CN106046086B - It is a kind of to prepare the unformed method of tylonolide - Google Patents
It is a kind of to prepare the unformed method of tylonolide Download PDFInfo
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- CN106046086B CN106046086B CN201610396694.4A CN201610396694A CN106046086B CN 106046086 B CN106046086 B CN 106046086B CN 201610396694 A CN201610396694 A CN 201610396694A CN 106046086 B CN106046086 B CN 106046086B
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- tylonolide
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- isopropyl ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The present invention relates to a kind of unformed preparation methods of tylonolide.The tylonolide is unformed to have endothermic peak to have exothermic peak between 186 DEG C~210 DEG C in TG-DSC map between 135 DEG C~171 DEG C；Its XPRD map does not have identifiable diffraction peak type.Preparation method is to select isopropyl ether for solvent dissolution, and then plus elutriation goes out solid, thoroughly dries wet sample after filtering, obtains amorphous products.The amorphous products have good stability, and can save for a long time without there is signs of degradation.It is used to prepare pharmaceutical preparation, dosage form can be pre-mixing agent, tablet, pill, powder, granule, capsule or injection.Compared with other crystal forms of tylonolide, solubility is more preferable, bioavilability is higher.
Description
Technical field
The invention belongs to medical sciences and veterinary antibiotic preparation technical field, and in particular to it is a kind of prepare tylonolide without
The method of sizing.
Background technique
Tylonolide is a kind of safety and effectively treats by haemolysis Mannheim bacterium, pasteurella multocida and the bloodthirsty bar of sleep
The broad-spectrum antibiotic of microbial livestock and poultry respiratory infection diseases.Tylonolide is by Intervet-Schering Plough
Company's exploitation, the injection of European Union's in March, 2011 approval listing tylonolide.
Solid drugs polymorphic state is to study the important content of drug existence, for most chemicals,
It is usually present polymorphism.The polymorphism of drug will have a direct impact on the stability, solubility, biological utilisation of drug
Degree, safety, validity and preparation processing performance etc..There are solvated compounds and a variety of shapes of non-solvent compound for tylonolide
State, such as: world patent WO 2009/013351 A2, Chinese patent CN applied by Intervet Internat B. V.
4 kinds of Thailands are reported and characterized in 101778858 B, CN 103360445 A of 103360446 A, CN and 103467548 A of CN
Solvated compounds in the polymorphic of ground Luo Xin non-solvent compound, i.e. crystal form I, crystal form II, crystal form III and crystal form IV and 7,
That is ethyl acetate solvent compound, alcohol solvent compound, diethyl ketone solvent compound, methyl tert-butyl ether solvent chemical combination
Object, tetrahydrofuran solvent compound, methyl acetate solvated compounds and Ethyl formate solvated compounds.Chinese patent CN
103554203 A report a kind of precipitate by acid-base reaction and prepare the unformed method of tylonolide.Acid-base reaction is quickly sunk
Forming sediment, obtained product is small, and heap density is low, not regular shape.
The present inventor is prepared during studying tylonolide crystal form by solvated compounds desolventizing phase inversion
A kind of unformed tylonolide, the unformed solid powder controllable for granularity, is easy to save, almost without hygroscopicity.One
As unformed preparation method be spray drying, melting and solidification, fast evaporating solvents solidify or acid-base reaction precipitation method etc., this
A little methods industrialize higher cost, and have certain difficulty, bad control.And the unformed preparation method of the present invention is simple, also
Can play the role of purifying, and prepare it is unformed be different from the unformed of above-mentioned conventional method, granularity is controllable, granularity
Be distributed it is uniform, more advantage be the preparation method be suitable for industrialized production.
Unformed tylonolide stability prepared by the present invention is good, is not easy the moisture absorption and degradation, and particle has been bar-like rule
Whole shape has preferable solubility and rate of dissolution compared with the tylonolide crystal-form compound of patent report.
Summary of the invention
The unformed method of tylonolide is prepared the purpose of the present invention is to provide a kind of, the unformed preparation process letter
List, chemical stability are good, are suitable for several formulations and industrialized production.
Tylonolide of the invention is unformed, and X-ray powder diffraction collection does not have apparent characteristic peak.
Tylonolide of the invention is unformed, and differential thermal zero-g aircraft (DSC-TGA) has suction between 135 DEG C~171 DEG C
Thermal spike especially reaches peak value at 154 DEG C or so；There is exothermic peak between 186 DEG C~210 DEG C, is especially reached at 196 DEG C or so
To peak value.
Tylonolide of the invention is unformed, differential thermal zero-g aircraft (DSC-TGA) before decomposition temperature almost without
Weightlessness illustrates that this is unformed without solvent.
The unformed X-ray powder diffraction analysis of tylonolide of the invention is to complete to survey under environment temperature and humidity
Examination.
The purpose of the present invention, which is taken notice of, provides a kind of unformed preparation method of tylonolide, and this method includes will be containing Thailand
The solution dissolved cooling of ground Luo Xin makes it solidify out.
Specific technical solution is as follows:
A method of unformed tylonolide being prepared, steps are as follows:
(1) tylonolide solution and anti-solvent are configured；
(2) anti-solvent is added in tylonolide solution recrystallizes tylonolide；
(3) tylonolide slurry obtained in collection step (2), is obtained by filtration wet sample；
(4) it is completely dried the wet sample to obtain tylonolide unformed.
Tylonolide solution is that tylonolide is dissolved in the solution in isopropyl ether in the step 1), tylonolide with it is different
The mass ratio of propyl ether are as follows: 1:10~30, solution solution temperature are 40 DEG C~70 DEG C.
Anti-solvent refers to water in the step 1), and the water and isopropyl ether mass ratio of addition are in 1:3~15.
The step 4) is thoroughly to be dried the wet sample prepared in step 3), and concrete operations are to be placed on wet sample
It is completely dried under 40 DEG C~100 DEG C temperature, vacuum or condition of normal pressure；It is tylonolide isopropyl ether solvent chemical combination before wet sample is dry
Object is transformed into unformed after dry.Tylonolide prepared by the present invention is unformed, and X-ray powder diffraction collection is not distinguishable
The diffraction maximum recognized, differential thermal zero-g aircraft (DSC-TGA) have endothermic peak between 135 DEG C~171 DEG C, 186 DEG C~210 DEG C it
Between have exothermic peak.
In the above-described embodiment, the precipitation of tylonolide solid is usually completed under agitation.The preparation method
In water must be selected for anti-solvent, the solid only prepared under isopropyl ether-aqueous systems by heat drying handle can be transformed into
It is unformed.
Preparation step 3) obtained in wet sample be tylonolide isopropyl ether solvated compounds, will by the heated drying of step 4)
It is unformed to be transformed into tylonolide after tylonolide isopropyl ether solvated compounds removing solvent.The tylonolide prepared in step 3)
Isopropyl ether solvated compounds in TGA test before 80 DEG C about 12.6% weightlessness, according to calculating tylonolide and isopropyl ether
Molar ratio should be 1:1, theoretical weightless is 12.2%, so practical weightless value and theoretical value are relatively identical.It will by step 4)
After the dry removing solvent of the tylonolide isopropyl ether solvated compounds prepared in step 3), solid is transformed into unformed.
Tylonolide of the invention is unformed, can be used for preparing pharmaceutical preparation, and dosage form can be pre-mixing agent, tablet, ball
Agent, powder, granule, capsule or injection.Compared with other crystal forms of tylonolide, solubility is more preferable, biological utilisation
It spends higher.
In order to verify the unformed stability of tylonolide in the present invention, this amorphous products and acid-base precipitation are reacted
The unformed of preparation has been cooked stability contrast experiment test, and experimental condition is to be placed at room temperature for 60 days.Experimental result discovery: both
Do not turn brilliant, all without obvious hygroscopicity, but acid-base reaction precipitating prepares product and Partial digestion occurs, and content is by original
98.31% is reduced to 97.46%, and the amorphous content prepared in the present invention there is no variation, maintains 99.26% left side
It is right.Unformed the reason of degrading of conjecture acid-base reaction precipitating preparation, is likely to be that acid-base reaction is too fast, and satiety degree is very big,
Solid is quickly generated, soda acid can be contained by having a large amount of solvent and containing in the solvent in solids, contained, so product is saving
During, soda acid may promote the degradation of solid.And soda acid is not used in the unformed preparation method in the present invention, institute
It is more stable during being stored with solid, do not degrade.
By tylonolide amorphous products obtained in the present invention and before the tylonolide crystal form product of patent report into
The comparison of row solubility, it is found that solubility in water improves nearly 10 times, rate of dissolution is preferable.
Detailed description of the invention
Fig. 1 is in embodiment 1 according to preparation step 3 in the present invention) obtained wet sample, tylonolide isopropyl ether solvent chemical combination
The powder x-ray diffraction figure of object, axis of ordinates indicate that diffracted intensity, axis of abscissas indicate angle of diffraction.
Fig. 2 is in embodiment 1 according to preparation step 3 in the present invention) obtained wet sample, tylonolide isopropyl ether solvent chemical combination
The thermogravimetric analysis TGA map of object.
Fig. 3 is in embodiment 1 according to preparation step 3 in the present invention) obtained wet sample, tylonolide isopropyl ether solvent chemical combination
The scanning electron microscope map of object.
Fig. 4 is the unformed powder x-ray diffraction figure of tylonolide prepared in embodiment 1.Axis of ordinates indicates that diffraction is strong
Degree, axis of abscissas indicate angle of diffraction.
Fig. 5 is the unformed powder thermogravimetric TGA analysis map of tylonolide prepared in embodiment 1.
Fig. 6 is the unformed powder differential calorimetric dsc analysis map of tylonolide prepared in embodiment 1.
Fig. 7 is the unformed stereoscan photograph of tylonolide prepared in embodiment 1.
Specific embodiment
The specific embodiment that embodiment form will be passed through below, makees further specifically above content of the invention
It is bright, but the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all above-mentioned interior based on the present invention
Hold realized technology to all belong to the scope of the present invention.
Embodiment is the unformed preparation of tylonolide
Embodiment 1
5g tylonolide raw material is added in 70g isopropyl ether, it is constant in 65 DEG C of stirring and dissolvings, it is molten that clarification is obtained by filtration
Water 15mL is added dropwise in liquid, stirs 2h, obtains white solid, and suction filtration obtains wet sample.
It is as shown in Fig. 1 that wet sample is made into XRD analysis map, there is apparent diffraction maximum, 2 θ=4.70 ± 0.2,6.26 ±
0.2、8.22±0.2、8.64±0.2、9.56±0.2、10.39±0.2、10.97±0.2、12.80±0.2、13.42±
0.2、14.44±0.2、15.06±0.2、15.28±0.2、15.78±0.2、16.84±0.2、17.28±0.2、17.84±
0.2, there is feature at 18.35 ± 0.2,18.78 ± 0.2,19.34 ± 0.2,20.30 ± 0.2,21.08 ± 0.2,21.58 ± 0.2
Peak.The thermogravimetric weightlessness map of wet sample is as shown in Fig. 2, there is 12.6% weightlessness before 100 DEG C；The stereoscan photograph of wet sample
As shown in Fig. 3, it is long rodlike crystal form, illustrates that wet sample is isopropyl ether solvated compounds.
Wet sample is placed on 70 DEG C of drying box constant pressure and dry 4h, obtains tylonolide solid product 4.8g, the XRD diagram of product
As shown in Fig. 4, without apparent characteristic peak, whole be in steamed bun peak to spectrum, and product is unformed after illustrating drying.Test product heat
Weight analysis finds to illustrate product without solvent without weightlessness before degradation as shown in Fig. 5.The scanning differential calorimetric of test sample
It is as shown in Fig. 6 to analyze result, has an exothermic peak at 135 DEG C or so, 187 DEG C or so have an endothermic peak, illustrate unformed
Inversion of phases takes place to 135 DEG C in high-temperature heating in product, is converted to crystal, then starts to melt at 187 DEG C or so.Test specimens
The morphology analysis scanning electron microscope (SEM) photograph of product is as shown in Fig. 7, and final amorphous products are long rodlike.
Embodiment 2
4g tylonolide raw material is added in 60g isopropyl ether, it is constant in 50 DEG C of stirring and dissolvings, it is molten that clarification is obtained by filtration
Liquid continues to stir 1h, obtains white solid after water 10mL is added dropwise, and suction filtration obtains wet sample.Wet sample is done into XRD analysis map and attached drawing
1 is consistent, there is identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.5%.Wet sample is placed on 80 DEG C of vacuum drying
Case constant pressure and dry 3h obtains the unformed solid product 3.68g of tylonolide, and the XRD spectrum and attached drawing 4 of sample are identical, not bright
Aobvious peak type, thermogravimetric analysis is without weightlessness.
Embodiment 3
2g tylonolide raw material is added in 60g isopropyl ether, clear solution is obtained by filtration in 40 DEG C of stirring and dissolvings, is added dropwise
Continue to stir 1h after water 20mL, obtain white solid, suction filtration obtains wet sample.It is consistent with attached drawing 1 that wet sample is made into XRD analysis map,
There are identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.3%.Wet sample is placed on 60 DEG C of vacuum oven vacuum
Dry 3h, obtains the unformed solid product 1.69g of tylonolide, the XRD spectrum and attached drawing 4 of sample are identical, without apparent peak
Type, thermogravimetric analysis is without weightlessness.
Embodiment 4
3g tylonolide raw material is added in 50g isopropyl ether, clear solution is obtained by filtration in 55 DEG C of stirring and dissolvings, is added dropwise
Continue to stir 2h after water 8mL, obtain white solid, suction filtration obtains wet sample.It is consistent with attached drawing 1 that wet sample is made into XRD analysis map, is had
Identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 11.9%.Wet sample is placed on 100 DEG C of vacuum oven normal pressures to do
Dry 1h obtains the unformed solid product 2.76g of tylonolide, and the XRD spectrum and attached drawing 4 of sample are similar, without apparent peak type,
Thermogravimetric analysis is without weightlessness.
Embodiment 5
5g tylonolide raw material is added in 50g isopropyl ether, clear solution is obtained by filtration in 70 DEG C of stirring and dissolvings, will be female
Liquid is constant at 45 DEG C, continues to stir 2h after water 6mL is added dropwise, obtains white solid, suction filtration obtains wet sample.Wet sample is done into XRD analysis
Map is consistent with attached drawing 1, there is identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.9%.Wet sample is placed on 40
DEG C vacuum oven is dried in vacuo 6h, obtains the unformed solid product 3.74g of tylonolide, 4 phase of XRD spectrum and attached drawing of sample
Seemingly, without apparent peak type, thermogravimetric analysis is without weightlessness.
Embodiment 6
1.8g tylonolide raw material is added in 54g isopropyl ether, clear solution is obtained by filtration in 40 DEG C of stirring and dissolvings, will
Mother liquor is constant at 40 DEG C, continues to stir 4h after water 3mL is added dropwise, obtains white solid, suction filtration obtains wet sample.Wet sample is XRD points
It is consistent with attached drawing 1 to analyse map, there is identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.5%.Wet sample is placed on
85 DEG C of vacuum oven constant pressure and dry 1.5h obtain the unformed solid product 1.5g of tylonolide, the XRD spectrum and attached drawing of sample
4 is similar, and without apparent peak type, thermogravimetric analysis is without weightlessness.
Embodiment 7
3.5g tylonolide raw material is added in 80g isopropyl ether, clear solution is obtained by filtration in 40 DEG C of stirring and dissolvings, will
Mother liquor is constant at 40 DEG C, continues to stir 3h after water 7mL is added dropwise, obtains white solid, suction filtration obtains wet sample.Wet sample is XRD points
It is consistent with attached drawing 1 to analyse map, there is identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.0%.Wet sample is placed on
55 DEG C of vacuum ovens are dried in vacuo 1.5h, obtain the unformed solid product 3.1g of tylonolide, the XRD spectrum and attached drawing of sample
4 is similar, and without apparent peak type, thermogravimetric analysis is without weightlessness.
Embodiment 8
2.4g tylonolide raw material is added in 65g isopropyl ether, clear solution is obtained by filtration in 45 DEG C of stirring and dissolvings, will
Mother liquor is constant at 45 DEG C, continues to stir 2.5h after water 10mL is added dropwise, obtains white solid, suction filtration obtains wet sample.Wet sample is done into XRD
It is consistent with attached drawing 1 to analyze map, there is identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.7%.Wet sample is placed
It is dried in vacuo 4h in 45 DEG C of vacuum ovens, obtains the unformed solid product 2.0g of tylonolide, the XRD spectrum and attached drawing of sample
4 is similar, and without apparent peak type, thermogravimetric analysis is without weightlessness.
Claims (2)
1. a kind of method for preparing unformed tylonolide, it is characterized in that steps are as follows:
(1) tylonolide isopropyl ethereal solution is configured；
(2) it adds water in tylonolide isopropyl ethereal solution and carries out dilution crystallization；
(3) slurry of solids obtained in collection step (2), is obtained by filtration wet sample；
(4) it is completely dried the wet sample to obtain tylonolide unformed；
The mass ratio of tylonolide and isopropyl ether is 1:10~30 in the step 1), and solution solution temperature is 40 DEG C~70
℃；The water and isopropyl ether mass ratio being added in the step 2) are in 1:3~15；Wet sample is completely dried in the step 4)
Method is: wet sample being placed under 40 DEG C~100 DEG C temperature, vacuum or condition of normal pressure dry；It is Tai Diluo before wet sample is dry
New isopropyl ether solvated compounds, are transformed into unformed after dry.
2. prepared tylonolide is unformed according to claim 1, X-ray powder diffraction collection does not have identifiable spread out
Peak is penetrated, differential thermal zero-g aircraft (DSC-TGA) has endothermic peak between 135 DEG C~171 DEG C, puts between 186 DEG C~210 DEG C
Thermal spike.
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| CN201610396694.4A CN106046086B (en) | 2016-06-02 | 2016-06-02 | It is a kind of to prepare the unformed method of tylonolide |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109721633A (en) * | 2017-10-31 | 2019-05-07 | 齐鲁晟华制药有限公司 | A kind of tylonolide crystal form A and preparation method thereof |
| CN111349130A (en) * | 2018-12-21 | 2020-06-30 | 齐鲁动物保健品有限公司 | Tildipirosin crystal form B and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554203A (en) * | 2013-08-17 | 2014-02-05 | 齐鲁动物保健品有限公司 | Amorphous crystal of tylonolide, and preparation method thereof |
| CN104774223A (en) * | 2015-03-26 | 2015-07-15 | 宁夏泰瑞制药股份有限公司 | Method for producing tildipirosin by using tylosin alkali |
| CN105440093A (en) * | 2015-11-17 | 2016-03-30 | 宁夏泰瑞制药股份有限公司 | Synthetic method of tildipirosin |
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- 2016-06-02 CN CN201610396694.4A patent/CN106046086B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554203A (en) * | 2013-08-17 | 2014-02-05 | 齐鲁动物保健品有限公司 | Amorphous crystal of tylonolide, and preparation method thereof |
| CN104774223A (en) * | 2015-03-26 | 2015-07-15 | 宁夏泰瑞制药股份有限公司 | Method for producing tildipirosin by using tylosin alkali |
| CN105440093A (en) * | 2015-11-17 | 2016-03-30 | 宁夏泰瑞制药股份有限公司 | Synthetic method of tildipirosin |
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