CN104447291A - Fenofibric acid crystal forms and preparation method thereof - Google Patents
Fenofibric acid crystal forms and preparation method thereof Download PDFInfo
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- CN104447291A CN104447291A CN201310432118.7A CN201310432118A CN104447291A CN 104447291 A CN104447291 A CN 104447291A CN 201310432118 A CN201310432118 A CN 201310432118A CN 104447291 A CN104447291 A CN 104447291A
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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
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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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
Abstract
The invention relates to six new crystal forms of fenofibric acid and a preparation method thereof, concretely relates to fenofibric acid crystal forms A, B, C, D, E and F, a preparation method of the six crystal forms, and a pharmaceutical composition containing the six new crystal forms, and application of the six new crystal forms to prepare blood-fat-reducing medicines treating blood fat diseases. The six crystal forms are stable, easy to prepare and beneficial for manufacturing of a preparation.
Description
technical field:
The present invention relates to organic chemistry filed and field of medicaments, six kinds of new crystal being specifically related to Fenofibric Acid and preparation method thereof, the pharmaceutical composition containing these six kinds of new crystal, and these six kinds of new crystal are for the manufacture of the application be applicable in blood lipid-lowering medicine.
technical background:
This product is chlorine shellfish butanoic acid derivative class blood lipid regulation medicine, is the interior metabolism product of fenofibrate, and it, by suppressing the generation of vldl and triglyceride level and make its katabolism increase simultaneously, reduces blood low-density lipoprotein, cholesterol and triglyceride level; Also make Apolipoprotein A1 and A11 generate to increase, thus high density lipoprotein increasing.This product still has the blood uric acid effect reducing normal people and Patients with Hyperuricemia.The hydrophobicity of fenofibrate causes its bioavailability low, and it is large by the impact of food, contrary with fenofibrate, Fenofibric Acid has higher solubleness in small intestine district, because this increasing the bioavailability of Fenofibric Acid, and the impact of bioavailability unable to take food thing, such advantage improves the Compliance of patient.
Fenofibric Acid:
English name: Fenofibric acid
Chemical name: 2-4-(4-chlorobenzoyl) and phenoxy group ］-2 Methylpropionic acid
Molecular formula: C
17h
15clO
4
Structural formula:
Fenofibric Acid belongs to slightly water-soluble compound, generally uses in solid form in the formulation, is therefore of great significance the research tool of its crystal formation.At present, have no the document description about Fenofibric Acid crystal formation both at home and abroad, the present inventor is in the research process of Fenofibric Acid crystal formation, pleasantly surprised discovery Fenofibric Acid has heteromorphism and prepares six kinds of crystal formations of Fenofibric Acid, they have crystal formation X-ray powder diffraction feature, and preparation method is simple, chemical stability is excellent, is applicable to several formulations.
summary of the invention:
The object of the present invention is to provide six kinds of new crystal of Fenofibric Acid, be defined as the crystal form A of Fenofibric Acid, crystal form B, crystal C, crystal formation D, crystal formation E and crystal formation F respectively.These stable crystal forms, be suitable for use in several formulations and preparation technology is easy, industrial applicibility is strong.
Fenofibric Acid crystal form A of the present invention, the feature of its X-ray powder diffraction is: be about the position of 5.421 °, 11.401 °, 18.360 °, 19.120 °, 20.120 °, 21.360 °, 21.960 °, 23.020 °, 24.920 °, 40.980 ° in 2 θ values to having characteristic diffraction peak.
Fenofibric Acid crystal form A of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 1.
Fenofibric Acid crystal form B of the present invention, the feature of its X-ray powder diffraction is: be about the position of 5.571 °, 18.525 °, 19.291 °, 20.291 °, 21.514 °, 23.163 °, 25.118 °, 26.523 °, 30.243 ° in 2 θ values to having characteristic diffraction peak.
Fenofibric Acid crystal form B of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 2.
Fenofibric Acid crystal C of the present invention, the feature of its X-ray powder diffraction is: be about the position of 5.506 °, 15.797 °, 21.449 °, 22.141 °, 27.781 ° in 2 θ values to having characteristic diffraction peak.
Fenofibric Acid crystal C of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 3.
Fenofibric Acid crystal formation D of the present invention, the feature of its X-ray powder diffraction is: be about the position of 7.955 °, 15.917 °, 16.632 °, 19.327 °, 22.167 °, 23.957 ° in 2 θ values to having characteristic diffraction peak.
Fenofibric Acid crystal formation D of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 4.
Fenofibric Acid crystal formation E of the present invention, the feature of its X-ray powder diffraction is: be about the position of 18.446 °, 20.215 °, 22.570 °, 23.095 °, 23.747 °, 25.031 °, 30.182 ° in 2 θ values to having characteristic diffraction peak.
Fenofibric Acid crystal formation E of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 5.
Fenofibric Acid crystal formation F of the present invention, the feature of its X-ray powder diffraction is: be about 5.441 ° in 2 θ values, 7.859 °, 15.821 °, 18.400 °, 19.180 °, 20.140 °, 21.380 °, 22.099 °, 22.520 °, 23.039 °, 24.980 °, 26.401 ° 26.719 °, 27.739 °, 28.841 °, 30.121 °, 31.320 °, 32.140 ° 33.460 °, 35.480 °, 35.899 °, 36.540 °, 38.320 °, 41.040 ° 42.000 °, 43.680 °, 44.760 °, 46.398 °, 46.780 °, the position of 49.200 ° is to having characteristic diffraction peak.
Fenofibric Acid crystal formation F of the present invention has the feature representated by X-ray powder diffraction as shown in Figure 6.
Fenofibric Acid crystal form A provided by the invention, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F, its content (mass content) is generally greater than 80%, is preferably greater than 90%, is most preferably greater than 95%.
The X-ray powder diffraction of Fenofibric Acid crystal form A provided by the invention, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F is listed in accompanying drawing." representational X-ray powder diffraction " refers to that the X-ray powder diffraction feature of crystal formation of the present invention meets the overall pattern of this collection of illustrative plates display, be understandable that in test process, due to be subject to many factors (as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc.) impact, the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference.Therefore, crystal formation of the present invention, in its X-ray powder diffraction the experimental error of diffraction peak 2 θ value can be ± 0.2 °.
The invention provides the preparation method of the above-mentioned six kinds of crystal formations of Fenofibric Acid.
The invention provides a kind of preparation method of Fenofibric Acid crystal form A, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in anhydrous ethanol solvent by Fenofibric Acid (comprising dry product or wet product) under heated reflux condition, add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods dehydrated alcohol; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
The invention provides a kind of preparation method of Fenofibric Acid crystal form B, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in acetone solvent by Fenofibric Acid (comprising dry product or wet product) under heated reflux condition, add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods acetone; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
The invention provides a kind of preparation method of Fenofibric Acid crystal C, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in 50% acetone soln under heated reflux condition by Fenofibric Acid (comprising dry product or wet product), add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods 50% acetone; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
The invention provides the preparation method of a kind of Fenofibric Acid crystal formation D, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in isopropanol solvent by Fenofibric Acid (comprising dry product or wet product) under heated reflux condition, add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods Virahol; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
The invention provides the preparation method of a kind of Fenofibric Acid crystal formation E, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in ethyl acetate solvent by Fenofibric Acid (comprising dry product or wet product) under heated reflux condition, add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods ethyl acetate; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
The invention provides the preparation method of a kind of Fenofibric Acid crystal formation F, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.The method specifically comprises the following steps:
Be dissolved in 50% ethanolic soln under heated reflux condition by Fenofibric Acid (comprising dry product or wet product), add Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C, filtration or centrifugal, filtration cakes torrefaction obtains white solid.
Recrystallisation solvent described is in the above-mentioned methods 50% ethanol; Described crystallization can be at quiescent conditions, carries out under may also be agitation condition; Described drying, its drying temperature is generally 20 ~ 100 DEG C, preferably 30 ~ 70 DEG C; Can constant pressure and dry, also can drying under reduced pressure, during decompression, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
In order to investigate the stability of six kinds of Fenofibric Acid crystal formations of the present invention, carry out influence factor test, test is as following table:
| temperature 25 ± 2 DEG C, humidity RH90% ± 5% time is placed 10 days | place 10 days at temperature 60 ± 2 DEG C | place 10 days under illumination 4500 ± 500Lx | |
| crystal form A | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
| crystal form B | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
| crystal C | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
| crystal formation D | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
| crystal formation E | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
| crystal formation F | place without obvious moisture absorption after 10 days, crystal formation remains unchanged. | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged | place that after 10 days, related substance is without considerable change, crystal formation remains unchanged |
Above-mentioned test shows, Fenofibric Acid crystal form A of the present invention, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F have stable physicochemical property and stablize, and is suitable for long storage periods and the manufacture being applied to preparation.
An object of the present invention also provides containing Fenofibric Acid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F pharmaceutical composition.
In order to realize this object, pharmaceutical composition of the present invention, comprises the pharmaceutical composition of the Fenofibric Acid crystal form A of effective therapeutic dose, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F and pharmaceutical excipient.Be generally the Fenofibric Acid crystal form A for the treatment of significant quantity, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F are mixed with one or more pharmaceutical excipients or contacted make pharmaceutical composition or preparation, this pharmaceutical composition or preparation are prepared in the mode known in pharmacy field.
Another object of the present invention there is provided Fenofibric Acid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F for the manufacture of the application being applicable to treat reducing blood-fat disease medicament.Wherein said blood lipid disorder comprises serious HTC, primary hypercholesterolemia or mixed dyslipidemia.
Preferably, Fenofibric Acid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F are for the manufacture of being applicable to the application for the treatment of reducing blood-fat disease medicament.
Of the present invention containing Fenofibric Acid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F pharmaceutical composition or preparation, its formulation comprises: tablet, drageeing, granule, Sublingual tablet, capsule, lozenge, ointment, ointment, skin gel, injectable formulation, drinkable suspensoid and disintegratable paste etc. are suitable for formulation that is oral, enteron aisle (intravenously or subcutaneous) or intranasal use outward.
The useful dosage of above-mentioned composition or preparation was mediated according to the age, body weight etc. of the character of disorder and seriousness, route of administration and patient, changed, in single or divided doses in every day between 0.1mg to 1g.
Can containing conventional auxiliary material when pharmaceutical composition of the present invention is solid orally ingestible, such as weighting agent, disintegrating agent, tackiness agent, lubricant etc., can carry out dressing to tablet if desired.
Described weighting agent generally comprises Microcrystalline Cellulose, starch, silicon-dioxide, lactose, maltodextrin, pregelatinized Starch, N.F,USP MANNITOL, Xylitol, sorbyl alcohol, glucose etc., they can be used alone also can be used in combination, wherein preferably microcrystalline cellulose, starch, silicon-dioxide, lactose, maltodextrin, pregelatinized Starch, N.F,USP MANNITOL.
Described disintegrating agent generally comprises primojel, starch, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Xylo-Mucine, agar, calcium carbonate and sodium bicarbonate etc., they can be used alone also can be used in combination, is wherein preferably cross-linked polyvinylpyrrolidone, primojel, starch, polyvinylpyrrolidone.
Described tackiness agent generally comprises the ethanolic soln of polyvidone, Microcrystalline Cellulose, hydroxypropylcellulose, starch slurry, Vltra tears, polyvinyl alcohol, water, various concentration, they can be used alone also can be used in combination, wherein preferred polyvidone, Microcrystalline Cellulose, Vltra tears.
Described lubricant generally comprises stearic acid, Magnesium Stearate, calcium stearate, palmitinic acid, pure aluminium silicate, stearylamide, talcum powder, solid ethylene glycol, silicon-dioxide.They can be used alone also can be used in combination, wherein preferred Magnesium Stearate, stearic acid, magnesium calcium stearate.
If necessary, other auxiliary materials can also be added in pharmaceutical composition of the present invention, as sweeting agent, tinting material, odor mask, stablizer etc.
Can according to preparing any one ordinary method that oral solid formulation adopts to prepare pharmaceutical composition of the present invention, as: encapsulated after wet granule compression tablet, direct powder compression, granulation.Use conventional coating device, by this pharmaceutical composition coating, film coated tablet or sugar coated tablet can be made.Coated substrate comprises cellulose family, crylic acid resin, carbohydrate, as hydroxypropyl level methylcellulose gum, Eudragit L, sucrose.Also softening agent, antisticking agent, opalizer can be added in this coated substrate.Solid composite medicament of the present invention can by carrying out granulation step, encapsulation step or flaking step and coating steps (if necessary) obtains with conventional dosage form successively, is generally the tablet of tablet or surface coatings, powder, granule, the granule of surface coatings or capsule dosage form.Said tablet comprises conventional sheet, slow releasing tablet, buccal tablet, orally disintegrating tablet, chewable tablet, effervescent tablet etc.
Pharmaceutical composition of the present invention can be prepared by pharmaceutics routine techniques.As tablet can adopt wet granulation compressing tablet and dry powder direct tabletting method.
The experiment proved that, Fenofibric Acid crystal form A provided by the invention, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F preparation have satisfactory stability with active in preparation and storage.
In sum, Fenofibric Acid crystal form A provided by the invention, crystal form B, crystal C, crystal formation D, crystal formation E, crystal formation F are the intrinsic crystal habits of Fenofibric Acid.They have easy preparation method, and the advantages such as satisfactory stability and preparation adaptability, have industrialization practicality.
accompanying drawing illustrates:
[0050]fig. 1 is the x-ray diffraction pattern of FENOBRATE acid crystal form A.
Fig. 2 is the x-ray diffraction pattern of FENOBRATE acid crystal form B.
Fig. 3 is the x-ray diffraction pattern of FENOBRATE acid crystal C.
Fig. 4 is the x-ray diffraction pattern of FENOBRATE acid crystals type D.
Fig. 5 is the x-ray diffraction pattern of FENOBRATE acid crystals type E.
Fig. 6 is the x-ray diffraction pattern of FENOBRATE acid crystals type F.
embodiment:
Below in conjunction with embodiment, the invention will be further described, and professional and technical personnel in the field can be made more fully to understand the present invention, but the scope do not limited the present invention in any way.
Embodiment 1:
The preparation of Fenofibric Acid crystal form A:
In 100ml flask, add Fenofibric Acid 5g, 50ml ethanol, 80 DEG C of heating in water bath, are stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filter, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal form As.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 18.360 | 4.828 | 100 |
| 19.120 | 4.638 | 23.5 |
| 20.120 | 4.410 | 12.3 |
| 21.360 | 4.156 | 32.8 |
| 21.960 | 4.044 | 12.0 |
| 23.020 | 3.860 | 77.2 |
| 24.920 | 3.570 | 14.2 |
| 40.980 | 2.201 | 11.5 |
| 28.145 | 3.168 | 26.4 |
| 30.497 | 2.929 | 100.0 |
| 33.821 | 2.648 | 33.7 |
| 36.226 | 2.394 | 15.1 |
Embodiment 2:
The preparation of Fenofibric Acid crystal form B:
In 100ml flask, add Fenofibric Acid 5g, 50ml acetone, 80 DEG C of heating in water bath, are stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filter, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal form Bs.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 5.571 | 15.851 | 14.5 |
| 18.525 | 4.786 | 58.7 |
| 19.291 | 4.597 | 30.3 |
| 20.291 | 4.373 | 26.7 |
| 21.514 | 4.127 | 41.6 |
| 23.163 | 3.837 | 100 |
| 25.118 | 3.542 | 28.7 |
| 26.523 | 3.358 | 23.4 |
| 30.243 | 2.953 | 33.9 |
Embodiment 3:
The preparation of Fenofibric Acid crystal C:
In 100ml flask, add Fenofibric Acid 5g, 80ml50% acetone, 80 DEG C of heating in water bath, be stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filters, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal Cs.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 5.506 | 16.039 | 28.7 |
| 15.797 | 5.605 | 16.3 |
| 21.449 | 4.139 | 18.2 |
| 22.141 | 4.012 | 100.0 |
| 27.781 | 3.209 | 41.2 |
Embodiment 4:
The preparation of Fenofibric Acid crystal formation D:
In 100ml flask, add Fenofibric Acid 5g, 50ml Virahol, 80 DEG C of heating in water bath, be stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filters, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal formation D.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 7.955 | 11.105 | 55.5 |
| 15.917 | 5.564 | 100.0 |
| 16.632 | 5.326 | 17.8 |
| 19.327 | 4.589 | 15.6 |
| 22.167 | 4.007 | 17.8 |
| 23.957 | 3.711 | 26.6 |
Embodiment 5:
The preparation of Fenofibric Acid crystal formation E:
In 100ml flask, add Fenofibric Acid 5g, 50ml Virahol, 80 DEG C of heating in water bath, be stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filters, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal formation E.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 18.446 | 4.806 | 16.2 |
| 20.215 | 4.389 | 25.4 |
| 22.570 | 3.936 | 14.9 |
| 23.095 | 3.848 | 100.0 |
| 23.747 | 3.744 | 17.1 |
| 25.031 | 3.555 | 18.5 |
| 30.182 | 2.959 | 26.2 |
Embodiment 6:
The preparation of Fenofibric Acid crystal formation F:
In 100ml flask, add Fenofibric Acid 5g, 50ml Virahol, 80 DEG C of heating in water bath, be stirred to dissolution of solid, add 0.1g Medicinal Charcoal, stir 15 minutes, filtered while hot, cooling crystallization (0 DEG C ~ 5 DEG C), filters, and filter cake is at 60 DEG C of dry Fenofibric Acid crystal formation F.The crystal formation obtained is done X-ray powder diffraction, and its diffracting spectrum is shown in Fig. 1, and its 2 θ value is as following table.(relative intensity value is more than or equal to 10%)
| 2 θ angles | Interplanar distance | Relative intensity |
| 5.441° | 16.228 | 19.3% |
| 15.821° | 5.597 | 32.9% |
| 18.400° | 4.818 | 32.9% |
| 19.180° | 4.624 | 28.3% |
| 20.140° | 4.405 | 61.1% |
| 21.380° | 4.153 | 72.6% |
| 22.099° | 4.019 | 49.8% |
| 22.520° | 3.945 | 38.9% |
| 23.039° | 3.857 | 91.2% |
| 24.980° | 3.562 | 73.9% |
| 26.401° | 3.373 | 78.6% |
| 26.719° | 3.334 | 12.5% |
| 27.739° | 3.213 | 27.0% |
| 28.841° | 3.093 | 38.7% |
| 30.121° | 2.965 | 100.0% |
| 31.320° | 2.853 | 23.3% |
| 32.140° | 2.783 | 23.0% |
| 33.460° | 2.676 | 46.8% |
| 35.480° | 2,528 | 20.0% |
| 35.899° | 2.499 | 36.4% |
| 36.540° | 2.457 | 20.3% |
| 38.320° | 2.347 | 11.5% |
| 41.040° | 2.197 | 48.4% |
| 42.000° | 2.149 | 55.1% |
| 43.680° | 2.071 | 41.5% |
| 44.760° | 2.023 | 10.4% |
| 46.780° | 1.940 | 25.1% |
| 49.200° | 1.850 | 17.0% |
Embodiment 7:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 35mg:
Fenofibric Acid crystal form A 35g
Microcrystalline Cellulose 30g
Polyvinylpolypyrrolidone 3.0g
PVP K30 5.0g
Magnesium Stearate 0.36g
70% appropriate amount of ethanol
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone, PVP K30 and Microcrystalline Cellulose are mixed according to equal increments method.
3, appropriate 70% ethanol of powder after mixing is made softwood.
4, softwood 24 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 24 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 6mm is taken.
Embodiment 8:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 35mg:
Fenofibric Acid crystal form B 35g
Microcrystalline Cellulose 55g
Polyvinylpolypyrrolidone 4.5g
PVP K30 7.0g
Magnesium Stearate 0.5g
50% appropriate amount of ethanol
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone, PVP K30 and Microcrystalline Cellulose are mixed according to equal increments method.
3, appropriate 50% ethanol of powder after mixing is made softwood.
4, softwood 20 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 20 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 7mm is taken.
Embodiment 9:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 35mg:
Fenofibric Acid crystal C 35g
Microcrystalline Cellulose 60g
Polyvinylpolypyrrolidone 4.5g
Magnesium Stearate 0.5g
The 5% PVP K30 aqueous solution is appropriate
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone and Microcrystalline Cellulose are mixed according to equal increments method.
3, the appropriate 5% PVP K30 aqueous solution of powder after mixing is made softwood.
4, softwood 20 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 20 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 6mm is taken.
Embodiment 10:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 105mg:
Fenofibric Acid crystal form A 105g
Microcrystalline Cellulose 90g
Polyvinylpolypyrrolidone 9.0g
PVP K30 15.0g
Magnesium Stearate 1.08g
70% appropriate amount of ethanol
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone, PVP K30 and Microcrystalline Cellulose are mixed according to equal increments method.
3, appropriate 70% ethanol of powder after mixing is made softwood.
4, softwood 24 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 24 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 9mm is taken.
Embodiment 11:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 105mg:
Fenofibric Acid crystal form B 105g
Microcrystalline Cellulose 165g
Polyvinylpolypyrrolidone 13.5g
PVP K30 21g
Magnesium Stearate 1.5g
50% appropriate amount of ethanol
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone, PVP K30 and Microcrystalline Cellulose are mixed according to equal increments method.
3, appropriate 50% ethanol of powder after mixing is made softwood.
4, softwood 20 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 20 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 9mm is taken.
Embodiment 12:
Pharmaceutical composition:
The prescription of preparation 1000 tablets of tablets, every sheet contains the dosage of 105mg:
Fenofibric Acid crystal C 105g
Microcrystalline Cellulose 180g
Polyvinylpolypyrrolidone 13.5g
Magnesium Stearate 1.5g
The 5% PVP K30 aqueous solution is appropriate
Technique:
1, Fenofibric Acid was pulverized 100 mesh sieves, for subsequent use; Microcrystalline Cellulose and polyvinylpolypyrrolidone pulverized 80 mesh sieves, for subsequent use.
2, Fenofibric Acid, polyvinylpolypyrrolidone and Microcrystalline Cellulose are mixed according to equal increments method.
3, the appropriate 5% PVP K30 aqueous solution of powder after mixing is made softwood.
4, softwood 20 mesh sieves are made wet granular.
5, dry at wet granular being placed in 75 DEG C, obtain dry particle.
6, dry particle is crossed 20 mesh sieves and carry out whole grain.
7, Magnesium Stearate is added
7, detect the granule content of dry particle, calculate sheet weight.
8, the punch die compressed tablets that the heavy particle diameter of sheet is 9mm is taken.
Embodiment 13:
The crystal form A of Fenofibric Acid, crystal form B, crystal C, crystal formation D, crystal formation E and the crystal formation F test of pesticide effectiveness:
The crystal form A of Fenofibric Acid, crystal form B, crystal C, crystal formation D, crystal formation E and crystal formation F are on the impact of High fat diet rats blood fat and liver PPAR-α mrna expression
Get 80 Wister rats respectively and be divided into each 10 of control group, hyperlipidemia model group, Fenofibric Acid crystal form A, crystal form B, crystal C, crystal formation D, crystal formation E and crystal formation F group at random.Control group normal diet is fed, and excess-three group is given high lipid food and fed, all continuous 8 weeks.Wherein 5th ~ 8 weeks, Fenofibric Acid group gave Fenofibric Acid 35/kg gavage, and all the other two groups respectively with normal saline gavage.After 8 weeks, each group is all got blood from postcava and is measured serum TC, TG; And put to death animal and get liver and prepare homogenate, measure TC and TG level, and apply RT-PCR and detect peroxisome proliferators-activated receptors-α (PPAR-α) mrna expression situation.Result shows, and compares with control group, and hyperlipidemia model group serum and liver homogenate TG, TC level all obviously raise (P<0.01), and liver PPAR-α/β-actin obviously declines (P<0.01).Compare with hyperlipidemia model group, Fenofibric Acid high and low dose group serum and liver homogenate TG, TC level all obviously reduce (P<0.05,0.01), and liver PPAR-α/β-actin all obviously raises (P<0.05,0.01).Compare with Fenofibric Acid low dose group, Fenofibric Acid high dose group serum and liver homogenate TG level obviously reduce (P<0.05), and liver PPAR-α/β-actin obviously raises (P<0.01).The results are shown in following table.
Each group of Testing index compares
| Group | Serum TG | Serum TC | Liver homogenate TG | Liver homogenate TC | PPAR-α/β-actin |
| Hyperlipidemia model group | 2.8±0.34 | 3.1±0.45 | 0.55±0.11 | 0.045±0.010 | 0.45±0.09 |
| Fenofibric Acid crystal form A | 1.4±0.74 | 2.7±0.40 | 0.38±0.12 | 0.042±0.016 | 1.06±0.19 |
| Fenofibric Acid crystal form B | 1.4±0.54 | 2.7±0.63 | 0.20±0.05 | 0.041±0.006 | 1.52±0.30 |
| Fenofibric Acid crystal C | 1.4±0.34 | 2.7±0.43 | 0.20±0.05 | 0.041±0.016 | 1.46±0.25 |
| Fenofibric Acid crystal formation D | 1.4±0.56 | 2.7±0.40 | 0.20±0.08 | 0.041±0.013 | 1.38±0.20 |
| Fenofibric Acid crystal formation E | 1.4±0.43 | 2.7±0.38 | 0.20±0.06 | 0.041±0.012 | 1.50±0.32 |
| Fenofibric Acid crystal formation F | 1.4±0.28 | 2.7±0.47 | 0.20±0.02 | 0.041±0.019 | 1.50±0.28 |
| Control group | 1.3±0.41 | 1.6±0.28 | 0.26±0.07 | 0.025±0.009 | 1.41±0.22 |
Result shows: the crystal form A of Fenofibric Acid, crystal form B, crystal C, crystal formation D, crystal formation E and crystal formation F can reduce High fat diet rats serum and hepatic tissue blood lipid level, and in dose-dependently; Raise liver PPAR-α mrna expression and adjust one of fat mechanism for it.
Detail the present invention above, comprise its preferred embodiment.But it should be understood that and consider content disclosed by the invention, those skilled in the art can change the present invention and/or improve in the scope of following claims, and these improvements and modifications also should be considered as protection scope of the present invention.
Claims (11)
1. Fenofibric Acid crystal form A, is characterized in that: its X-ray powder diffraction is about the position of 5.421 °, 11.401 °, 18.360 °, 19.120 °, 20.120 °, 21.360 °, 21.960 °, 23.020 °, 24.920 °, 40.980 ° to having characteristic diffraction peak in 2 θ values.
2. Fenofibric Acid crystal form B, is characterized in that: its X-ray powder diffraction is about the position of 5.571 °, 18.525 °, 19.291 °, 20.291 °, 21.514 °, 23.163 °, 25.118 °, 26.523 °, 30.243 ° to having characteristic diffraction peak in 2 θ values.
3. Fenofibric Acid crystal C, is characterized in that: its X-ray powder diffraction is about the position of 5.506 °, 15.797 °, 21.449 °, 22.141 °, 27.781 ° to having characteristic diffraction peak in 2 θ values.
4. Fenofibric Acid crystal formation D, is characterized in that: its X-ray powder diffraction is about the position of 7.955 °, 15.917 °, 16.632 °, 19.327 °, 22.167 °, 23.957 ° to having characteristic diffraction peak in 2 θ values.
5. Fenofibric Acid crystal formation E, is characterized in that: its X-ray powder diffraction is being about the position of 18.446 °, 20.215 °, 22.570 °, 23.095 °, 23.747 °, 25.031 °, 30.182 ° to having characteristic diffraction peak in 2 θ values.
6. Fenofibric Acid crystal formation F, it is characterized in that: its X-ray powder diffraction is about 5.441 ° in 2 θ values, 7.859 °, 15.821 °, 18.400 °, 19.180 °, 20.140 °, 21.380 °, 22.099 °, 22.520 °, 23.039 °, 24.980 °, 26.401 ° 26.719 °, 27.739 °, 28.841 °, 30.121 °, 31.320 °, 32.140 ° 33.460 °, 35.480 °, 35.899 °, 36.540 °, 38.320 °, 41.040 ° 42.000 °, 43.680 °, 44.760 °, 46.398 °, 46.780 °, the position of 49.200 ° is to having characteristic diffraction peak.
7. the Fenofibric Acid crystal form A of claim 1 ~ 6, the preparation method of B, C, D, E, F, the method comprises Fenofibric Acid stirring and dissolving under heated reflux condition, then adds Medicinal Charcoal, filtration or centrifugal, crystallization at-10 DEG C ~ 10 DEG C.
8. the method as described in claim 7, said suitable solvent comprises acetone, ethyl acetate, methyl acetate, tetrahydrofuran (THF), ethanol, methyl alcohol, Virahol, ethylene glycol, acetonitrile, methylene dichloride, trichloromethane, tetracol phenixin, dioxane, acetic acid, formic acid, N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, water etc. or their mixture.
9. the method as described in claim 8, said suitable solvent comprises acetone, ethyl acetate, ethanol, Virahol, water or their mixture.
10. a pharmaceutical composition, comprises Fenofibric Acid crystal form A, B, C, D, E, F and pharmaceutical excipient.
11. Fenofibric Acid crystal form As, B, C, D, E, F as activeconstituents for the manufacture of the application in the following disease medicament for the treatment of: serious HTC, primary hypercholesterolemia or mixed dyslipidemia.
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Address after: 710075 Shaanxi city of Xi'an province high tech Zone Three New Road No. 2 building 30803 commercial sea cloud chamber Applicant after: Shaanxi Hecheng Pharmaceutical Co., Ltd. Address before: 710075 room 2003, building D, fortune three, Gaoxin Road, Shaanxi, Xi'an Applicant before: Shaanxi Synthetic Pharmaceutical Co, Ltd. |
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Application publication date: 20150325 |