CN108558655A - 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph and preparation method thereof and pharmaceutical composition - Google Patents
2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph and preparation method thereof and pharmaceutical composition Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses 2 [4 (4 chlorobenzene formacyl) phenoxy group] 2 methylpropanoic acid polymorphs, 2 θ values have diffraction maximum at 5.5 ± 0.2,7.9 ± 0.2,15.9 ± 0.2,19.3 ± 0.2,20.3 ± 0.2,22.2 ± 0.2,22.6 ± 0.2,23.1 ± 0.2,25.1 ± 0.2,26.5 ± 0.2,27.9 ± 0.2,30.2 ± 0.2,33.6 ± 0.2,36.0 ± 0.2 in XRPD collection of illustrative plates.In addition, also disclosing the preparation method of the polymorph, pharmaceutical composition.2 [4 (4 chlorobenzene formacyl) phenoxy group] 2 methylpropanoic acid polymorphs of the present invention have good stability, its XRPD collection of illustrative plates shows that crystal form does not change yet in long-term and accelerated test, is conducive to long-term preservation；Moreover, polymorph preparation method provided by the invention is easy to operate, it is not necessarily to critical operation equipment and technology, and solvent green, dosage are few, production cost is low, is more suitable for industrialized production.
Description
The application be submit on October 31st, 2014 application No. is 201410607321.8, entitled " 2- [4-
(4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph and preparation method thereof and pharmaceutical composition " application division Shen
Please.
Technical field
The invention belongs to pharmaceutical fields, are specifically related to a kind of 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props
Sour polymorph and preparation method thereof and pharmaceutical composition.
Background technology
Fenofibric Acid, entitled 2- [4- (4- chlorobenzene formacyls) the phenoxy group] -2 Methylpropionic acid of chemistry, structural formula (1) are as follows：
The medicine is the kind new medicine for treating hyperlipidemia, recommends hyperlipemic patients clinical treatment criterion to use fenofibrate acids
Drug further improves blood fat with statins drug combination.Drug combination treatment is notable compared with statins are used alone
High-density lipoprotein (HDL) and triglyceride levels are improved, high-density lipoprotein is significantly improved compared with this product independent medication
(LDL).All drug combinations and statins all have the clinical effect for reducing high-density lipoprotein (LDL).
US20050148594A1 discloses the medicinal several salt of Fenofibric Acid, especially choline Fenofibric Acid, as one kind
Slow releasing medicinal can reduce drug dose；US20090187040A1 discloses two kinds of Fenofibric Acid polymorphics and its preparation method, wherein
2 θ values of the XRPD characteristic diffraction peaks of crystal form A 15.4,2 θ values of the XRPD characteristic diffraction peaks of crystal form B 7.7,7.9,17.4,
There is characteristic peak at 24.5.
In recent years, the polymorphism of drug molecule increasingly causes scientist's note that due to different polymorphic shapes
State in stability, degree of dissociation, bioavilability is first-class prodigious difference, it is therefore necessary to drug molecule is carried out as far as possible
More polymorphic research, to ensure to obtain best crystal form, to obtain higher stability, degree of dissociation, bioavilability etc.,
To generate higher bioactivity.Therefore the research and control of crystal form become the important content in drug development process.Pass through
Select the polymorphic with different solubilities and intrinsic dissolution rate that can advantageously influence the practical blood level of drug.
Fenofibric Acid has good market prospects, but the Fenofibric Acid crystal form type reported at present is few, steady to find
Determine medicinal crystal-form, further carrying out research to its polymorphic is very important.
Invention content
The present inventor has surprisingly been discovered a kind of stabilization, new 2- [4- (4- chlorobenzene formacyls) benzene oxygen through research
Base] -2 Methylpropionic acid polymorph.
The object of the present invention is to provide a kind of new 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorphics
Object.
Second object of the present invention is to provide above-mentioned new 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid
The preparation method of polymorph.
Third object of the present invention is to provide include above-mentioned new 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl
The pharmaceutical composition of propionic acid polymorph.
Specifically, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is more
Crystal form object, 2 θ values are 5.5 ± 0.2,7.9 ± 0.2,15.9 ± 0.2,22.2 ± 0.2,22.6 ± 0.2,23.1 in XRPD collection of illustrative plates
There is diffraction maximum at ± 0.2,27.9 ± 0.2,30.2 ± 0.2.
In preferred embodiment provided by the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls)
Phenoxy group] -2 Methylpropionic acid polymorph, 2 θ values are 5.5 ± 0.2,7.9 ± 0.2,15.9 ± 0.2,19.3 in XRPD collection of illustrative plates
±0.2、20.3±0.2、22.2±0.2、22.6±0.2、23.1±0.2、25.1±0.2、26.5±0.2、27.9±0.2、
There is diffraction maximum at 30.2 ± 0.2,33.6 ± 0.2,36.0 ± 0.2.
In more preferred provided by the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph, XRPD collection of illustrative plates is substantially as shown in Figure 1.
In the present embodiment of the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls) benzene oxygen
Base] -2 Methylpropionic acid polymorph, DSC endothermic transitions are at about 183.7 DEG C.
In preferred embodiment provided by the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls)
Phenoxy group] -2 Methylpropionic acid polymorph, DSC collection of illustrative plates is substantially as shown in Figure 2.
In the present embodiment of the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls) benzene oxygen
Base] -2 Methylpropionic acid polymorph is anhydrous crystal forms.
In the present embodiment of the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls) benzene oxygen
Base] -2 Methylpropionic acid polymorph, infrared absorption spectrum is in 3400~2500cm-1、3076cm-1、2991cm-1、2900cm-1、1707cm-1、1647cm-1、1597cm-1, 1500cm-1,1468cm-1、1398cm-1、1382cm-1, 1365cm-1、1303cm-1、
1285cm-1、1236cm-1, 930cm-1、1148cm-1、858cm-1There is absorption peak.
In the present embodiment of the invention, the present invention provides a kind of new 2- [4- (4- chlorobenzene formacyls) benzene oxygen
Base] -2 Methylpropionic acid polymorph, infrared absorption spectrum is substantially as shown in Figure 3.
On the other hand, the present invention provides above-mentioned 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorphics
The preparation method of object, includes the following steps：
A) 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is mixed with stirring solvent, it is complete is heated to solid
It dissolves in portion；
B) it cools, crystallization；
C) precipitation is recovered by filtration, dries to obtain 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorphic.
In embodiments of the invention, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props provided by the invention
The preparation method of sour polymorph, wherein solvent for use is one or more in methanol, ethyl alcohol, isopropanol, tert-pentyl alcohol, water
Mixture, preferred solvent be isopropanol and/or water.
In embodiments of the invention, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props provided by the invention
The preparation method of sour polymorph, wherein in cooling Crystallization Process, cooling down to -10~10 DEG C, preferably -5~0 DEG C.
In embodiments of the invention, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props provided by the invention
The preparation method of sour polymorph, wherein the temperature heated in step a) is 20 DEG C -100 DEG C, preferably 50-80 DEG C.
In embodiments of the invention, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props provided by the invention
The preparation method of sour polymorph, wherein solvent and 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
Proportionate relationship be 2mL/g-10mL/g.
In embodiments of the invention, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2- methyl-props provided by the invention
The preparation method of sour polymorph, wherein the temperature of the drying is 30-80 DEG C, it is therefore preferable to 40-60 DEG C.
The present invention has investigated the stabilization of above-mentioned 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
Property, it has done and has accelerated (temperature is 40 ± 2 DEG C, and humidity is 75% ± 5%, and the time be 6 months) and (temperature is 25 ± 2 DEG C, wet for a long time
Degree is 60% ± 10%, and the time is 12 months) stability test.The experimental results showed that：2- [4- (4- chlorine prepared by the present invention
Benzoyl) phenoxy group] -2 Methylpropionic acid polymorph is with good stability, its XRPD in long-term and accelerated test
Collection of illustrative plates shows that crystal form does not change (Fig. 4 and Fig. 5) yet, is conducive to long-term preservation.
On the other hand, 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph system provided by the invention
Preparation Method is easy to operate, is not necessarily to critical operation equipment and technology, and solvent green, dosage are few, production cost is low, is more suitable for industry
Metaplasia is produced.
For the crystal form of the same race of same compound, XRPD collection of illustrative plates has similitude on the whole, due to instrumentation and testing
Its characterization peak position of the difference of condition will produce error, so determining the XRPD figures in specification and claims of the invention
When 2 θ of the angle of diffraction of spectrum, the value of gained is interpreted as in the range of ± 1.0 degree of the value, preferably ± 0.2 degree in the value
In the range of；Fusing point in DSC thermograms, the value of gained are interpreted as in the range of ± 3.0 DEG C of the value, preferably existing
In the range of ± 1 DEG C of the value.
The third aspect, the present invention provides one kind containing pharmacologically a effective amount of above-mentioned 2- [4- (4- chlorobenzene formacyls)
Phenoxy group] -2 Methylpropionic acid polymorph and its pharmacologically acceptable carrier pharmaceutical composition.
In embodiments of the invention, provided by the invention to contain pharmacologically a effective amount of 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph pharmaceutical composition, wherein the pharmacologically acceptable carrier can be selected from
One or more combinations in filler, disintegrant, adhesive, glidant, and/or lubricant.
In embodiments of the invention, provided by the invention to contain pharmacologically a effective amount of 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph pharmaceutical composition, wherein the filler be selected from lactose, maltodextrin,
Any one in mannitol, microcrystalline cellulose, pre-gelatinized starch and sucrose ester or two or more mixtures；The disintegration
Agent is any one in Crospovidone, cross-linked carboxymethyl cellulose sodium, primojel, microcrystalline cellulose and pre-gelatinized starch
Kind or two or more mixtures；Described adhesive includes hydroxypropyl cellulose, hypromellose, povidone, copolymerization dimension
Any one in ketone or two or more mixtures；The glidant is colloidal silicon dioxide, talcum powder, magnesium stearate and sweet
Reveal any one in sugar alcohol or two or more mixtures；The magnesium stearate lubricant, calcium stearate, glycerol monostearate
Ester, rilanit special, NaLS, stearyl fumarate, stearic acid, zinc stearate, talcum powder, microcrystalline cellulose and
Any one in sucrose ester or two or more mixtures.
In embodiments of the invention, provided by the invention to contain pharmacologically a effective amount of 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph pharmaceutical composition, it is preferable that the filler be microcrystalline cellulose, disintegration
Agent is Crospovidone, adhesive is copolyvidone, glidant is colloidal silicon dioxide, lubricant is magnesium stearate.
In embodiments of the invention, provided by the invention to contain pharmacologically a effective amount of 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph pharmaceutical composition, wherein the pharmaceutical composition, including above-mentioned 2- [4-
(4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 35.0mg, microcrystalline cellulose 57.2mg, Crospovidone
2.7mg, copolyvidone 2.4mg, colloidal silicon dioxide 1.2mg, magnesium stearate 0.7mg；Or including 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorphic 105.0mg, microcrystalline cellulose 171.6mg, Crospovidone 8.1mg, copolyvidone
7.2mg, colloidal silicon dioxide 3.6mg, magnesium stearate 2.1mg.
In embodiments of the invention, provided by the invention to contain pharmacologically a effective amount of 2- [4- (4- chlorobenzoyls
Base) phenoxy group] -2 Methylpropionic acid polymorph pharmaceutical composition, wherein above-mentioned pharmaceutical composition be direct powder compression
It is made.
Fourth aspect, the present invention provides above-mentioned 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorphics
Application of the object in treating hyperlipemia drug.
Tests prove that 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph conduct of the invention
After tablet is made in drug major ingredient, grinds drug with original and made detailed dissolution and stability contrast research, experiments have shown that the present invention is brilliant
The drug that type is prepared and the drug of Yuan Yan companies are dissolving out and are stablizing the uniform cause of sexual behaviour, meet medicinal.
Description of the drawings
Fig. 1 is that the x-ray powder of 2- of the present invention [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph spreads out
Penetrate figure.
Fig. 2 is the dsc analysis figure of 2- of the present invention [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph.
Fig. 3 is the fourier infrared of 2- of the present invention [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
Spectrogram.
Fig. 4 is the accelerated test 6 of 2- of the present invention [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
Month X-ray powder diffraction figure.
Fig. 5 is long-term 12 months X of 2- of the present invention [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
Ray powder diffraction pattern.
Specific implementation mode
The present invention is explained further with reference to specific embodiment, but these embodiments are only for illustrating this hair
It is bright, rather than limiting the scope of the invention.
In the present invention, the method and condition of coherent detection are as follows：
1. infrared absorption spectrum (IR)
Instrument：27 type infrared spectrometers of Bruker TENSOR
Instrumental correction：(traditional Chinese medicines in reference are corrected to instrument wave number with the infrared spectrum absorpting peak of polystyrene film
Two IV C of annex of allusion quotation version in 2010)
Method：KBr pressed disc methods
2. differential thermal analysis (DSC)
Instrument：204 type differential thermal analyzers of NETZSCH DSC
Temperature range：40-220℃
Heating rate：10℃/min
3. powder x-ray diffraction (PXRD)
1. measuring unit：Institute of Analysis of China Medicine University
Instrument：Bruker D8Advance X-ray diffractometers
Test condition：40kv 40mA slits：1.0/1.0/Ni/0.1 step-length：0.02 ° of target type：Cu
Range:3.00-40.00Deg scan Rate：10.00Deg/min
Definition and abbreviation
Unless otherwise indicated, hereinbefore and its following abbreviation that uses in the whole text of description of the invention is construed as having
Following meanings：
XRPD X-ray powder diffractions
DSC differential scanning calorimetries
ML milliliters
Mg milligrams
L liters
Kg kilograms
The preparation of 1 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2g 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 50mL three-necked flasks, is added different
Propyl alcohol 32mL after being heated to 65 DEG C of dissolving stirring half an hour, is added 0.03g medicinal carbons and continues to take out while hot after stirring half an hour
Filter, filtrate are precipitated solid, filter again after being cooled to 10 DEG C, gained white solid powder obtains 2- after 55 DEG C of forced air drying 3h
[4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 2.8g, yield 87.5%.Its X-ray powder diffraction
Figure such as Fig. 1, DSC spectrograms are as shown in Fig. 2, infrared spectrogram is as shown in Figure 3.
The preparation of 2 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2g 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 50mL three-necked flasks, first is added
Alcohol 32mL, be heated to 55 DEG C dissolving stirring 1 hour after, continue stir half an hour after filter while hot, filtrate is precipitated after being cooled to 8 DEG C
Solid filters again, and gained white solid powder obtains 2- [4- (4- chlorobenzene formacyls) phenoxy group]-after 40 DEG C of forced air drying 3h
2 Methylpropionic acid polymorph 2.9g, yield 90.6%.Its X-ray powder diffraction figure, DSC spectrograms, infrared spectrum and implementation
Spectrogram is identical in example 1.
The preparation of 3 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2g 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 50mL three-necked flasks, second is added
Alcohol 32mL, be heated to 60 DEG C dissolving stirring 1 hour after, be added 0.03g medicinal carbons continue stir half an hour after filter while hot,
Solid is precipitated in filtrate after being cooled to 8 DEG C, filter again, and gained white solid powder obtains 2- [4- (4- after 60 DEG C of forced air drying 3h
Chlorobenzene formacyl) phenoxy group] -2 Methylpropionic acid polymorph 2.8g, yield 87.5%.Its X-ray powder diffraction figure, DSC
Spectrogram is identical in spectrogram, infrared spectrum and embodiment 1.
The preparation of 4 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2g 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 50mL three-necked flasks, second is added
Alcohol 31mL, distilled water 1mL, be heated to 60 DEG C dissolving stirring 1 hour after, be added 0.03g medicinal carbons continue stir half an hour
It filters while hot afterwards, solid is precipitated in filtrate after being cooled to 8 DEG C, filter again, and gained white solid powder is in 60 DEG C of forced air drying 3h
2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 3.1g, yield 93.7% are obtained afterwards.Its X-ray powder
Spectrogram is identical in last diffraction pattern, DSC spectrograms, infrared spectrum and embodiment 1.
The preparation of 5 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2g 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 50mL three-necked flasks, uncle is added
Amylalcohol 35mL, be heated to 60 DEG C dissolving stirring 0.5 hour after, be added 0.03g medicinal carbons continue stirring 1 hour after take out while hot
Filter, filtrate are precipitated solid, filter again after being cooled to -10 DEG C, gained white solid powder obtains 2- after 55 DEG C of forced air drying 3h
[4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 2.5g, yield 78.1%.Its X-ray powder diffraction
Figure, DSC spectrograms, infrared spectrum are identical with spectrogram in embodiment 1.
The preparation of 6 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
3.2Kg 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 100L three-necked flasks, is added
Isopropanol 31L, distilled water 0.8L, be heated to 65 DEG C dissolving stirring 1 hour after, be added 0.03Kg medicinal carbons continue stirring 1
It is filtered while hot after hour, solid is precipitated in filtrate after being cooled to 0 DEG C, filter again, and gained white solid powder is dry in 60 DEG C of air blast
2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 3.05Kg, yield 95.3% are obtained after dry 3h.Its X
Spectrogram is identical in ray powder diffraction pattern, DSC spectrograms, infrared spectrum and embodiment 1.
The preparation of 7 2- of embodiment [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph
1.60Kg 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is added into 100L three-necked flasks, is added
Methanol 16L, distilled water 0.2L, after being heated to 50 DEG C of dissolving stirrings 1 hour, 0.01Kg medicinal carbons are added, and to continue stirring 1 small
When after filter while hot, filtrate be cooled to -5 DEG C place 3h after filter again, gained white solid powder is in 60 DEG C of forced air drying 3h
2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph 1.47Kg, yield 92.0% are obtained afterwards.Its X-ray
Spectrogram is identical in powder diagram, DSC spectrograms, infrared spectrum and embodiment 1.
Embodiment 8 prepares sample and dissolves out comparative experiment
Resulting product is prepared in embodiment 6 and 7 as major ingredient to amplify, and different rule are prepared using the formula in the following table 1
The tablet of lattice, according to technique of direct powder compression flow：Bulk pharmaceutical chemicals+auxiliary material → sieving → mixing → (adding lubricant) mixing → pressure
Piece method.
Table 1
Above-mentioned obtained tablet is produced with MUTUAL PHARMACEUTICAL COMPANY with the following method
FIBRICOR (specifications：35mg, lot number：6561702) stripping curve comparative study is carried out.
Test method：According to dissolution method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the second methods of C), dissolution medium
900ml, rotating speed 75rpm.Separately sampled 5ml when 5,10,15,20,30,45,60min is filtered through 0.45 μm of filter membrane, is taken continuous
Filtrate is test solution.It separately takes Fenofibric Acid reference substance appropriate, the dissolving of pH6.8 phosphate buffers is added to be made in every 1ml about
The solution of the 0.035mg containing Fenofibric Acid, as a contrast product solution.According to high performance liquid chromatography (Chinese Pharmacopoeia version two in 2010
V D of portion's annex), it is filler with octadecylsilane chemically bonded silica, with water phase (5ml phosphoric acid is diluted with water to 1000ml)-first
Alcohol (20:80) it is mobile phase, Detection wavelength 290nm, flow velocity 1ml/min, column temperature is 25 DEG C.Precision measures reference substance solution
With each 10 μ l of test solution, it is injected separately into liquid chromatograph, records chromatogram.By external standard method with calculated by peak area dissolution rate simultaneously
Draw accumulation stripping curve.
Dissolution medium：0.1M hydrochloric acid solutions, pH=4.5 acetate buffers, pH=5.5 phosphate buffers and pH=
6.8 phosphate buffer.
Self-control sample and the former similitude ground between stripping curve are compared using F2 similarity estimates, the results showed that the two it
Between stripping curve it is consistent, the comparison of the stripping curves of 35mg specifications is shown in Table 2.
Table 2
1In 0.1M hydrochloric acid solutions, self-control sample and former triturate are substantially without dissolution；In the phosphate buffer of pH6.8
In, self-control sample and the dissolution of former triturate in 15min >=85%, F2 need not be calculated, stripping curve is consistent；In remaining Jie
F2 ＞ 50 in matter, dissolved corrosion is consistent.
Similitude between self-control sample and former triturate stripping curve is compared using F2 similarity estimates, the results showed that two
Stripping curve is consistent between person, and the stripping curve comparison of 105mg specifications is shown in Table 3.
Table 3
1In 0.1M hydrochloric acid solutions, piece is ground certainly and original grinds piece substantially without dissolution；In the phosphate buffer of pH6.8, from
Grind piece and original grind piece dissolution in 15min >=85%, F2 need not be calculated, stripping curve is consistent, the F2 ＞ in remaining medium
50, dissolved corrosion is consistent.
Embodiment 9 prepares sample stability comparative study
Comparing self-control sample, (embodiment 8 prepares gained, specification：35mg) with former triturate (specification：35mg, lot number：
6561702) bare die places 10 days, band packaging acceleration Key Quality attribute change situation in June under high temperature, high humidity, illumination condition,
Stability contrast result see the table below 4.The result shows that self-control sample stability is consistent with former triturate.
Table 4
Remarks："/" is represented grinds data without detection original.
Embodiment 8 and embodiment 9 statistics indicate that the novel crystal forms that the present invention prepares be prepared into after drug in dissolution rate and
Stability is ground unanimously with original, meets drug correlated quality requirement.
Claims (10)
1. a kind of 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorph, 2 θ values are 5.5 in XRPD collection of illustrative plates
±0.2、7.9±0.2、15.9±0.2、19.3±0.2、20.3±0.2、22.2±0.2、22.6±0.2、23.1±0.2、
There is diffraction maximum at 25.1 ± 0.2,26.5 ± 0.2,27.9 ± 0.2,30.2 ± 0.2,33.6 ± 0.2,36.0 ± 0.2.
2. polymorph according to claim 1, wherein the polymorph has XRPD collection of illustrative plates diffraction shown in FIG. 1
Peak.
3. the polymorph according to any claim in claim 1 to 2, DSC figures, endothermic transition is about 183.7
℃。
4. polymorph according to claim 3, wherein the polymorph is anhydrous crystal forms.
5. a kind of method being used to prepare the polymorph according to any one of claim 1-4, includes the following steps：
A) 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid is mixed with stirring solvent, it is all molten is heated to solid
Solution；
B) it cools, crystallization；
C) precipitation is recovered by filtration, dries to obtain 2- [4- (4- chlorobenzene formacyls) phenoxy group] -2 Methylpropionic acid polymorphic.
6. preparation method according to claim 5, wherein the solvent is in methanol, ethyl alcohol, isopropanol, tert-pentyl alcohol, water
One or more mixtures；Preferred solvent is isopropanol and/or water.
7. preparation method according to claim 5, wherein in step b), cool to -10~10 DEG C.
The obtained 2- of claim 5-7 any one of them preparation methods 8. [4- (4- chlorobenzene formacyls) phenoxy group] -2- first
Base propionic acid polymorph.
9. a kind of pharmaceutical composition, the composition contains more described in pharmacologically any one of a effective amount of claim 1-4
Crystal form object and pharmacologically acceptable carrier.
10. polymorph or pharmaceutical composition as claimed in claim 9 are high in treatment as described in any one of claim 1-4
Application in blood fat disease drug.
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| CN201810167207.6A CN108558655B (en) | 2014-10-31 | 2014-10-31 | 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof |
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| CN104628554A (en) * | 2015-02-09 | 2015-05-20 | 徐州工程学院 | Fenofibric acid crystal form and preparation method thereof |
| CN107550875A (en) * | 2017-08-21 | 2018-01-09 | 赵剑锋 | A kind of Fenofibric Acid piece of stabilization and preparation method thereof |
| CN110041191A (en) * | 2019-04-30 | 2019-07-23 | 湖南九典宏阳制药有限公司 | A kind of purification process of pelubiprofen |
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| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| US20050148594A1 (en) * | 2002-12-17 | 2005-07-07 | Cink Russell D. | Salts of fenofibric acid and pharmaceutical formulations thereof |
| US20090187040A1 (en) * | 2008-01-18 | 2009-07-23 | Tong Sun | Fenofibric acid polymorphs; methods of making; and methods of use thereof |
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| CN102659609A (en) * | 2012-05-17 | 2012-09-12 | 安润医药科技（苏州）有限公司 | Fenofibric acid salt, and preparation method, application and medicinal composition thereof |
| CN103965038A (en) * | 2013-01-24 | 2014-08-06 | 肖广常 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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| CN103922925B (en) * | 2014-05-09 | 2015-12-30 | 成都医路康医学技术服务有限公司 | A kind of production technique of Fenofibric Acid |
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| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| US20050148594A1 (en) * | 2002-12-17 | 2005-07-07 | Cink Russell D. | Salts of fenofibric acid and pharmaceutical formulations thereof |
| US20090187040A1 (en) * | 2008-01-18 | 2009-07-23 | Tong Sun | Fenofibric acid polymorphs; methods of making; and methods of use thereof |
| CN102304103A (en) * | 2011-06-03 | 2012-01-04 | 郑州泰基鸿诺药物科技有限公司 | Fenofibrate acid salt, preparation method, pharmaceutical composition and application |
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| CN103965038A (en) * | 2013-01-24 | 2014-08-06 | 肖广常 | Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid |
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