CN106046086A - Method for preparing amorphous tildipirosin - Google Patents
Method for preparing amorphous tildipirosin Download PDFInfo
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- CN106046086A CN106046086A CN201610396694.4A CN201610396694A CN106046086A CN 106046086 A CN106046086 A CN 106046086A CN 201610396694 A CN201610396694 A CN 201610396694A CN 106046086 A CN106046086 A CN 106046086A
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- tylonolide
- unformed
- wet sample
- solution
- diisopropyl 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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- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention relates to a method for preparing amorphous tildipirosin. The amorphous tildipirosin has an endothermic peak at 135-171 DEG C and has an exothermic peak at 186-210 DEG C in a TG-DSC spectrum and has no recognizable diffraction peak in an XPRD spectrum. The preparation method comprises steps as follows: selecting isopropyl ether as a solvent for dissolution, then adding water to precipitate solids, and drying a wet sample thoroughly after filtration to obtaining an amorphous product. The amorphous product has good stability and can be preserved for a long period without degradation. The amorphous tildipirosin is used for preparing a pharmaceutical preparation, and the dosage form of the pharmaceutical preparation can be premix, tablets, pills, powder, granules, capsules or injections. Compared with other crystal forms of tildipirosin, the amorphous tildipirosin has better solubility and higher bioavailability.
Description
Technical field
The invention belongs to medical science and veterinary antibiotic preparing technical field, be specifically related to one prepare tylonolide without
The method of sizing.
Background technology
Tylonolide is that one is effectively treated by haemolysis Mannheim bacterium, pasteurella multocida and bloodthirsty bar of sleeping safely
Microbial livestock and the broad-spectrum antibiotic of poultry respiratory infection diseases.Tylonolide is by Intervet Schering Plough
Company develops, the injection of in March, 2011 European Union's approval listing tylonolide.
Solid drugs polymorphic state is the important content of drugs existence, for most chemicalses,
It is usually present polymorphism.The polymorphism of medicine can directly affect the stability of medicine, dissolubility, biological utilisation
Degree, safety, effectiveness and preparation processing performance etc..There is solvated compounds and the multiple shape of non-solvated compound in tylonolide
State, such as: world patent WO 2009/013351 A2, Chinese patent CN applied for by Intervet Internat B. V.
101778858 B, CN 103360446 A, CN 103360445 A and CN 103467548 A reports and characterizes 4 kinds of Thailands
The polymorphic of the ground non-solvated compound of Luo Xin, i.e. crystal formation I, crystal formation II, crystal formation III and crystal formation IV, and solvated compounds in 7,
I.e. ethyl acetate solvent compound, alcohol solvent compound, diethyl ketone solvent compound, methyl tert-butyl ether solvent chemical combination
Thing, tetrahydrofuran solvent compound, methyl acetate solvated compounds and Ethyl formate solvated compounds.Chinese patent CN
103554203 A report a kind of by the acid-base reaction precipitation preparation unformed method of tylonolide.Acid-base reaction is quickly sunk
The product obtained that forms sediment is little, and bulk density is low, does not has regular shape.
The present inventor, during research tylonolide crystal formation, is prepared by solvated compounds desolventizing phase inversion
A kind of unformed tylonolide, this unformed pressed powder controlled for granularity, easily preserve, almost without hygroscopicity.One
As unformed preparation method be spray drying, melting and solidification, fast evaporating solvents solidification or the acid-base reaction sedimentation method etc., this
A little method industrialization are relatively costly, and have certain difficulty, bad control.And the unformed preparation method of the present invention is simple, also
Can play the effect of purification, and prepare unformed be different from the unformed of above-mentioned conventional method, its granularity is controlled, granularity
Being distributed homogeneous, more advantage is that this preparation method is applicable to industrialized production.
Unformed tylonolide good stability prepared by the present invention, is difficult to the moisture absorption and degraded, and particle has been bar-like rule
Whole shape, compared with the tylonolide crystal-form compound of patent report, has preferable dissolubility and rate of dissolution.
Summary of the invention
It is an object of the invention to provide one and prepare the unformed method of tylonolide, this unformed preparation technology letter
List, chemical stability are good, it is adaptable to several formulations and industrialized production.
The tylonolide of the present invention is unformed, and its X ray powder diffraction does not has obvious characteristic peak.
The tylonolide of the present invention is unformed, and its differential thermal zero-g aircraft (DSC TGA) has suction between 135 DEG C～171 DEG C
Thermal spike, particularly reaches peak value at about 154 DEG C；Between 186 DEG C～210 DEG C, there is exothermic peak, particularly reach at about 196 DEG C
To peak value.
The tylonolide of the present invention is unformed, its differential thermal zero-g aircraft (DSC TGA) before decomposition temperature almost without
Weightlessness, illustrates that this is unformed without solvent.
The tylonolide unformed X ray powder diffraction analysis of the present invention is to complete to survey under ambient temperature and humidity
Examination.
The purpose of the present invention is taken notice of and is provided a kind of unformed preparation method of tylonolide, and the method includes will be containing Thailand
The solution dissolved cooling of ground Luo Xin makes it solidify out.
Concrete technical scheme is as follows:
A kind of method preparing unformed tylonolide, step is as follows:
(1) configuration tylonolide solution and anti-solvent；
(2) anti-solvent is joined in tylonolide solution and make tylonolide recrystallization；
(3) collect the tylonolide slurry obtained in step (2), be filtrated to get wet sample；
(4) wet sample carries out being completely dried to obtain tylonolide unformed.
Described step 1) in tylonolide solution be the solution that tylonolide is dissolved in diisopropyl ether, tylonolide is with different
The mass ratio of propyl ether is: 1:10～30, and solution solution temperature is 40 DEG C～70 DEG C.
Described step 1) in anti-solvent refer to water, the water of addition and diisopropyl ether mass ratio are at 1:3～15.
Described step 4) be by step 3) in preparation wet sample be thoroughly dried, concrete operations are to be placed on by wet sample
It is completely dried under 40 DEG C～100 DEG C of temperature, vacuum or condition of normal pressure；Wet sample is tylonolide diisopropyl ether solvent chemical combination before being dried
Thing, is transformed into unformed after drying.Tylonolide prepared by the present invention is unformed, and its X ray powder diffraction does not has to distinguish
The diffraction maximum recognized, its differential thermal zero-g aircraft (DSC TGA) has 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 and completes under agitation.This preparation method
In must to select water be anti-solvent, only under diisopropyl ether aqueous systems, the solid of preparation is transformed into by comprehending at heat drying
Unformed.
Preparation process 3) in the wet sample that obtains be tylonolide diisopropyl ether solvated compounds, by step 4) heated drying will
It is transformed into tylonolide unformed after tylonolide diisopropyl ether solvated compounds desolvation.Step 3) the middle tylonolide prepared
Diisopropyl ether solvated compounds weightlessness of about 12.6% before 80 DEG C in TGA tests, according to calculating tylonolide and diisopropyl ether
Mol ratio should be 1:1, theoretical weightlessness is 12.2%, so actual weightless value and theoretical value are more identical.By step 4) will
Step 3) in preparation tylonolide diisopropyl ether solvated compounds be dried desolvation after, solid transition becomes unformed.
The tylonolide of the present invention is unformed, can be used for preparing pharmaceutical preparation, and its dosage form can be pre-mixing agent, tablet, ball
Agent, powder, granule, capsule or injection.Compared with other crystal formations of tylonolide, its dissolubility is more preferable, biological utilisation
Spend 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 that room temperature is placed 60 days.Experimental result finds: both
Not turning brilliant, all do not have obvious hygroscopicity, but acid-base reaction precipitation is prepared product and Partial digestion occurred, content is by original
98.31% is reduced to 97.46%, and in the present invention, the amorphous content of preparation there is no change, maintains 99.26% left
Right.It is too fast that the reason of the unformed appearance degraded of conjecture acid-base reaction precipitation preparation is likely to be acid-base reaction, and satiety degree is very big,
Quickly generate solid, have substantial amounts of solvent and contain in solids, the solvent contained can contain soda acid, so product is preserving
During, soda acid may promote the degraded of solid.And the unformed preparation method in the present invention is not used soda acid, institute
During depositing with solid more stable, not degraded.
The tylonolide crystal formation product of the tylonolide amorphous products obtained in the present invention and patent report before is entered
Row dissolubility contrasts, and finds that the dissolubility in water improves nearly 10 times, and rate of dissolution is preferable.
Accompanying drawing explanation
Fig. 1 is according to preparation process 3 in the present invention in embodiment 1) the wet sample that obtains, tylonolide diisopropyl ether solvent chemical combination
The powder X-ray x ray diffration pattern x of thing, axis of ordinates represents that diffracted intensity, axis of abscissas represent angle of diffraction.
Fig. 2 is according to preparation process 3 in the present invention in embodiment 1) the wet sample that obtains, tylonolide diisopropyl ether solvent chemical combination
The thermogravimetric analysis TGA collection of illustrative plates of thing.
Fig. 3 is according to preparation process 3 in the present invention in embodiment 1) the wet sample that obtains, tylonolide diisopropyl ether solvent chemical combination
The scanning electron microscope collection of illustrative plates of thing.
Fig. 4 is the tylonolide unformed powder X-ray x ray diffration pattern x of preparation in embodiment 1.Axis of ordinates represents that diffraction is strong
Degree, axis of abscissas represents angle of diffraction.
Fig. 5 is that in embodiment 1, tylonolide unformed powder thermogravimetric TGA of preparation analyzes collection of illustrative plates.
Fig. 6 is the tylonolide unformed powder differential calorimetric dsc analysis collection of illustrative plates of preparation in embodiment 1.
Fig. 7 is the unformed stereoscan photograph of tylonolide of preparation in embodiment 1.
Detailed description of the invention
Below by the detailed description of the invention by embodiment form, the foregoing of the present invention is made the most specifically
Bright, but this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.All above-mentioned interior based on the present invention
Hold the technology realized and belong to the scope of the present invention.
Embodiment is the unformed preparation of tylonolide
Embodiment 1
5g tylonolide raw material is joined in 70g diisopropyl ether, constant 65 DEG C of stirring and dissolving, it is filtrated to get clarification molten
Liquid, drips water 15mL, stirs 2h, obtains white solid, and sucking filtration obtains wet sample.
Wet sample is made XRD analysis collection of illustrative plates as shown in Figure 1, has obvious diffraction maximum, in 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 collection of illustrative plates of wet sample as shown in Figure 2, had the weightlessness of 12.6% before 100 DEG C；The stereoscan photograph of wet sample
As shown in Figure 3, it is long bar-shaped crystal formation, illustrates that wet sample is diisopropyl ether solvated compounds.
Wet sample is placed on 70 DEG C of drying baker constant pressure and dry 4h, obtains tylonolide solid product 4.8g, the XRD figure of product
Spectrum as shown in Figure 4, does not has obvious characteristic peak, overall in steamed bread peak, illustrates that dried product is unformed.Test product heat
Weight analysis finds do not have weightlessness before degraded as shown in Figure 5, illustrates that product is without solvent.The scanning differential calorimetric of test sample
Analysis result as shown in Figure 6, has an exothermic peak at about 135 DEG C, and about 187 DEG C have an endothermic peak, illustrate unformed
Product starts inversion of phases at high-temperature heating to 135 DEG C, changes into crystal, then starts fusing at about 187 DEG C.Test specimens
As shown in Figure 7, final amorphous products is long bar-shaped to the morphology analysis scanning electron microscope (SEM) photograph of product.
Embodiment 2
4g tylonolide raw material is joined in 60g diisopropyl ether, constant 50 DEG C of stirring and dissolving, it is filtrated to get clarification molten
Liquid, continues stirring 1h, obtains white solid after dropping water 10mL, sucking filtration obtains wet sample.Wet sample is done XRD analysis collection of illustrative plates and accompanying drawing
1 is consistent, has 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 tylonolide unformed solid product 3.68g, and the XRD figure spectrum of sample is identical with accompanying drawing 4, the brightest
Aobvious peak type, thermogravimetric analysis does not has weightlessness.
Embodiment 3
2g tylonolide raw material is joined in 60g diisopropyl ether, 40 DEG C of stirring and dissolving, it is filtrated to get settled solution, dropping
Continuing stirring 1h after water 20mL, obtain white solid, sucking filtration obtains wet sample.Wet sample is made XRD analysis collection of illustrative plates consistent with accompanying drawing 1,
There are identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.3%.Wet sample is placed on 60 DEG C of vacuum drying oven vacuum
Being dried 3h, obtain tylonolide unformed solid product 1.69g, the XRD figure spectrum of sample is identical with accompanying drawing 4, does not has obvious peak
Type, thermogravimetric analysis does not has weightlessness.
Embodiment 4
3g tylonolide raw material is joined in 50g diisopropyl ether, 55 DEG C of stirring and dissolving, it is filtrated to get settled solution, dropping
Continuing stirring 2h after water 8mL, obtain white solid, sucking filtration obtains wet sample.Wet sample is made XRD analysis collection of illustrative plates consistent with accompanying drawing 1, have
Identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 11.9%.Wet sample is placed on 100 DEG C of vacuum drying oven normal pressures do
Dry 1h, obtains tylonolide unformed solid product 2.76g, and the XRD figure spectrum of sample is similar with accompanying drawing 4, does not has obvious peak type,
Thermogravimetric analysis does not has weightlessness.
Embodiment 5
5g tylonolide raw material is joined in 50g diisopropyl ether, 70 DEG C of stirring and dissolving, it is filtrated to get settled solution, by mother
Liquid is constant at 45 DEG C, continues stirring 2h, obtain white solid after dropping water 6mL, and sucking filtration obtains wet sample.Wet sample is done XRD analysis
Collection of illustrative plates is consistent with accompanying drawing 1, has identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.9%.Wet sample is placed on 40
DEG C vacuum drying oven vacuum drying 6h, obtains tylonolide unformed solid product 3.74g, the XRD figure spectrum of sample and accompanying drawing 4 phase
Seemingly, not having obvious peak type, thermogravimetric analysis does not has weightlessness.
Embodiment 6
1.8g tylonolide raw material is joined in 54g diisopropyl ether, 40 DEG C of stirring and dissolving, it is filtrated to get settled solution, will
Mother solution is constant at 40 DEG C, continues stirring 4h, obtain white solid after dropping water 3mL, and sucking filtration obtains wet sample.Wet sample is XRD divide
Analysis collection of illustrative plates is consistent with accompanying drawing 1, has identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.5%.Wet sample is placed on
85 DEG C of vacuum drying oven constant pressure and dry 1.5h, obtain tylonolide unformed solid product 1.5g, the XRD figure spectrum of sample and accompanying drawing
4 is similar, does not has obvious peak type, and thermogravimetric analysis does not has weightlessness.
Embodiment 7
3.5g tylonolide raw material is joined in 80g diisopropyl ether, 40 DEG C of stirring and dissolving, it is filtrated to get settled solution, will
Mother solution is constant at 40 DEG C, continues stirring 3h, obtain white solid after dropping water 7mL, and sucking filtration obtains wet sample.Wet sample is XRD divide
Analysis collection of illustrative plates is consistent with accompanying drawing 1, has identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.0%.Wet sample is placed on
55 DEG C of vacuum drying oven vacuum drying 1.5h, obtain tylonolide unformed solid product 3.1g, the XRD figure spectrum of sample and accompanying drawing
4 is similar, does not has obvious peak type, and thermogravimetric analysis does not has weightlessness.
Embodiment 8
2.4g tylonolide raw material is joined in 65g diisopropyl ether, 45 DEG C of stirring and dissolving, it is filtrated to get settled solution, will
Mother solution is constant at 45 DEG C, continues stirring 2.5h, obtain white solid after dropping water 10mL, and sucking filtration obtains wet sample.Wet sample is XRD
Analyze collection of illustrative plates consistent with accompanying drawing 1, have identical peak spectral position and shape；Thermogravimetric analysis weightlessness is 12.7%.Wet sample is placed
It is vacuum dried 4h at 45 DEG C of vacuum drying ovens, obtains tylonolide unformed solid product 2.0g, the XRD figure spectrum of sample and accompanying drawing
4 is similar, does not has obvious peak type, and thermogravimetric analysis does not has weightlessness.
Claims (5)
1. prepare the unformed method of tylonolide, it is characterized in that step is as follows:
(1) configuration tylonolide solution and anti-solvent；
(2) anti-solvent is joined in tylonolide solution and make tylonolide recrystallization；
(3) collect the tylonolide slurry obtained in step (2), be filtrated to get wet sample；
(4) wet sample carries out being completely dried to obtain tylonolide unformed.
Method the most according to claim 1, wherein said step 1) in tylonolide solution be that tylonolide is dissolved in
Solution in diisopropyl ether, tylonolide is 1:10～30 with the mass ratio of diisopropyl ether, and solution solution temperature is 40 DEG C～70 DEG C.
Method the most according to claim 1, wherein said step 1) in anti-solvent refer to water, the water of addition and diisopropyl ether
Mass ratio is at 1:3～15.
Method the most according to claim 1, is characterized in that needing step 4) in wet sample carry out being completely dried method and be: will
Wet sample is placed under 40 DEG C～100 DEG C of temperature, vacuum or condition of normal pressure and is dried；Wet sample is that tylonolide diisopropyl ether is molten before being dried
Immunomodulator compounds, is transformed into unformed after drying.
5. unformed according to the tylonolide prepared by claim 1, its X-ray powder diffraction spectrum does not has identifiable spreading out
Penetrating peak, its 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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| Application Number | Priority Date | Filing Date | Title |
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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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| 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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