CN105175473B - A kind of Austria shellfish cholic acid crystal form I and preparation method thereof, pharmaceutical composition and purposes - Google Patents
A kind of Austria shellfish cholic acid crystal form I and preparation method thereof, pharmaceutical composition and purposes Download PDFInfo
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- CN105175473B CN105175473B CN201510520721.XA CN201510520721A CN105175473B CN 105175473 B CN105175473 B CN 105175473B CN 201510520721 A CN201510520721 A CN 201510520721A CN 105175473 B CN105175473 B CN 105175473B
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- crystal form
- cholic acid
- shellfish cholic
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- 239000004380 Cholic acid Substances 0.000 title claims abstract description 48
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The present invention relates to crystal form I (such as following figure) of shellfish cholic acid difficult to understand (Obeticholic Acid) and preparation method thereof；
Description
Technical field
The invention belongs to pharmaceutical chemistry crystallization technique fields.In particular to a kind of shellfish cholic acid crystal form I difficult to understand, further relate to
Preparation method, its pharmaceutical composition and the purposes of the crystal form I.
Background technique
Shellfish cholic acid difficult to understand is a kind of potent agonist of farnesoid X receptor (farnesoid X receptor), is adjusting bile
It plays a role during sour water is flat.Animal experiment, which is proved it, to be improved insulin resistance (IR) and mitigates the effect of hepatic fat content.
Later phase clinical experiments have shown that, shellfish cholic acid difficult to understand has significantly to the rare liver diseases sign of one of middle-aged women is occurred mainly in
Improve, the liver transfer operation demand and mortality risk of patient is reduced, in addition, it is also used to treat nonalcoholic steatohepatitis.
Shellfish cholic acid difficult to understand is a kind of chenodeoxycholic acid derivative, and its chemical name is 6- ethyl chenodeoxycholic acid, English names
For Obeticholic Acid also known as OCA, structural formula is as follows:
The conceptual phase before Medicine prescription, it is often necessary to which medicine is selected according to the requirement of the property of drug and target formulation
The solid forms of object.The difference of medical solid form will lead to physicochemical property, such as stability, solubility, dissolution rate, hygroscopicity
Difference, and then influence its drug effect and Pharmacology, the selection of medical solid form is the weight to be considered in preparation research
Want factor, it is therefore desirable to find a kind of high shellfish cholic acid crystalline form difficult to understand of stability.
Patent document WO2013192097A1 discloses the crystalline form 1 (unformed) of shellfish cholic acid difficult to understand, crystal form A, crystalline form C, crystalline form
D, crystalline form F and crystalline form G, wherein crystal form A, C, D are mixed type hydrate/solvate containing water and a certain range organic solvent
Crystalline form, above-mentioned crystal form there are still stability it is poor the problem of, nitromethane, acetonitrile etc. are used in crystalline form F, G preparation process
Solvent pollutes environment.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of shellfish cholic acid novel crystal forms I difficult to understand.It is of the present invention
Crystal form I has the characteristics that stability is higher.The invention further relates to the preparation method of the crystal form I, its pharmaceutical composition and purposes.
Purpose according to the present invention, the crystal form I that the present invention provides shellfish cholic acid difficult to understand is an anhydride, the following institute of structural formula
Show:
In one embodiment of the invention, it is radiated using Cu-K α, the X-ray that the crystal form I is indicated with 2 θ angles
Powder diagram has characteristic peak: 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 12.7 ± 0.2 °, 16.7 in following position
± 0.2 ° and 19.4 ± 0.2 °.
It in a currently preferred embodiment, is radiated using Cu-K α, the X- that the crystal form I is indicated with 2 θ angles
Ray powder diffraction pattern following position have characteristic peak: 4.2 ± 0.2 °, 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °,
9.4 ± 0.2 °, 10.2 ± 0.2 °, 12.5 ± 0.2 °, 12.7 ± 0.2 °, 15.6 ± 0.2 °, 16.3 ± 0.2 °, 16.7 ± 0.2 ° and
19.4±0.2°。
In the preferred embodiment of the present invention, radiated using Cu-K α, the crystal form I is indicated with 2 θ angles
X-ray powder diffraction figure has characteristic peak and its relative intensity in following position:
Without limitation, a representative instance of the crystal form I has X-ray powder diffraction figure as shown in Figure 2.
The monocrystalline of the crystal form I, 100K at a temperature of measure, have monocrystalline cell parameter below: axial length isDihedral angle be α=92.788 (2) °, β=
90.398 (2) °, γ=97.281 (2) °；Space group: P1 (1)；Each structure cell includes 8 shellfish cholic acid molecules difficult to understand；Unit cell volume isStructure cell density is 0.825505g/cm3；Flack parameter is 0.018 (136).
In one embodiment of the invention, the FTIR spectrum of the crystal form I wave number be 2930,1707,
1450,1364,1262,1242,1161,1121,1062,1045,973,954 and 808cm-1Place has characteristic peak.
The DSC map of the crystal form I is shown: having an endothermic peak at 60~90 DEG C.
The fusing point of the crystal form I is 77 DEG C
The TGA map of the crystal form I is shown: having 7.07% weightlessness before 100 DEG C, has 11.79% mistake before 150 DEG C
Weight.
The weight change that the adsorption isothermal curve of the crystal form I is shown in 20%~80% RH range is
0.57%.
Compared with known shellfish cholic acid solid forms difficult to understand, crystal form I of the invention has stability good, and simple process is easy to produce
The characteristics of industry.
Purpose according to the present invention, the present invention provide the preparation method of crystal form I and exist the following steps are included: forming shellfish cholic acid difficult to understand
Solution in organic solvent, the organic solvent are selected from halogenated alkane or ester, evaporate into dry, obtain the crystal form I；
Preferably, the halogenated alkane is selected as methylene chloride and chloroform, more preferably methylene chloride；The ester is selected as
C3~C6Ester, more preferably n-butyl acetate；
Preferably, the concentration of the solution of the shellfish cholic acid difficult to understand in organic solvent is 10~200mg/mL；
Preferably, the operation temperature of the preparation method is 10~50 DEG C, more preferably room temperature.
In above-mentioned preparation method, " the C3~C6Ester " refers to formic acid, acetic acid, propionic acid, butyric acid and methanol, ethyl alcohol, positive third
All esters of the C number that alcohol, isopropanol, n-butanol, sec-butyl alcohol, the tert-butyl alcohol are formed 3~6.
The crystal form I that above-mentioned preparation method obtains, is dried using the conventional method of this field." drying " method,
Such as it forced air drying, is dried under reduced pressure；Drying equipment uses draught cupboard, convection oven or vacuum drying oven；Can decompression or not
It is dried under decompression, preferably pressure is less than 0.09MPa；Drying temperature is 10~40 DEG C, preferably room temperature；Drying time is 1
~72 hours, preferably 1~10 hour, more preferably 1~2 hour.
The preparation method step of crystal form I of the present invention is simple, easily operated.
In the present invention, " room temperature " refers to about 10~30 DEG C.
In the present invention, shellfish cholic acid form A difficult to understand is referred to 6 description of the reaction of patent document W02013192097A1 embodiment 1
Method be prepared or be available commercially.
Crystal form I of the present invention be it is pure, single, do not mix any other crystal, crystal form or amorphous state substantially.
" not having substantially " refers to that other crystal, crystal form or the amorphous state that wherein contain less than 20% (weight), more refer to less than 10% (weight
Amount), it is especially less than 5% (weight), is particularly related to less than 1% (weight).
Purpose according to the present invention, the present invention provide a kind of pharmaceutical composition, described pharmaceutical composition include treatment and/or
The above-mentioned crystal form I that the active pharmaceutical ingredient of prevention effective dose is selected from crystal form I of the invention or is obtained by preparation method of the present invention,
And at least one pharmaceutically acceptable carrier or auxiliary agent.Described pharmaceutical composition generally comprises, by weight about 1%~
99% shellfish cholic acid crystal form I difficult to understand of the invention, and by weight about 99%~1% at least one are pharmaceutically acceptable suitable
When carrier or auxiliary agent.In addition, described pharmaceutical composition can also comprising the other pharmaceutical salt of shellfish cholic acid difficult to understand, solvate,
The crystal or amorphous state of hydrate.Optionally, described pharmaceutical composition can also include one or more other pharmaceutical activity
Ingredient.
Described pharmaceutical composition can be prepared as the dosage form of solid-state, semisolid or liquid, solid oral dosage form, for example including piece
Agent, capsule, granule, pill and powder；Liquid oral dosage form, for example including solution, syrup, suspension, dispersing agent
And emulsion；Injectable formulation, for example including solution, dispersing agent and the freeze-dried powder for being re-dubbed solution.It is living that formula may be adapted to drug
Quick-release, sustained release or the controlled release of property ingredient, can be conventional, dispersible, masticable, Orally dissolving or rapid melting
Preparation.Administration route includes oral, intravenous injection, subcutaneous injection, cutaneous penetration, rectally, intranasal administration etc..In order to prepare
When keep crystal form of the invention, pharmaceutical composition of the invention is preferably solid oral dosage form comprising tablet, capsule,
Granula, pill and powder, can more preferably be sustained or the solid oral dosage form of realizing controlled-release.
In the case where solid dosage forms, pharmaceutically acceptable carrier of the present invention or auxiliary agent include but is not limited to: dilute
Release agent, for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate, mannitol,
Sorbierite, sugar etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl
Ylmethyl cellulose, polyethylene glycol etc.；Disintegrating agent, for example, starch, sodium starch glycollate, pregelatinized starch, crospovidone,
Croscarmellose sodium, colloidal silicon dioxide etc.；Lubricant, such as stearic acid, magnesium stearate, zinc stearate, benzoic acid
Sodium, sodium acetate etc.；Glidant, such as colloidal silicon dioxide etc.；Complex forming agents, such as cyclodextrin and the tree of various ranks
Rouge；Rate of release controlling agent, for example, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose,
Methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable carriers or auxiliary agent include but is not limited to
Film forming agent, plasticizer, colorant, flavoring agent, viscosity modifier, preservative, antioxidant etc..
Described pharmaceutical composition can be used that well known to a person skilled in the art methods in the prior art to prepare.When preparation
By the crystal form I of shellfish cholic acid difficult to understand of the invention and one or more pharmaceutically acceptable carriers or auxiliary agent, optional one kind or more
The other active components of kind mix.Solid pharmaceutical preparation can be prepared by the techniques such as directly mixing, pelletizing.
Purpose according to the present invention, the present invention provide the crystal form I of shellfish cholic acid difficult to understand of the invention preparation for treating and/or
Prevent FXR and mediates insufficiency of accommodation, cardiovascular disease or cholestatic liver disease and high HDL cholesterol, high triglyceride and fiber
Purposes in the drug of neuodegenerative disorder.
Purpose according to the present invention, the present invention provides a kind for the treatment of and/or prevention FXR mediates insufficiency of accommodation, cardiovascular disease
The method of disease or cholestatic liver disease and high HDL cholesterol, high triglyceride and fibrosis conditions, the method includes
It gives patient's treatment of needs and/or the crystal form I of the invention of prevention effective dose or method produced according to the present invention obtains
Crystal form I or foregoing pharmaceutical composition of the invention；The patient refers to mammal including humans.In some implementations
In scheme, dosage range can be about 0.01 milligram of per kg body weight per day Dao about 100 milligrams, and convenient daily dosage can be used
Mode.Type and extent, the general health of patient, the characteristic of formula and administration route of the visual illness of dosage etc. and adjust
Section.
Above-mentioned FXR mediates insufficiency of accommodation, cardiovascular disease or cholestatic liver disease and high HDL cholesterol, high glycerine three
Ester and fibrosis conditions include but is not limited to biliary atresia, cholestatic liver disease, chronic liver disease, non-alcoholic fatty liver
Scorching (NASH), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), due to progressive fibre modification, liver
Fibre modification and cardiovascular disease (including atherosclerosis, arteriosclerosis, hypercholesterolemia and hyperlipemia) cause
Hepatic disorder.
Detailed description of the invention
Fig. 1 is the XRPD figure of Austria shellfish cholic acid form A disclosed in WO2013192097A1
Fig. 2 is the XRPD figure of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Fig. 3 is the TGA figure of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Fig. 4 is the DSC figure of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Fig. 5 is the DVS figure of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Fig. 6 is the adsorption isothermal curve of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Fig. 7 is the IR figure of shellfish cholic acid crystal form I difficult to understand prepared by embodiment 1
Specific embodiment
The present invention is with further reference to following embodiment, the embodiment detailed description of the present invention crystal form I, preparation method
And application.It will be apparent for a person skilled in the art that for many changes of both material and method this can be not being departed from
Implement in the case where invention scope.
Detecting instrument and method:
X-ray powder diffraction (XRPD): instrument is Bruker D8Advance diffractometer, using copper target wave
The Ka X-ray of a length of 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ angular instrument, Mo monochromator, Lynxeye spy
Survey device.Instrument is calibrated using preceding with diamond dust.Acquisition software is Diffrac Plus XRD Commander.Sample is in room temperature
Lower test, sample is placed on areflexia plate.Testing conditions are as follows: angular range: 3-40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.2
Second/step.
Differential thermal analysis (DSC) data are picked up from TA Instruments Q200MDSC, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.Usually take 1~10 milligram of sample be placed in it is uncapped (unless
Illustrate) aluminium crucible in, with the heating rate of 10 DEG C/min in the dry N of 50mL/min2Protection under by sample from room temperature
Rise to 250 DEG C, while thermal change of the TA software records sample in temperature-rise period.In this application, fusing point is by starting temperature
It spends to report.
Thermogravimetric analysis (TGA) data are picked up from TA Instruments Q500TGA, and instrument control software is Thermal
AdVantage, analysis software is Universal Analysis.It usually takes the sample of 5~15mg to be placed in platinum crucible, adopts
With the mode of segmentation high resolution detection, with the heating rate of 10 DEG C/min under the protection of the dry N2 of 50mL/min by sample from room
Temperature rise is to 300 DEG C, while weight change of the TA software records sample in temperature-rise period.
Adsorption isothermal curve data are picked up from TA Instruments Q5000 TGA, and instrument control software is Thermal
Advantage, analysis software is Universal Analysis.The sample of 1~10mg is usually taken to be placed in platinum crucible, TA
Software records sample is in relative humidity to the weight change in 0% change procedure from 0% to 80%.According to the specific feelings of sample
Condition also can use different absorption and De contamination step to sample.It can get adsorption isothermal curve by analysis software.
Single crystal diffractometer: Eos CCD detector, four circle Kappa survey instrument, enhanced Mo light source and enhanced Cu light source.Inspection
Survey parameter: environment temperature 100K, enhanced Cu light source, graphite monochromator, wavelengthData Analysis Software is
Crysalispro.It is handled again through shelxtl software analysis, schematic arrangement can be obtained.
Infrared spectrum analysis (IR) data are picked up from Bruker Tensor 27, instrument control software and Data Analysis Software
It is all OPUS.ATR equipment is generallyd use, in 600~4000cm-1In range, infrared absorption spectrum, sample and blank background are acquired
Sweep time be 16 seconds, instrumental resolution 4cm-1。
Preparation example 1
Shellfish cholic acid form A difficult to understand is made according to the embodiment 1 of patent document WO2013192097A1 reaction 6, concrete operations are such as
Under:
By 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone group-cholane-24- acid (86g, 205.4mmol), water (688mL) and 50%
(w/w) mixture of sodium hydroxide solution (56.4mL) and sodium borohydride (7.77g, 205.4mmol) are in 50% (w/w) hydroxide
Sodium solution (1.5mL) is reacted with the mixture of water (20mL) with 90 DEG C to 105 DEG C.It is heated to reflux at least 3 hours under stirring, instead
After having answered, reaction solution is cooled to 80 DEG C.In 30 DEG C to 50 DEG C addition citric acids (320.2g, anhydrous), n-butyl acetates
The mixture of (860mL) and water (491mL) guarantee that pH value is acidity, by aqueous phase separation.Organic phase is distilled, distillation is remained
Object is diluted with n-butyl acetate, slowly cools to 15 DEG C to 20 DEG C, centrifugal filtration.Crude product is crystallized from n-butyl acetate.Ao Bei
Cholic acid is washed after isolating with n-butyl acetate (43mL, 4 times), and sample is dried in vacuo at 80 DEG C.Obtain 67.34g (77.9%)
Crystalloid form A Austria shellfish cholic acid.
The XRPD map of crystal form C is as shown in Figure 1.
Embodiment 1
It takes 50mg Austria shellfish cholic acid form A, the dissolution of 1mL n-butyl acetate is added, volatilizing at 50 DEG C, dry to obtain shellfish cholic acid difficult to understand brilliant
Type I.
The XRPD map of crystal form I is as shown in Figure 2.It is shown as crystalline state substance.
The DSC map of crystal form I is as shown in Figure 3.77 DEG C of fusing point of display.
The TGA map of crystal form I is as shown in Figure 4.There is 7.07% weightlessness before 100 DEG C of display, has 11.79% before 150 DEG C
It is weightless.
The DVS map and adsorption isothermal curve of crystal form I is as shown in Figure 5 and Figure 6.Show 20%-80% RH range
Interior weight change 0.57%, whole weight change 0.69%.
The infared spectrum of crystal form I is as shown in Figure 7.Display: wave number be 2930,1707,1450,1364,1262,1242,
1161,1121,1062,1045,973,954 and 808cm-1Place has characteristic peak.
Embodiment 2
50mg Austria shellfish cholic acid form A is taken, the dissolution of 0.25mL n-butyl acetate is added, it is brilliant to obtain shellfish cholic acid difficult to understand for volatilization at room temperature
Type I monocrystalline.
Monocrystalline cell parameter is as shown in table 1.
The monocrystalline cell parameter of 1 crystal form I of table
In table 1, a, b, c indicate structure cell axial length, and α, β, γ indicate that dihedral angle, Z indicate the number of molecule in each structure cell, V
Indicate unit cell volume, DcalcIndicate structure cell density.
Monocrystalline parses relevant parameter: residual error factor R 1=0.0568, weighted R-values wR2=0.1453, goodness of fit GooF
(S)=0.917.R1 value less than 0.06, wR2 value less than 0.15, S value close to 1, illustrate that single crystal data is reasonable.
As a result it proves that crystal form I is made of shellfish cholic acid molecules difficult to understand, is anhydride.
Embodiment 3
50mg Austria shellfish cholic acid form A is taken, the dissolution of 5.0mL methylene chloride is added, volatilization obtains shellfish cholic acid crystal form difficult to understand at 10 DEG C
I。
Embodiment 4
50mg Austria shellfish cholic acid form A is taken, the dissolution of 1.0mL chloroform is added, volatilization obtains shellfish cholic acid crystal form difficult to understand at room temperature
I。
Embodiment 5
50mg Austria shellfish cholic acid form A is taken, the dissolution of 1.0mL chloroform is added, volatilization obtains shellfish cholic acid crystal form difficult to understand at room temperature
I。
Embodiment 6
50mg Austria shellfish cholic acid form A is taken, the dissolution of 2.0mL ethyl acetate is added, volatilization obtains shellfish cholic acid crystal form difficult to understand at room temperature
I。
Embodiment 7
50mg Austria shellfish cholic acid form A is taken, the dissolution of 2.5mL isopropyl acetate is added, it is brilliant to obtain shellfish cholic acid difficult to understand for volatilization at room temperature
Type I.
Sample prepared by embodiment 3- embodiment 7 have same as Example 1 or similar XRPD map, TGA map,
DSC map, IR map.The sample of the sample and embodiment 1 that illustrate embodiment 3- embodiment 7 is phase homomorphism.
Embodiment 8
Crystal form I of the invention is prepared into the tablet of different size in following table.
The concrete operations for preparing tablet are: according to the prescription of table 2, taking shellfish cholic acid crystal form I difficult to understand, the microcrystalline cellulose of recipe quantity
Element, Explotab, magnesium stearate (25mg specification adds colloidal silicon dioxide) are pressed into plain piece after mixing, then use
The coating solution of Opday II is coated to target weight.
2 tablet formulation of table
The amount of the cholic acid crystal form I of Austria shellfish described in table is assumed to be a hundred percent anhydrous state, and actual amount is based on different batches
The surface solvent of raw material is weightless, guarantees the shellfish cholic acid active constituent difficult to understand in every by reducing the amount of corresponding microcrystalline cellulose
Reach specification requirement.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
Those skilled in the art within the technical scope disclosed by the invention, can without the variation that creative work is expected or
Replacement, should be covered by the protection scope of the present invention.
Claims (8)
1. structural formula shellfish cholic acid difficult to understand (Obeticholic Acid) crystal form I as follows,
It is characterized in that, being radiated using Cu-K α, the X-ray powder diffraction figure that the crystal form I is indicated with 2 θ angles is with bottom
Set with characteristic peak: 4.2 ± 0.2 °, 5.1 ± 0.2 °, 5.4 ± 0.2 °, 6.3 ± 0.2 °, 9.4 ± 0.2 °, 10.2 ± 0.2 °,
12.5 ± 0.2 °, 12.7 ± 0.2 °, 15.6 ± 0.2 °, 16.3 ± 0.2 °, 16.7 ± 0.2 ° and 19.4 ± 0.2 °；
The FTIR spectrum of the crystal form I wave number be 2930,1707,1450,1364,1262,1242,1161,1121,
1062,1045,973,954 and 808cm-1Place has characteristic peak.
2. Austria shellfish cholic acid crystal form I according to claim 1, which is characterized in that the crystal form I is penetrated with the X- that 2 θ angles indicate
Line powder diagram has characteristic peak and its relative intensity in following position:
3. Austria shellfish cholic acid crystal form I according to claim 1 or 2, which is characterized in that the monocrystalline of the crystal form I is 100K's
At a temperature of measure, have following monocrystalline cell parameter: axial length is Dihedral angle is α=92.788 (2) °, β=90.398 (2) °, γ=97.281 (2) °；Space
Group: P1 (1).
4. the preparation method of Austria shellfish cholic acid crystal form I according to any one of claim 1-3, which is characterized in that the system
Preparation Method the following steps are included: form the solution of shellfish cholic acid difficult to understand in organic solvent, the organic solvent be selected from halogenated alkane or
Ester, evaporates into dry, and the operation temperature of the preparation method is 10~50 DEG C, the crystal form I is obtained, wherein the halogenated alkane
It is selected as methylene chloride and chloroform, the ester is selected as C3~C6 ester.
5. the preparation method of Austria shellfish cholic acid crystal form I according to claim 4, which is characterized in that the halogenated alkane is selected as
Methylene chloride, the ester are selected as n-butyl acetate.
6. a kind of pharmaceutical composition, the active pharmaceutical ingredient comprising treatment and/or prevention effective dose is appointed in claim 1-3
Shellfish cholic acid crystal form I difficult to understand described in one, and at least one pharmaceutically acceptable carrier or auxiliary agent.
7. Austria shellfish cholic acid crystal form I of any of claims 1-3 mediates tune for treating and/or preventing FXR in preparation
Save the medicine of obstacle, cardiovascular disease or cholestatic liver disease and high HDL cholesterol, high triglyceride and fibrosis conditions
Purposes in object；The FXR mediates insufficiency of accommodation, cardiovascular disease or cholestatic liver disease and high HDL cholesterol, height sweet
Oily three esters and fibrotic illness are selected from biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic fatty liver disease
(NASH), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), due to progressive fibre modification, liver it is fine
Hepatic disorder caused by dimension denaturation and cardiovascular disease.
8. purposes according to claim 7, wherein the cardiovascular disease is atherosclerosis, arteriosclerosis, high gallbladder
Sterol mass formed by blood stasis or hyperlipemia.
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| US11578097B2 (en) | 2014-11-26 | 2023-02-14 | Enanta Pharmaceuticals, Inc. | Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof |
| US10208081B2 (en) | 2014-11-26 | 2019-02-19 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof |
| CN105801653B (en) * | 2014-12-30 | 2018-04-17 | 苏州晶云药物科技有限公司 | Crystal form A of shellfish cholic acid difficult to understand and preparation method thereof |
| BR112017017238A2 (en) | 2015-02-11 | 2018-04-10 | Enanta Pharm Inc | bile acid analogues as fxr / tgr5 agonists and methods of using them |
| RS62110B1 (en) | 2015-03-31 | 2021-08-31 | Enanta Pharm Inc | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
| CZ2015504A3 (en) * | 2015-07-16 | 2017-01-25 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
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