above contrast test explanation, inventor adopts the method for comparative example 6 ~ 9 can prepare Gefitinib alpha-crystal form, but yield is lower, does not meet industrialized production demand.
Embodiment 26,
Prepare Gefitinib Form1 crystal formation according to prior art CN03809162.3 embodiment 4, the alpha-crystal form Gefitinib Form1 crystal formation of gained and the embodiment of the present invention 6 being made according to prior art CN03804616.4 embodiment 2 is made respectively 1000, tablet, investigates relevant nature in blocks. Result is relatively in table 3.
The relevant nature comparison in blocks of table 3 product
Visible, tablet prepared by alpha-crystal form 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 defect rate is low; The uniformity of dosage units of gained alpha-crystal form tablet is obviously better than Form1 crystal formation; Alpha-crystal form Dissolution of Tablet is obviously better than Form1 crystal formation tablet, and 24 months time, its related substances is also starkly lower than Form1 crystal formation tablet, illustrates that alpha-crystal form has preferably stability. More than illustrate that alpha-crystal form provided by the invention has good preparations shaping performance, and have good stripping property and stability, be suitable for and prepare oral solid formulation.
Claims (3)
1. a preparation method for Gefitinib crystal formation, is characterized in that, the method comprises following steps:
(a), Gefitinib is added in intensive polar solvent and dissolved;
(b), in solution, add the anti-solvent that polarity is less, crystallization;
(c), filter, dry, obtain off-white color solid, the intensive polar solvent in step (a) is selected from N, N-dimethylOne or more in formamide, chloroform and acetonitrile, the anti-solvent in step (b) be t-butyl methyl ether with justHexane, with the mixed solvent of the ratio combination of 1:0.03～30, also adds work in step (a) in intensive polar solventProperty carbon decoloring and filter, described crystal formation has XRPD collection of illustrative plates as shown in Figure 1.
2. the preparation method of Gefitinib crystal formation as claimed in claim 1, is characterized in that controlling step (a)Temperature is 40～150 DEG C.
3. the preparation method of Gefitinib crystal formation as claimed in claim 1, is characterized in that controlling step (b)Temperature is-20～35 DEG C.
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| RU2577518C2 (en) * | 2014-06-02 | 2016-03-20 | Олег Ростиславович Михайлов | CRYSTALLINE ANHYDROUS γ-MODIFICATION OF 4-(3'-CHLOR-4'-FLUORANILINO)-7-METHOXY-6-(3-MORPHOLINOPROPOXY)QUINAZOLINE, METHOD FOR PRODUCING IT AND BASED PHARMACEUTICAL COMPOSITION |
| US10259805B2 (en) * | 2015-12-30 | 2019-04-16 | Synthon B.V. | Process for making crystalline form a of gefitinib |
| CN106083739B (en) * | 2016-05-31 | 2019-05-14 | 华南理工大学 | New gefitinib crystal form and its preparation method based on super-critical anti-solvent technology |
| CN110101668B (en) * | 2019-05-29 | 2021-09-07 | 华东理工大学 | Preparation method of gefitinib composite particles |
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