CN103130857A - Difluprednate II crystal form and preparation method thereof - Google Patents
Difluprednate II crystal form and preparation method thereof Download PDFInfo
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- CN103130857A CN103130857A CN2011103920562A CN201110392056A CN103130857A CN 103130857 A CN103130857 A CN 103130857A CN 2011103920562 A CN2011103920562 A CN 2011103920562A CN 201110392056 A CN201110392056 A CN 201110392056A CN 103130857 A CN103130857 A CN 103130857A
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Abstract
The invention provides a difluprednate II crystal form and a preparation method thereof. The X-ray powder diffraction of the difluprednate II crystal form has a characteristic peak when a diffraction angle 2theta is 6.1 degrees, 13.1 degrees, 15.4 degrees and 16.9 degrees. According to the preparation method of the difluprednate II crystal form, difluprednate is dissolved in one solution or multiple solutions of acetone, tetrahydrofuran, ethanol or isopropanol, and the difluprednate II crystal form is obtained by using evaporative crystallization, cooling crystallization or elution methods.
Description
Technical field:
The invention belongs to and relate to a kind of steroidal compounds polymorphic, particularly difluprednate II crystal formation and preparation method thereof.
Background technology:
Its chemical structural formula of difluprednate (Difluprednate, CAS:23674-86-4) is as follows:
Difluprednate is the bifluoride derivative of reflunomide prednisolone, has stronger anti-inflammatory and analgesic effect.It is gelifying agent and the creme of the exploitation of Pfizer company originally, obtains the mandate of ophthalmic emulsion from Japanese Senju Pharma Co., Ltd by Sirion company in 2006.The difluprednate ophthalmic preparation of at present U.S.'s listing is that Sirion Therapeutics company produces, and the 0.05% difluprednate ophthalmic emulsion of commodity Durezol by name is used for the treatment of post-operation inflammatory and pain.The III clinical trial phase of difluprednate ophthalmic emulsion has obtained the certainty result, but in this test the eye inflammation after this medicine quick solution ophthalmologic operation, not only effectively but also safety.The unique texture of this medicine makes pharmaceutical cpd can enter fast the steroid stratum corneum, can solve sooner inflammation and the front aqueous flare problem of anterior chamber's cell.
Polymorph medicine produces different crystal formations along with the difference of processing condition, because crystalline network is different, may there be significant difference in the physical properties of same medicine and stability, thereby can exert an influence to security, the validity of medicine.The crystal formation research work of medicine has at present become more and more important, and the crystallization polymorphic that Chinese patent ZL200580026414.0 discloses certain drug is usually the interior pharmacological important factor of judgment of difficulty or ease, stability, solubleness, stability in storage, preparation difficulty or ease and body of medicine preparation.We conduct in-depth research its crystal formation situation in exploitation difluprednate bulk drug, do not find about the polymorphous report of difluprednate.
Summary of the invention:
Present polymorphous preparation mainly contains: method of evaporation, method of cooling and dissolved method, wherein method of evaporation be use optimum dissolution with solvents product again evaporate to dryness make it to separate out.Method of cooling be in the situation that high temperature use optimum dissolution with solvents product more cooling making it separate out.The dissolved method refers to use optimum dissolution with solvents product to add poor solvent to make it to separate out again.
We have found the crystal formation of two kinds of difluprednates in the research process that carries out the difluprednate crystal formation, be respectively difluprednate I crystal formation (hereinafter to be referred as " I crystal formation ") and difluprednate II crystal formation (hereinafter to be referred as " II crystal formation ").The X-ray powder diffraction of I crystal formation has been located characteristic peak diffraction angle 2 θ=8.9 °, 11.6 °, 17.6 °, the X-ray powder diffraction of II crystal formation has been located characteristic peak diffraction angle 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, and the relative diffracted intensity of crystal formation I and crystal form II is respectively in fact shown in its detailed spectrogram (Fig. 2 and Fig. 1).Described term " in fact ", the diffracted intensity that should be understood to characteristic peak also should be within the scope of the invention along with the difference of crystal preparing technology, sample installation method and surveying instrument can change to some extent.In addition, the difference of instrument and other factors may affect diffraction angle 2 θ values, so the above-mentioned diffraction angle 2 θ values that characteristic peak arranged can be in variation in existing value ± 0.2 °.
We utilize purple to study the solubility behavior of two kinds of crystal formations in the aqueous solution with external spectrum, find that II crystal formation provided by the invention shows better solvability in water, but the stability in water is not as the I crystal formation.Specifically with the 0.15g micronization, median size is that difluprednate crystal I and the II of 10um adds respectively in 50ml water, keeps stirring velocity constant, by 5 minutes, 10 minutes, 15 minutes, 20 minutes and the sampling of spending the night, filter immediately after sampling, filtrate is done the uv-absorbing analysis, finds that the uv-absorbing of crystal form II is maximum when stirring 5 minutes, be about 0.28, rear slow decreasing be down to 0.13 after spending the night, and the uv-absorbing of crystal formation I is stabilized in 0.13 substantially.Although the stability of crystal form II in water is not as the I crystal formation, but better solvability is arranged but, therefore may have higher bioavailability, certainly to avoid contacting with water in the preparation process, for example to avoid preparing the suspendible aqueous solution preparation, but can be used for preparing powder inhalation or capsule or utilize dry granulation to prepare tablet etc.
Detailed Description Of The Invention:
Difluprednate I crystal formation can obtain by following method:
Dissolved method of the present invention is after being dissolved in difluprednate in solvent, then adds poor solvent to make the preparation method of crystallization.
(1) difluprednate is dissolved in acetonitrile, utilizes one or more methods in evaporative crystallization, crystallisation by cooling or dissolved method to obtain difluprednate I crystal formation.The poor solvent of described dissolved method can be water, normal hexane, and perhaps ethers, for example: ether, sherwood oil, isopropyl ether etc.
Difluprednate II crystal formation can obtain by following method:
(1) difluprednate is dissolved in one or more solvents in acetone, tetrahydrofuran (THF) or Virahol, utilizes evaporative crystallization, crystallisation by cooling or dissolved method to obtain.The poor solvent preferably water of described dissolved method, normal hexane, ether, sherwood oil, isopropyl ether.
(2) difluprednate is dissolved in ethanol, utilizes evaporative crystallization, crystallisation by cooling, obtain.
(3) difluprednate is dissolved in ethanol, then adds the poor solvent normal hexane, obtain.
Difluprednate crystallization provided by the invention is analyzed with the X-ray powder diffraction.The wavelength of the X-ray powder diffraction that experiment is adopted
The invention provides a kind of difluprednate II crystal formation, its X-ray powder diffraction has been located characteristic peak diffraction angle 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
The present invention also provides a kind of powder inhalation of difluprednate, it is characterized in that described difluprednate is the difluprednate crystal form II.
Described powder inhalation is made of difluprednate powder and support powder, and described carrier is selected from lactose, N.F,USP MANNITOL, one or more in glycine.The median size of difluprednate powder is 0.1～10 μ m; Preferred 0.1～5 μ m.The weight ratio of difluprednate and carrier is 1: 1～1000, preferred 1: 10～200.
Description of drawings:
Fig. 1 is the X-ray powder diffraction spectrogram of the difluprednate II crystal formation that makes of embodiment 1-1～1-4
Fig. 2 is the X-ray powder diffraction spectrogram of the difluprednate I crystal formation that makes of embodiment two
Embodiment:
The below will the invention will be further described by embodiment, and these descriptions are not that content of the present invention is done further to limit.The technician who understands crystallization knowledge should be understood that and is equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, within still belonging to protection scope of the present invention.
The crystal formation determining instrument that embodiment is used: Rigaku (Rigaku) D/max-2500 type monochromatic x-rays diffractometer, the CuK alpha-ray (λ=1.54056A), graphite monochromator, scanning speed 1s/step
The preparation of embodiment one difluprednate ∏ crystal formation
Embodiment 1-1
Get the 0.5kg difluprednate and be dissolved in 3.5L acetone, be heated to molten clear, then after reduction vaporization, cooling after crystal, filtration, drying appear, obtain difluprednate crystal Z1.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, as shown in Fig. 1-Z1.
Embodiment 1-2
Get the 10g difluprednate and be dissolved in 50mL ethanol, be heated to molten clear, then after reduction vaporization, cooling after crystal, filtration, drying appear, obtain difluprednate crystal Z3.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, as shown in Fig. 1-Z3.
Embodiment 1-3
Get the 1g difluprednate and be dissolved in the 2mL tetrahydrofuran (THF), be heated to molten clear, then after reduction vaporization, cooling after crystal, filtration, drying appear, obtain difluprednate crystal Z4.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.5 °, 16.9 °, as shown in Fig. 1-Z4.
Embodiment 1-4
Get the 1g difluprednate and be dissolved in the 8mL Virahol, be heated to molten clear, then after reduction vaporization, cooling after crystal, filtration, drying appear, obtain difluprednate crystal Z5.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, as shown in Fig. 1-Z5.
Embodiment 1-5
The 1g difluprednate is added in 5mL acetone, be heated to molten clearly, then the speed with 0.1 ℃/min is cooled to 10 ℃, separates out the difluprednate crystallization, filters, drying, obtains the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.2 °, 13.1 °, 15.5 °, 16.9 °.
Embodiment 1-6
The 10g difluprednate is added in 50mL ethanol, be heated to molten clearly, then the speed with 0.1 ℃/min is cooled to 15 ℃, separates out the difluprednate crystallization, filters, drying, obtains the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-7
The 1g difluprednate is added in the 2mL tetrahydrofuran (THF), be heated to molten clearly, then the speed with 0.1 ℃/min is cooled to 5 ℃, separates out the difluprednate crystallization, filters, drying, obtains the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-8
The 1g difluprednate is added in the 4mL Virahol, be heated to molten clearly, then the speed with 0.1 ℃/min is cooled to 10 ℃, separates out the difluprednate crystallization, filters, drying, obtains the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-9
Get the 10g difluprednate and be dissolved in 50mL acetone, be heated to molten clearly, more slowly add 200mL water, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-10
Get the 5g difluprednate and be dissolved in the 15mL Virahol, be heated to molten clearly, more slowly add 60mL water, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-11
Get the 1g difluprednate and be dissolved in 6mL acetone, be heated to molten clearly, more slowly add the 24mL normal hexane, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.8 °.
Embodiment 1-12
Get the 1g difluprednate and be dissolved in 5mL ethanol, be heated to molten clearly, more slowly add the 20mL normal hexane, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-13
Get the 5g difluprednate and be dissolved in the 10mL tetrahydrofuran (THF), be heated to molten clearly, more slowly add the 40mL normal hexane, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-14
Get the 1g difluprednate and be dissolved in the 5mL Virahol, be heated to molten clearly, more slowly add the 20mL normal hexane, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.8 °.
Embodiment 1-15
Get the 1g difluprednate and be dissolved in 6mL acetone, be heated to molten clearly, more slowly add the 24mL ether, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-16
Get the 10g difluprednate and be dissolved in the 15mL tetrahydrofuran (THF), be heated to molten clearly, more slowly add 30mL normal hexane and 30mL sherwood oil, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.5 °, 16.9 °.
Embodiment 1-17
Get the 1g difluprednate and be dissolved in the 5mL Virahol, be heated to molten clearly, more slowly add 10mL water and 10mL isopropyl ether, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.8 °.
Embodiment 1-18
Get the 1g difluprednate and be dissolved in 6mL acetone, be heated to molten clearly, more slowly add 10mL sherwood oil and 14mL isopropyl ether, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
Embodiment 1-19
Get the 10g difluprednate and be dissolved in the 15mL tetrahydrofuran (THF), be heated to molten clearly, more slowly add 25mL ether and 35mL isopropyl ether, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.5 °, 16.9 °.
Embodiment 1-20
Get the 1g difluprednate and be dissolved in the 5mL Virahol, be heated to molten clearly, more slowly add 10mL ether and 10mL sherwood oil, add fashionable wanting and slowly stir while adding, after finishing, filtration, drying, obtain the difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.8 °.
The preparation of embodiment two difluprednate I crystal formations
Get the 10g difluprednate and be dissolved in the 20mL acetonitrile, be heated to molten clearly, cooling after crystal, filtration, drying appear in reduction vaporization then, obtain difluprednate crystal Z2.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions and be 2 θ=8.9 °, 11.6 °, 17.6 °.As shown in Figure 2
The preparation of embodiment three difluprednate II crystal formation powder inhalations
Embodiment 3-1
With micronization, median size reaches the difluprednate II crystal formation 1g of 0.1 μ m, and the micronization median size reaches the glycine 100g of 200 μ m, and the micronization median size reaches the N.F,USP MANNITOL 100g mixing of 200 μ m, crosses 200 mesh sieve 3 times, in No. 4 capsules of packing into.
Embodiment 3-2
With micronization, median size reaches the difluprednate II crystal formation 1g of 5 μ m and the lactose 100g that the micronization median size reaches 100 μ m, and mixing is crossed 200 mesh sieve 3 times, in No. 4 capsules of packing into.
Embodiment 3-3
With micronization, median size reaches the difluprednate II crystal formation 1g of 10 μ m, and the micronization median size reaches 10 μ m glycine 5g, and the micronization median size reaches the lactose 10g mixing of 200 μ m, and mixing is crossed 200 mesh sieve 3 times, in No. 4 capsules of packing into.
Claims (10)
1. difluprednate II crystal formation, its X-ray powder diffraction has been located characteristic peak diffraction angle 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °.
2. the preparation method of a difluprednate II crystal formation as claimed in claim 1, it is characterized in that: difluprednate is dissolved in one or more solvents in acetone, alcohol, tetrahydrofuran (THF) or Virahol, utilize evaporative crystallization, crystallisation by cooling or dissolved method obtain.
3. the preparation method of difluprednate II crystal formation as claimed in claim 2 is characterized in that the poor solvent preferably water of described dissolved method, normal hexane, ether, sherwood oil, one or more in isopropyl ether.
4. the preparation method of a difluprednate II crystal formation as claimed in claim 1 is characterized in that: adopt evaporative crystallization or crystallisation by cooling method to obtain, preferred solvent is ethanol.
5. the preparation method of a difluprednate II crystal formation as claimed in claim 1 is characterized in that: adopt the dissolved method, solvent is ethanol, and poor solvent is normal hexane.
6. the powder inhalation of a difluprednate, it is characterized in that: difluprednate used is difluprednate II crystal formation as claimed in claim 1.
7. powder inhalation as claimed in claim 6, it is characterized in that: described powder inhalation is made of difluprednate and support powder, and the median size of difluprednate powder is 0.1～10 μ m; The weight ratio of difluprednate and carrier is 1: 1～1000.
8. powder inhalation as claimed in claim 7, it is characterized in that: the weight ratio of difluprednate and carrier is 1: 10～200.
9. powder inhalation as claimed in claim 7, it is characterized in that: the median size of difluprednate powder is 0.1～5 μ m.
10. powder inhalation as claimed in claim 7, it is characterized in that: described carrier is selected from lactose, N.F,USP MANNITOL, one or more in glycine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964412A (en) * | 2012-11-27 | 2013-03-13 | 山东省医药工业研究所 | Novel crystal form and preparation method of difluprednate |
| CN108659085A (en) * | 2018-04-03 | 2018-10-16 | 广州仁恒医药科技股份有限公司 | A method of high-purity Difluprednate is prepared by crude product |
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| US3780177A (en) * | 1967-06-16 | 1973-12-18 | Warner Lambert Co | 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use |
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
| CN102170865A (en) * | 2009-07-14 | 2011-08-31 | 国立大学法人山形大学 | Eye drop with difluprednate for macular edema treatment |
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2011
- 2011-11-30 CN CN2011103920562A patent/CN103130857A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3780177A (en) * | 1967-06-16 | 1973-12-18 | Warner Lambert Co | 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use |
| CN1200926A (en) * | 1997-05-14 | 1998-12-09 | 千寿制药株式会社 | Composition containing diflucortolone acetate butyrate |
| CN102170865A (en) * | 2009-07-14 | 2011-08-31 | 国立大学法人山形大学 | Eye drop with difluprednate for macular edema treatment |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964412A (en) * | 2012-11-27 | 2013-03-13 | 山东省医药工业研究所 | Novel crystal form and preparation method of difluprednate |
| CN108659085A (en) * | 2018-04-03 | 2018-10-16 | 广州仁恒医药科技股份有限公司 | A method of high-purity Difluprednate is prepared by crude product |
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Application publication date: 20130605 |