CN103130859B - Difluprednate crystal form I and preparation method thereof - Google Patents
Difluprednate crystal form I and preparation method thereof Download PDFInfo
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Abstract
Difluprednate crystal form I and preparation method thereof, provides a kind of Difluprednate crystal form I, its X-ray powder diffraction in diffraction angle 2 θ=8.9 °, there is characteristic peak at 11.6 °, 17.6 ° places.Additionally provide the preparation method of this crystal formation I, for difluprednate being dissolved in acetonitrile or containing in the mixed solvent of more than 50% acetonitrile, utilizing evaporative crystallization or crystallisation by cooling to obtain.
Description
Technical field:
The invention belongs to and relate to a kind of steroidal compounds polymorphic, particularly difluprednate polymorphic 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, within 2006, is obtained from Japanese Senju Pharma Co., Ltd the mandate of ophthalmic emulsion by Sirion company.The difluprednate ophthalmic preparation of current U.S. listing is that SirionTherapeutics company produces, and commodity are called the 0.05% difluprednate eye emulsion of Durezol, are used for the treatment of post-operation inflammatory and pain.The III clinical trial phase of difluprednate ophthalmology emulsion obtains certainty result, and in this test, this medicine can eye inflammation after quick solution ophthalmologic operation, not only effectively but also safety.The unique texture of this medicine makes pharmaceutical cpd can enter steroid stratum corneum fast, can solve the inflammation of anterior chamber's cell and front aqueous flare problem sooner.
Polymorph medicine produces different crystal formations along with the difference of processing condition, because crystalline network is different, the physical properties of same medicine and stability may exist significant difference, thus can have an impact to Drug safety, validity.The crystal formation research work of current medicine has become more and more important, and the crystalline polymorphs that Chinese patent ZL200580026414.0 discloses certain drug is usually a pharmacological important factor of judgment in medicine difficulty or ease, stability, solubleness, stability in storage, preparation difficulty or ease and the body prepared.We, when exploitation difluprednate bulk drug, conduct in-depth research its crystal formation situation, do not find about the polymorphous report of difluprednate.
Summary of the invention:
Current polymorphous preparation mainly contains: method of evaporation, method of cooling and dissolved method, wherein method of evaporation be use good solvent dissolved product again evaporate to dryness make it to separate out.Method of cooling uses good solvent dissolved product to cool in the event of high temperatures to make it to separate out again.Dissolved method refers to that using good solvent dissolved product to add poor solvent again makes it to separate out.We utilize this three kinds of methods and common solvent, have studied difluprednate polymorphic problem, find the different crystal forms of two kinds of difluprednates, be respectively Difluprednate crystal form I (hereinafter referred to as " crystal formation I ") and Difluprednate crystal form II (hereinafter referred to as " crystal form II ").
The X-ray powder diffraction of crystal formation I in diffraction angle 2 θ=8.9 °, there is characteristic peak at 11.6 °, 17.6 ° places, the X-ray powder diffraction of crystal form II in diffraction angle 2 θ=6.1 °, there is characteristic peak at 13.1 °, 15.4 °, 16.9 ° places, crystal formation I and the relative diffracted intensity of crystal form II are respectively in fact shown in its detailed spectrogram (Fig. 1 and Fig. 2).Described term " in fact ", the diffracted intensity that should be understood to characteristic peak can change to some extent along with the difference of crystal preparing technology, sample mounting procedure and surveying instrument, also should be within the scope of the invention.In addition, the difference of instrument and other factors may affect diffraction angle 2 θ value, have the diffraction angle 2 θ value of characteristic peak can change in existing value ± 0.2 ° so above-mentioned.The wavelength of the X-ray powder diffraction that experiment adopts
The invention provides a kind of Difluprednate crystal form I, its X-ray powder diffraction in diffraction angle 2 θ=8.9 °, there is characteristic peak at 11.6 °, 17.6 ° places.As shown in Figure 2.
The preparation method 1 of described Difluprednate crystal form I, for being dissolved in acetonitrile or containing in the mixed solvent of more than 50% acetonitrile, utilizing evaporative crystallization or crystallisation by cooling to obtain by difluprednate.
The preparation method 2 of described Difluprednate crystal form I, for difluprednate is dissolved in acetonitrile or containing more than 50% acetonitrile mixed solvent in, then add poor solvent make it separate out.The poor solvent preferably water adopted, normal hexane, isopropyl ether, ether, one or more in sherwood oil.
Described preparation method 1 and preparation method 2, other solvents in mixed solvent used except acetonitrile are one or more in acetone, tetrahydrofuran (THF), Virahol, ethanol, chloroform, methylene dichloride, methyl alcohol.
Described preparation method 1 and preparation method 2, preferably containing acetonitrile more than 70% in mixed solvent used.
The preparation method 3 of described Difluprednate crystal form I, is characterized in that: be dissolved in by difluprednate in ethanol or methanol solvate, then adds water and make it precipitation and obtain.
The present invention also provides a kind of suspendible aqueous solution preparation containing difluprednate, it is characterized in that the difluprednate adopted is described Difluprednate crystal form I.Described suspendible aqueous solution preparation is preferred eye drops.
The present invention also provides a kind of lipomul containing difluprednate, it is characterized in that the difluprednate adopted is described Difluprednate crystal form I.
The degree of described mixed solvent is volumn concentration.
We find under study for action, Difluprednate crystal form II becomes more readily available, being dissolved in by difluprednate in one or more solvents in acetone, ethanol, tetrahydrofuran (THF) or Virahol, is utilize evaporative crystallization, crystallisation by cooling all can obtain Difluprednate crystal form II.With acetone, tetrahydrofuran (THF) or Virahol for good solvent, with water, normal hexane, ether, sherwood oil, isopropyl ethers etc., as poor solvent, utilize during the crystallization of dissolved method and also can obtain Difluprednate crystal form II; Or dissolved by difluprednate in ethanol, with normal hexane, ether, sherwood oil, isopropyl ether etc., as poor solvent, utilize dissolved method also can obtain Difluprednate crystal form II.Patent documentation US3780177 mentions and makees solvent with methylene dichloride/ether/sherwood oil and obtain difluprednate crystallization in difluprednate preparation, and we carry out this repeating to obtain Difluprednate crystal form II.
Relative to the preparation of Difluprednate crystal form II, the preparation of Difluprednate crystal form I has certain selectivity to solvent, find in surprise by studying us, (1) when difluprednate being dissolved in acetonitrile or containing in the mixed solvent of more than 50% acetonitrile, utilizing evaporative crystallization, crystallisation by cooling or dissolved method all can obtain Difluprednate crystal form I; When using dissolved method, the poor solvent preferably water of use, normal hexane, sherwood oil, or ethers, such as: ether, isopropyl ether etc.(2) in addition, we also find, when difluprednate is dissolved in ethanol or methanol solvate, then adds poor solvent water and also can obtain Difluprednate crystal form I.
The prescription of " pharmaceutical preparation production technique and note " middle hydrocortisone acetate injection liquid that we reference Xu Rongzhou etc. writes and hydrocortisone acetate eye drop and method for making, difluprednate injection liquid and eye drop has been prepared respectively with Difluprednate crystal form I and crystal form II, find suspension injection prepared by employing Difluprednate crystal form II and eye drop, unstable, in placement after 24 hours, have larger particles to precipitate to generate, and crystal formation I does not exist such problem, be more suitable for preparing difluprednate suspendible aqueous solution preparation.Reference examples is shown in by concrete prescription.Because the solvent that suspension injection and eye drop adopt is water for injection, we utilize purple external spectrum to have studied two kinds of crystal formations solubility behavior in aqueous, find that difluprednate II crystal formation solubleness is in aqueous unstable.The difluprednate crystal I of 0.15g and II micro mist are added in 50ml water respectively, keeps stirring velocity constant, by 5 minutes, 10 minutes, 15 minutes, 20 minutes and sampling of spending the night, filtered after sampling immediately, filtrate does uv-absorbing analysis, find that the uv-absorbing of crystal form II is maximum when 5 minutes in stirring, be about 0.28, rear slow decline, be down to 0.13 after spending the night, and the uv-absorbing of crystal formation I is stabilized in 0.13 substantially.This illustrates that crystal form II is unstable in aqueous, it may be the reason causing suspension injection and the eye drop instability utilizing Difluprednate crystal form II to prepare, illustrate simultaneously and prepare in the process of suspendible aqueous solution preparation by crystal formation I, quality is more controlled, and crystal formation I is more suitable for than crystal form II and prepares suspendible aqueous solution preparation.
Lipomul as pharmaceutical carrier have reduce the toxicity of medicine or pungency, targeting or lymphsystem distributivity, the advantage such as the controllability that improves drug solubility, technique and quality, be recently subject to extensive concern as Novel Drug Delivery Systems.The preparation method of high-fat emulsion is generally by two step emulsion processes, first by medicine dissolution or be dispersed in oil phase, emulsifying agent, isotonic regulator etc. are dissolved or dispersed in aqueous phase, then by two-phase mixtures, slightly breast is being obtained by emulsify at a high speed device (agitator, tissue mashing machine etc.) high speed dispersion.Thick breast, through high pressure dispersing emulsification machine or microfluidizer emulsification, obtains submicron emulsion.Adjust ph, crosses and filters macroparticle, packing, pressure sterilizing, to obtain final product.All operations carries out all under nitrogen flowing.We have investigated Difluprednate crystal form I and crystal form II produce impurity in oil and oil and emulsifying agent situation in dissolution characteristics and dissolution process, find compared with crystal form II, crystal formation I just can be dissolved in oil at a lower temperature, the impurity produced in the process of dissolving is less, illustrates that Difluprednate crystal form I is more suitable for preparing lipomul than crystal form II.Concrete detailed in Example three.
Difluprednate crystallization X-ray powder diffraction provided by the invention is analyzed.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction spectrogram of the Difluprednate crystal form II that reference examples 1 ~ 3 obtains
Fig. 2 is the X-ray powder diffraction spectrogram of the Difluprednate crystal form I that embodiment 1 ~ 4 obtains
Embodiment:
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.The technician understanding crystallization knowledge should be understood that the equivalent replacement done technical characteristic of the present invention, or improves accordingly, still belongs within 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, CuK alpha-ray
), graphite monochromator, scanning speed 1s/step.
Comparative examples:
The preparation of comparative examples 1 Difluprednate crystal form II
Get 0.5kg difluprednate to be dissolved in 3.5L acetone, be heated to clearly molten, then reduction vaporization, occur cooling after crystal, filter, dry, obtain difluprednate crystal Z1.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, be the charateristic avsorption band of crystal form II, as shown in Fig. 1-Z1.
The preparation of comparative examples 2 Difluprednate crystal form II
Added in 2mL tetrahydrofuran (THF) by 1g difluprednate, be heated to clearly molten, be then cooled to 5 DEG C with the speed of 0.1 DEG C/min, separate out difluprednate crystallization, filtration, drying, obtain difluprednate crystal Z3.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, be the charateristic avsorption band of crystal form II, as shown in Fig. 1-Z3.
The preparation of comparative examples 3 Difluprednate crystal form II
Get 1g difluprednate to be dissolved in 5mL ethanol, be heated to clearly molten, more slowly add 20mL normal hexane, add fashionable wanting slowly, stir while adding, after finishing, filter, dry, obtain difluprednate crystal Z4.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=6.1 °, 13.1 °, 15.4 °, 16.9 °, be the charateristic avsorption band of crystal form II, as shown in Fig. 1-Z4.
The preparation of comparative examples 4 Difluprednate crystal form II injection liquid
Prescription:
Collocation method:
1. get Thiomersalate to add in about 3000ml water for injection, and add Xylo-Mucine and stir evenly placement and spend the night, with 200 order nylon mesh filtrations after dissolving, airtight for subsequent use.
2. getting sodium-chlor is dissolved in about 4000ml water for injection, filters through No. 4 sintered glass funnels, for subsequent use;
3. will 1. be placed in water-bath and heat by item liquid, add 2. item liquid and tween 80 to stir evenly simultaneously, after water boil in water-bath, add difluprednate I crystal particulate and stir evenly, continue heating 30 minutes, taking-up is chilled to room temperature, inject and modulate cumulative volume with water, sieve 1 ~ 2 time by 200 order nylon mesh, be distributed in 5ml bottle under stirring, capping plug tying seals, and both obtains with 100 DEG C of flowing steam sterilization 30min.
The preparation of comparative examples 5 Difluprednate crystal form II suspendible eye drop
Prescription:
Method for making:
1. get Xylo-Mucine to be dissolved in water for injection about 30% (full dose) volume, placement is spent the night, with the sieving of Büchner funnel pad 200 order nylon cloth, for subsequent use.
2. get oil of mirbane mercury to be dissolved in the water for injection of 50% amount, be heated to 40 ~ 50 DEG C, then add boric acid, stir and make it dissolve, filter with G3 sintered glass funnel, for subsequent use.
3. will 1. be placed in water-bath and heat by item liquid, add difluprednate, stir, continue heating 30 minutes, taking-up is chilled to room temperature, adds Phenylmercurinitrate, boric acid solution and Polysorbate 80 successively and stirs, mix, inject and modulate cumulative volume with water, with the sieved filter of Büchner funnel pad 200 order nylon cloth 2 times.
4. be distributed in eye drop bottle under stirring, sealing, with 100 DEG C of flowing steam sterilization 30min, to obtain final product.
Inventive embodiments:
The preparation of embodiment 1 Difluprednate crystal form I
Get 10g difluprednate to be dissolved in 20mL acetonitrile, be heated to clearly molten, then reduction vaporization, occur cooling after crystal, filter, dry, obtain difluprednate crystal Z2.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I, as shown in Fig. 2-Z2.
The preparation of embodiment 2 Difluprednate crystal form I
Added in 2mL acetonitrile by 1g difluprednate, be heated to clearly molten, be then cooled to 5 DEG C with the speed of 0.1 DEG C/min, separate out difluprednate crystallization, filtration, drying, obtain difluprednate crystal L2.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I, as shown in Fig. 2-L2.
The preparation of embodiment 3 Difluprednate crystal form I
Get 1kg difluprednate to be dissolved in 2L acetonitrile, be heated to clearly molten, more slowly add 8L water, add fashionable wanting slowly, stir while adding, after finishing, filter, dry, obtain difluprednate crystal K21.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I, as shown in Fig. 2-K21.
The preparation of embodiment 4 Difluprednate crystal form I
Get 1kg difluprednate to be dissolved in 5L ethanol, be heated to clearly molten, more slowly add 20L water, add fashionable wanting slowly, stir while adding, after finishing, filter, dry, obtain difluprednate crystal K31.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I, as shown in Fig. 2-K31.
The preparation of embodiment 5 Difluprednate crystal form I
Get 10g difluprednate to be dissolved in the mixing solutions of 18mL acetonitrile and 5mL ethanol, be heated to clearly molten, then reduction vaporization, occur cooling after crystal, filter, dry, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.7 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 6 Difluprednate crystal form I
Added by 10g difluprednate in the mixing solutions of 16mL acetonitrile, 4mL chloroform and 8mL methylene dichloride, be heated to clearly molten, be then cooled to 5 DEG C with the speed of 0.1 DEG C/min, separate out difluprednate crystallization, filtration, drying, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 7 Difluprednate crystal form I
Get 10g difluprednate to be dissolved in the mixing solutions of 16mL acetonitrile, 5mL acetone and 1.5mL tetrahydrofuran (THF), be heated to clearly molten, more slowly add 116mL ether, add fashionable slow, stir while adding, after finishing, filter, dry, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.5 °, 17.6 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 8 Difluprednate crystal form I
Get 10g difluprednate to be dissolved in the mixing solutions of 18mL acetonitrile and 3mL Virahol, be heated to clearly molten, more slowly add 60mL normal hexane and 24mL sherwood oil, add fashionable slow, stir while adding, after finishing, filter, dry, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 9 Difluprednate crystal form I
Get 10g difluprednate to be dissolved in the mixing solutions of 18mL acetonitrile and 15mL methyl alcohol, be heated to clearly molten, more slowly add 132mL isopropyl ether, add fashionable wanting slowly, stir while adding, after finishing, filter, dry, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.7 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 10 Difluprednate crystal form I
Get 1kg difluprednate to be dissolved in 10L methyl alcohol, be heated to clearly molten, more slowly add 20L water, add fashionable wanting slowly, stir while adding, after finishing, filter, dry, obtain difluprednate crystal.
To axonometry X-ray powder diffraction after drying, record characteristic peak positions be 2 θ=8.9 °, 11.6 °, 17.6 °, be the charateristic avsorption band of crystal formation I.
The preparation of embodiment 11 Difluprednate crystal form I injection liquid
Concrete prescription and operation are see comparative example 4.
The preparation of embodiment 12 Difluprednate crystal form I suspendible eye drop
Concrete prescription and operation are see comparative example 5
Embodiment three solvability comparative example
Difluprednate crystal form I and crystal form II are placed in mortar porphyrize by us, are dissolved in the mixture of Viscotrol C or Viscotrol C and tween-80 respectively, and oil temperature is initially 40 DEG C, dissolve in stirring, as do not dissolved completely after stirring 15min, then heat up 5 DEG C DEG C and continue to stir 15min, by that analogy.
Grouping and dissolve situation as follows
Difluprednate castor oil solution after dissolving is detected its related substances, and contrasts with its related substances before dissolving
Its related substances sees the following form
| Raw material | Experimental group 1 | Experimental group 2 | Experimental group 3 | Experimental group 4 |
| Its related substances % before dissolving | 1.03 | 0.99 | 1.03 | 0.99 |
| Its related substances % after dissolving | 1.07 | 1.83 | 1.04 | 1.96 |
Detected by solubility test and related substance and show, crystal form II is when dissolving with Viscotrol C, be heated to 70 DEG C can not dissolve completely, and add emulsifier tween-after 80s and also need to be heated to 70 DEG C of ability and dissolve completely, and crystal formation I is with when being heated to 40 DEG C and solubilized when Viscotrol C and emulsifiers dissolve, and only with during Viscotrol C when being heated to 50 DEG C and solubilized, and crystal formation I all can keep stable upon dissolution, and the related substance produced after dissolving is lower than crystal form II.
Claims (10)
1. a Difluprednate crystal form I, its X-ray powder diffraction in diffraction angle 2 θ=8.9 °, there is characteristic peak at 11.6 °, 17.6 ° places.
2. a preparation method for Difluprednate crystal form I as claimed in claim 1, is characterized in that: difluprednate is dissolved in acetonitrile or containing in the mixed solvent of more than 50% acetonitrile, utilizes evaporative crystallization or crystallisation by cooling to obtain.
3. a preparation method for Difluprednate crystal form I as claimed in claim 1, is characterized in that: difluprednate is dissolved in acetonitrile or containing more than 50% acetonitrile mixed solvent in, then add poor solvent make it separate out.
4. the preparation method of Difluprednate crystal form I as claimed in claim 3, is characterized in that: the poor solvent of employing is selected from water, normal hexane, isopropyl ether, ether, one or more in sherwood oil.
5. the preparation method of the Difluprednate crystal form I as described in any one of claim 2 ~ 4, is characterized in that: in mixed solvent used, containing acetonitrile more than 70%.
6. the preparation method of the Difluprednate crystal form I as described in any one of claim 2-4, is characterized in that: other solvents in acetonitrile mixed solvent used are one or more in acetone, tetrahydrofuran (THF), Virahol, ethanol, chloroform, methylene dichloride, methyl alcohol.
7. a preparation method for Difluprednate crystal form I as claimed in claim 1, is characterized in that: be dissolved in by difluprednate in ethanol or methanol solvate, then adds water and make it precipitation and obtain.
8. the suspendible aqueous solution preparation containing difluprednate, is characterized in that the difluprednate adopted is Difluprednate crystal form I as claimed in claim 1.
9. suspendible aqueous solution preparation as claimed in claim 8, is characterized in that described suspendible aqueous solution preparation is eye drops.
10. the preparation method of Difluprednate crystal form I as claimed in claim 5, is characterized in that: other solvents in acetonitrile mixed solvent used are one or more in acetone, tetrahydrofuran (THF), Virahol, ethanol, chloroform, methylene dichloride, methyl alcohol.
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| CN114702539B (en) * | 2022-04-01 | 2023-06-02 | 河南利华制药有限公司 | Refining method of difluprednate |
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 |
-
2011
- 2011-11-30 CN CN201110392058.1A patent/CN103130859B/en active Active
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 |
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