CN104649969A - Salts of gefitinib medicine and preparation method of salts - Google Patents

Salts of gefitinib medicine and preparation method of salts Download PDF

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Publication number
CN104649969A
CN104649969A CN201410676653.1A CN201410676653A CN104649969A CN 104649969 A CN104649969 A CN 104649969A CN 201410676653 A CN201410676653 A CN 201410676653A CN 104649969 A CN104649969 A CN 104649969A
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peak
ray powder
powder diffraction
diffraction pattern
hours
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CN104649969B (en
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沈安雄
唐冬军
寇景平
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Abstract

The invention relates to novel crystal forms of L-malate and hydrobromide of an anti-cancer drug N-(4-{[6,7-bis(methoxy)quinoline-4-yl] oxo} phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboamide and a preparation method of the novel crystal forms. Peaks are formed at the positions of 2theta being 9.33 degrees, 11.75 degrees, 13.44 degrees, 15.16 degrees, 19.72 degrees, 23.14 degrees and 25.92 degrees in an X-ray powder diffraction pattern of the novel crystal form of the malate; and peaks are formed at the positions of 2theta being 8.68 degrees, 13.01 degrees, 17.45 degrees, 19.52 degrees, 20.05 degrees, 21.71 degrees, 23.29 degrees and 26.28 degrees in the X-ray powder diffraction pattern of the novel crystal form of the hydrobromide. The novel crystal forms have relatively good physical and chemical properties, are beneficial to operation in production and can be applied to a pharmaceutical preparation.

Description

A kind of salt for Buddhist nun's class medicine and preparation method thereof
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of salt, crystal formation and preparation method thereof for Buddhist nun's class medicine.
Background technology
Cabozantinib (its Chinese name is translated into card cloth for Buddhist nun by the present invention), chemistry N-(4-{ [6 by name, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide, its structure is such as formula shown in (01), and the structure of its L MALIC ACID salt is such as formula shown in (I); In November, 2012, U.S. FDA approval card cloth is used for the treatment of Progressive symmetric erythrokeratodermia metastatic medullary thyroid carcinoma (MTC) for Buddhist nun's L MALIC ACID salt:
PCT application WO2005030140 discloses card cloth and has the active function regulating signal transduction of kinases for the preparation method of Buddhist nun and its; The different crystal forms of card cloth for Buddhist nun's malate is disclosed in China application CN201080012656.5, cue card cloth is poor for the solvability of Buddhist nun, card cloth has different physico-chemical property for the different salt of Buddhist nun, card cloth, has better for the preparation of the character of pharmaceutical composition relative to other salt enumerated for Buddhist nun's malate.Because of the common phenomenon that polymorph in pharmaceuticals is in drug research and development, it is the important factor affecting drug quality.The different crystal forms of same medicine may have remarkable difference in outward appearance, mobility, solubleness, stability in storage etc., can shift, apply, stability, bioavailability, curative effect etc. produce different impacts on the storage of medicine; Huge difference may be there is in the physico-chemical property etc. of different salt and/or crystal formation; In order to obtain more effective salt and/or crystal formation, still need to replace the salt of Buddhist nun and Ka Bu comprehensively to investigate for the crystallization behavior of Buddhist nun's malate, to be met favourable salt and/or the crystal formation of the production requirements such as preparation to card cloth.
Summary of the invention
Summary of the invention
First aspect present invention provides the crystal form A 1, A2 of card cloth for Buddhist nun's malate.
Second aspect present invention provides the hydrobromate of card cloth for Buddhist nun.
Third aspect present invention provides card cloth and replaces the new crystal that Buddhist nun's hydrobromate is substantially pure, called after crystal formation I of the present invention.
Fourth aspect present invention provides described card cloth replaces Buddhist nun's hydrobromate and hydrobromate crystal formation I preparation method for Buddhist nun's malate crystal form A 1, A2 and card cloth.
Term definition
" crystal formation " refers to ordered arrangement and/or the conformation of the uniqueness of the molecule of compound in lattice.
" substantially pure " refers to that a kind of crystal formation is substantially free of another or multiple crystal formation, the i.e. purity at least 60% of crystal formation, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or containing other crystal formation in crystal formation, the per-cent of other crystal formation described in the cumulative volume or gross weight of crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 3%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
" be substantially free of " one or more other crystal formations and refer to that the per-cent of other crystal formation in the cumulative volume or gross weight of crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 4%, or be less than 3%, or be less than 2%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.
X-ray powder diffraction " substantially as shown in the figure " refers in X-ray powder diffraction pattern to have 50% at least, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or the peak display of at least 99% is in the drawings.
When " relative intensity " refers to that the intensity at the last the first peak in all diffraction peaks of X-ray powder diffraction pattern (XRPD) is 100%, the ratio of the intensity at the intensity at other peak and the last the first peak.
When mentioning spectrogram or/and when there are data in the drawings, " peak " refers to the feature that can not belong to background noise that those skilled in the art can identify.
In the present invention, 2 θ values in X-ray powder diffraction pattern are all to spend (°) for unit.
In the present invention, the X-ray powder diffraction (XRPD) of described crystal formation, 2 θ of its X-ray powder diffraction or diffraction peak measured experimental error, between a machine and another machine and between a sample and another sample, measuring of 2 θ of X-ray powder diffraction or diffraction peak may slightly difference, the numerical value of described experimental error or difference may be +/-0.2 unit or +/-0.1 unit, and therefore the numerical value of described 2 θ or diffraction peak can not be considered as absolute.
In the present invention, the means of differential scanning calorimetry figure (DSC) of described crystal formation has experimental error, between a machine and another machine and between a sample and another sample, the position of endotherm(ic)peak and peak value may slightly difference, the numerical value of experimental error or difference may be +/-5 units, +/-4 units, +/-3 units, +/-2 units, +/-1 unit, +/-0.5 unit, or +/-0.1 unit, therefore the peak position of described DSC endotherm(ic)peak or the numerical value of peak value can not be considered as absolute.
In the present invention, the thermogravimetric analysis (TGA) of described crystal formation has experimental error, between a machine and another machine and between a sample and another sample, weightless temperature and weightless amount may slightly difference, the numerical value of experimental error or difference may be +/-0.2 unit or +/-0.1 unit, and therefore the numerical value of described weightless temperature and weightless amount can not be considered as absolute.
Detailed Description Of The Invention
First aspect, contriver is by having researched and developed the crystal form A 1, A2 of card cloth for Buddhist nun's malate.
Card cloth, for the crystal form A 1 of Buddhist nun's malate, has following characteristic: there is peak the position being 13.47 degree at 2 θ in its X-ray powder diffraction pattern.
In some embodiments, be 13.47,15.23 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 1 of Buddhist nun's malate, there is peak the position of 26.10 degree.
In some embodiments, be 9.44,13.47 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 1 of Buddhist nun's malate, there is peak the position of 15.23,22.79,26.10,27.08 degree.
In some embodiments, be 9.44,10.99 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 1 of Buddhist nun's malate, 11.79,13.47,15.23,18.94,19.72,21.12,22.79,23.37, there is peak the many places, position of 26.10,27.08 degree.
In some embodiments, be 6.70,7.79,9.44,10.99,11.79 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 1 of Buddhist nun's malate, 13.47,15.23,17.30,18.94,19.72,21.12,22.79,23.37,26.10, there is peak the many places of the position of 27.08 degree.
Substantially as shown in Figure 1, wherein diffraction angle 2 θ is that the relative intensity at the peak of 13.47 degree is greater than 50% to the X-ray powder diffraction pattern of crystal form A 1, or is greater than 60%, or be greater than 70%, or be greater than 80%, or be greater than 90%, or be greater than 99%, or be 100%.
The means of differential scanning calorimetry of crystal form A 1 measures (DSC) and has endotherm(ic)peak at 120 DEG C-130 DEG C places and 170 DEG C of-180 DEG C of places; In certain embodiments, its endotherm(ic)peak summit value is respectively at 127 DEG C and 176 DEG C; In certain embodiments, its DSC as shown in Figure 2.
The thermogravimetric analysis (TGA) of crystal form A 1 has weightlessness, weightless 4%-5% between 35 DEG C-130 DEG C; In certain embodiments, its TGA as shown in Figure 3, weightless 4.85%.
Crystal form A 1 is dry for a long time through high temperature, can obtain crystal form A 2.
Card cloth, for the crystal form A 2 of Buddhist nun's malate, has following characteristic: there is peak the position being 13.44 degree at 2 θ in its X-ray powder diffraction pattern.
In some embodiments, be 13.44,15.16 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 2 of Buddhist nun's malate, there is peak the position of 25.92 degree.
In some embodiments, be 9.33,13.44 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 2 of Buddhist nun's malate, 15.16,19.72, there is peak the position of 25.92 degree.
In some embodiments, be 9.33,11.75 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 2 of Buddhist nun's malate, 13.44,15.16,19.72,23.14, there is peak the position of 25.92 degree.
In some embodiments, be 6.70,7.73,9.33,10.97 at 2 θ in the X-ray powder diffraction pattern of card cloth for the crystal form A 2 of Buddhist nun's malate, 11.75,13.44,15.16,17.27,18.86,19.72,20.97,23.14,25.92, there is peak the many places of the position of 26.90 degree.
In certain embodiments, in the X-ray powder diffraction pattern of crystal form A 2, diffraction angle 2 θ is that the relative intensity at the peak of 13.44 degree is greater than 50%, or is greater than 60%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.
In certain embodiments, substantially as shown in Figure 4, wherein diffraction angle 2 θ is that the relative intensity at the peak of 13.44 degree is greater than 80% to the X-ray powder diffraction pattern of crystal form A 2, or is greater than 90%, or is greater than 99%.
Crystal form A 2 has the XRPD figure substantially identical with crystal form A 1, but its means of differential scanning calorimetry mensuration (DSC) only has endotherm(ic)peak at 120 DEG C of-130 DEG C of places; In certain embodiments, its endotherm(ic)peak summit value is at 123.8 DEG C; In certain embodiments, its DSC as shown in Figure 5.
Detect immediately after 105 DEG C, crystal form A 2 sample is dried to constant weight, its water content is 1.4%, for a part card cloth replaces the crystallization of Buddhist nun's malate and 0.5 molecular water; Crystal form A 2 sample is placed in air, has water absorbability; In some cases, detect its thermogravimetric analysis (TGA) after placing in air and between 35 DEG C-150 DEG C, have weightlessness, weightless 1.5%-2.5%; In some cases, its TGA as shown in Figure 6, weightless 2.39%.
Second aspect, the invention provides the hydrobromate of card cloth for Buddhist nun, its structure is such as formula shown in (2); Card cloth has identical free base with card cloth for Buddhist nun's malate for Buddhist nun's hydrobromate, and have equally and suppress generation that is multiple and tumour, progress, shifts the effect of relevant kinase whose activity,
The third aspect, the invention provides card cloth and replaces the new crystal that Buddhist nun's hydrobromate is substantially pure, called after crystal formation I of the present invention.Card cloth, for the substantially pure crystal formation I of Buddhist nun's hydrobromate, has following characteristic: there is peak the position being 23.29 degree at 2 θ in its X-ray powder diffraction pattern.
In some embodiments, be 13.01,17.45 at 2 θ in the X-ray powder diffraction pattern of card cloth for the substantially pure crystal formation I of Buddhist nun's hydrobromate, there is peak the position of 23.29,26.28 degree.
In some embodiments, be 8.68,13.01 at 2 θ in the X-ray powder diffraction pattern of card cloth for the substantially pure crystal formation I of Buddhist nun's hydrobromate, 17.45,19.52,20.05,21.71, there is peak the position of 23.29,26.28 degree.
In some embodiments, be 8.68,12.17 at 2 θ in the X-ray powder diffraction pattern of card cloth for the substantially pure crystal formation I of Buddhist nun's hydrobromate, 13.01,16.71,17.45,19.52,20.05,21.71,23.29,23.86,24.52,26.28,27.49,29.95, there is peak the many places of the position of 32.13 degree.
In some embodiments, be 6.48,8.68,9.33,11.89 at 2 θ in the X-ray powder diffraction pattern of card cloth for the substantially pure crystal formation I of Buddhist nun's hydrobromate, 12.17,13.01,13.55,16.28,16.71,17.45,19.13,19.52,20.05,20.68,21.71,23.29,23.53,23.86,24.52,25.22,26.28,27.49,27.81, there is peak the many places of the position of 29.95,31.00,32.13,32.85 degree.
In some embodiments, be 6.48,8.68,9.33 at 2 θ in the X-ray powder diffraction pattern of card cloth for the substantially pure crystal formation I of Buddhist nun's hydrobromate, 11.89,12.17,13.01,13.55,16.28,16.71,17.45,19.13,19.52,20.05,20.68,21.25,21.71,22.47,22.64,23.29,23.53,23.86,24.52,25.22,25.45,26.28,27.21,27.49,27.81,29.69,29.95,30.25,30.76,31.00,31.36,32.13, there is peak the many places of the position of 32.85 degree.
In certain embodiments, in the X-ray powder diffraction pattern of substantially pure crystal formation I, diffraction angle 2 θ is that the relative intensity at the peak of 23.29 degree is greater than 50%, or is greater than 60%, or is greater than 70%, or is greater than 80%, or is greater than 90%, or is greater than 99%.
In certain embodiments, substantially as shown in Figure 7, wherein diffraction angle 2 θ is that the relative intensity at the peak of 23.29 degree is greater than 99% to the X-ray powder diffraction pattern of substantially pure crystal formation I.
Substantially pure crystal formation I can also otherwise characterize, and such as, in certain embodiments, its means of differential scanning calorimetry measures (DSC) and has endotherm(ic)peak at 215 DEG C of-240 DEG C of places; In certain embodiments, its means of differential scanning calorimetry mensuration (DSC) has endotherm(ic)peak at 220 DEG C of-235 DEG C of places; In certain embodiments, its endotherm(ic)peak summit value is at 235 DEG C; In certain embodiments, its DSC as shown in Figure 8.
Substantially pure crystal formation I can also otherwise characterize, and such as, in certain embodiments, its thermogravimetric analysis (TGA) has weightlessness between 40 DEG C-150 DEG C, and weightless 0.75%; In certain embodiments, its TGA as shown in Figure 9.
Substantially pure crystal formation I can also otherwise characterize, and such as, in certain embodiments, use karl-Fischer method (KF method) to measure its moisture content, water content is 0.81%.
Fourth aspect, present invention also offers described card cloth replaces Buddhist nun's hydrobromate and hydrobromate crystal formation I preparation method for Buddhist nun's malate crystal formation and card cloth.
One prepares card cloth for Buddhist nun's malate crystal form A 1 or A2, or the method for hydrobromate and crystal formation I thereof, and it carries out recrystallization with ethanol/water mixed solvent.
Card cloth comprises for the preparation method of Buddhist nun's malate crystal form A 1, A2: card cloth is heated to temperature T1 for Buddhist nun and aqueous ethanolic solution, adds L MALIC ACID, reacting by heating for some time; Then be slow cooling to temperature T2 and separate out solid; Stirring and crystallizing, removes solvent, collects solid; Gained solid is dry at a certain temperature, obtains crystal.
Card cloth comprises for the preparation method of Buddhist nun's hydrobromate: card cloth is heated to temperature T1 for Buddhist nun and aqueous ethanolic solution, adds Hydrogen bromide, reacting by heating for some time; Then be slow cooling to temperature T2 and separate out solid; Stirring and crystallizing, removes solvent, collects solid; Gained solid is dry at a certain temperature, obtains crystal.
Described temperature T1 be 50 DEG C to solvent reflux temperature, in some embodiments, described temperature T1 is 50 DEG C-80 DEG C; In some embodiments, described temperature T1 is 55 DEG C-70 DEG C.
The time of described reacting by heating is 0.5 hour-3 hours; In some embodiments, the described reaction times is 0.5 hour-1.5 hours.
Described slow cooling refers to, within for some time, system temperature is reduced to precipitation solid; In some embodiments, in 0.1 hour-4 hours, system temperature is reduced to precipitation solid; In some embodiments, in 0.5 hour-2 hours, system temperature is reduced to precipitation solid.
The temperature T2 of described precipitation solid is 30 DEG C-60 DEG C; In some embodiments, temperature T2 is 30 DEG C-50 DEG C; In some embodiments, temperature T2 is 30 DEG C-40 DEG C.
The temperature of described stirring and crystallizing is-10 DEG C-10 DEG C; In some embodiments, the temperature of described stirring and crystallizing is-5 DEG C-5 DEG C; In some embodiments, described stirring and crystallizing temperature is 0 DEG C.
The time of described stirring and crystallizing is 0.5 hour-3 hours; In some embodiments, the time of described stirring and crystallizing is 1 hour-2 hours.
When preparing card cloth for the crystal of Buddhist nun's malate, in described aqueous ethanolic solution, the content of ethanol is no more than 85% (volume ratio); In some embodiments, in described aqueous ethanolic solution, the content of ethanol is no more than 80% (volume ratio).
When preparing card cloth for the crystal of Buddhist nun's hydrobromate, in described aqueous ethanolic solution, the content of ethanol is no more than 95% (volume ratio); In some embodiments, in described aqueous ethanolic solution, the content of ethanol is no more than 90% (volume ratio).
Described drying temperature is 65 DEG C, and time of drying is 24 constantly little, obtains crystal form A 1.
Described drying temperature is 90 DEG C or 105 DEG C, is dried to constant weight, obtains crystal form A 2; In some embodiments, time of drying is 24 or 48 hours.
Described drying temperature is 65 DEG C, and time of drying is 24 hours, obtains crystal formation I.
In some embodiments, the method preparing crystal form A 2 comprises: card cloth is for Buddhist nun, i.e. N-(4-{ [6, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide, be heated to 50 DEG C-80 DEG C with aqueous ethanolic solution, add L MALIC ACID, reacting by heating 0.5 hour-1.5 hours; Then in 0.5 hour-2 hours, cool to 30 DEG C-40 DEG C separate out solid; Then-5 DEG C of-5 DEG C of stirring and crystallizing 1 hour-2 hours; Remove solvent, collect solid; Gained solid is dried to constant weight 90 DEG C or 105 DEG C, obtains A2 crystal.
In some embodiments, the method preparing hydrobromate crystal formation I comprises: card cloth is for Buddhist nun, i.e. N-(4-{ [6, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide, be heated to 50 DEG C-80 DEG C with aqueous ethanolic solution, add Hydrogen bromide, reacting by heating 0.5 hour-1.5 hours; Then in 0.5 hour-2 hours, cool to 30 DEG C-40 DEG C separate out solid; Then-5 DEG C of-5 DEG C of stirring and crystallizing 1 hour-2 hours; Remove solvent, collect solid; Gained solid, 65 DEG C of dryings 24 hours, obtains I crystal.
Card cloth of the present invention replaces the crystal form A 2 of Buddhist nun's malate and Ka Bu to replace the crystal formation I of Buddhist nun's hydrobromate to have good performance in stability, solvability, mobility or bioavailability etc., be conducive to operation in storage, production technique, be conducive to for the preparation of the various salt of one-tenth, for the preparation of the medicine of the diseases such as treatment Progressive symmetric erythrokeratodermia metastatic medullary thyroid carcinoma.
Card cloth of the present invention replaces the crystal form A 2 of Buddhist nun's malate and Ka Bu to replace the crystal formation I of Buddhist nun's hydrobromate can mix with the pharmaceutically acceptable inert excipient of at least one or carrier, is prepared into the various solid dosages of oral medicine, comprises capsule, tablet etc.; Solid dispersion etc. can also be prepared into various vehicle or carrier, then be prepared into various solid preparation.
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diffraction pattern (XRPD) of card cloth for the crystal form A 1 of Buddhist nun's malate;
Fig. 2 shows the DSC figure of card cloth for the crystal form A 1 of Buddhist nun's malate;
Fig. 3 shows the TGA figure of card cloth for the crystal form A 1 of Buddhist nun's malate;
Fig. 4 shows the X-ray powder diffraction pattern of card cloth for the crystal form A 2 of Buddhist nun's malate;
Fig. 5 shows the DSC figure of card cloth for the crystal form A 2 of Buddhist nun's malate;
Fig. 6 shows the TGA figure of card cloth for the crystal form A 2 of Buddhist nun's malate;
Fig. 7 shows the X-ray powder diffraction pattern of card cloth for the crystal formation I of Buddhist nun's hydrobromate;
Fig. 8 shows the DSC figure of card cloth for the crystal formation I of Buddhist nun's hydrobromate;
Fig. 9 shows the TGA figure of card cloth for the crystal formation I of Buddhist nun's hydrobromate.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, mmol represents mmole, and h represents hour, and g represents gram, and mL represents milliliter.
In the present invention, X-ray powder diffraction testing conditions is: Cu target k α, wavelength in X-ray powder diffraction pattern, ordinate zou is the diffracted intensity represented with counting (counts), and X-coordinate is diffraction angle 2 θ (2Theta) that expenditure (°) represents.
The testing conditions of means of differential scanning calorimetry mensuration (DSC) of crystal form A 1 is under nitrogen atmosphere, and with 10 DEG C/min of intensifications, temperature range is 40 DEG C-300 DEG C.
The testing conditions of means of differential scanning calorimetry mensuration (DSC) of crystal form A 2 is under nitrogen atmosphere, and with 10 DEG C/min of intensifications, temperature range is 25 DEG C-300 DEG C.
The testing conditions of means of differential scanning calorimetry mensuration (DSC) of crystal formation I is under nitrogen atmosphere, and with 10 DEG C/min of intensifications, temperature range is 25 DEG C-300 DEG C.
Thermogravimetric analysis (TGA) testing conditions is under nitrogen atmosphere, and with 10 DEG C/min of intensifications, temperature range is room temperature to 300 DEG C.
The condition that karl-Fischer method (KF method) measures moisture content is: instrument and reagent: moisture content tester, 100,000/balance, karl Fischer titrating solution (5mg/mL), anhydrous methanol (analytical pure); Measuring method: demarcate karl Fischer titrating solution concentration: after the pre-titration of instrument completes, ultrapure water about 10 μ L (being equivalent to 10 μ L standard water sample) is got with microsyringe, precise weighing, rapid injection titration cup, input weight (g), starts to demarcate, demarcates three parts continuously, average and relative standard deviation (RSD, must not more than 1.0%); Sample moisture determination: pump into appropriate anhydrous methanol in titration cup, flood electrode (about 50mL), get trial-product and be about 0.2g, precise weighing, in titration cup, is stirred to dissolve, and measures moisture according to aquametry; Parallel running two parts take mean value as moisture content result.
Embodiment 1
4.00g card cloth mixes with the ethanol of 60mL 70% (volume ratio) for Buddhist nun, be heated to 75 DEG C, add 70% aqueous ethanolic solution (volume ratio) that 20mL contains 1.6g L MALIC ACID, after dripping off, add the ethanol of 20mL 70%, heating, reflux 1 hour, be slow cooling to 40 DEG C in 1 hour and separate out solid, then cool to 0 DEG C of insulated and stirred 2 hours, filter, gained solid 65 DEG C of vacuum-dryings 24 hours, obtain 3.71g solid; Detecting XRPD, DSC, TGA, is crystal form A 1; Gained crystal form A 1 is continued dry 24 hours at 105 DEG C, obtains crystal form A 2.
Embodiment 2
4.00g card cloth mixes for the ethanol 60mL of Buddhist nun and 75% (volume ratio), is heated to 75 DEG C, clearly molten, adds the aqueous ethanolic solution that 20mL contains 75% (volume ratio) of 1.6g L MALIC ACID, and heating, refluxes 1 hour; Be slow cooling to 38 DEG C in 1.5 hours, separate out solid; Cool to 0 DEG C of insulated and stirred 2 hours again, filter, 105 DEG C of dryings 24 hours, obtain 3.77g solid, and detecting XRPD, DSC, TGA, is crystal form A 2.
Embodiment 3
4.00g card cloth mixes with the ethanol of 100mL 80% (volume ratio) for Buddhist nun, be heated to 80 DEG C, add the aqueous ethanolic solution of 80% (volume ratio) containing 1.6g L MALIC ACID, reflux 1 hour, be slow cooling to 38 DEG C in 1.5 hours and separate out solid, then cool to 0 DEG C of insulated and stirred 2 hours, filter, gained solid 105 DEG C of vacuum-dryings 24 hours, obtain 3.78g solid; Detecting XRPD, DSC, TGA, is crystal form A 2.
Embodiment 4
4.00g card cloth mixes with the ethanol of 100mL 60% (volume ratio) for Buddhist nun, be heated to 80 DEG C, add the aqueous ethanolic solution of 60% (volume ratio) containing 1.6g L MALIC ACID, reflux 1.5 hours, be slow cooling to 35 DEG C in 1.5 hours and separate out solid, then cool to-5 DEG C of-0 DEG C of insulated and stirred 2.5 hours, filter, gained solid 90 DEG C of vacuum-dryings 48 hours, obtain 3.75g solid; Detecting XRPD, DSC, TGA, is crystal form A 2.
Embodiment 5
5.00g card cloth mixes for the ethanol 75mL of Buddhist nun and 95% (volume ratio), be heated to 78 DEG C, add the hydrobromic acid aqueous solution 3.00g of 40%, add rear solid clearly molten, reflux 0.5 hour, be slow cooling to 40 DEG C in 2 hours and separate out solid, then cool to 30 DEG C, add 25mL water, cool to 0 DEG C of insulated and stirred 2 hours again, filter, 65 DEG C of vacuum-dryings, obtain 5.05g solid; Detect XRPD, DSC, TGA, for crystal formation I, KF method detects moisture 0.81%.
Embodiment 6 solubleness is tested
Add enough each crystal form samples in 1.5mL centrifuge tube, 37 DEG C of water-baths, jolting 24 hours, is then cooled to 25 DEG C, constant temperature 4 hours, then centrifugal 5 minutes, and get supernatant liquor dilution, high performance liquid phase detects; The solubility results recording each crystal formation is as follows:
Crystal form samples Solubleness (ug/mL)
Crystal form A 1 2.82
Crystal form A 2 43.58
Crystal formation N-1 10.58
Hydrobromate crystal formation I 3.04
Crystal formation N-1 refers to N-1 crystal formation disclosed in patent application CN201080012656.5.
Embodiment 7 stability test
By crystal form A 2 and the monolayer polyethylene bag tying encapsulation of hydrobromate crystal formation I sample, room temperature is placed X-ray powder diffraction after 3 months and is detected, and finds that crystal formation is unchanged.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.

Claims (10)

  1. The crystal form A 2 of 1.N-(4-{ [6,7-two (methoxyl group) quinolyl-4] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide L MALIC ACID salt; Be 9.33,11.75 at 2 θ in the X-ray powder diffraction pattern of described crystal form A 2,13.44,15.16,19.72,23.14, there is peak the position of 25.92 degree.
  2. 2. crystal form A 2 according to claim 1 is 6.70,7.73 at 2 θ in its X-ray powder diffraction pattern, 9.33,10.97,11.75,13.44,15.16,17.27,18.86,19.72, and there is peak the position of 20.97,23.14,25.92,26.90 degree; Or its X-ray powder diffraction pattern substantially as shown in Figure 1, wherein diffraction angle 2 θ is that the relative intensity at the peak of 13.44 degree is greater than 80%.
  3. 3.N-(4-{ [6, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1, the crystal formation I of 1-diformamide hydrobromate is 8.68,13.01 at 2 θ in its X-ray powder diffraction pattern, 17.45,19.52,20.05,21.71, there is peak the position of 23.29,26.28 degree.
  4. 4. crystal formation I according to claim 3 is 8.68,12.17 at 2 θ in its X-ray powder diffraction pattern, 13.01,16.71,17.45,19.52,20.05,21.71,23.29,23.86,24.52,26.28,27.49,29.95, and there is peak the position of 32.13 degree; Or be 6.48,8.68,9.33,11.89,12.17 at 2 θ in its X-ray powder diffraction pattern, 13.01,13.55,16.28,16.71,17.45,19.13,19.52,20.05,20.68,21.71,23.29,23.53,23.86,24.52,25.22,26.28,27.49,27.81, there is peak the position of 29.95,31.00,32.13,32.85 degree; Or be 6.48,8.68,9.33,11.89,12.17,13.01 at 2 θ in its X-ray powder diffraction pattern, 13.55,16.28,16.71,17.45,19.13,19.52,20.05,20.68,21.25,21.71,22.47,22.64,23.29,23.53,23.86,24.52,25.22,25.45,26.28,27.21,27.49,27.81,29.69,29.95,30.25,30.76,31.00,31.36, there is peak the position of 32.13,32.85 degree; Or its X-ray powder diffraction pattern substantially as shown in Figure 7, wherein diffraction angle 2 θ is that the relative intensity at the peak of 23.29 degree is greater than 99%.
  5. 5. the preparation method of the crystal form A 2 described in claim 1 or 2, comprise: N-(4-{ [6, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide and aqueous ethanolic solution are heated to 50 DEG C-80 DEG C, add L MALIC ACID, reacting by heating 0.5 hour-1.5 hours; Then cool to 30 DEG C-40 DEG C in 0.5 hour-2 hours and separate out solid; Then-5 DEG C of-5 DEG C of stirring and crystallizing 1 hour-2 hours, remove solvent, collect solid; Gained solid is dry at a certain temperature, obtains crystal.
  6. 6. preparation method according to claim 5, gained solid is 90 DEG C or 105 DEG C of dryings.
  7. 7. preparation method according to claim 5, in described aqueous ethanolic solution, the content of ethanol is no more than 85%.
  8. 8. the preparation method of the crystal formation I described in claim 3 or 4, comprise: N-(4-{ [6, two (methoxyl group) quinolyl-4 of 7-] oxygen base } phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-diformamide and aqueous ethanolic solution are heated to 50 DEG C-80 DEG C, add Hydrogen bromide, reacting by heating; Then cool to 30 DEG C-40 DEG C in 0.5 hour-2 hours and separate out solid; Then-5 DEG C of-5 DEG C of stirring and crystallizing 1 hour-2 hours, remove solvent, collect solid; Gained solid is dry at a certain temperature, obtains crystal.
  9. 9. preparation method according to claim 8, gained solid was 65 DEG C of dryings 24 hours.
  10. 10. preparation method according to claim 8, in described aqueous ethanolic solution, the content of ethanol is no more than 95%.
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US11814356B1 (en) 2023-03-29 2023-11-14 Apotex Inc. Salt of cabozantinib

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