CN108084237A - Monohydrate of Suo Feibuwei and preparation method thereof - Google Patents
Monohydrate of Suo Feibuwei and preparation method thereof Download PDFInfo
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- CN108084237A CN108084237A CN201711144756.3A CN201711144756A CN108084237A CN 108084237 A CN108084237 A CN 108084237A CN 201711144756 A CN201711144756 A CN 201711144756A CN 108084237 A CN108084237 A CN 108084237A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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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
The present invention provides a kind of monohydrates of Suo Feibuwei and preparation method thereof, belong to medicinal chemistry art.There is diffraction maximum in the position that 2 θ are 7.6 degree in the X ray powder diffraction patterns of the monohydrate.The monohydrate has preferable performance in solubility etc., can be used for being prepared into pharmaceutical preparation.
Description
Technical field
The present invention relates to a kind of monohydrates of Suo Feibuwei and preparation method thereof, belong to medicinal chemistry art.
Background technology
Suo Feibuwei (Sofosbuvir) is a kind of NS5B polymerase inhibitors, to the hepatitis C virus of some genotype
Malicious (HCV) can reduce side effect, have the effect of good without the use of interferon.The structure of Suo Feibuwei (Sofosbuvir)
It is shown below：
There are a variety of crystal forms that more documents disclose Suo Feibuwei, different property is individually present in these crystal forms.Because of drug
Polymorphic is the common phenomenon in drug research and development, is an important factor for influencing drug quality.The different crystal forms of same drug are outside
It might have in terms of the physicochemical properties such as sight, mobility, solubility, storage stability, bioavilability dramatically different, it is understood that there may be
Huge difference can generate different influences to the storage transfer of drug, application, stability, curative effect etc.；Effective profit in order to obtain
In pharmaceutical preparation crystal form, it is necessary to comprehensively be investigated to the crystallization behavior of drug, to obtain the crystal form for meeting production requirement.
The content of the invention
Summary of the invention
One aspect of the present invention provides the monohydrate and its crystal form of Suo Feibuwei, its X-ray powder diffraction of the crystal form
There is diffraction maximum in the position that 2 θ are 7.6,14.2,20.5 degree in figure.
Second aspect of the present invention provides the preparation method of the monohydrate crystal form of the Suo Feibuwei.
Third aspect present invention provides the monohydrate of Suo Feibuwei for treating the purposes of hepatitis.
Fourth aspect present invention provides the pharmaceutical composition of the monohydrate comprising Suo Feibuwei.
Term defines
The invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in claim such as and determine
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 document, patent and the class combined
Like one or more of material are different from the application or (term, term defined in including but not limited in the case of contradicting
Using, described technology etc.), it is subject to the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments
Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity,
It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, 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 identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Term "comprising" or " comprising " are open language, that is, include the content specified by the present invention, but be not precluded from it
Content in terms of him.
Term " crystal form " or " crystal " are used for describing the existence of solid chemical compound, describe ion, the original of crystals
Son or the different kinds of parameters aggregate of molecular composition, symmetric property and periodic arrangement rule.
Term " substantially as shown in the figure " refers in certain essentially pure " crystal form " 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
It appears in given X-ray powder diffraction figure.When the content of certain crystal form in sample continuously decreases, X-ray powder
Some diffraction maximums for belonging to the crystal form 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 form
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, 2 θ in X-ray powder diffraction figure (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 form, 2 θ of X-ray powder diffraction collection or the measurement of diffraction maximum have 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 the measurement of diffraction maximum may slightly have difference, and the numerical value of the experimental error or difference may be +/- 0.2 list
Position or +/- 0.1 unit or +/- 0.05 unit, thus 2 θ or the numerical value of diffraction maximum cannot be considered as it is absolute.
The differential scanning calorimetric curve (DSC) of the crystal form 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 cannot be considered as it is absolute.
The thermal gravimetric analysis curve (TGA) of the crystal form has experimental error, between a machine and another machine and
Between one sample and another sample, weight loss and weightless temperature may slightly have difference, the experimental error or difference of weight loss
Other numerical value is likely less than 0.3%.
In the context of the present invention, wordings such as " about " or " about " whether or not using, all numbers being disclosed that
It is approximation.Each digital numerical value is it is possible that be present with the differences such as 1%, 2% or 5%.Spread out when being related to X-ray powder
When penetrating 2 θ (the also known as 2theta or diffraction maximum) value at peak, about represent that the 2 θ values there may be +/- 0.2 unit or 0.1 +/-
Unit or +/- 0.05 unit difference.
" environment temperature " refers to the natural temperature around things present position, and the environment temperature can according to residing
Area, residing season, residing time are different, generally between -20 DEG C -45 DEG C.
" 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.
In the present invention, crystal form 6 and crystal form 1 refer to patent application CN201180017181.3 (publication No.s respectively
CN102858790A form 6 and form 1 in).Crystal form A refers to patent application CN201410391177.9 (publication No.s
CN104130302A the crystal form A in).
Detailed description of the invention
In the prior art, it has been reported that Suo Feibuwei crystal forms there are many, wherein, solvate has dichloromethane solvent
Object, chloroform solvated compounds, methanol solvate compound, alcohol solvent compound and diphenyl ether solvated compounds are closed, due to
Solvent toxicity or it is molten residual exceeded the problems such as, these solvated compounds are dfficult to apply among preparation.Therefore, a kind of each side is developed
The crystal form for being relatively easy to application is necessary.For this purpose, the present invention provides a kind of new Suo Feibuwei monohydrates and
Its crystal form.
In a first aspect, inventor is by having researched and developed the monohydrate of Suo Feibuwei.
Inventor also developed the monohydrate crystal form of Suo Feibuwei by research.
In some embodiments, the monohydrate of Suo Feibuwei has at least 95% crystallinity.In some embodiment party
In formula, the monohydrate of Suo Feibuwei has at least 98% crystallinity.In some embodiments, a hydration of Suo Feibuwei
Object has at least 99% crystallinity.
The monohydrate crystal form of Suo Feibuwei, has the property that：In 2 θ it is 7.6 degree in its X-ray powder diffraction figure
There is diffraction maximum in position.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
14.2,16.9,20.5,23.3,30.2 there is diffraction maximum in the position of degree.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
12.7,14.2,15.9,16.9,18.0,19.6,20.5,23.3,30.2 there is diffraction maximum in the position of degree.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
12.7,14.2,15.9,16.4,16.9,18.0,19.6,20.5,21.9,23.0,23.3,2 the position of 5.6,30.2 degree, which has, spreads out
Penetrate peak.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
11.4,12.7,13.4,14.2,15.9,16.4,16.9,18.0,19.6,20.5,21.2,21.9,23.0,23.3,24.1,
25.6,26.3,26.6,27.3,28.6,30.2 there is diffraction maximum in the position of degree.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
10.4,11.4,12.2,12.7,13.4,14.2,15.3,15.9,16.4,16.9,18.0,19.1,19.6,20.5,21.2,
21.9,23.0,23.3,24.1,25.6,26.3,26.6,26.9,27.3,28.6,30.2,3 the position of 2.2,34.6 degree has
Diffraction maximum.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei 2 θ be 7.6,
10.4,11.4,12.2,12.7,13.4,14.2,15.3,15.9,16.4,16.9,18.0,19.1,19.6,20.5,21.2,
21.9,22.2,23.0,23.3,24.1,25.6,26.3,26.6,26.9,27.3,28.6,30.2,30.8,32.2,32.8,
34.6,40.9 there is diffraction maximum in the position of degree.
In some embodiments, in the X-ray powder diffraction figure of the monohydrate crystal form of the Suo Feibuwei, it is in 2 θ
The relative intensity of 20.5 degree of diffraction maximum is more than 90% or more than 99%.
In some embodiments, the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei is substantially such as attached drawing Fig. 1
It is shown.
In some embodiments, the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei is as shown in attached drawing Fig. 1.
The monohydrate crystal form of the Suo Feibuwei, also has the property that：Its differential scanning calorimetric curve (DSC) is 70
There is endothermic peak at DEG C -90 DEG C.In some embodiments, differential scanning calorimetric curve (DSC) is at 70 DEG C -80 DEG C
With endothermic peak.In some embodiments, differential scanning calorimetric curve (DSC) has heat absorption at 74 DEG C -77 DEG C
Peak.In some embodiments, the differential scanning calorimetric curve (DSC) of the monohydrate crystal form of Suo Feibuwei is substantially such as attached drawing
Shown in Fig. 2.In some embodiments, differential scanning calorimetric curve (DSC) such as attached drawing of the monohydrate crystal form of Suo Feibuwei
Shown in Fig. 2.
In some embodiments, the monohydrate crystal form of the Suo Feibuwei, also has the property that：Its thermogravimetric analysis
There is weightlessness in graph in the range of 60 DEG C -120 DEG C.In some embodiments, the monohydrate of the Suo Feibuwei is brilliant
There is larger weightlessness in the range of 60 DEG C -120 DEG C, weight loss is about 3.27% in the thermal gravimetric analysis curve figure of type.At some
In embodiment, the thermal gravimetric analysis curve figure of the monohydrate crystal form of the Suo Feibuwei is substantially as shown in attached drawing Fig. 3.One
In a little embodiments, the thermal gravimetric analysis curve figure of the monohydrate crystal form of the Suo Feibuwei is as shown in attached drawing Fig. 3.
The monohydrate crystal form of above-mentioned Suo Feibuwei has at least 95% crystallinity.In some embodiments, it is above-mentioned
The monohydrate crystal form of Suo Feibuwei has at least 98% crystallinity.In some embodiments, the one of above-mentioned Suo Feibuwei
Hydrate crystal forms have at least 99% crystallinity.
Inventor, which passes through, confirms the Advances in crystal X-ray diffraction experiment of the monohydrate of the Suo Feibuwei and crystal structure,
It can confirm that the crystal form of the monohydrate of the Suo Feibuwei belongs to rhombic system, space group P212121, cell parameter： α=90.00 °, β=90.00 °, γ=90.00 °；Unit cell volumeStructure cell includes asymmetric cell number Z=4, and the stoichiometric equation in an asymmetric cell is
C22H31FN3O10P, molecular weight 699.65, crystalline density d are 1.372g/cm3.Advances in crystal X-ray diffraction structural analysis confirms
Contain 1 in the monohydrate crystal form lattice of the Suo Feibuwei:1 hydrone.
The monohydrate crystal form of the Suo Feibuwei is rodlike.In some real-time modes, a water of the Suo Feibuwei
It is corynebacterium to close object crystal form.
In some embodiments, the monohydrate crystal form water content of the Suo Feibuwei is about 3.27%.
Solubility test, a hydration of Suo Feibuwei are carried out by the monohydrate crystal form to Suo Feibuwei of the present invention
Object crystal form has good performance in dissolubility, mobility and/or bioavilability etc., is conducive to, in production technology
Transfer operation can be used in pharmaceutical preparation production process.Inventor has found in the course of the research, a water of the Suo Feibuwei
It is corynebacterium to close object crystal form, with preferable mobility, in crystal preparation process, is easy to being filtered lock out operation of Denging,
Be conducive to the operations such as transfer from production equipment；The crystal form 6 of Suo Feibuwei is difficult to filter in preparation process to separate with filtrate, rope
The needle-shaped crystal form A of Fei Buwei is easy to be separated by filtration with respect to crystal form 6, but it still has certain difficulty for separating, drying with filtrate
Degree, mobility is poor compared with the monohydrate crystal form of corynebacterium, and monohydrate crystal form is easier to filtering in production, storage, bag
Dress and preparation.
Stability test is carried out by the monohydrate crystal form to Suo Feibuwei of the present invention, finds the one of Suo Feibuwei
Hydrate crystal forms are in high humility (25 DEG C, RH 92.5% ± 5%) or illumination (visible ray 4500Lux ± 500Lux, ultraviolet light
1.7W*h/m2,25 DEG C, RH 60% ± 5%) under the conditions of crystal form it is constant, but at high temperature (40 DEG C or 60 DEG C, RH 75% ± 5%)
Under the conditions of it is unstable, be easily converted into crystal form 6.
Second aspect, the present invention also provides the preparation methods of the monohydrate crystal form of the Suo Feibuwei.
A kind of method for the monohydrate crystal form for preparing Suo Feibuwei, including：Suo Feibuwei crystal forms I and water are mixed, stirred
It mixes, solid is converted into colloidal solid, stands a period of time, and corynebacterium crystal is precipitated, and colloidal solid is fully converted to crystal,
Separation, obtains the monohydrate crystal form product of Suo Feibuwei；Wherein, Mei mono- Ke Suofeibuwei, the dosage of water is 3mL-15mL.Institute
State time of standing for 10 it is small when -36 it is small when.
A kind of method for the monohydrate crystal form for preparing Suo Feibuwei, including：Suo Feibuwei is dissolved in alcoholic solvent, is obtained
Solution be added dropwise in the water of certain temperature, stir, stir certain time after being added dropwise, separate solid, obtain Suo Feibuwei
Monohydrate crystal form product.
The alcoholic solvent is methanol, ethyl alcohol, normal propyl alcohol, isopropanol or its combination.Mei mono- Ke Suofeibuwei, the alcohol are molten
Agent dosage is 3mL-10mL.In some embodiments, a Ke Suofeibuwei, the alcoholic solvent dosage are 5mL.
The temperature-controllable of the water is made as 0 DEG C -50 DEG C.In some embodiments, the water temperature control for 5 DEG C-
30℃.In some embodiments, the temperature control of the water is 5 DEG C -20 DEG C.In some embodiments, the temperature of the water
Degree control is 10 DEG C -20 DEG C.
In some embodiments, after being added dropwise, stirring 12 it is small when -30 it is small when.In some embodiments, dripping
After adding, stirring 20 it is small when -30 it is small when.
In some embodiments, Suo Feibuwei being dissolved in ethyl alcohol, obtained solution is added in 10 DEG C -20 DEG C of water,
Stirring, finish, stirring 22 it is small when -28 it is small when, then separate solid, obtain the monohydrate crystal form product of the Suo Feibuwei.
The third aspect, the present invention provides Suo Feibuwei monohydrate crystal form treatment hepatitis drug in application.
The monohydrate crystal form of the Suo Feibuwei can be used for the drug for preparing the diseases such as treatment hepatitis.
Fourth aspect, the present invention provides the pharmaceutical compositions of the monohydrate crystal form comprising Suo Feibuwei.
The monohydrate crystal form of the Suo Feibuwei can be at least one pharmaceutically acceptable inert excipient or load
Body mixes, and the various solid dosage forms of oral medicine is prepared into, including capsule, tablet etc.；It can also be with various excipient or carrier system
For into solid dispersions etc., various solid pharmaceutical preparations are then prepared into.
The inert excipient or carrier are selected from croscarmellose sodium, microcrystalline cellulose etc..
The therapeutically effective amount weight percent of the monohydrate crystal form of Suo Feibuwei accounted in entire preparation about 0.1% to
99.5%, it is that the weight percent of about 0.5% to 95% weight is present in said medicine preparation in some embodiments；One
It is that the weight percent of about 20% to 90% weight is present in said medicine preparation in a little embodiments.
Description of the drawings
Fig. 1 shows the X-ray powder diffraction figure of the monohydrate crystal form of Suo Feibuwei.
Fig. 2 shows the differential scanning thermal map (DSC) of the monohydrate crystal form of Suo Feibuwei.
Fig. 3 shows the thermogravimetric analysis figure (TGA) of the monohydrate crystal form of Suo Feibuwei.
Specific embodiment
In order to which those skilled in the art is made to more fully understand technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can be bought or can be by method system described in the invention from the market
It is standby and obtain.
In the present invention, g expressions gram, mL represents milliliter, and h represents hour, and mg/mL represents mg/ml, rpm expressions rev/min
Clock, RH represent relative humidity.
Instrument parameter
Except making separate stipulations in nonparametric, all analyses below all carry out at room temperature.
X-ray powder diffraction (XRPD)
On PANalytical diffractometers, carried out using equipped with the x'celerator detectors with 120 ° of 2 θ scopes
X-ray powder diffraction (XRPD) is analyzed.It is radiated using Cu-K αIt is 3 ° of beginnings in 2 θ, scanning step is
0.0168 ° of 2 θ, sweep speed walk for 10s/, collect real time data.Tube voltage and amperage are respectively set as 45kV and 40mA.
Antiscatter slits are set as 6.6mm, and divergent slit is 1 degree.2 θ patterns of 3 ° -60 ° of display.Suitable sample is taken to be placed in zero background
It at specimen holder circular groove, is gently pressed with clean glass slide, obtains a smooth plane, and zero Background Samples frame is fixed,
To obtain the final product, sample is placed on automatic sampling apparatus, successively sample introduction.Using silicon instrument calibration is carried out with reference to standard specimen.
In X-ray powder diffraction figure, ordinate is the diffracted intensity represented with (counts) is counted, and abscissa is to use
2 θ of the angle of diffraction that degree (°) represents.
X-ray single crystal diffraction
Cu K α radiations are used on Agilent Technologies Gemini A Ultra diffractometersIt receives
Collect data, being indexed and handle using CrysAlis PRO programs for the intensity data of measurement determines structure cell by preliminary experiment
Parameter formulates data collection strategy to carry out data collection according to cell parameter.Make crystal during data collection in Oxford
Cryo systems (Oxford Cryosystems：Crystream Controller 700) nitrogen cold flow in cool down.
Structure elucidation and refine use SHELX-97 (Sheldrick, G.M.SHELXTL-97, Program for
Crystal Structure Solution and Refinement；University of Gottingen:Gottingen,
Germany, 1997.) program progress, it is parsed by direct method.Atomic parameter (coordinate and temperature factor) everywhere passes through
Perfect matrix least square refinement.Minimized in amendment function ∑ w (| Fo |-| Fc |) 2.R is defined as ∑ | | Fo |-| Fc
| |/∑ | Fo |, and Rw=[∑ w (| Fo |-| Fc |) 2/ ∑ w | Fo | 2] 1/2, wherein w is the error in the intensity based on observation
It is suitble to weighting function.Difference plot checks in modified all stages.Except the position of hydrogen atom H1N and H2N are using in difference Fu
Outside leaf figure determines, the position of remaining hydrogen atom is obtained by theoretical calculation.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) is carried out using TA Instruments differential scanning calorimetry (DSC)s Q2000.Sample is put
Enter in aluminium DSC disks and accurately record weight.The disk is covered with lid, is then crimped.Sample cell is balanced and at 25 DEG C in nitrogen
Air-blowing is swept under (50mL/min) and 300 DEG C of final temperature is heated to the rate of 10 DEG C/min.It is marked using indium metal as calibration
Sample.In DSC figures, abscissa expression temperature (Temperature, DEG C), ordinate represents the heat that the substance of unit mass is released
Flow (Heat Flow, watt/gram, W/g).
Thermogravimetry (TGA)
TGA data are gathered on TA Instruments Q500.Use the temperature of the nickel calibration instrument of certification.Usually will
8-12mg samples are loaded on pre-weighed platinum crucible, and are heated to 300 DEG C from room temperature with 10 DEG C/min.It is protected above sample
Hold the nitrogen purge of 60mL/min.In TGA figures, abscissa expression temperature (Temperature, DEG C), ordinate represents weightless
Percentage composition (Weight (%)).
Embodiment 1
Under the conditions of room temperature (28.0 DEG C), 10.00g Suo Feibuwei crystal form I and 100mL water, magnetic force are added in 250mL flasks
Stirring, rate 200rpm, stirring 10min or so, solid is converted into colloidal solid；Stand 24 it is small when, stub is precipitated in flask walls
Shape crystal, and colloidal solid is fully converted to crystal；Filtering, obtained solid obtain solid when room temperature in vacuo drying 24 is small
9.50g is analyzed by X-ray powder diffraction, confirms as Suo Feibuwei hydrate crystal forms.
Embodiment 2
Under the conditions of room temperature (28.0 DEG C), 10.00g Suo Feibuwei crystal form I and 50mL water, magnetic force are added in 250mL flasks
Stirring, rate 200rpm, stirring 10min or so, solid is converted into colloidal solid, when standing 26 is small, is precipitated in flask walls short
Rhabdolith, and colloidal solid is fully converted to crystal；Filtering, obtained solid room temperature in vacuo drying 24 it is small when, consolidate
Body 9.51g, is analyzed by X-ray powder diffraction, confirms as Suo Feibuwei hydrate crystal forms.
Embodiment 3
Under the conditions of room temperature (28.0 DEG C), 2.00g Suo Feibuwei are dissolved in 10mL ethyl alcohol；50mL water is packed into another flask
In, it is 15.0 DEG C to measure water temperature, magnetic agitation, rate 150rpm；By foregoing obtained Suo Feibuwei ethanol solutions with
The drop rate of 0.20mL/min is added dropwise in the above-mentioned flask equipped with water, magnetic agitation speed 150rpm, after being added dropwise
When persistently stirring 24 is small；Filtering, obtained solid obtain crystal 1.80g, by X-ray powder when room temperature in vacuo drying 24 is small
Diffraction analysis confirms as Suo Feibuwei hydrate crystal forms, referring to attached drawing Fig. 1-Fig. 3.
Embodiment 4
Under the conditions of room temperature (28.0 DEG C), 12.00g Suo Feibuwei are dissolved in 60mL ethyl alcohol；300mL water is packed into another flask
In, water temperature is 15.0 DEG C, magnetic agitation, rate 150rpm；By foregoing obtained Suo Feibuwei ethanol solutions with 1.20mL/
The drop rate of min is added dropwise in above-mentioned 300mL water, magnetic agitation speed 150rpm, and it is small that 24 are persistently stirred after being added dropwise
When；Filtering, obtained solid obtains crystal 11.50g when room temperature in vacuo drying 24 is small, through being analyzed by X-ray powder diffraction,
Confirm as Suo Feibuwei hydrate crystal forms.
Embodiment 5：Solubility test
Experimental method：Advance weigh test tube and stirrer, accurately weigh 6 sample of hydrate crystal forms sample and crystal form, add in
In bottle, water, same way stirring is added dropwise, until solid dissolving stops plus water.During without visual visible particle, it is considered as and is completely dissolved.
The total weight for test tube, stirrer and the aqueous solution of weighing after dissolving calculates the weight of added water, then calculates solubility；Water
Density calculated according to 1.0g/mL.Solubility of both crystal form samples in 25 DEG C or 37 DEG C of water is tested respectively.
Experimental result：
| Temperature | Crystal form | Solubility |
| 25℃ | Hydrate | 1.69mg/mL |
| 25℃ | Crystal form 6 | 1.62mg/mL |
| 37℃ | Hydrate | 2.86mg/mL |
| 37℃ | Crystal form 6 | 2.57mg/mL |
Embodiment 6：Study on the stability
Hot test：Take sample appropriate, tiling is put in measuring cup, respectively at 40 DEG C ± 2 DEG C or 60 ± 5 DEG C, RH 75% ±
It is placed in 5% climatic chamber, then took above-mentioned sample about 50mg respectively at 5,10 and 15 days, test its crystal form situation；
High wet test：Take sample appropriate, tiling is put in measuring cup, in 25 DEG C, 92.5% ± 5% climatic chambers of RH
It places, then took above-mentioned sample about 50mg respectively at 5,10 and 15 days, test its crystal form situation；
Exposure experiments to light：It takes sample appropriate, tiles into measuring cup, in visible ray 4500Lux ± 500Lux, ultraviolet light
It places, was then taken respectively at 5,10 and 15 days above-mentioned under the conditions of the climatic chamber (25 DEG C, RH 60% ± 5%) of 1.7W*h/m2
Sample about 50mg tests its crystal form situation；As a result see the table below：
According to result, the monohydrate crystal form is under the conditions of hot and humid (40 DEG C or 60 DEG C, RH75% ± 5%)
Unstable, it is crystal form 6 that can turn brilliant, but is stablized under high humidity (25 DEG C, RH 92.5% ± 5%) and illumination condition, will not turn brilliant.
By drawing moist test to the monohydrate crystal form, it is found that it is moist without drawing.
The method of the present invention is described by preferred embodiment, related personnel can substantially hold within the present invention,
Method described herein and application are modified or suitably changed with combining in spirit and scope, 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, it should be pointed out that institute
Have similar replacement and change it is apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (13)
1. a kind of monohydrate of Suo Feibuwei.
2. monohydrate described in claim 1, there is diffraction maximum in the position that 2 θ are 7.6 degree in X-ray powder diffraction figure.
3. in 2 θ it is 7.6,14.2,16.9,20.5 in X-ray powder diffraction figure monohydrate described in claim 1,
23.3,30.2 there is diffraction maximum in the position of degree；Or in its X-ray powder diffraction figure 2 θ be 7.6,12.7,14.2,15.9,
16.9,18.0,19.6,20.5,23.3,30.2 there is diffraction maximum in the position of degree；Or it is in 2 θ in its X-ray powder diffraction figure
7.6,12.7,14.2,15.9,16.4,16.9,18.0,19.6,20.5,21.9,23.0,23 the position of .3,25.6,30.2 degree
There is diffraction maximum；Or in its X-ray powder diffraction figure 2 θ be 7.6,11.4,12.7,13.4,14.2,15.9,16.4,
16.9,18.0,19.6,20.5,21.2,21.9,23.0,23.3,24.1,25.6,26.3,2 6.6,27.3,28.6,30.2 degree
Position have diffraction maximum；Or in its X-ray powder diffraction figure 2 θ be 7.6,10.4,11.4,12.2,12.7,13.4,
14.2,15.3,15.9,16.4,16.9,18.0,19.1,19.6,20.5,21.2,21.9,23.0,23.3,24.1,25.6,
26.3,26.6,26.9,27.3,28.6,30.2,32.2,34.6 there is diffraction maximum in the position spent；Or its X-ray powder spreads out
Penetrate in figure 2 θ be 7.6,10.4,11.4,12.2,12.7,13.4,14.2,15.3,15.9,16.4,16.9,18 .0,19.1,
19.6,20.5,21.2,21.9,22.2,23.0,23.3,24.1,25.6,26.3,26.6,26.9,27.3,28.6,30.2,
30.8,32.2,32.8,34.6,40.9 there is diffraction maximum in the position of degree.
4. the monohydrate described in claim 2, in the opposite of the diffraction maximum that 2 θ are 20.5 degree in X-ray powder diffraction figure
Intensity is more than 90% or more than 99%.
5. the monohydrate described in claim 2 is rodlike.
6. the monohydrate described in claim 2, differential scanning calorimetric curve has endothermic peak at 70 DEG C -80 DEG C.
7. the monohydrate described in claim 2, thermogravimetric analysis has weightlessness in the range of 60 DEG C -120 DEG C.
8. monohydrate described in claim 1, cell parameter：α
=90.00 °, β=90.00 °, γ=90.00 °.
9. any monohydrates of claim 1-8 have at least 95% crystallinity.
10. a kind of method for preparing any monohydrates of claim 1-9, including：Suo Feibuwei crystal forms I and water are mixed
Close, stirring, solid is converted into colloidal solid, stand 10 it is small when -36 it is small when, corynebacterium crystal is precipitated, and colloidal solid is complete
Crystal is converted into, separates, obtains the monohydrate product of Suo Feibuwei；Wherein, Mei mono- Ke Suofeibuwei, the dosage of water is 3mL-
15mL。
11. a kind of method for preparing any monohydrates of claim 1-9, including：Suo Feibuwei is dissolved in alcoholic solvent
In, obtained solution is added in 0 DEG C -50 DEG C of water, stirring, finish, stirring 12 it is small when -30 it is small when, separate solid, obtain Suo Fei
The monohydrate product of cloth Wei；The alcoholic solvent for methanol, ethyl alcohol, normal propyl alcohol, isopropanol or its combination, Mei mono- Ke Suofeibu
Wei, the alcoholic solvent dosage are 3mL-10mL.
12. the method described in claim 11, wherein, the temperature of water is 5 DEG C -30 DEG C.
13. the method described in claim 11, including：Suo Feibuwei is dissolved in ethyl alcohol, obtained solution is added dropwise to 10 DEG C -20
DEG C water in, stirring, after being added dropwise stir 20 it is small when -30 it is small when, then separate solid, obtain a water of the Suo Feibuwei
Close object product.
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