CN104447924B - Crystal formation of rope fluorine cloth Wei and preparation method thereof - Google Patents
Crystal formation of rope fluorine cloth Wei and preparation method thereof Download PDFInfo
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Abstract
The invention discloses crystal formation H1, crystal formation H2, crystal formation H3 and the crystal formation H4 of four kinds of new rope fluorine cloth Weis, and for the method preparing these four crystal formation.Structure and the cell parameter of these four rope fluorine cloth Wei novel crystal forms all use monocrystalline X x ray diffraction analysis x to be determined.The crystal formation H1 angle of diffraction 2 θ has characteristic peak at 4.9 °, 6.6 °, 7.1 °, 8.2 °, 9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc.；The crystal formation H2 angle of diffraction 2 θ has characteristic peak at 6.7 °, 7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc.；The crystal formation H3 angle of diffraction 2 θ has characteristic peak at 5.1 °, 6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc.；The crystal formation H4 angle of diffraction 2 θ has characteristic peak at 5.5 °, 5.6 °, 10.0 °, 10.9 °, 10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc..The crystal formation of the rope fluorine cloth Wei that these four is new is respectively provided with the advantages such as physicochemical property is excellent, good stability, dissolubility are good, preparation manipulation is simple.
Description
Technical field
The present invention relates to rope fluorine cloth Wei (isopropyl (2S)-2-[[[(2R, 3R, 4R, 5R)-5-(2,4-uracil-1-
Base)-4-fluoro-3-hydroxy-4-methyl-oxolane-2-base]-Difluoro-phenoxy-phosphoryl] amino] propionic ester, chemistry
Formula: C22H29FN3O9P) four kinds of novel crystalline form and preparation method thereof.
Background technology
Rope fluorine cloth Wei (sofosbuvir), chemical entitled isopropyl (2S)-2-[[[(2R, 3R, 4R, 5R)-5-(2,4-bis-
Oxygen pyrimidine-1-base)-4-fluoro-3-hydroxy-4-methyl-oxolane-2-base]-Difluoro-phenoxy-phosphoryl] amino] propanoic acid
Ester, the numbered 1190307-88-0 of CAS, chemical structural formula is as follows:
Rope fluorine cloth Wei is a kind of NS5B AG14361 developed by Ji Leadd B.V of the U.S. (Glead Sciences),
It, when individually or being used in combination with other medicines, can block a kind of specific proteins required for hepatitis c viral replication
Matter, thus for the treatment of hepatitis C.Rope fluorine cloth Wei in December, 2013 by the approval of U.S. food Drug Administration
City, trade name Sovaldi.Rope fluorine cloth Wei is the first granted medicine that can be used for the full oral medication of hepatitis C, for spy
When determining the treatment of genotype chronic hepatitis C, the demand to conventional injection interfering effects of drug element (IFN) can be eliminated, it is contemplated that 2014 complete
Ball sales volume, more than 10,000,000,000 dollars, has wide market prospect.
United States Patent (USP) US20110251152 describes 6 kinds of crystal formations of rope fluorine cloth Wei and teaches wherein crystal formation form's 6
Preparation method.6 kinds of crystal formations described in this document are as follows:
Crystal formation Form 1, its powder X-ray diffraction characteristic peak is 5.2 °, 7.5 °, 9.6 °, 16.7 °, 18.3 °, 22.2 °.Specially
Profit US20110251152 does not instructs the concrete preparation method of crystal formation form 1, it is indicated that crystal formation form 1 can be by crystal formation
Form2～5 is transformed.The hygroscopicity of crystal formation form 1 own is relatively strong, is easily transformed into spawn or turns in open-top receptacle
Turn to crystal formation form 6.
Crystal formation form 2 is dichloromethane solvate crystallization, its powder X-ray diffraction characteristic peak is 4.9 °, 6.9 °,
9.8°、19.8°、20.6°、24.7°、26.1.Crystal formation form 2 crystallizes from dichloromethane and obtains, and is converted into crystal formation time dry
form 1。
Crystal formation form 3 is chloroform crystalline solvate, its powder X-ray diffraction characteristic peak is 6.9 °, 9.8 °,
19.7°、20.6°、24.6°.Crystal formation form 3 crystallizes from chloroform and obtains, and is converted into crystal formation form 1 time dry.
Crystal formation form 4, its powder X-ray diffraction characteristic peak is 5.0 °, 6.8 °, 19.9 °, 20.6 °, 24.6 °.Crystal formation
Form 4 crystallizes from acetonitrile and obtains, and character is unstable, filters and is converted into crystal formation form 1 when separating.
Crystal formation form 5, its powder X-ray diffraction characteristic peak is 5.2 °, 6.6 °, 7.1 °, 15.7 °, 19.1 °, 25.0 °.Brilliant
Type form 5 crystallizes from methyl phenyl ethers anisole and obtains, and character is unstable, filters and is converted into crystal formation form 1 when separating.
Crystal formation form 6, its powder X-ray diffraction characteristic peak is 6.1 °, 8.2 °, 10.4 °, 12.7 °, 17.2 °, 17.7 °,
18.0°、18.8°、19.4°、19.8°、20.1°、20.8°.Patent US20110251152 discloses following two and prepares crystal formation
The method of form 6, is all to convert from crystal formation form 1 to obtain:
1) gelling material was formed by under crystal formation form 1 powder humidity disposed within several days, by gelling material grind into powder
(its powder X-ray diffraction is identical with form 1).This powder is placed in open containers sample after 6-10 week and slowly becomes brilliant
Type form 6.
2) by the water adding 5～50 mg/ml under crystal formation form 1 room temperature, stir at room temperature or 50 DEG C, crystal formation
Form 1 is converted into crystal formation form 6 within a few hours.
The crystal formation existence and stability to some extent of existing six kinds of rope fluorine cloth Weis is relatively low, dissolubility is relatively low, production technology
The shortcomings such as repeatability is poor, this directly affects production, storage and the pharmaceutical preparation thereof of rope fluorine cloth Wei crude drug the third type liver
Effect in scorching treatment.
It is known that the crystal habit of medicine can affect the characteristic of medicine to a great extent, such as chemical stability,
Fusing point, dissolubility, rate of dissolution etc..And these characteristics can directly affect crude drug and the production of preparation, store and use.
Therefore, the crystal form of control cord fluorine cloth Wei is most important for obtaining outstanding rope fluorine cloth Wei pharmaceutical preparation, it is intended that exploitation
Make new advances has higher stability, higher solubility and is easier to the novel crystalline form of the rope fluorine cloth Wei prepared.
Summary of the invention
It is an object of the invention to provide the new rope fluorine cloth Wei crystal formation with more excellent physicochemical property, and be used for preparing
The method of these crystal formations.
The present inventor etc. are concentrated on studies to solve described problem, and result have surprisingly been discovered that four kinds newly
Crystal formation H1, crystal formation H2, crystal formation H3 and the crystal formation H4 of rope fluorine cloth Wei.Wherein, crystal formation H1 is the hydrate knot containing 1:1 hydrone
Crystalline substance, crystal formation H2 is the methanol solvate crystallization containing 1:1 methanol molecules, and crystal formation H3 is the ethanolates crystallization containing 1:1 ethanol molecule, brilliant
Type H4 is the diphenyl ether compound crystallization containing 1:1 diphenyl ether molecule.It addition, the present inventors have additionally discovered that and respectively selectively obtain crystal formation
H1, crystal formation H2, crystal formation H3 and the preparation method of crystal formation H4.It is excellent, stable that these four novel crystalline form state is respectively provided with physicochemical property
The advantage such as property is good, dissolubility is good, preparation manipulation is simple, has superiority in commercial production and medical applications.
The crystal formation H1 that the present invention the announces angle of diffraction 2 θ in using Cu-K Alpha-ray x-ray diffractogram of powder spectrum exists
4.9 °, 6.6 °, 7.1 °, 8.2,9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc. have characteristic peak.
Confirming after single crystal X-ray diffraction experiment and crystal structure calculate, crystal formation H1 belongs to monoclinic system, space group P21,
Cell parameter:α=90.00 °, β=108.05 (3) °, γ
=90.00 °；Unit cell volumeStructure cell includes asymmetry unit number Z=2, the change in an asymmetry unit
Metering-type is C22H31FN3O10P, molecular weight is 547.47, crystalline density d=1.251g/cm3.Single crystal X-ray diffraction structure is divided
Analysis confirms the hydrone in crystal formation H1 lattice containing 1:1.
The crystal formation H1 of the present invention, in DSC figure (means of differential scanning calorimetry figure), has 65～80 in the range of 50-200 DEG C
Endothermic peak (its peak temperature is 100.6 DEG C) bigger at endothermic peak less at DEG C and 95～110 DEG C.
The present invention provides the preparation method of crystal formation H1, wherein, rope fluorine cloth Wei and water joins methyl phenyl ethers anisole and butyl oxide
In the mixed solvent of mixed solvent or methyl phenyl ethers anisole and diisopropyl ether, it is heated to 70～95 DEG C, is then cooled to 0～35 DEG C, analyses
Crystalline substance, the crystallize time is 1～10 day, is derived from the crystal formation H1 of colourless needles.
In the present invention for preparing in the method for crystal formation H1, methyl phenyl ethers anisole is 3 with the volume ratio of butyl oxide or diisopropyl ether:
1～1:1, preferably 1:1；Rope fluorine cloth Wei weight (g) is 1:5～1:20 with the ratio of mixed solvent volume (mL), more preferably
1:10；Water and rope fluorine cloth Wei part by weight are 1:100～1:20, more preferably 3:100；Heating-up temperature is preferably 80～85 DEG C；
Preferably it is cooled to 20～25 DEG C；The crystallize time is preferably 3 days.
The crystal formation H2 of the present invention use Cu-K Alpha-ray x-ray diffractogram of powder spectrum in the angle of diffraction 2 θ 6.7 °,
7.0 °, 9.7 °, 19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc. have characteristic peak.
Confirming after single crystal X-ray diffraction experiment and crystal structure calculate, crystal formation H2 belongs to monoclinic system, space group P21, crystalline substance
Born of the same parents' parameter:α=90.00 °, β=108.86 (3) °, γ=
90.00°；Unit cell volumeStructure cell includes asymmetry unit number Z=2, the chemistry in an asymmetry unit
Metering-type is C23H33FN3O10P, molecular weight is 561.49, crystalline density d=1.313g/cm3.Single crystal X-ray diffraction structural analysis
Confirm the methanol solvate molecule containing 1:1 in crystal formation H2 lattice.
The crystal formation H2 of the present invention, in DSC figure, has a suction at 84～100 DEG C in the range of 50～200 DEG C
Thermal spike, peak temperature is 89.1 DEG C.
The present invention provides the preparation method of crystal formation H2, wherein, phenylene dimethyl ether solvent between rope fluorine cloth Wei and methanol are added,
In phenylene dimethyl ether and the mixed solvent of butyl oxide, or the mixed solvent of a phenylene dimethyl ether and diisopropyl ether, it is heated to 70～95 DEG C, so
After be cooled to 0～35 DEG C, carry out crystallize, the crystallize time is 1～10 day, is derived from the crystal formation H2 of colourless needles.
In the present invention for preparing in the method for crystal formation H2, a phenylene dimethyl ether and butyl oxide or the volume ratio of diisopropyl ether
For 3:1～1:1, more preferably 1:1；Rope fluorine cloth Wei weight (g) is 1:5～1:20 with the ratio of solvent volume (mL), is preferably
1:8；Methanol and rope fluorine cloth Wei part by weight are 1:20～3:20, more preferably 1:10；Heating-up temperature is preferably 80～85 DEG C；Excellent
Choosing is cooled to 20～25 DEG C；The crystallize time is preferably 3 days.
The crystal formation H3 of the present invention use Cu-K Alpha-ray x-ray diffractogram of powder spectrum in the angle of diffraction 2 θ 5.1 °,
6.7 °, 7.1 °, 9.6 °, 15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc. have characteristic peak.
Confirming after single crystal X-ray diffraction experiment and crystal structure calculate, crystal formation H3 belongs to monoclinic system, space group P21, crystalline substance
Born of the same parents' parameter:α=90.00 °, β=108.78 (3) °,
γ=90.00 °；Unit cell volumeStructure cell includes asymmetry unit number Z=2, in an asymmetry unit
Stoichiometric equation is C24H35FN3O10P, molecular weight is 575.52, crystalline density d=1.342g/cm3.Single crystal X-ray diffraction structure
It is analyzed to identify in crystal formation H3 lattice the alcohol solvent molecule containing 1:1
The crystal formation H3 of the present invention, in DSC figure, has the endothermic peak at 70～88 DEG C in the range of 50～200 DEG C,
Peak temperature is 74.4 DEG C.The crystal formation H3 of the present invention is the rope fluorine cloth Wei ethanol solvate containing a part ethanol.
The present invention provides the preparation method of crystal formation H3, wherein adds in benzyl ether solvent by rope fluorine cloth Wei and ethanol, heating
To 70～95 DEG C, being then cooled to 0～35 DEG C, carry out crystallize, the crystallize time is 1～10 day, is derived from the crystalline substance of colorless plate
Type H3.
In the present invention for preparing in the method for crystal formation H3, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL)
For 1:10～1:20, preferably 1:10；Ethanol and rope fluorine cloth Wei part by weight are 1:50～1:10, preferably 1:20；Heating temperature
Degree is preferably 85～90 DEG C；Preferably it is cooled to 20～25 DEG C；The crystallize time is preferably 3 days.
The crystal formation H4 of the present invention use Cu-K Alpha-ray x-ray diffractogram of powder spectrum in the angle of diffraction 2 θ 5.5 °,
5.6 °, 10.0 °, 10.9 °, 10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc. have characteristic peak.
Confirming after Single Crystal X-ray experiment and crystal structure calculate, crystal formation H4 belongs to monoclinic system, space group P21, and structure cell is joined
Number:α=90.00 °, β=116.64 (3) °, γ=
90.00°；Unit cell volumeStructure cell includes asymmetry unit number Z=2, the chemistry in an asymmetry unit
Metering-type is C34H39FN3O10P, molecular weight is 699.65, crystalline density d=1.313g/cm3.Single crystal X-ray diffraction structural analysis
Confirm the diphenyl ether solvent molecule containing 1:1 in crystal formation H4 lattice.
The crystal formation H4 of the present invention, in DSC figure, has a heat absorption at 64～76 DEG C in the range of 50～200 DEG C
Peak, peak temperature is 68.1 DEG C.
The present invention provides the preparation method of crystal formation H4, is wherein added in diphenyl ether solvent by rope fluorine cloth Wei, be heated to 70～
95 DEG C, being then cooled to 0～35 DEG C, carry out crystallize, the crystallize time is 1～10 day, is derived from the crystal formation H4 of colourless needles.
In the present invention for preparing in the method for crystal formation H4, the ratio of rope fluorine cloth Wei weight (g) and solvent volume (mL)
For 1:3～1:20, preferably 1:10；Heating-up temperature is preferably 85～90 DEG C；Preferably it is cooled to 20～25 DEG C；The crystallize time is preferred
It it is 3 days.
Accompanying drawing explanation
Fig. 1 is the X-ray monocrystalline molecular structure ellipsoid figure of the rope fluorine cloth Wei crystal formation H1 according to embodiments of the invention 1；
Fig. 2 is the X-ray powder diffraction figure of the rope fluorine cloth Wei crystal formation H1 according to embodiments of the invention 1；
Fig. 3 is the DSC-TGA figure of the rope fluorine cloth Wei crystal formation H1 according to embodiments of the invention 1；
Fig. 4 is the X-ray monocrystalline molecular structure ellipsoid figure of the rope fluorine cloth Wei crystal formation H2 according to embodiments of the invention 2；
Fig. 5 is the X-ray powder diffraction figure of the rope fluorine cloth Wei crystal formation H2 according to embodiments of the invention 2；
Fig. 6 is the DSC-TGA figure of the rope fluorine cloth Wei crystal formation H2 according to embodiments of the invention 2；
Fig. 7 is the X-ray monocrystalline molecular structure ellipsoid figure of the rope fluorine cloth Wei crystal formation H3 according to embodiments of the invention 3；
Fig. 8 is the X-ray powder diffraction figure of the rope fluorine cloth Wei crystal formation H3 according to embodiments of the invention 3；
Fig. 9 is the DSC-TGA figure of the rope fluorine cloth Wei crystal formation H3 according to embodiments of the invention 3；
Figure 10 is the X-ray monocrystalline molecular structure ellipsoid figure of the rope fluorine cloth Wei crystal formation H4 according to embodiments of the invention 4；
Figure 11 is the X-ray powder diffraction figure of the rope fluorine cloth Wei crystal formation H4 according to embodiments of the invention 4；
Figure 12 is the DSC-TGA figure of the rope fluorine cloth Wei crystal formation H4 according to embodiments of the invention 4；
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be described in more detail, but the most therefore limits the present invention to described
Within scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, is conventionally carried out with condition.
Heretofore described room temperature refers to 10 DEG C～30 DEG C.
In the preparation method of four crystal formations of present invention announcement, rope fluorine cloth Wei Jun uses the method by existing document report
Rope fluorine cloth Wei (J.Med.Chem.2010,53:7202 7218) of preparation；Other solvents and reagent all use commercially available chemical pure or
Analytical pure product.
Four kinds of novel crystalline form that the present invention announces all are tested with single crystal X-ray diffraction structural analysis and characterize.Single
Brilliant X-ray diffraction structural analysis can directly obtain molecular number, structure cell internal solvent in the cell parameter of crystal, space group, structure cell
And the stereochemical structure information of molecule, it is the most direct, accurate and effective Crystalline form analysis method in current Crystal study means.
The crystal structure determination instrument that the embodiment of the present invention is used is Enraf Noius&Enraf Noius company
CAD4/PC single crystal X-ray diffraction instrument, test temperature is 293 (2) K.With graphite monochromatised MoK alpha rayMake
Structure elucidation and correction is carried out with SHELXS-97 (Sheldrick, 1990) and SHELXL-97 (Sheldrick, 1997).Use
Program ORTEP obtains monocrystalline molecular structure ellipsoid figure (Fig. 1, Fig. 4, Fig. 7, Figure 10).
Obtained by crystal structure determination, cell parameter has a following meanings:
A, b, c are the length of side of unit structure cell；
α, beta, gamma is the crystal face angle of unit structure cell；
V is unit cell volume；
Z is contained asymmetry unit number in structure cell.
The x-ray powder diffraction instrument device that the embodiment of the present invention is used is that PANalytical company X'pert PRO type X is penetrated
Line powder diffractometer.Using Cu-K alpha ray, measured power is 40kV × 250mA, and scanning speed is 5 °/minute, sweep limits 4
～θ-2 θ of 80 ° (2 θ) scans continuously.
In the embodiment of the present invention obtained X-ray powder diffraction figure (Fig. 2, Fig. 5, Fig. 8, Figure 11), transverse axis is diffraction maximum 2 θ
Position (unit: degree)；The longitudinal axis is diffraction peak intensity.
It is Mettler that differential scanning amount hot-hot weight (DSC-TGA) that the embodiment of the present invention is used analyzes determining instrument
The TGA/DSC 1 type synchronous solving of Toledo company.Measurement scope is 25～350 DEG C, and programming rate is 10 DEG C/min,
Employing nitrogen is protected.
In the embodiment of the present invention obtained differential scanning amount hot-hot weight (DSC-TGA) figure (Fig. 3, Fig. 6, Fig. 9, Figure 12), heat
Weight (TGA) figure and calorimetric (DSC) figure are to represent the most side by side.Wherein in thermal multigraph, transverse axis is temperature (DEG C), the longitudinal axis be quality (in the least
Gram), in calorimetric figure, transverse axis is temperature (unit: DEG C), and the longitudinal axis is power (unit: milliwatt).
Embodiment 1: the preparation of crystal formation H1 monocrystalline
0.5 gram of rope fluorine cloth Wei and 15 milligrams of water are added 2.5 milliliters of methyl phenyl ethers anisoles and the mixed solvent of 2.5 milliliters of butyl oxides,
Heating this mixture makes solid be completely dissolved to 80～85 DEG C and stirring, then slowly cools to the speed of 1～3 DEG C/min
Room temperature also at room temperature stands 72 hours, by filtering the crystal formation H1 monocrystalline taking out the colourless needles separated out.
Alternatively, the mixed solvent in above-mentioned preparation method can be replaced with between 2.5 milliliters phenylene dimethyl ether and 2.5 milliliters
The mixed solvent of diisopropyl ether.
The mensuration of the x-ray structure of the crystal formation H1 monocrystalline in embodiment 1
The rope fluorine cloth Wei crystal formation H1 choosing a size of 0.30mm × 0.20mm × 0.10mm in the crystal that embodiment 1 obtains is mono-
Crystalline substance, is placed on single crystal X-ray diffraction instrument, collects 5532 diffraction datas in the range of 1.20 °≤2 θ≤25.42 °, wherein independent
Point diffraction 5310.The data collected correct through the Lp factor and empirical absorption.Use direct method, and through taking turns difference Fourier more
Synthesis, finds out whole hydrogen atom.All non-hydrogen atom coordinates and equivalence anisotropy displacement parameter thereof are all minimum with complete matrix
Square law carries out refine.
Confirming after single crystal X-ray diffraction test and crystal structure calculate, rope fluorine cloth Wei crystal formation H1 belongs to monoclinic system, empty
Between group P21, cell parameter:α=90.00 °, β=108.05
(3) °, γ=90.00 °；Z=2, the stoichiometric equation in an asymmetry unit is C22H31FN3O10P,
Molecular weight is 547.47, crystalline density d=1.251g/cm3.Measure the monocrystalline molecular structure ellipsoid obtaining rope fluorine cloth Wei crystal formation H1
Figure is as it is shown in figure 1, its non-hydrogen atom coordinate data is as shown in table 1.
The non-hydrogen atom coordinate parameters of table 1 crystal formation H1
The powder x-ray diffraction analysis of the crystal formation H1 monocrystalline of embodiment 1:
Crystal formation H1 monocrystalline grind into powder embodiment 1 obtained, carries out powder x-ray diffraction analysis to it, its result
As shown in Figure 2.Corresponding to Fig. 2, the X ray diffracting data of crystal formation H1 is as shown in table 2.
The powder x-ray diffraction analysis of table 2 crystal formation H1
According to X-ray diffraction result, the position of characteristic diffraction peak 2 θ of crystal formation H1 is 4.9 °, 6.6 °, 7.1 °,
8.2 °, 9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, 24.9 ° etc..
This powder sample is carried out means of differential scanning calorimetry-thermogravimetric analysis, and its result is as shown in Figure 3.
According to Fig. 3, crystal formation H1 in thermogravimetric spectrogram, have at 65～80 DEG C less in the range of 50～200 DEG C
Endothermic peak and 95～110 DEG C at bigger endothermic peak.Its differential thermal spectrogram shows that weight-loss ratio is in the range of room temperature to 150 DEG C
2.3%, the structure obtained with single-crystal X-ray diffraction analysis in range of error matches.
Embodiment 2: the preparation of crystal formation H2 monocrystalline
Phenylene dimethyl ether solvent between 0.5 gram of rope fluorine cloth Wei and 0.05 gram of methanol are added 5.0 milliliters, is heated to 85～90 DEG C and makes
Solid is completely dissolved, and is then slowly cooled to room temperature with the speed of 1～3 DEG C/min and at room temperature stands 24～72 hours, logical
Filter the crystal formation H2 taking out colourless needles.
Alternatively, phenylene dimethyl ether solvent between 5.0 milliliters in above-mentioned preparation method can be replaced with the isophthalic two of 5.0 milliliters
The mixed solvent of the diisopropyl ether of methyl ether and 5.0 milliliters.
The mensuration of the crystal formation H2 crystal structure in embodiment 2
The rope fluorine cloth Wei crystal formation H2 choosing a size of 0.20mm × 0.10mm × 0.10mm in the crystal that embodiment 2 obtains is mono-
Crystalline substance, is placed on single crystal X-ray diffraction instrument, collects 5446 diffraction datas in the range of 1.21 °≤2 θ≤25.40 °, wherein independent
Point diffraction 5216.The data collected correct through the Lp factor and empirical absorption.Use direct method, and through taking turns difference Fourier more
Synthesis, finds out whole hydrogen atom.All non-hydrogen atom coordinates and equivalence anisotropy displacement parameter thereof are all minimum with complete matrix
Square law carries out refine.
Confirming after single crystal X-ray diffraction test and crystal structure calculate, rope fluorine cloth Wei crystal formation H2 belongs to monoclinic system, space
Group P21, cell parameter:α=90.00 °, β=108.86
(3) °, γ=90.00 °；Z=2, the stoichiometric equation in an asymmetry unit is
C23H33FN3O10P, molecular weight is 561.49, crystalline density d=1.313g/cm3。
Measure and obtain the monocrystalline molecular structure ellipsoid figure of rope fluorine cloth Wei crystal formation H2 as shown in Figure 4, its non-hydrogen atom number of coordinates
According to as shown in table 3.
The non-hydrogen atom coordinate parameters of table 3 crystal formation H2
The powder x-ray diffraction analysis of the crystal formation H2 monocrystalline of embodiment 2:
Crystal formation H2 monocrystalline grind into powder embodiment 2 obtained, carries out powder x-ray diffraction analysis to it, its result
As shown in Figure 5.The X ray diffracting data of this crystal formation H2 is as shown in table 4.
The X-ray diffraction analysis of table 4 crystal formation H2 powder
According to X-ray diffraction result, the position of characteristic diffraction peak 2 θ of crystal formation H2 is 6.7 °, 7.0 °, 9.7 °,
19.1 °, 19.3 °, 19.8 °, 20.3 °, 24.9 °, 25.1 °, 25.6 ° etc..
This powder sample is carried out means of differential scanning calorimetry-thermogravimetric analysis, and its result is as shown in Figure 6.
According to Fig. 6, crystal formation H2 in thermogravimetric spectrogram, in the range of 50-200 DEG C, there is an endothermic peak at 84-100
℃.Its differential thermal spectrogram shows that weight-loss ratio is 5.5% in the range of room temperature to 180 DEG C, divides with single crystal X-ray diffraction in range of error
The structure that analysis obtains matches.
Embodiment 3: the preparation of crystal formation H3 monocrystalline
0.5 gram of rope fluorine cloth Wei is mixed with 25 milligrams of ethanol and 5 milliliters of benzyl ether, heats this mixture to 85～90 DEG C also
Stirring makes solid be completely dissolved, and is then slowly cooled to room temperature with the speed of 1～3 DEG C/min and at room temperature stands 72 hours,
By filtering the crystal formation H3 monocrystalline taking out the colourless needles separated out.
The mensuration of the crystal formation H3 crystal structure of embodiment 3
The rope fluorine cloth Wei crystal formation H3 choosing a size of 0.30mm × 0.20mm × 0.10mm in the crystal that embodiment 3 obtains is mono-
Crystalline substance, is placed on single crystal X-ray diffraction instrument, collects 5460 diffraction datas in the range of 1.20 °≤2 θ≤25.38 °, wherein independent
Point diffraction 5230.The data collected correct through the Lp factor and empirical absorption.Use direct method, and through taking turns difference Fourier more
Synthesis, finds out whole hydrogen atom.All non-hydrogen atom coordinates and equivalence anisotropy displacement parameter thereof are all minimum with complete matrix
Square law carries out refine.
Confirming after single crystal X-ray diffraction test and crystal structure calculate, rope fluorine cloth Wei crystal formation H3 belongs to monoclinic system, space
Group P21, cell parameter:α=90.00 °, β=108.78
(3) °, γ=90.00 °；Z=2, the stoichiometric equation in an asymmetry unit is C24H35FN3O10P,
Molecular weight is 575.52, crystalline density d=1.342g/cm3。
Measure and obtain the monocrystalline molecular structure ellipsoid figure of rope fluorine cloth Wei crystal formation H3 as it is shown in fig. 7, its non-hydrogen atom number of coordinates
According to as shown in table 5.
The non-hydrogen atom coordinate parameters of table 5 crystal formation H3
The powder x-ray diffraction analysis of the crystal formation H3 monocrystalline of embodiment 3:
Crystal formation H3 monocrystalline grind into powder embodiment 3 obtained, carries out powder x-ray diffraction analysis to it, its result
As shown in Figure 8.Corresponding with Fig. 8, the X ray diffracting data of crystal formation H3 is as shown in table 6.
The powder x-ray diffraction analysis of table 6 crystal formation H3
According to X-ray diffraction result, the position of diffraction maximum 2 θ of crystal formation H3 is 5.1 °, 6.7 °, 7.1 °, 9.6 °,
15.8 °, 17.2 °, 19.3 °, 19.9 °, 20.7 °, 24.9 ° etc..
This powder sample is carried out means of differential scanning calorimetry-thermogravimetric analysis, and its result is as shown in Figure 9.
According to the thermogravimetric spectrogram of crystal formation H3 in Fig. 9, crystal formation H3 has an endothermic peak 70 in the range of 50～200 DEG C
～88 DEG C.Its differential thermal spectrogram shows that weight-loss ratio is 5.3% in the range of room temperature to 180 DEG C, spreads out with Single Crystal X-ray in range of error
Penetrate and analyze the structure that obtains and match.
Embodiment 4: the preparation of crystal formation H4 monocrystalline
By 0.5 gram of rope fluorine cloth Wei and 5 milliliters of diphenyl ether solvent mixing, it is heated to 85～90 DEG C and forms oily mixture, connect
And be slowly cooled to room temperature with the speed of 1～3 DEG C/min and at room temperature stand 72 hours, take out colourless needles by filtering
Crystal formation H4 monocrystalline.
The mensuration of the crystal formation H4 crystal structure of embodiment 4
The rope fluorine cloth Wei crystal formation H4 choosing a size of 0.20mm × 0.10mm × 0.10mm in the crystal that embodiment 4 obtains is mono-
Crystalline substance, is placed on single crystal X-ray diffraction instrument, collects 6737 diffraction datas in the range of 1.28 °≤2 θ≤25.39 °, wherein independent
Point diffraction 6514.The data collected correct through the Lp factor and empirical absorption.Use direct method, and through taking turns difference Fourier more
Synthesis, finds out whole hydrogen atom.All non-hydrogen atom coordinates and equivalence anisotropy displacement parameter thereof are all minimum with complete matrix
Square law carries out refine.
Confirming after single crystal X-ray diffraction test and crystal structure calculate, rope fluorine cloth Wei crystal formation H4 belongs to monoclinic system, space
Group P21, cell parameter:α=90.00 °, β=116.64
(3) °, γ=90.00 °；Z=2, the stoichiometric equation in an asymmetry unit is
C34H39FN3O10P, molecular weight is 699.65, crystalline density d=1.313g/cm3。
Measure and obtain the monocrystalline molecular structure ellipsoid figure of rope fluorine cloth Wei crystal formation H4 as shown in Figure 10, its non-hydrogen atom number of coordinates
According to as shown in table 7.
The non-hydrogen atom coordinate parameters of table 7 crystal formation H4
The powder x-ray diffraction analysis of the crystal formation H4 monocrystalline of embodiment 4:
Crystal formation H4 monocrystalline grind into powder embodiment 4 obtained, carries out powder x-ray diffraction analysis to it, its result
As shown in figure 11.Corresponding with Figure 11, the X ray diffracting data of crystal formation H4 is as shown in table 8.
The X-ray diffraction analysis of table 8 crystal formation H4 powder
According to X-ray diffraction result, the position of diffraction maximum 2 θ of crystal formation H4 is 5.5 °, 5.6 °, 10.0 °, 10.9 °,
10.9 °, 16.6 °, 19.8 °, 20.0 °, 20.4 °, 25.0 ° etc..
This powder sample is carried out means of differential scanning calorimetry-thermogravimetric analysis, and its result is as shown in figure 12.
According to the thermogravimetric spectrogram of crystal formation H4 in Figure 12, crystal formation H4 has an endothermic peak to exist in the range of 50～200 DEG C
64～76 DEG C.Its differential thermal spectrogram shows that weight-loss ratio is 17.4% in the range of room temperature to 200 DEG C, penetrates with monocrystalline X in range of error
The structure that line diffraction analysis obtains matches.
Test example 1
The crystal formation H1 obtained according to embodiment 1-4, crystal formation H2, crystal formation H3, crystal formation H4 are carried out the Stability Determination of resistance to high humidity,
And compare with crystal formation form1 and form6 of known rope fluorine cloth Wei.
The sample of the various crystal formations of rope fluorine cloth Wei is uniformly spread out cloth in open-top receptacle, thickness of sample≤5 millimeter, it is placed in temperature
Spending 25 ± 2 DEG C, relative humidity is in the constant temperature and humidity incubator of 60 ± 5%, is observed and with initial after fixed time intervals t
Crystal form samples contrasts.Result is as shown in table 9.
Table 9 rope fluorine cloth Wei crystal formation stability (25 DEG C/60% relative humidity) under damp condition
| Crystal formation | T=2 hour | T=4 hour | T=24 hour | T=72 hour |
| Crystal formation H1 | Without deliquescence | Without deliquescence | Without deliquescence | Part deliquescence |
| Crystal formation H2 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation H3 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation H4 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation form 1 | Without deliquescence | Without deliquescence | Part deliquescence | Deliquescence |
| Crystal formation form 6 | Without deliquescence | Without deliquescence | Without deliquescence | Part deliquescence |
Changing temperature and humidity condition, same sample is placed in temperature 40 ± 2 DEG C, relative humidity is the constant temperature of 75 ± 5%
In constant humidity incubator, it is observed after fixed time intervals t and contrasts with initial sample crystal formation.Result is as shown in table 10.
Table 10 rope fluorine cloth Wei crystal formation stability (40 DEG C/75% relative humidity) under damp condition
| Crystal formation | T=2 hour | T=4 hour | T=24 hour | T=72 hour |
| Crystal formation H1 | Without deliquescence | Without deliquescence | Part deliquescence | Deliquescence |
| Crystal formation H2 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation H3 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation H4 | Without deliquescence | Without deliquescence | Without deliquescence | Without deliquescence |
| Crystal formation form 1 | Part deliquescence | Deliquescence | Deliquescence | Deliquescence |
| Crystal formation form 6 | Without deliquescence | Without deliquescence | Part deliquescence | Deliquescence |
Test result shows, crystal formation H2, crystal formation H3 and crystal formation H4 all show less under different temperatures, damp condition
Hygroscopicity, has good stability, efficiently solves the existing rope fluorine cloth more deliquescent problem of Wei crystal formation
Test example 2
The crystal formation H1 obtained according to embodiment 1-4, crystal formation H2, crystal formation H3, crystal formation H4 are carried out solubility test in water, and
Compare with crystal formation form1 and form6 of known rope fluorine cloth Wei.Method of testing is all with reference to 2010 editions two ministerial standards of Chinese Pharmacopoeia
The fixed method of convention is tested.Concrete grammar is as follows: precision weighs appropriate different crystal forms rope fluorine cloth Wei, is slowly added to certain
Amount water, as solvent, every strength shaking in 5 minutes 30 seconds, observes 30 minutes interior dissolving situations.Test result is shown in Table 11.
The different crystal forms of table 11 rope fluorine cloth Wei dissolubility in water
Test result shows, crystal formation H1, crystal formation H2 and crystal formation H3 dissolubility in water are above existing known rope fluorine
Cloth Wei crystal formation, efficiently solves the problem that existing rope fluorine cloth Wei crystal formation dissolubility is the best.
Claims (4)
1. the x-ray diffractogram of powder spectrum of the crystal formation H1 of a rope fluorine cloth Wei, it is characterised in that use Cu-K alpha ray, crystal formation H1
In the angle of diffraction 2 θ 4.9 °, 6.6 °, 7.1 °, 8.2 °, 9.6 °, 16.5 °, 19.0 °, 19.2 °, 19.9 °, there is spy at 24.9 °
Levy peak.
2. crystal formation H1 as claimed in claim 1, it is characterised in that the differential scanning calorimetric thermogram of crystal formation H1 is at 65～80 DEG C
Endothermic peak is had at 95～110 DEG C.
3. for obtaining the preparation method of the crystal formation H1 of rope fluorine cloth Wei as claimed in claim 1 or 2, it is characterised in that by rope
Fluorine cloth Wei and water join in the mixed solvent of methyl phenyl ethers anisole and the mixed solvent of butyl oxide or methyl phenyl ethers anisole and diisopropyl ether, are heated to
70～95 DEG C, being then cooled to 0～35 DEG C, carry out crystallize, the crystallize time is 1～10 day, is derived from crystal formation H1.
4. preparation method as claimed in claim 3, it is characterised in that methyl phenyl ethers anisole with the volume ratio of butyl oxide or diisopropyl ether is
3:1～1:1；Described rope fluorine cloth Wei by gram based on weight and described mixed solvent ratio of volume based on milliliter be 1:5～1:20；Water
It is 1:100～1:20 with rope fluorine cloth Wei part by weight.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610518132.2A CN106083964B (en) | 2014-11-07 | 2014-11-07 | The crystal form H2 and preparation method thereof of rope fluorine cloth Wei |
| CN201410624111.XA CN104447924B (en) | 2014-11-07 | 2014-11-07 | Crystal formation of rope fluorine cloth Wei and preparation method thereof |
| CN201610515840.0A CN106046088B (en) | 2014-11-07 | 2014-11-07 | Crystal form H3 of rope fluorine cloth Wei and preparation method thereof |
| CN201610511226.7A CN106188195B (en) | 2014-11-07 | 2014-11-07 | The crystal form H4 and preparation method thereof of rope fluorine cloth Wei |
| PCT/CN2015/076124 WO2016070569A1 (en) | 2014-11-07 | 2015-04-09 | Sofosbuvir crystal and preparation method thereof |
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| CN201610511226.7A Division CN106188195B (en) | 2014-11-07 | 2014-11-07 | The crystal form H4 and preparation method thereof of rope fluorine cloth Wei |
| CN201610515840.0A Division CN106046088B (en) | 2014-11-07 | 2014-11-07 | Crystal form H3 of rope fluorine cloth Wei and preparation method thereof |
| CN201610518132.2A Division CN106083964B (en) | 2014-11-07 | 2014-11-07 | The crystal form H2 and preparation method thereof of rope fluorine cloth Wei |
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| CN201610511226.7A Expired - Fee Related CN106188195B (en) | 2014-11-07 | 2014-11-07 | The crystal form H4 and preparation method thereof of rope fluorine cloth Wei |
| CN201410624111.XA Expired - Fee Related CN104447924B (en) | 2014-11-07 | 2014-11-07 | Crystal formation of rope fluorine cloth Wei and preparation method thereof |
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| SI3524234T1 (en) | 2014-06-13 | 2021-05-31 | Ratiopharm Gmbh | Solid state forms of sofosbuvir |
| WO2016042576A1 (en) | 2014-09-16 | 2016-03-24 | Cadila Healthcare Limited | Co-crystal of sofosbuvir and amino acid and process for preparation thereof |
| CN105985394B (en) * | 2015-02-26 | 2020-09-22 | 石药集团中奇制药技术（石家庄）有限公司 | Novel Sofosbuvir crystal form and preparation method thereof |
| CN104829673B (en) * | 2015-03-12 | 2017-10-27 | 南京旗昌医药科技有限公司 | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 |
| CN106146589B (en) * | 2015-04-10 | 2019-03-05 | 正大天晴药业集团股份有限公司 | The crystallization of deuterated nucleoside derivates |
| CN104804054B (en) * | 2015-04-17 | 2017-10-24 | 南京旗昌医药科技有限公司 | A kind of crystal formation of rope fluorine cloth Wei and its application |
| CN105017359A (en) * | 2015-07-08 | 2015-11-04 | 苏州晶云药物科技有限公司 | Preparation method of Sofosbuvir crystal form |
| US10738071B2 (en) | 2016-03-17 | 2020-08-11 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
| CN106496295A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | The preparation method of Suo Feibuwei crystal formations 6 |
| CN108084237A (en) * | 2016-11-23 | 2018-05-29 | 广东东阳光药业有限公司 | Monohydrate of Suo Feibuwei and preparation method thereof |
| WO2019025600A1 (en) | 2017-08-03 | 2019-02-07 | Sandoz Ag | Sofosbuvir hydrate |
| WO2021203409A1 (en) * | 2020-04-10 | 2021-10-14 | 南京正大天晴制药有限公司 | Novel non-hygroscopic low-variability crystalline form for treatment of hepatitis c |
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