CN106986868A - Eutectic comprising Eliquis and preparation method thereof - Google Patents
Eutectic comprising Eliquis and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
- C07C273/14—Separation; Purification; Stabilisation; Use of additives
- C07C273/16—Separation; Purification
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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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
Invention broadly provides four kinds comprising Eliquis eutectics and its preparation method, belong to pharmaceutical chemistry technical field.Four kinds of eutectics are respectively Eliquis/oxalic acid, Eliquis/nicotimine, the aminopyridine of Eliquis/3 and Eliquis/urea, correspond to eutectic I, eutectic II, eutectic III and eutectic IV；Four kinds of eutectics are free of solvent or the crystallization water, suitable for being prepared into its oral formulations.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, and in particular to eutectic of Eliquis and preparation method thereof.
Background technology
Eliquis is a kind of direct Xa factor inhibitor of new oral, and chemical formula is 1- (4- methoxyphenyls) -7- oxygen
Generation -6- [4- (2- oxo-piperidine -1- bases) phenyl] -4,5,6,7- tetrahydrochysene -1H- pyrazolos [3,4-c] pyridine-3-carboxamides, be
The anticoagulant that Bristol Myers Squibb and Pfizer research and develop jointly, directly acts on factor Xa, includes deeply for treating
Vein including phlebothrombosis (deep venous thrombosis, DVT) and pulmonary embolism (pulmonary embolism, PE)
Thrombus disease.In May, 2011, European Union ratifies direct inhibitor Eliquis (trade name Eliquis) listing of oral Xa factor, uses
In the adult patients of select a time hip joint or replacement knee in arthroplasty, to prevent venous thronbosis (venous
Thrombembolic events, VTE).Shown in Eliquis structure such as following formula (1)：
Eliquis is water insoluble, haves the shortcomings that dissolution velocity is slow, dissolution in vitro is low, bioavilability is low, to medicine
The absorption of thing has a certain impact.So the method for seeking to improve Eliquis dissolution rate is extremely urgent.To solve this problem,
Patent CN102770126, CN102908324 and CN103830199 etc. provide a variety of crystal formations of Eliquis, but these are invented
There are problems that time-consuming, energy consumption consumes big, low production efficiency and product yield in industrialized production.
The content of the invention
Summary of the invention
The invention mainly relates to the eutectic that Eliquis and predetermined substance are formed together.With their free form ratio
Compared with specific Eliquis eutectic is favourable, because the form of this eutectic enables to the dissolution rate of Eliquis
It is improved to some extent, preferably solves that Eliquis dissolution velocity is slow, dissolution in vitro is low, bioavilability is low lacks
Point.
First aspect present invention provides four kinds of eutectics for including Eliquis, respectively Eliquis/oxalic acid eutectic
Body, Eliquis/nicotimine eutectic, Eliquis/3- aminopyridine eutectics, Eliquis/urea eutectic, correspondence claims
For eutectic I, eutectic II, eutectic III and eutectic IV.
Second aspect of the present invention provides eutectiferous preparation method of four kinds of Eliquis, i.e. Eliquis/grass
Sour eutectic I, Eliquis/nicotimine eutectic II, Eliquis/3- aminopyridine eutectic III and Eliquis/urea
Eutectic IV preparation method.
Term is defined
The invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in as claim is fixed
In the scope of the invention of justice.Those skilled in the art will appreciate that many and similar or equivalent method described herein and material
It can be used in the practice present invention.The present invention is not limited to method described herein and material.In the document combined, patent and class
One or more or contradict in the case of (include but is not limited to defined in term, terms different from the application like material
Using, described technology etc.), it is defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, carried out in multiple independent embodiments
Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity,
It is described in single embodiment, but it is also possible to individually or with any appropriate sub-portfolio provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element with
Periodic table of elements CAS editions, and 1994 the 75th edition《Handbook of Chemistry and Physics》Unanimously.In addition, organic chemistry General Principle can join
Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999,
With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John
Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
Term "comprising" or " comprising " are open language, i.e., including the content specified by the present invention, but be not precluded from it
Content in terms of him.
Term " eutectic " refers to the phase composition by two or more；Mutually refer to composition, crystal structure, performance all phases
Same thing.
Term " substantially as shown in the figure " refers in certain essentially pure " crystal formation " its X-ray powder diffraction figure extremely
Few 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% peak
Appear in given X-ray powder diffraction figure.When the content of the crystal formation of certain in sample is gradually reduced, its X-ray powder
Some diffraction maximums for belonging to the crystal formation in last diffraction pattern may be tailed off due to the factor of the detection sensitivity of instrument.
Term " relative intensity " refers to the strength definition at the last the first peak in one group of diffraction maximum for belonging to a certain crystal formation
For 100% when, the ratio of the intensity at other peaks and the intensity at the last the first peak.
In the context of the present invention, in X-ray powder diffraction figure 2 θ (also known as 2theta or diffraction maximum) value is with degree
(°) is unit.
When referring to data in collection of illustrative plates and/or figure, term " diffraction maximum " refers to that those skilled in the art will not belong to the back of the body
One feature of scape noise.
The X-ray powder diffraction peak of the crystal, 2 θ of its X-ray powder diffraction collection or diffraction maximum have measured reality
Error is tested, between a machine and another machine and between a sample and another sample, X-ray powder diffraction
2 θ of collection of illustrative plates or measuring for diffraction maximum may slightly have difference, and the numerical value of the experimental error or difference is probably +/- 0.2 list
Position or +/- 0.1 unit or +/- 0.05 unit, therefore 2 θ or the numerical value of diffraction maximum can not be considered as it is absolute.
The differential scanning calorimetric curve (DSC) of the crystal has experimental error, between a machine and another machine
And between a sample and another sample, the position of endothermic peak and peak value may slightly have difference, experimental error or difference
Numerical value be likely less than equal to 5 DEG C, or less than or equal to 4 DEG C, or less than or equal to 3 DEG C, or less than or equal to 2 DEG C, or less than or equal to 1
DEG C, thus the peak position of the DSC endothermic peaks or the numerical value of peak value can not be considered as it is absolute.
The thermal gravimetric analysis curve (TGA) of the crystal has experimental error, between a machine and another machine and
Between one sample and another sample, endothermic curve or weight-loss ratio may slightly have the numerical value of difference, experimental error or difference
It is likely less than equal to 0.004% or 0.003% or 0.002% or 0.001%, therefore the thermal gravimetric analysis curve or its weight-loss ratio
It can not be considered as absolute.
In the context of the present invention, regardless of whether using the wording, all numerals being disclosed that such as " about " or " about "
It is approximation.Each digital numerical value is possible to that the difference such as 1%, 2%, or 5% occurs.When with about describing that X- is penetrated
During 2 θ (the also known as 2theta or diffraction maximum) value at line powder diffraction peak, about represent the 2 θ values may have +/- 0.2 unit or
+/- 0.1 unit or +/- 0.05 unit difference.
" room temperature " refers to temperature at about 20 DEG C -35 DEG C or about 23 DEG C -28 DEG C or about 25 DEG C.
Term " good solvent " can be single solvent or mixed solvent, refer to Eliquis in the single solvent or mixed solvent
In solubility be more than 1g/L, or more than 2g/L, or more than 3g/L, or more than 4g/L, or more than 5g/L, or more than 6g/L, or
More than 7g/L, or more than 8g/L, or more than 9g/L, or more than 10g/L, or more than 15g/L, or more than 20g/L, or more than 30g/
L, or more than 40g/L, or more than 50g/L, or more than 60g/L, or more than 70g/L, or more than 80g/L, or more than 100g/L.
In some embodiments, solubility of the Eliquis in good solvent is bigger than poor solvent；In certain embodiments, good solvent and not
Good solvent be about to the difference of the solubility of Eliquis 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or
90%；In certain embodiments, good solvent is bigger than poor solvent to the solubility of Eliquis, more than 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80% or 90%.
Detailed description of the invention
In a first aspect, inventor is by having researched and developed four kinds of eutectics for including Eliquis, respectively Eliquis/
Oxalic acid eutectic, Eliquis/nicotimine eutectic, Eliquis/3- aminopyridines eutectic and Eliquis/urea are common
Crystal, correspondence is referred to as eutectic I, eutectic II, eutectic III and eutectic IV.
The eutectic I of Eliquis/oxalic acid, has the property that：It is about in 2 θ in its X-ray powder diffraction figure
7.770、9.138、15.707、17.030、18.813、19.921、20.612、21.459、23.533、24.851、25.463、
There is peak 27.232 degree of position.
In some embodiments, in eutectic I X-ray powder diffraction figure 2 θ be about 7.770,8.361,9.138,
9.876、12.691、13.348、14.267、14.815、15.707、17.030、18.813、19.921、20.612、21.459、
23.533rd, 24.851,25.463, one or more of 27.232 degree of position have peak.
In some embodiments, in eutectic I X-ray powder diffraction figure 2 θ be about 7.770,8.361,9.138,
9.876、12.691、13.348、14.267、14.815、15.707、17.030、18.813、19.921、20.612、21.081、
21.912、22.260、22.524、23.262、21.459、23.533、24.111、24.514、24.851、25.463、26.451、
26.889th, one or more of 27.232 degree of position have peak.
In some embodiments, in eutectic I X-ray powder diffraction figure 2 θ be about 7.770,8.361,9.138,
9.876、12.691、13.348、14.267、14.815、15.707、17.030、18.813、19.921、20.612、21.081、
21.912、22.260、22.524、23.262、21.459、23.533、24.111、24.514、24.851、25.463、26.451、
26.889、27.232、27.749、28.303、28.877、29.440、29.781、30.091、30.488、31.080、31.608
One or more of the position of degree have peak.
In some embodiments, in eutectic I X-ray powder diffraction figure 2 θ be about 7.770,8.361,9.139,
9.876、12.691、13.348、14.267、14.815、15.707、16.386、17.030、17.280、17.937、18.315、
18.546、18.813、19.921、20.282、20.612、21.081、21.459、21.912、22.260、22.524、23.262、
23.533、24.111、24.514、24.851、25.463、25.628、26.451、26.889、27.232、27.749、28.303、
28.877、29.440、29.781、30.091、30.488、31.080、31.608、31.968、32.302、32.748、33.210、
33.651st, 34.10,35.029,35.914,37.160, one or more of 37.920 degree of position have peak.
In some embodiments, eutectic I X-ray powder diffraction figure is as shown in figure 1, be about 19.92 in 2 θ wherein
The relative intensity at the peak of degree is more than 50%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
The eutectic I, also has the property that：Its differential scanning calorimetric curve (DSC) has at about 200 DEG C -204 DEG C
There is endothermic peak.In an embodiment, the eutectic I differential scanning calorimetric curves (DSC) are at about 200 DEG C -203 DEG C
With endothermic peak, endothermic peak summit value is about 202 DEG C.In some embodiments, the means of differential scanning calorimetry of the eutectic I is bent
Line (DSC) is as shown in Figure 2.
The eutectic I is non-hygroscopic, without recrystallisation solvent or the crystallization water, is non solvate or non-hydrate.At some
In embodiment, the thermal gravimetric analysis curve (TGA) of the eutectic I is as shown in Figure 3.
The eutectic I of the Eliquis is the powder with good appearance and mobility, in the side such as dissolution rate, mobility
Face has good performance, is conducive to storing, shifts, operating in production technology, suitable for being prepared into its oral formulations.
The eutectic II of Eliquis/nicotimine, has the property that：In 2 θ it is about in its X-ray powder diffraction figure
5.827th, 8.780,11.666,13.491,16.102,17.544,21.580,22.128,23.465,30.253 degree of position has
Peak.
In some embodiments, in eutectic II X-ray powder diffraction figure 2 θ be about 5.827,7.311,8.780,
11.666、13.491、15.720、16.102、17.544、17.891、18.819、21.580、22.128、23.465、30.253
One or more of the position of degree have peak.
In some embodiments, in eutectic II X-ray powder diffraction figure 2 θ be about 5.827,7.311,8.780,
11.666、13.491、15.720、16.102、17.544、17.891、18.819、19.179、19.850、20.271、20.515、
21.119th, 21.580,22.128,22.690,23.465,24.894, one or more of 30.253 degree of position have peak.
In some embodiments, in eutectic II X-ray powder diffraction figure 2 θ be about 5.827,7.311,8.780,
11.666、13.491、15.720、16.102、17.544、17.891、18.819、19.179、19.850、20.271、20.515、
21.119、21.580、22.128、22.690、23.465、24.894、25.667、26.470、28.650、29.480、30.253
One or more of the position of degree have peak.
In some embodiments, in eutectic II X-ray powder diffraction figure 2 θ be about 5.827,7.311,8.780,
11.666、13.491、15.720、16.102、17.544、17.891、18.819、19.179、19.850、20.271、20.515、
21.119、21.580、22.128、22.690、23.465、24.894、25.667、26.470、28.650、29.480、30.253、
30.957th, 33.221, one or more of 38.40 degree of position have peak.
In some embodiments, the X-ray powder diffraction figure of the eutectic II as shown in figure 4, wherein, be about in 2 θ
The relative intensity at 11.66 degree of peak is more than 50%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
The eutectic II of Eliquis/nicotimine, also has the property that：Its differential scanning calorimetric curve (DSC) is about
There is endothermic peak at 199 DEG C -204 DEG C.In an embodiment, eutectic II differential scanning calorimetric curves (DSC) are about
There is endothermic peak, endothermic peak summit value is about 203 DEG C at 199 DEG C -204 DEG C.In some embodiments, eutectic II differential
Scanning calorimetric curve (DSC) is as shown in Figure 5.
The eutectic II is non-hygroscopic, without recrystallisation solvent or the crystallization water, is non solvate or non-hydrate.At some
In embodiment, the thermal gravimetric analysis curve (TGA) of the eutectic II is as shown in Figure 6.
The eutectic II of the Eliquis is the powder with good fluidity, is had in terms of dissolution rate, mobility
There is good performance, be conducive to storing, shift, operating in production technology, suitable for being prepared into its oral formulations.
The eutectic III of Eliquis/3- aminopyridines, has the property that：In 2 θ in its X-ray powder diffraction figure
It is about 5.792,11.578,13.418,17.865,18.697,20.083,23.501,24.652,30.032 degree of position has
Peak.
In some embodiments, in eutectic III X-ray powder diffraction figure 2 θ be about 5.792,7.350,
8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、17.865、18.697、
20.083rd, 23.501,24.652, one or more of 30.032 degree of position have peak.
In some embodiments, in eutectic III X-ray powder diffraction figure 2 θ be about 5.792,7.350,
8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、17.865、18.697、
19.50、20.083、20.651、21.549、22.190、23.501、24.652、25.173、25.794、26.161、26.623、
One or more of 30.032 degree of position have peak.
In some embodiments, in eutectic III X-ray powder diffraction figure 2 θ be about 5.792,7.350,
8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、17.865、18.697、
19.50、20.083、20.651、21.549、22.190、23.501、24.652、25.173、25.794、26.161、26.623、
27.323rd, 28.575,29.221,30.032,30.727,31.15,32.290,32.982, at the one of 34.470 degree of position or
There is peak many places.
In some embodiments, in eutectic III X-ray powder diffraction figure 2 θ be about 5.792,7.350,
8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、17.865、18.697、
19.50、20.083、20.651、21.549、22.190、23.501、24.652、25.173、25.794、26.161、26.623、
27.323、28.575、29.221、30.032、30.727、31.15、32.290、32.982、34.470、35.326、36.023、
38.132nd, one or more of 38.811 degree of position have peak.
In some embodiments, the X-ray powder diffraction figure of the eutectic III as shown in fig. 7, wherein, be about in 2 θ
The relative intensity at 11.58 degree of peak is more than 50%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
The eutectic III of Eliquis/3- aminopyridines, also has the property that：Its differential scanning calorimetric curve (DSC)
There is endothermic peak at about 216 DEG C -220 DEG C.In an embodiment, the means of differential scanning calorimetry of the eutectic III is bent
Line (DSC) has endothermic peak at about 216 DEG C -218 DEG C, and endothermic peak summit value is about 217 DEG C.In some embodiments, institute
State eutectic III differential scanning calorimetric curve (DSC) as shown in Figure 8.
The eutectic III is non-hygroscopic, without recrystallisation solvent or the crystallization water, is non solvate or non-hydrate.One
In a little embodiments, the thermal gravimetric analysis curve (TGA) of the eutectic III is as shown in Figure 9.
The eutectic III of the Eliquis is the powder with good fluidity, is had in terms of dissolution rate, mobility
There is good performance, be conducive to storing, shift, operating in production technology, suitable for being prepared into its oral formulations.
The eutectic IV of Eliquis/urea, has the property that：It is about in 2 θ in its X-ray powder diffraction figure
5.771st, 11.577,13.442,17.849,19.933,22.149, there is peak 23.476 degree of position.
In some embodiments, in eutectic IV X-ray powder diffraction figure 2 θ be about 5.771,6.988,8.862,
11.577、13.442、15.636、16.041、16.415、17.453、17.849、18.717、19.501、19.933、20.134、
20.536th, 21.150,21.548,22.149,22.592, one or more of 23.476 degree of position have peak.
In some embodiments, in eutectic IV X-ray powder diffraction figure 2 θ be about 5.771,6.988,8.862,
11.577、13.442、15.636、16.041、16.415、17.453、17.849、18.717、19.501、19.933、20.134、
20.536、21.150、21.548、22.149、22.592、23.476、24.548、25.042、25.739、26.548、30.633、
One or more of 31.030 degree of position have peak.
In some embodiments, eutectic IV X-ray powder diffraction figure is as shown in Figure 10, wherein, it is about in 2 θ
The relative intensity at 22.149 degree of peak is more than 50%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
The eutectic IV, also has the property that：Its differential scanning calorimetric curve (DSC) is at about 191 DEG C -195 DEG C
With endothermic peak.In an embodiment, the eutectic IV differential scanning calorimetric curves (DSC) are at about 191 DEG C -194
There is endothermic peak, endothermic peak summit value is about 193 DEG C at DEG C.In some embodiments, the differential scanning of the eutectic IV
Calorimetric curve (DSC) is as shown in figure 11.
In some embodiments, the thermal gravimetric analysis curve (TGA) of the eutectic IV is as shown in figure 12.
The eutectic IV of the Eliquis is the powder with good appearance and mobility, in dissolution rate, mobility etc.
Aspect has good performance, is conducive to storing, shifts, operating in production technology, suitable for being prepared into its oral formulations.
Second aspect, the invention provides eutectic I, eutectic II, eutectic III and the eutectic for preparing Eliquis
IV method.
A kind of method for the eutectic I for preparing Eliquis, including：Eliquis and oxalic acid are dissolved in good solvent, then
Trifluoroethanol is added, stirs at room temperature, then removes solvent, obtain eutectic I；The good solvent is acetone, ethyl acetate, second
Nitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, Ethyl formate, first
One or more in acid butyl ester, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
In certain embodiments, in the method for preparing eutectic I, the molar ratio of Eliquis and oxalic acid is 1:
0.5-1:2.5.In some embodiments, the mol ratio of Eliquis and oxalic acid is 1:0.75.
In certain embodiments, in the method for preparing eutectic I, room temperature suspension mixing time is 1~24h.
In certain embodiments, in the method for preparing eutectic I, the ratio of Eliquis and good solvent is 5-
500mg/mL。
A kind of method for the eutectic II for preparing Eliquis includes：Eliquis and nicotimine are dissolved in good solvent,
Trifluoroethanol is added, is stirred at room temperature, solvent is then removed, eutectic II is obtained；The good solvent is acetone, acetic acid second
Ester, acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, formic acid second
One or more in ester, butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
In certain embodiments, in the method for preparing eutectic II, the molar ratio of Eliquis and nicotimine
For 1:0.5-1:2.0.In some embodiments, the mol ratio of Eliquis and nicotimine is 1:1.
In certain embodiments, in the method for preparing eutectic II, room temperature suspension mixing time is 1~24h.
In certain embodiments, in the method for preparing eutectic II, the ratio of Eliquis and good solvent is 5-
500mg/mL。
A kind of method for the eutectic III for preparing Eliquis includes：Eliquis and 3- aminopyridines are dissolved in good molten
In agent, trifluoroethanol is added, is stirred at room temperature, solvent is then removed, obtain eutectic III；The good solvent is acetone, second
Acetoacetic ester, acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, first
One or more in acetoacetic ester, butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
In certain embodiments, in the method for preparing eutectic III, Eliquis rubs with feeding intake for 3- aminopyridines
You are than being 3:0.5-3:3.0.In some embodiments, the mol ratio of Eliquis and 3- aminopyridines is 3:1.
In certain embodiments, in the method for preparing eutectic III, room temperature suspension mixing time is 1~24h.
In certain embodiments, in the method for preparing eutectic III, the ratio of Eliquis and good solvent is 5-
500mg/mL。
A kind of method for the eutectic IV for preparing Eliquis, including：Eliquis and urea are dissolved in good solvent, then
Trifluoroethanol is added, stirs at room temperature, then removes solvent, obtain eutectic IV；The good solvent be acetone, ethyl acetate,
Acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, Ethyl formate,
One or more in butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
In certain embodiments, in the method for preparing eutectic IV, the molar ratio of Eliquis and urea is
4:0.5-4:2.5.In some embodiments, the mol ratio of Eliquis and urea is 4:1.
In certain embodiments, in the method for preparing eutectic IV, room temperature suspension mixing time is 1~24h.
In certain embodiments, in the method for preparing eutectic IV, the ratio of Eliquis and good solvent is 5-
500mg/mL。
Brief description of the drawings
Fig. 1 shows the eutectic I of Eliquis/oxalic acid X-ray powder diffraction figure.
Fig. 2 shows the eutectic I of Eliquis/oxalic acid differential scanning heating curve (DSC).
Fig. 3 shows the eutectic I thermogravimetric analysis figures (TGA) of Eliquis/oxalic acid.
Fig. 4 shows the eutectic II of Eliquis/nicotimine X-ray powder diffraction figure.
Fig. 5 shows the eutectic II of Eliquis/nicotimine differential scanning heating curve (DSC).
Fig. 6 shows the eutectic II thermogravimetric analysis figures (TGA) of Eliquis/nicotimine.
Fig. 7 shows the eutectic III of Eliquis/3- aminopyridines X-ray powder diffraction figure.
Fig. 8 shows the eutectic III of Eliquis/3- aminopyridines differential scanning heating curve (DSC).
Fig. 9 shows the eutectic III thermogravimetric analysis figures (TGA) of Eliquis/3- aminopyridines.
Figure 10 shows the eutectic IV of Eliquis/urea X-ray powder diffraction figure.
Figure 11 shows the eutectic IV of Eliquis/urea differential scanning heating curve (DSC).
Figure 12 shows the eutectic IV thermogravimetric analysis figures (TGA) of Eliquis/urea.
Dissolution figures of Figure 13 eutectics I, II and III in pH1.2 hydrochloric acid salt buffer.
Dissolution figures of Figure 14 eutectics I, II and III in pH6.8 phosphate buffer solution.
Embodiment
In order that those skilled in the art more fully understands technical scheme, some are disclosed further below non-
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can from the market be bought or can be by method system described in the invention
It is standby and obtain.
In the present invention, g is represented gram, and mL represents milliliter, and L represents to rise, and h represents hour.
Instrument parameter
Except being made separate stipulations in nonparametric, all analyses below are all carried out at room temperature.
Powder x-ray diffraction (XRPD) is studied
In the Dutch PANalytical for the Transflective sample stage for being equipped with the automation Background Samples framves of 3,*15 zero
X-ray powder diffraction (XRPD) pattern is collected on Empyrean x-ray diffractometers.Radiation source used is (Cu, k α, K α 1
1.540598；Kα21.544426；The intensities of K α 2/K α 1：0.50), wherein voltage is set in 45KV, and current settings exist
The effective dimensions that X-ray is constrained in the divergence of 40mA.X- rays, i.e. sample, is that 10mm. continuously scans mould using θ-θ
Formula, obtains 3 °~40 ° of effective 2 θ scopes.Take appropriate amount of sample under environmental condition (about 18 DEG C~32 DEG C) in zero Background Samples frame
At circular groove, gently pressed with clean slide, obtain a smooth plane, and zero Background Samples frame is fixed.By sample
Traditional XRPD patterns are produced in the range of 3~40 ° of 2 θ ± 0.2 ° with 0.0168 ° of scanning step.For the soft of Data Collection
Part is Data Collector, and data are analyzed and shown with Data Viewer and HighScore Plus.
Differential scanning calorimetry (DSC)
Dsc measurement is carried out in TA InstrumentsTM models Q2000 with sealed disk assembly.By sample (about 1~3mg)
Weighed in aluminium dish, use Tzero glands, precision recorded 1 percent milligrams, and sample is transferred in instrument measured.
Instrument is purged with nitrogen with 50mL/min.In room temperature to collecting data with the 10 DEG C/min rate of heat addition between 300 DEG C.To absorb heat
Peak is drawn downwards, and data are analyzed and shown with TA Universal Analysis.
Thermogravimetry (TGA)
TGA data are gathered on TA Instruments Q500.Use the temperature of the nickel calibration instrument of certification.Generally will
8-12mg samples are loaded on preweighted platinum crucible, and are heated to 300 DEG C from room temperature with 10 DEG C/min.Protected above sample
Hold 60mL/min nitrogen purge.In TGA figures, abscissa represents temperature (Temperature, DEG C), and ordinate represents weightless
Percentage composition (Weight (%)).
Embodiment 1 prepares eutectic I
0.05g oxalic acid is added in 1mL acetone, stirring is obtained after settled solution, add 0.34g Eliquis, then add
Enter 2mL trifluoroethanols, be suspended stirring 24 hours at room temperature, and suction filtration obtains white solid, be placed in room temperature in vacuo in drying box and do
It is dry, obtain white crystal about 0.08g.Eutectic I is determined to, its X-ray powder diffraction pattern and Fig. 1 are basically identical, its
DSC, TGA collection of illustrative plates respectively with Fig. 2,3 basically identical.Embodiment 2 prepares eutectic I
0.07g oxalic acid is added in 1mL ethyl acetate, stirring is obtained after settled solution, adds 0.47g Eliquis,
2mL trifluoroethanols are added, be suspended stirring 15 hours at room temperature, and suction filtration obtains white solid, is placed in room temperature in drying box true
Sky is dried, and obtains white crystal about 0.11g.Eutectic I is determined to, its X-ray powder diffraction pattern and Fig. 1 are basically identical,
Its DSC, TGA collection of illustrative plates respectively with Fig. 2,3 basically identical.
Embodiment 3 prepares eutectic II
0.06g nicotimine is added in 1mL acetone, 0.23g Eliquis is added, 3mL trifluoroethanols is added, in room
The lower stirring 24 hours that is suspended of temperature, suction filtration obtains white solid, is placed in room temperature in drying box and is dried in vacuo, obtains white crystal about
0.09g.Be determined to eutectic II, its X-ray powder diffraction pattern and Fig. 4 are basically identical, its DSC, TGA collection of illustrative plates respectively with figure
5th, 6 is basically identical.
Embodiment 4 prepares eutectic III
0.07g 3- aminopyridines are added in 3mL acetone, stirring is obtained after settled solution, add 1.02g Ah piperazines husky
Class, adds 2mL trifluoroethanols, and be suspended stirring 24 hours at room temperature, and suction filtration obtains white solid, is placed in room temperature in drying box
Vacuum drying, obtains white crystal about 0.09g.Eutectic III is determined to, its X-ray powder diffraction pattern and Fig. 7 basic one
Cause, its DSC, TGA collection of illustrative plates respectively with Fig. 8,9 basically identical.
Embodiment 5 prepares eutectic IV
0.05g urea is added in 5mL acetone, stirring is obtained after settled solution, add 1.51g Eliquis, then add
Enter 2mL trifluoroethanols, be suspended stirring 24 hours at room temperature, and suction filtration obtains white solid, be placed in room temperature in vacuo in drying box and do
It is dry, obtain white crystal about 0.08g.Eutectic I is determined to, its X-ray powder diffraction pattern and Figure 10 are basically identical, its
DSC, TGA collection of illustrative plates respectively with Figure 11,12 basically identical.
The dissolution rate test of embodiment 6
According to the Dissolution Rate Testing guideline of existing Chinese Pharmacopoeia, contrived experiment investigates three kinds of Eliquis altogether respectively
Dissolution rates of the brilliant I/II/III under different pH buffer salt, as a result as shown in Figure 13,14.
As a result show that three kinds of eutectiferous dissolution rates are all higher than Eliquis, wherein：
Eliquis/oxalic acid eutectic I dissolution rate highests, can reach 2 times of Eliquis, decline gradually afterwards quickly.
Eliquis/nicotimine eutectic II and Eliquis/3- aminopyridine eutectic III dissolution rates can reach Ah
1.5 times of piperazine sand class, and for a long time concentration can be kept constant.
The present invention method be described by preferred embodiment, related personnel substantially can present invention,
Method described herein and application are modified in spirit and scope or suitably change is with combining, to realize and using the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, institute
There is similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (22)
1. a kind of eutectic I, the eutectic I comprising in Eliquis and oxalic acid, and X-ray powder diffraction figure in 2 θ about
For 7.770,9.138,15.707,17.030,18.813,19.921,20.612,21.459,23.533,24.851,25.463,
There is peak 27.232 degree of position.
2. in eutectic I according to claim 1, its X-ray powder diffraction figure 2 θ be about 7.770,8.361,
9.138、9.876、12.691、13.348、14.267、14.815、15.707、17.030、18.813、19.921、20.612、
21.459th, 23.533,24.851,25.463, there is peak 27.232 degree of position；Or it is big in 2 θ in its X-ray powder diffraction figure
About 7.770,8.361,9.138,9.876,12.691,13.348,14.267,14.815,15.707,17.030,18.813,
19.921、20.612、21.081、21.912、22.260、22.524、23.262、21.459、23.533、24.111、24.514、
24.851st, 25.463,26.451,26.889, there is peak 27.232 degree of position；Or it is big in 2 θ in its X-ray powder diffraction figure
About 7.770,8.361,9.138,9.876,12.691,13.348,14.267,14.815,15.707,17.030,18.813,
19.921、20.612、21.081、21.912、22.260、22.524、23.262、21.459、23.533、24.111、24.514、
24.851、25.463、26.451、26.889、27.232、27.749、28.303、28.877、29.440、29.781、30.091、
30.488th, 31.080, there is peak 31.608 degree of position；Or in its X-ray powder diffraction figure 2 θ be about 7.770,
8.361、9.139、9.876、12.691、13.348、14.267、14.815、15.707、16.386、17.030、17.280、
17.937、18.315、18.546、18.813、19.921、20.282、20.612、21.081、21.459、21.912、22.260、
22.524、23.262、23.533、24.111、24.514、24.851、25.463、25.628、26.451、26.889、27.232、
27.749、28.303、28.877、29.440、29.781、30.091、30.488、31.080、31.608、31.968、32.302、
32.748th, 33.210,33.651,34.10,35.029,35.914,37.160, there is peak 37.920 degree of position；Or its X- is penetrated
Line powder diagram is as shown in figure 1, wherein, the relative intensity in 2 θ being about 19.92 degree of peak is more than 50%, or is more than
70%, or more than 80%, or more than 90%, or more than 99%.
3. eutectic I according to claim 1, its differential scanning calorimetric curve has heat absorption at about 200 DEG C -204 DEG C
Peak.
4. a kind of method for preparing eutectic I described in claim 1, including：Eliquis and oxalic acid are dissolved in good solvent, then
Trifluoroethanol is added, is stirred at room temperature, solvent is removed, obtains eutectic I；The good solvent be acetone, ethyl acetate, acetonitrile,
Ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, Ethyl formate, formic acid
One or more in butyl ester, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
5. method according to claim 4, the molar ratio of the Eliquis and oxalic acid is 1:0.5-1:2.5.
6. method according to claim 4, the ratio of the Eliquis and good solvent is 5-300mg/mL.
7. a kind of eutectic II, the eutectic II are included in Eliquis and nicotimine, and X-ray powder diffraction figure in 2 θ
About 5.827,8.780,11.666,13.491,16.102,17.544,21.580,22.128,23.465,30.253 degree
There is peak position.
8. in eutectic II according to claim 7, its X-ray powder diffraction figure 2 θ be about 5.827,7.311,
8.780、11.666、13.491、15.720、16.102、17.544、17.891、18.819、21.580、22.128、23.465、
There is peak 30.253 degree of position；Or in its X-ray powder diffraction figure 2 θ be about 5.827,7.311,8.780,
11.666、13.491、15.720、16.102、17.544、17.891、18.819、19.179、19.850、20.271、20.515、
21.119th, 21.580,22.128,22.690,23.465,24.894, there is peak 30.253 degree of position；Or its X-ray powder
In diffraction pattern 2 θ be about 5.827,7.311,8.780,11.666,13.491,15.720,16.102,17.544,
17.891、18.819、19.179、19.850、20.271、20.515、21.119、21.580、22.128、22.690、23.465、
24.894th, 25.667,26.470,28.650,29.480, there is peak 30.253 degree of position；Or its X-ray powder diffraction figure
In 2 θ be about 5.827,7.311,8.780,11.666,13.491,15.720,16.102,17.544,17.891,
18.819、19.179、19.850、20.271、20.515、21.119、21.580、22.128、22.690、23.465、24.894、
25.667th, 26.470,28.650,29.480,30.253,30.957,33.221, there is peak 38.40 degree of position；Or its X- is penetrated
Line powder diagram is as shown in figure 4, wherein, the relative intensity in 2 θ being about 11.66 degree of peak is more than 50%, or is more than
70%, or more than 80%, or more than 90%, or more than 99%.
9. eutectic II according to claim 7, its differential scanning calorimetric curve has heat absorption at about 199 DEG C -204 DEG C
Peak.
10. a kind of method for preparing eutectic II described in claim 7, including：Eliquis and nicotimine are dissolved in good solvent
In, trifluoroethanol is added, is stirred at room temperature, solvent is removed, obtains eutectic II；The good solvent be acetone, ethyl acetate,
Acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, Ethyl formate,
One or more in butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
11. method according to claim 10, the molar ratio of the Eliquis and nicotimine is 1:0.5-1:
2.0。
12. method according to claim 10, the ratio of the Eliquis and good solvent is 5-300mg/mL.
13. a kind of eutectic III, the eutectic III include Eliquis and 3- aminopyridines, and X-ray powder diffraction figure
In 2 θ be about 5.792,11.578,13.418,17.865,18.697,20.083,23.501,24.652,30.032 degree
There is peak position.
14. in eutectic III according to claim 13, its X-ray powder diffraction figure 2 θ be about 5.792,
7.350、8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、17.865、
18.697th, 20.083,23.501,24.652, there is peak 30.032 degree of position；Or it is big in 2 θ in its X-ray powder diffraction figure
About 5.792,7.350,8.890,11.578,12.510,13.418,13.871,15.823,16.044,16.552,
17.419、17.865、18.697、19.50、20.083、20.651、21.549、22.190、23.501、24.652、25.173、
25.794th, 26.161,26.623, there is peak 30.032 degree of position；Or in 2 θ be about in its X-ray powder diffraction figure
5.792、7.350、8.890、11.578、12.510、13.418、13.871、15.823、16.044、16.552、17.419、
17.865、18.697、19.50、20.083、20.651、21.549、22.190、23.501、24.652、25.173、25.794、
26.161st, 26.623,27.323,28.575,29.221,30.032,30.727,31.15,32.290,32.982,34.470 degree
Position have peak；Or in its X-ray powder diffraction figure 2 θ be about 5.792,7.350,8.890,11.578,12.510,
13.418、13.871、15.823、16.044、16.552、17.419、17.865、18.697、19.50、20.083、20.651、
21.549、22.190、23.501、24.652、25.173、25.794、26.161、26.623、27.323、28.575、29.221、
30.032nd, 30.727,31.15,32.290,32.982,34.470,35.326,36.023,38.132,38.811 degree of position
There is peak；It is about that the relative intensity at 11.58 degree of peak is more than in 2 θ or its X-ray powder diffraction figure is as shown in figure 4, wherein
50%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
15. eutectic III according to claim 13, its differential scanning calorimetric curve has at about 216 DEG C -220 DEG C
Endothermic peak.
16. a kind of method for preparing eutectic III described in claim 13, including：Eliquis and 3- aminopyridines are dissolved in
In good solvent, trifluoroethanol is added, is stirred at room temperature, removed solvent, obtain eutectic III；The good solvent is acetone, second
Acetoacetic ester, acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, first
One or more in acetoacetic ester, butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
17. the molar ratio of method according to claim 16, the Eliquis and 3- aminopyridines is 3:0.5-
3:3.0。
18. method according to claim 16, the ratio of the Eliquis and good solvent is 5-300mg/mL.
19. a kind of eutectic IV, the eutectic IV are comprising big in 2 θ in Eliquis and urea, and X-ray powder diffraction figure
About 5.771,11.577,13.442,17.849,19.933,22.149,23.476 degree of position have peak.
20. in eutectic IV according to claim 19, its X-ray powder diffraction figure 2 θ be about 5.771,
6.988、8.862、11.577、13.442、15.636、16.041、16.415、17.453、17.849、18.717、19.501、
19.933rd, 20.134,20.536,21.150,21.548,22.149,22.592, there is peak 23.476 degree of position；Or its X-
In ray powder diffraction pattern 2 θ be about 5.771,6.988,8.862,11.577,13.442,15.636,16.041,
16.415、17.453、17.849、18.717、19.501、19.933、20.134、20.536、21.150、21.548、22.149、
22.592nd, 23.476,24.548,25.042,25.739,26.548,30.633, there is peak 31.030 degree of position；Or its X-
Ray powder diffraction pattern is as shown in figure 4, wherein, the relative intensity in 2 θ being about 22.149 degree of peak is more than 50%, or is more than
70%, or more than 80%, or more than 90%, or more than 99%.
21. eutectic III according to claim 19, its differential scanning calorimetric curve has at about 191 DEG C -195 DEG C
Endothermic peak.
22. a kind of method for preparing eutectic IV described in claim 19, including：Eliquis and urea are dissolved in good solvent
In, trifluoroethanol is added, is stirred at room temperature, solvent is removed, obtains eutectic IV；The good solvent be acetone, ethyl acetate,
Acetonitrile, ethanol, methanol, normal propyl alcohol, n-butanol, sec-butyl alcohol, isobutanol, isopropyl acetate, hexamethylene, normal heptane, Ethyl formate,
One or more in butyl formate, methyl acetate, ether, isopropyl ether, glycol dimethyl ether.
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