CN106892952A - A kind of Loteprednol etabonate novel crystal forms and preparation method thereof - Google Patents
A kind of Loteprednol etabonate novel crystal forms and preparation method thereof Download PDFInfo
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- CN106892952A CN106892952A CN201510977122.0A CN201510977122A CN106892952A CN 106892952 A CN106892952 A CN 106892952A CN 201510977122 A CN201510977122 A CN 201510977122A CN 106892952 A CN106892952 A CN 106892952A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention discloses a kind of Loteprednol etabonate novel crystal forms I, its X-ray powder diffraction is θ=5.6 ° of the angle of diffraction 2,7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °, can be prepared using supercritical fluid technique or by the saturated solution M of Loteprednol etabonate, adding crystal seed, cooling crystallization is obtained, the solution M by 1 parts by volume acetone, the n-hexane of 0.2~0.3 parts by volume, 0.2~0.3 parts by volume acetonitrile composition.
Description
Technical field
The present invention relates to a kind of novel crystal forms of steroidal compounds, more particularly to Loteprednol etabonate novel crystal forms I and its preparation
Method.Belong to pharmaceutical technology field.
Background technology
Loteprednol etabonate (CAS：82034-46-6, Loteprednol etabonate), it is a kind of new sugared cortical hormone
Element, by the development and production of PharmoS companies of the U.S., forms according to " soft medicine " principle design, Loteprednol etabonate suspension drop in 1998
Ocular fluid is ratified to list in the U.S., has listed afterwards and successively ophthalmically acceptable ointment and gel for eye use, for treating inflammation of eye section, especially fits
For eyelid and the medicine of the sensitive inflammation of the anterior steroidal of bulbar conjunctiva, cornea and eyeball and Post operation eye symptom.2005
Year, the compound Loteprednol etabonate/gernebcin suspension eye drops of FDA approval bausch ＆ lombs companyListing, is used for
Treatment intraocular cortex adrenaline hormone medicine responsive inflammatory conditions.
The crystal formation research work of current medicine has become more and more important, and the different polymorphics of a bulk drug can have
Different chemically and physically characteristics, including fusing point, chemical reactivity, apparent solubility, rate of dissolution, optically and mechanically property,
Vapour pressure and density, these characteristics can directly affect the treatment and/or production of bulk drug and preparation, and can influence preparation
Stability, solubility and bioavilability.Therefore, polymorphic can influence quality, security and the validity of pharmaceutical preparation.But
It is, currently without on the polymorphous research of Loteprednol etabonate and report.We are in exploitation Loteprednol etabonate bulk drug
When, its crystal formation situation is conducted in-depth research, find marketable material, eye drops and according to current conventional synthesis side
Method such as US4996335, Journal of Steorid Biochem Molecular Biology, 1991,38 (2)：149-
154th, Chinese pharmaceutical chemistry magazine, 2003, Vol.13, NO.5, P299, analytical chemistry research notes, 2005 volume 33,
P351-354, CN103249716, CN101942001, CN103183714 etc. disclosed method, the Loteprednol etabonate for obtaining
Only a kind of crystal formation (referring to the content of the invention), the present invention is referred to as crystal formation II.We filter to isolate commercially available Loteprednol etabonate/
Gernebcin suspension eye dropsIn Loteprednol etabonate raw material, carry out X-ray powder diffraction measure, it is found that it is brilliant
Type II, we filter to isolate commercially available Loteprednol etabonate suspension eye drops(0.5% Loteprednol etabonate is ophthalmically acceptable
Supensoid agent) andLoteprednol etabonate raw material in (the ophthalmically acceptable supensoid agent of 0.2% Loteprednol etabonate), carries out X-ray
Powder diffraction is determined, it is found that it is also crystal formation II.
Commercially available Loteprednol etabonate suspension eye drops is found through investigatingReplaced according to carbon chlorine with commercially available
Sprinkle promise/gernebcin suspension eye dropsStability is bad, and impurity increases quickly.For example：At 12 months
The maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) of Loteprednol etabonate is 0.44%, and the total miscellaneous of Loteprednol etabonate is
0.88%, 1.78% is risen to its maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) at 24 months, it is total miscellaneous to have reached
2.21%.The maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) of Loteprednol etabonate is 0.50% at 12 months, according to carbon
The total miscellaneous of Loteprednol is 0.92%, and 1.85% is risen to its maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) at 24 months,
It is total miscellaneous to have reached 2.26%.Therefore, preparing a kind of stability Loteprednol etabonate formulation products higher becomes extremely important.
The content of the invention
Surprisingly, we are in Loteprednol etabonate crystal formation research process is carried out, it has been found that a kind of brand-new
Loteprednol etabonate crystal formation I, the brand-new Loteprednol etabonate crystal formation I are compared with existing anhydrous Loteprednol etabonate crystal formation II
It is more easy to crush, it is often more important that, the aqueous suspension being made of the micro mist of the Loteprednol etabonate crystal formation I of present invention offer, with
The aqueous suspension that the micro mist of existing Loteprednol etabonate crystal formation II is made is compared, and with more preferable stability, suspension effect is more
It is good.Therefore this brand-new Loteprednol etabonate crystal formation I bulk drugs can turn into the new selection of Loteprednol etabonate formulation products.
Loteprednol etabonate crystal formation I chemical structural formulas are shown below：
The invention provides a kind of Loteprednol etabonate crystal formation I, it is characterized in that the X-ray powder diffraction of described crystal formation I
In θ=5.6 ° of the angle of diffraction 2,7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, there is characteristic peak at place.
It is detailed that the relative diffracted intensity of the X-ray powder diffraction of described Loteprednol etabonate crystal formation I is substantially respectively its
Thin spectrogram is as shown in Figure 2.The term " substantial ", it should be understood that the diffracted intensity of characteristic peak with crystal preparing technology,
The difference of sample mounting procedure and measuring instrument can micro change, also should be within the scope of the invention.Additionally, instrument
Difference and other factors may influence the θ values of the angle of diffraction 2, so the above-mentioned θ values of the angle of diffraction 2 for having a characteristic peak can existing value ±
Change in 0.2 °.
A kind of preparation method of described Loteprednol etabonate crystal formation I, it is characterized in that prepared using supercritical fluid technique,
Step is as follows:
(1) Loteprednol etabonate solution is configured：By 5g Loteprednol etabonates be completely dissolved at 50 DEG C 200ml acetone and
In the mixed solution of 10ml n-hexanes；
(2) the Loteprednol etabonate solution by step (1) middle configuration is connected with solution pump, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump, is entered
Enter crystallization kettle, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
(4) the Loteprednol etabonate solution by above-mentioned steps (1) middle configuration is set by solution pump through supercritical fluid anti-solvent
Nozzle is rapidly sprayed into crystallization kettle in standby system, and nozzle temperature is 50 DEG C, and its jet length is 5cm；Flow is controlled to 1.5ml/
min；Operating time is 140min；It is continually fed into CO2Remaining solvent in crystallization kettle is cleaned；
(5) Loteprednol etabonate crystal formation I crystallizations are separated out；The Loteprednol etabonate separated out from solution is collected at crystallization kettle bottom
Crystal formation I.
The preparation method of described a kind of Loteprednol etabonate crystal formation I, it is characterized in that the saturation in Loteprednol etabonate is molten
In liquid M, add crystal seed, cooling crystallization, the solution M by 1 parts by volume acetone, the n-hexane of 0.2~0.3 parts by volume, 0.2~
The acetonitrile composition of 0.3 parts by volume, the X-ray powder diffraction of the crystal seed in θ=5.6 ° of the angle of diffraction 2,7.7 °, 11.9 °, 14.1 °,
16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.Can will pass through supercritical fluid technique surprisingly obtain according to
The crystallization of carbon Loteprednol crystal formation I is used as crystal seed.
Applications of the described Loteprednol etabonate crystal formation I in the medicine for the treatment of people or mammalian diseases is prepared.
The application of described Loteprednol etabonate crystal formation I, the formulation of described medicine be selected from aqua, ointment, supensoid agent,
One kind in inhalant, gel or emulsion.
The application of described Loteprednol etabonate crystal formation I, the formulation of described medicine is supensoid agent.
Find under study for action, Loteprednol etabonate crystal formation II becomes more readily available, except the document mentioned in background technology
Outside the method for report, Loteprednol etabonate is dissolved in acetone, ethanol, methyl alcohol, tetrahydrofuran, dioxane, chloroform, dichloromethane
In one or more solvents in alkane, acetonitrile or isopropanol, either all be can obtain according to carbon using evaporative crystallization, crystallisation by cooling
Loteprednol crystal formation II.With acetone, ethanol, tetrahydrofuran or isopropanol as good solvent, with water, n-hexane, ether, stone
Oily ether, isopropyl ether etc. also can obtain Loteprednol etabonate crystal formation II as poor solvent when being crystallized using dissolved method.
Relative to the preparation of Loteprednol etabonate crystal formation II, the preparation of Loteprednol etabonate crystal formation I has certain to solvent
Selectivity, finds, in the preparation method of above-mentioned Loteprednol etabonate crystal formation I, mixing is molten needed for recrystallization by the way that research is surprised
The volume ratio of acetone/n-hexane/acetonitrile is critically important in agent M, for example：When the volume ratio of acetone/n-hexane/acetonitrile is not in above-mentioned model
When enclosing, even if adding the crystal seed of Loteprednol etabonate crystal formation I, the product for obtaining is Loteprednol etabonate crystal formation II, for example, compare
Embodiment 1.On the other hand, the addition of the crystal seed of Loteprednol etabonate crystal formation I is also critically important, is being added without crystal seed, but other systems
In the case of standby condition identical, what is obtained is also Loteprednol etabonate crystal formation II, such as comparative examples 2.
From inventive embodiments 3 as can be seen that the Loteprednol etabonate crystal formation I that the present invention is provided under the same conditions is than existing
Loteprednol etabonate crystal formation II in technology is easier to be crushed, therefore for preparing the various pharmaceutical preparations for needing and being micronized
When, with potential advantage.Commercially available Loteprednol etabonate raw material (crystal formation II) is found in research in mechanical milling processes, due to
Reunite between electrostatic, particle serious.
From inventive embodiments 4 as can be seen that the water being made of the micro mist of the Loteprednol etabonate crystal formation I of present invention offer
Suspension, compared with the aqueous suspension that the micro mist of existing Loteprednol etabonate crystal formation II is made, with more preferable stability, mixes
Outstanding effect is more preferable.Therefore when the aqueous pharmaceutical composition with Loteprednol etabonate as active component is prepared, Loteprednol etabonate
Crystal formation I can provide more preferable stability.
Powder diffraction instrument used is Rigaku D/max-2500 powder diffractometers for Rigaku company produces in the present invention
Product.Laser Scattering Particle analyzer model：Mastersizer 2000.
Brief description of the drawings：
Fig. 1 is the X-ray powder diffraction spectrogram of Loteprednol etabonate crystal formation II obtained in comparative examples 1
Fig. 2 is the X-ray powder diffraction spectrogram of Loteprednol etabonate crystal formation I obtained in inventive embodiments 1
Fig. 3 is the connection of supercritical fluid anti-solvent equipment and schematic flow sheet in inventive embodiments 1
Wherein, 1 is Loteprednol etabonate solution, and 2 is solution pump, and 3 is nozzle, and 4 is crystallization kettle, and 5 is gas-liquid separation kettle, 6
It is gas discharge outlet, 7 is raffinate collector, and 8 is booster pump, and 9 is CO2, and P1 is equipment system pressure, and P2 is crystallization kettle work pressure
Power
Specific embodiment：
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.Person skilled should be understood that the equivalent made to technical characteristic of the invention, or be correspondingly improved,
Still fall within protection scope of the present invention.
Commercially available Loteprednol etabonate bulk drug (anhydride, crystal formation II), purchased from Tianjin Tian Yao limited companies.
Using the Loteprednol etabonate raw material of same lot number in following inventive embodiments 1 and comparative examples 1-13.
Content analysis method：
Loteprednol etabonate assay is analyzed with HPLC：
The chromatographic condition of HPLC is：Chromatographic column octadecylsilane chemically bonded silica
Mobile phase acetonitrile -0.1M glacial acetic acid (50：50)
Detection wavelength 254nm
The preparation of the Loteprednol etabonate crystal formation I of inventive embodiments 1
(1) Loteprednol etabonate solution 1 is configured：By 5g Loteprednol etabonates be completely dissolved at 50 DEG C 200ml acetone and
In the mixed solution of 10ml n-hexanes；
(2) the Loteprednol etabonate solution 1 by step (1) middle configuration is connected with solution pump 2, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump 8,
Into crystallization kettle 4, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
By above-mentioned steps (1) middle configuration Loteprednol etabonate solution 1 by solution pump 2 through supercritical fluid anti-solvent
Nozzle 3 is rapidly sprayed into crystallization kettle 4 in equipment system, and flow is controlled to 1.5ml/min, and nozzle temperature is 50 DEG C, its jet length
From being 5cm；Operating time is 140min；It is continually fed into CO2Remaining solvent in crystallization kettle 4 is cleaned；
(5) Loteprednol etabonate crystal formation I crystallizations are separated out；The Loteprednol etabonate separated out from solution is collected at crystallization kettle bottom 4
Crystal formation I.
Dried crystal is carried out into X-ray powder diffraction measure, characteristic peak positions is measured for 2 θ=5.6 °, 7.7 °,
11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, as shown in Figure 2.
Loteprednol etabonate crystal formation I prepared by inventive embodiments 1 does the crystal seed of inventive embodiments 2-1~2-4.
The preparation of the Loteprednol etabonate crystal formation I of inventive embodiments 2
Inventive embodiments 2-1
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
The crystal seed of the preparation of example 1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtained
Crystal carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.78；H, 6.75；Cl, 7.58
Inventive embodiments 2-2
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 30ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
The crystal seed of the preparation of example 1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtained
Crystal carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
Inventive embodiments 2-3
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 30ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
The crystal seed of the preparation of example 1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtained
Crystal carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.73；Cl, 7.63
Inventive embodiments 2-4
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 30ml adds in the mixed solution of the acetonitrile of 30ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
The crystal seed of the preparation of example 1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtain
Crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.91；H, 6.70；Cl, 7.55
Inventive embodiments 3 crush experiment
Experimental facilities：WLFM-P-85 type airslide disintegrating mills Beijing Wei Ling Hu Xin Mechanical Equipment Co., Ltd production particle diameter is surveyed
Measuring appratus：Easysizer20 laser particle analyzers, Zhuhai OMEC Technology Co., Ltd.
Sample is grouped：A groups are the made Loteprednol etabonate crystal formation I crystallization 500g of embodiment 2-1 methods, are equally divided into ten
Secondary crushing, feed size 80-100 mesh, five times crushing particle diameter d (0.9) carry out it is average again；
B groups are the made Loteprednol etabonate crystal formation II 500g of comparative examples 1, are equally divided into ten crushing, feed size
80-100 mesh, five times crushing particle diameter d (0.9) carry out it is average again.
Pulverization conditions：Crush air-flow 1.0Mpa；Charging rate 0.5kg/h
Above-mentioned A groups and B groups sample are carried out into air-flow crushing according to above-mentioned pulverization conditions respectively, the product granularity that will be obtained
For：The average d (0.9)=10.1 μm of A group samples, B group sample averages d (0.9)=19.5 μm.When B groups sample continues to crush,
Due to crushing the electrostatic for producing, particle aggregation is serious.
The ophthalmically acceptable suspension stability test data comparative example of inventive embodiments 4
Patent CN200580016030 discloses commercially available product(the ophthalmically acceptable suspension of 0.5% Lotepredenol etabonate
Agent) prescription：
The commercially available product of table 1Prescription
* 25.0mg/mL glycerine, 96% equivalent to 24mg/mL (2.4W/W) glycerine, 100%.
With reference to above-mentioned prescription, be prepared for 0.5% the ophthalmically acceptable supensoid agents of Loteprednol etabonate crystal formation I (a groups) and 0.5% according to
The ophthalmically acceptable supensoid agent of carbon Loteprednol (b groups), and for stability and commercially available product(0.5% Lotepredenol etabonate eye
With supensoid agent,Group) compare.A groups employ micronizing Loteprednol etabonate crystal formation I, and size distribution is d
(0.1)=2.501 μm, d (0.5)=5.275 μm, d (0.9)=10.758 μm.It is brilliant that b groups employ micronizing Loteprednol etabonate
Type II, size distribution is d (0.1)=2.512 μm, d (0.5)=5.232 μm, d (0.9)=10.456 μm.Two groups of suspensions
Preparation method is：
1. the water for injection for taking recipe quantity 60% is heated to 80 DEG C, adds auxiliary material, and stirring is to being completely dissolved；
2. in hundred grades of environment with 0.22 μm of filtering with microporous membrane twice；
3. add bacterium to examine qualified main ingredient, with homogenizer 30 minutes；
4. pH value is adjusted to 5.3-5.6 or so with 0.1M hydrochloric acid and/or 0.1M NaOH；
5. full dose is added water to, is stirred evenly, cross 200 mesh sieves, be stirred continuously in hundred grades of environment filling to low density polyethylene (LDPE) bottle
In.
4.1 stability
By Loteprednol etabonate crystal formation I groups (a groups) and Loteprednol etabonate crystal formation II groups (b groups) in embodiment 4 25
Store 24 months under DEG C ± 2 DEG C/40%RH ± 5%RH, high spot reviews relevant material, settling ratio, the grain of Loteprednol etabonate
Degree situation of change, it is specific as follows：
4.1.1 the relevant materials of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II investigate result
Respectively survey storage 0 when, 12 months and the relevant material after 24 months, measure result and see the table below, from result, 25
Storage is respectively adopted Loteprednol etabonate crystal formation I and Loteprednol etabonate is brilliant after 24 months under DEG C ± 2 DEG C/40%RH ± 5%RH
Sample prepared by type II, the relevant material of Loteprednol etabonate has growth, but uses prepared by Loteprednol etabonate crystal formation I
Sample, maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) and total miscellaneous growth are smaller in the relevant material of Loteprednol etabonate, compared with
Loteprednol etabonate crystal formation II groups and commercially available product are more stable.Maximum in following table it is single it is miscellaneous be PJ-91.
The relevant material of the Loteprednol etabonate of table 2 investigates result
4.1.2 the settling ratio of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II
50ml liquids are taken with 50ml tool plug graduated cylinders, close plug is firmly shaked 1 minute, writes down suspended matter elemental height H0, is stood
3 hours, the final height H of suspended matter is write down, settling ratio=H/H0 was determined with 24 months when 0, as a result see the table below, by tying
Fruit understands, after being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, with the sample prepared using Loteprednol etabonate crystal formation II
The settling ratio of product and 24 months commercial samples to the effect phase is compared, the sedimentation of the sample prepared using Loteprednol etabonate crystal formation I
It is more stable during placement than higher.
The settling ratio of table 3 investigates result
4.1.3 the particle diameter of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II
As a result we see the table below using laser particle analyzer is at 0 and detects within 24 months sample particle diameter respectively, can by result
Know, when 0, the sample particle diameter that Loteprednol etabonate crystal formation I and Loteprednol etabonate crystal formation II preparations are respectively adopted is basically identical, warp
After being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, the Loteprednol etabonate in two groups of samples has an aggregation, but according to
Particle diameter is more compared with sample and the commercial samples of 24 months prepared by crystal formation II for the particle diameter of sample prepared by carbon Loteprednol crystal formation I
Small, stability is more preferable.
The laser particle analyzer of table 4 determines Loteprednol etabonate particle size results (μm)
The preparation of the Loteprednol etabonate crystal formation I powder sprays of inventive embodiments 5
To be micronized, average grain diameter reaches 5 μm of Loteprednol etabonate crystal formation I 1g and micronizing average grain diameter reaches 100
μm lactose 100g, mix, cross 200 mesh sieve 3 times, be fitted into No. 4 capsules.
The preparation of the Loteprednol etabonate crystal formation I emulsions of inventive embodiments 6
Purified water is heated to about 70 DEG C, glycerine, sodium acetate, EDTA-2Na, boric acid, sorbic acid is added and is dissolved, use hydrogen
Sodium oxide molybdena adjusts pH to 5.5.Castor oil and Tween-80 are mixed and heated to 70 DEG C in addition, add Loteprednol etabonate crystal formation I molten
Solution obtains oil phase.Oil phase is added to obtain colostrum while water phase is sheared with clipper.Finally by colostrum at high pressure homogenizer
Reason, filtration sterilization obtains emulsion.
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 1
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 40ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
The crystal seed of the preparation of example 1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, filters, vacuum drying at room temperature, will
The crystal for obtaining carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °,
14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °, as shown in Figure 1.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.78；H, 6.75；Cl, 7.58
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 2
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter, cooling crystallization, filtering, vacuum drying at room temperature, the Loteprednol etabonate crystal that will be obtained to heat
X-ray powder diffraction measure is carried out, characteristic peak positions is measured for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °,
16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 3
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 50ml absolute ethyl alcohols of heat, heat filtering elimination insoluble matter, cooling crystallization,
Filtering, dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.73；Cl, 7.63
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 4
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 70ml methyl alcohol of heat, heat filtering filters off insoluble matter, cooling crystallization, mistake
Filter, dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.91；H, 6.70；Cl, 7.55
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 5
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 60ml isopropanols of heat, heat filtering filters off insoluble matter, cooling crystallization, mistake
Filter, dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.85；H, 6.73；Cl, 7.54
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 6
Take the 150ml acetone-petroleum ethers (V that the anhydrous Loteprednol etabonates of 5g are dissolved in heat：V=2：1) in, heat filtering is filtered off not
Molten thing, cooling crystallization is filtered, dried, and the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures spy
Levy peak position and be set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.88；H, 6.76；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 7
Take 5g Loteprednol etabonates and add 100ml acetone, in the mixed solution of 10ml water, be heated to 50 DEG C, heat filtering filter
Insoluble matter is removed, dried crystal is utilized Karl_Fischer method measured moisture content, confirmed by cooling crystallization, filtering, vacuum drying at room temperature
It is Loteprednol etabonate without hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures feature
Peak position is set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.92；H, 6.74；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 8
Take 5g Loteprednol etabonates and add 100ml acetone, in the mixed solution of 30ml water, be heated to 50 DEG C, heat filtering filter
Insoluble matter is removed, dried crystal is utilized Karl_Fischer method measured moisture content, confirmed by cooling crystallization, filtering, vacuum drying at room temperature
It is Loteprednol etabonate without hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures feature
Peak position is set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.90；H, 6.73；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 9
Take commercially available product(the ophthalmically acceptable supensoid agent of 0.5% Loteprednol etabonate), filtering, much filtrate is washed, vacuum
Drying at room temperature, Karl_Fischer method measured moisture content is utilized by dried crystal, confirms as Loteprednol etabonate without hydrate.Will
To Loteprednol etabonate crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 10
Take commercially available product(0.5% Loteprednol etabonate/0.3% gernebcin suspension eye drops), filtering, will leach
Thing is washed, vacuum drying at room temperature, and dried crystal is utilized into Karl_Fischer method measured moisture content, confirms as Loteprednol etabonate
Without hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 11
Take tetrahydrofuran-n-hexane (V that the anhydrous Loteprednol etabonates of 5g are dissolved in hot 40ml:V=3.3：1) mixed solvent
In, heat filtering filters off insoluble matter, and cooling crystallization is filtered, dried, and the Loteprednol etabonate crystal that will be obtained carries out x-ray powder
Diffraction, measures characteristic peak positions for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °,
19.7°。
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.72；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 12
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 100ml anhydrous propanones of heat, heat filtering filters off insoluble matter, cooling analysis
Crystalline substance, filters, dries, and the crystal that will be obtained carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.73；Cl, 7.64
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 13
Take commercially available product(the ophthalmically acceptable supensoid agent of 0.2% Loteprednol etabonate), filtering, much filtrate is washed, vacuum
Drying at room temperature, Karl_Fischer method measured moisture content is utilized by dried crystal, confirms as Loteprednol etabonate without hydrate.Will
To Loteprednol etabonate crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.71；Cl, 7.60.
Claims (6)
1. a kind of Loteprednol etabonate crystal formation I, it is characterized in that the X-ray powder diffraction of described crystal formation I the θ of the angle of diffraction 2=
5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, there is characteristic peak at place.
2. a kind of preparation method of Loteprednol etabonate crystal formation I as claimed in claim 1, it is characterized in that using supercritical fluid
Prepared by technology, step is as follows:
(1) Loteprednol etabonate solution is configured：5g Loteprednol etabonates are being completely dissolved in 200ml acetone and 10ml just at 50 DEG C
In the mixed solution of hexane；
(2) the Loteprednol etabonate solution by step (1) middle configuration is connected with solution pump, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump, into knot
Brilliant kettle, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
By above-mentioned steps (1) middle configuration Loteprednol etabonate solution by solution pump through supercritical fluid anti-solvent equipment body
Nozzle is rapidly sprayed into crystallization kettle in system, and nozzle temperature is 50 DEG C, and its jet length is 5cm；Flow is controlled to 1.5ml/min,
Operating time is 140min；It is continually fed into CO2Remaining solvent in crystallization kettle is cleaned；
(5) Loteprednol etabonate crystal formation I crystallizations are separated out；The Loteprednol etabonate crystal formation separated out from solution is collected at crystallization kettle bottom
I。
3. a kind of preparation method of Loteprednol etabonate crystal formation I as claimed in claim 1, it is characterized in that in Loteprednol etabonate
Saturated solution M in, add crystal seed, cooling crystallization, the solution M by 1 parts by volume acetone, 0.2~0.3 parts by volume just oneself
Alkane, the acetonitrile composition of 0.2~0.3 parts by volume, the X-ray powder diffraction of the crystal seed in θ=5.6 ° of the angle of diffraction 2,7.7 °,
11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.
4. the Loteprednol etabonate crystal formation I as described in claims 1 to 3 is any is preparing the medicine for the treatment of people or mammalian diseases
Application in thing.
5. the application of Loteprednol etabonate crystal formation I as claimed in claim 4, the formulation of described medicine is selected from aqua, ointment
One kind in agent, supensoid agent, inhalant, gel or emulsion.
6. the application of Loteprednol etabonate crystal formation I as claimed in claim 5, the formulation of described medicine is supensoid agent.
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| CN106279325A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate novel crystal forms and preparation method thereof |
| CN106279323A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | A kind of Loteprednol etabonate suspension eye drop composition |
| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
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| CN106279324A (en) * | 2015-05-27 | 2017-01-04 | 天津金耀集团有限公司 | Loteprednol etabonate monohydrate and crystal formation thereof and preparation method |
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