CN109721633A - A kind of tylonolide crystal form A and preparation method thereof - Google Patents
A kind of tylonolide crystal form A and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of tylonolide crystal form A and preparation method thereof.X-ray powder diffraction (XRPD) map that the tylonolide crystal form A is indicated with 2 θ contains characteristic peak 4.95 ± 0.2,7.03 ± 0.2,7.86 ± 0.2,9.20 ± 0.2,11.09 ± 0.2,11.52 ± 0.2,12.55 ± 0.2,13.32 ± 0.2,14.01 ± 0.2,15.16 ± 0.2,15.61 ± 0.2,16.73 ± 0.2,17.96 ± 0.2,19.08 ± 0.2,20.50 ± 0.2,21.50 ± 0.2.Tylonolide crystal form A purity is high of the present invention, impurity content is low, and stability is good.Preparation cost is cheap, and preparation method is easy to operate, and mild condition is easy to control, and is suitable for industrialized production.
Description
Technical field
The invention belongs to veterinary antibiotic preparation technical field, it is related to polymorphic form and its preparation of a kind of tylonolide
Method, and in particular to crystal form A of tylonolide and preparation method thereof.
Background technique
Tylonolide, molecular formula: C41H71N3O8Molecular weight: 734.02, chemical name: 20- deoxidation -23- deoxidation -5- oxygen-[3,
6- dideoxy -3- (dimethylamino)-β-D- glucopyranosyl] the safe happy lactone of -20,23- dipiperidino, structural formula is such as
It is a kind of macrolides broad-spectrum antibiotic shown in following formula I, is developed by Intervet-Schering Plough company.In March, 2011, European Union
(CVMP) approval lists its injection.It is mainly used for treatment in veterinary clinic by haemolysis Mannheim bacterium, pasteurella multocida
And bovine respiratory caused by Haemophilus somnus is infected and is lost by Actinobacillus pleuropneumoniae, pasteurella multocida, bronchus
Respiratory tract infection of pigs caused by blood boss bacillus and haemophilus parasuis.
There are polymorphism, tylonolide polycrystalline to deposit in mode of appearance, physicochemical property and bioactivity for tylonolide
In difference, the preparation processing performance of drug is directly affected, and will affect the stability, solubility and bioavilability of drug,
And then influence quality, safety, validity and its application of drug.There are a variety of polymorphics and solvations known to tylonolide
Object, patent WO2009/013351 is determining simultaneously to characterize 4 kinds of polycrystalline forms of tylonolide, i.e. polycrystalline I, polycrystalline II, polycrystalline III, more
Crystalline substance IV；7 kinds of solvated Forms, i.e. ethyl acetate solvent compound, alcohol solvent compound, diethyl ketone solvent compound, first
Base tert-butyl ether solvent compound, tetrahydrofuran solvent compound, methyl acetate solvated compounds, Ethyl formate solvent chemical combination
Object.It is amorphous and preparation method thereof that Chinese patent literature CN103554203A and CN106046086A report tylonolide,
CN106046084A, CN106083958A and CN106008629A report acetone solvate, cyclohexane solvate respectively
With 1,4- dioxane solvent compound and its corresponding preparation method.In conclusion the polycrystalline and amorphous form of patent report, produce
Product partial size is small, is easy condensation, poor fluidity；Solvated Form, organic solvent residual is high, does not meet ICH for bulk pharmaceutical chemicals solvent
Remain limit regulation.Have no in the prior art about tylonolide crystal form A with and preparation method thereof report.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of tylonolide crystal form A, the present invention
Another be designed to provide the preparation method of tylonolide crystal form A.
The technical solution of the present invention is as follows:
A kind of tylonolide crystal form A, is radiated using Cu-Ka, x-ray powder diffraction (XRPD) figure indicated with 2 θ angles
Spectrum 4.95 ± 0.2,7.03 ± 0.2,7.86 ± 0.2,9.20 ± 0.2,11.09 ± 0.2,11.52 ± 0.2,12.55 ± 0.2,
13.32±0.2、14.01±0.2、15.16±0.2、15.61±0.2、16.73±0.2、17.96±0.2、19.08±0.2、
There are characteristic peak in 20.50 ± 0.2,21.50 ± 0.2 positions.
It is preferred according to the present invention, map such as Fig. 1 institute of the X-ray powder diffraction spectrum of the tylonolide crystal form A
Show.
Tylonolide crystal form A of the present invention, infrared spectroscopy (IR) map is in wave number σ ± 2cm-1There are peak, the σ in position
For 3455,2936,2795,1750,1682,1631,1593,1458,1412,1375,1312,1277,1256,1194,1166,
1115、1088、1055、1008、984、963、935、909、858、839、782、757、639、573。
Preferred according to the present invention, infrared spectroscopy (IR) map of the tylonolide crystal form A is as shown in Figure 2.
Tylonolide crystal form A of the present invention, using aluminium crucible, in the closed cup with pin hole under flowing nitrogen
In, the rate of heat addition of 10 DEG C/min, 30~220 DEG C of temperature ranges obtain thermogravimetric-differential scanning calorimetry (TG-DSC) map,
30~110 DEG C there are solvent volatile weight loss 0.1%~5.0%；Have between 32~100 DEG C, 105~135 DEG C, 186~210 DEG C
Endothermic peak has exothermic peak between 145~186 DEG C.
It is preferred according to the present invention, thermogravimetric-differential scanning calorimetry (TG-DSC) map of the tylonolide crystal form A
As shown in Figure 3.
The preparation method of tylonolide crystal form A of the present invention, includes the following steps:
By tylonolide dissolution of raw material in organic solvent, the mass volume ratio of tylonolide raw material and organic solvent is 1:
2~20, unit g/mL；It is kept for 0~35 DEG C of reaction temperature, 40~200 revs/min of speed of agitator, obtains tylonolide solution；It will be safe
Ground sieve new soln is added dropwise in purified water, and tylonolide and purified water mass volume ratio are 1:10~100, unit g/mL；It is added dropwise
In the process, tylonolide is slowly precipitated, 1~5h of growing the grain, filtering, it is dry to get.
Preferred according to the present invention, the tylonolide raw material is polymorphic, solvated Form or amorphous, and market is commercially available
Or according to prior art preparation.
Preferred according to the present invention, the organic solvent is water-soluble organic solvent；It is further preferred that organic solvent
For methanol, ethyl alcohol, isopropanol, sec-butyl alcohol, N, N-dimethylformamide, acetone, dimethyl sulfoxide, in N-methyl pyrrolidones
Any or combinations thereof solvent；Still more preferably, the organic solvent is methanol, ethyl alcohol or isopropanol.
Preferred according to the present invention, the tylonolide and organic solvent mass volume ratio are 1:3~10, unit g/mL.
Preferred according to the present invention, the reaction temperature is 20~25 DEG C；The speed of agitator is 60-80 revs/min.
Preferred according to the present invention, the tylonolide solution is added dropwise in purified water, and time for adding is 30~200 points
Clock.
Preferred according to the present invention, the tylonolide and purified water mass volume ratio are 1:15~50, unit g/mL.
Preferred according to the present invention, the rearing crystal time is 2~3h.
Preferred according to the present invention, the drying mode is vacuum drying, and drying temperature is 40~90 DEG C.It is further excellent
Choosing, filtered tylonolide crystal form A is dried in vacuo 10~12 hours in 80 DEG C.
The present invention having the beneficial effect that compared with prior art:
(1) tylonolide crystal form A provided by the invention is easily prepared, and coherent detection data show that tylonolide crystal form A is pure
Degree is high, and impurity content is low, and stability is good.It can be used for preparing pharmaceutical preparation, dosage form can be pre-mixing agent, tablet, pill, dissipate
Agent, granule, capsule or injection.
(2) tylonolide crystal form A provided by the invention is compared with other crystal forms of tylonolide, organic solvent-free residual, surely
It is qualitative to be more preferably more suitable for industrial production, transport, storage and application.
(3) solvent needed for the preparation method of tylonolide crystal form A according to the present invention is Conventional solvents, preparation cost
Cheap, preparation method is easy to operate, and mild condition is easy to control, acquisition tylonolide crystal form A that can be stable, is suitable for industry
Metaplasia produces.
Detailed description of the invention
Fig. 1 is the XRPD map of tylonolide crystal form A made from embodiment 1.
Fig. 2 is the IR map of tylonolide crystal form A made from embodiment 1.
Fig. 3 is the TG-DSC map of tylonolide crystal form A made from embodiment 1.
Specific embodiment
Technical solution of the present invention is further elaborated below with reference to embodiment, the embodiment described is used only to illustrate
The present invention, and it is not considered as limitation of the present invention.Tylonolide raw material referenced patent used in embodiment
The preparation of method disclosed in CN102863487A, other raw materials are market purchase.
Embodiment 1: the preparation of tylonolide crystal form A
15ml methanol is added in tylonolide raw material 5g, stirring and dissolving obtains tylonolide methanol solution, keeps temperature 20
~25 DEG C, 60~70 revs/min of speed of agitator, tylonolide methanol solution is slowly added dropwise in 75ml purified water, control drop
30~40 minutes between added-time, tylonolide methanol solution is added dropwise, and is filtered after stirring 2h, 80 DEG C of vacuum drying 12h obtain Thailand
Ground sieve novel crystal forms A 4.0g, HPLC detect purity 99.40%.
Product XRPD diffracting spectrum is as shown in Figure 1, specific data see the table below 1:
Table 1XRPD diffracting spectrum tables of data
Product I R map as shown in Fig. 2, have a peak in the position wave number σ, the σ is 3455,2936,2795,1750,1682,
1631、1593、1458、1412、1375、1312、1277、1256、1194、1166、1115、1088、1055、1008、984、
963、935、909、858、839、782、757、639、573。
Product TG-DSC as shown in figure 3, at 30~110 DEG C there are solvent volatile weight loss 1.49%, 37.9~98.7 DEG C,
There is endothermic peak between 105~134 DEG C, 186~210 DEG C, has exothermic peak between 145~186 DEG C.
Embodiment 2: the preparation of tylonolide crystal form A
35ml methanol is added in tylonolide raw material 5g, stirring and dissolving obtains tylonolide methanol solution, keeps temperature 20
~25 DEG C, 65~75 revs/min of speed of agitator, tylonolide methanol solution is slowly added dropwise in 175ml purified water, control drop
90~100 minutes between added-time, after tylonolide methanol solution is added dropwise, filtered after stirring 3h.80 DEG C of vacuum drying 12h, obtain
Purity 99.51% is detected to tylonolide crystal form A 4.1g, HPLC.2 θ angle of product XRPD diffracting spectrum and relative intensity and figure
1 is almost the same, and IR TuPu method peak and Fig. 2 are almost the same, and TG-DSC map and Fig. 3 are almost the same.
Embodiment 3: the preparation of tylonolide crystal form A
50ml methanol is added in tylonolide raw material 5g, stirring and dissolving obtains tylonolide methanol solution, keeps temperature 20
~25 DEG C, 65~75 revs/min of speed of agitator, tylonolide methanol solution is slowly added dropwise in 250ml purified water, control drop
190~200 minutes between added-time, after tylonolide methanol solution is added dropwise, filtered after stirring 5h.80 DEG C of vacuum drying 15h, obtain
Purity 99.26% is detected to tylonolide crystal form A 4.3g, HPLC.2 θ angle of product XRPD diffracting spectrum and relative intensity and figure
1 is almost the same, and IR TuPu method peak and Fig. 2 are almost the same, and TG-DSC map and Fig. 3 are almost the same.
Embodiment 4: the preparation of tylonolide crystal form A
35ml ethyl alcohol is added in tylonolide raw material 5g, stirring and dissolving obtains tylonolide ethanol solution, keeps temperature 20
~25 DEG C, 65~75 revs/min of speed of agitator, tylonolide ethanol solution is slowly added dropwise in 175ml purified water, control drop
90~100 minutes between added-time, after tylonolide ethanol solution is added dropwise, filtered after stirring 3h.80 DEG C of vacuum drying 12h, obtain
Purity 99.18% is detected to tylonolide crystal form A 4.1g, HPLC.2 θ angle of product XRPD diffracting spectrum and relative intensity and figure
1 is almost the same, and IR TuPu method peak and Fig. 2 are almost the same, and TG-DSC map and Fig. 3 are almost the same.
Embodiment 5: the preparation of tylonolide crystal form A
35ml isopropanol is added in tylonolide raw material 5g, stirring and dissolving obtains tylonolide aqueous isopropanol, keeps temperature
20~25 DEG C of degree, tylonolide aqueous isopropanol is slowly added dropwise in 175ml purified water by 65~75 revs/min of speed of agitator,
Control time for adding 90~100 minutes after tylonolide aqueous isopropanol is added dropwise, is filtered after stirring 3h.80 DEG C of vacuum are dry
Dry 12h, obtains tylonolide crystal form A 4.1g, and HPLC detects purity 99.59%.2 θ angle of product XRPD diffracting spectrum and opposite
Intensity is almost the same with Fig. 1, and IR TuPu method peak and Fig. 2 are almost the same, and TG-DSC map and Fig. 3 are almost the same.
Embodiment 6: stability experiment
This experiment is prepared for polycrystalline I and polycrystalline III according to the preparation method that patent WO2009/013351 is reported, polycrystalline I is
The medicinal crystal-form of Yuan Yan company report.The tylonolide crystal form A of embodiment 1 and polycrystalline I, polycrystalline III are subjected to stability experiment pair
Than.
Under same terms of packing, accelerated stability comparative study in 6 months finds that product is total in appearance, content and impurity
There are notable differences with stability aspect, are specifically shown in Table 2- table 4:
The tylonolide crystal form A experimental result of 2 embodiment 1 of table
| Crystal form A | 0 month | 1 month | 2 months | 3 months | 6 months |
| Appearance | White powder | White powder | White powder | White powder | Off-white powder |
| Content | 99.2% | 99.3% | 99.1% | 99.0% | 99.0% |
| Impurity summation | 0.88% | 0.85% | 0.86% | 0.90% | 0.92% |
3 tylonolide crystal form of table, I experimental result
| Crystal form I | 0 month | 1 month | 2 months | 3 months | 6 months |
| Appearance | White powder | White powder | Off-white powder | Pale yellow powder | Pale yellow powder |
| Content | 98.9% | 98.4 | 98.5% | 98.2% | 98.2% |
| Impurity summation | 1.12% | 1.14% | 1.15% | 1.16% | 1.18% |
4 tylonolide crystal form of table, III experimental result
| Crystal form I | 0 month | 1 month | 2 months | 3 months | 6 months |
| Appearance | White powder | Off-white powder | Pale yellow powder | Pale yellow powder | Pale yellow powder |
| Content | 98.8% | 98.4 | 98.1% | 97.8% | 97.5% |
| Impurity summation | 1.22% | 1.34% | 1.53% | 2.01% | 2.24% |
Conclusion: accelerate comparative study experiment it is found that tylonolide crystal form prepared by the present invention by the above 6 months stability
For A compared with tylonolide polycrystalline I, product appearance is more stable, and content is slightly higher, and impurity is less slightly, and content changes phase with impurity in 6 months
When.For tylonolide crystal form A compared with polycrystalline III, each index is superior to polycrystalline III.Tylonolide crystal form A crystallization purity of the invention
Height, quality stability are more preferable.
Embodiment 7: organic solvent residual experiment
By the tylonolide crystal form A of embodiment 1 and tylonolide polycrystalline I, polycrystalline III (with 6 polycrystalline I of embodiment, polycrystalline III)
Dissolvent residual, TG- in other solvate crystal form dissolvent residual referenced patents WO2009/013351 are compared by vapor detection
FTIR testing result, detailed data are shown in Table 5.
5 tylonolide crystal form A of table and other crystal form dissolvent residuals compare
Note: space is to be not detected.
Conclusion: being compared by the above dissolvent residual, and ground prepared by the present invention sieve novel crystal forms A only contains a small amount of methanol, and its
His crystal form, especially solvated Form, dissolvent residual is higher, does not meet requirement of the ICH to bulk pharmaceutical chemicals dissolvent residual limit.
Claims (10)
1. a kind of tylonolide crystal form A, which is characterized in that radiated using Cu-Ka, the X-ray powder diffraction indicated with 2 θ angles
Method (XRPD) map 4.95 ± 0.2,7.03 ± 0.2,7.86 ± 0.2,9.20 ± 0.2,11.09 ± 0.2,11.52 ± 0.2,
12.55±0.2、13.32±0.2、14.01±0.2、15.16±0.2、15.61±0.2、16.73±0.2、17.96±0.2、
There are characteristic peak in 19.08 ± 0.2,20.50 ± 0.2,21.50 ± 0.2 positions.
2. tylonolide crystal form A as described in claim 1, which is characterized in that the X-ray powder of the tylonolide crystal form A
The map of last difraction spectrum is as shown in the XRPD map of tylonolide crystal form A.
3. tylonolide crystal form A as described in claim 1, which is characterized in that infrared spectroscopy (IR) map is in wave number σ ± 2cm-1
There is a peak in position, the σ is 3455,2936,2795,1750,1682,1631,1593,1458,1412,1375,1312,1277,
1256、1194、1166、1115、1088、1055、1008、984、963、935、909、858、839、782、757、639、573。
4. tylonolide crystal form A as described in claim 1, which is characterized in that the infrared spectroscopy of the tylonolide crystal form A
Map is as shown in the IR map of tylonolide crystal form A.
5. tylonolide crystal form A as described in claim 1, which is characterized in that the tylonolide crystal form A, using aluminium earthenware
Crucible, under flowing nitrogen in the closed cup with pin hole, the rate of heat addition of 10 DEG C/min, 30~220 DEG C of temperature ranges are obtained
Thermogravimetric-differential scanning calorimetry (TG-DSC) map, at 30~110 DEG C, there are solvent volatile weight loss 0.1%~5.0%；32
There is endothermic peak between~100 DEG C, 105~135 DEG C, 186~210 DEG C, has exothermic peak between 145~186 DEG C；Preferably, institute
The thermogravimetric of the tylonolide crystal form A stated-differential scanning calorimetry map is as shown in the TG-DSC map of tylonolide crystal form A.
6. the preparation method of tylonolide crystal form A as described in claim 1, which comprises the steps of:
By tylonolide dissolution of raw material in organic solvent, the mass volume ratio of tylonolide raw material and organic solvent be 1:2~
20, unit g/mL；It is kept for 0~35 DEG C of reaction temperature, 40~200 revs/min of speed of agitator, obtains tylonolide solution；By safe ground
Sieve new soln is added dropwise in purified water, and tylonolide and purified water mass volume ratio are 1:10~100, unit g/mL；It was added dropwise
Cheng Zhong, tylonolide are slowly precipitated, 1~5h of growing the grain, filtering, it is dry to get.
7. the preparation method of tylonolide crystal form A as claimed in claim 6, which is characterized in that the tylonolide raw material is
Polymorphic, solvated Form or amorphous, the organic solvent are water-soluble organic solvent；It is further preferred that organic molten
Agent is methanol, ethyl alcohol, isopropanol, sec-butyl alcohol, N, N-dimethylformamide, acetone, dimethyl sulfoxide, in N-methyl pyrrolidones
Any or combinations thereof solvent；Still more preferably, the organic solvent is methanol, ethyl alcohol or isopropanol.
8. the preparation method of tylonolide crystal form A as claimed in claim 6, which is characterized in that the tylonolide with it is organic
Solvent quality volume ratio is 1:3~10, unit g/mL；The reaction temperature is 20~25 DEG C；The speed of agitator is 60-80
Rev/min.
9. the preparation method of tylonolide crystal form A as claimed in claim 6, which is characterized in that the tylonolide solution drop
It is added in purified water, time for adding is 30~200 minutes；The tylonolide and purified water mass volume ratio are 1:15~50,
Unit g/mL；The rearing crystal time is 2~3h；The drying mode is vacuum drying, and drying temperature is 40~90 DEG C；It is preferred that
, filtered tylonolide crystal form A is dried in vacuo 10~12 hours in 80 DEG C.
10. a kind of composition of tylonolide, which is characterized in that brilliant comprising the described in any item tylonolides of Claims 1 to 5
Type A and one or more pharmaceutically acceptable carriers or excipient.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981926A (en) * | 2019-12-12 | 2020-04-10 | 河北远征药业有限公司 | Purification method of crude tildipirosin product |
| CN113201033A (en) * | 2020-12-21 | 2021-08-03 | 湖北龙翔药业科技股份有限公司 | Method for purifying tildipirosin |
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| WO2009013351A2 (en) * | 2007-07-26 | 2009-01-29 | Intervet International B.V. | Macrolide solid-state forms |
| 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 |
| CN104447919A (en) * | 2014-11-28 | 2015-03-25 | 武汉回盛生物科技有限公司 | Refining method of 20,23-dipiperidinyl-5-O-mycaminose-tylonolide bulk drug |
| CN106046086A (en) * | 2016-06-02 | 2016-10-26 | 天津大学 | Method for preparing amorphous tildipirosin |
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2017
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009013351A2 (en) * | 2007-07-26 | 2009-01-29 | Intervet International B.V. | Macrolide solid-state forms |
| 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 |
| CN104447919A (en) * | 2014-11-28 | 2015-03-25 | 武汉回盛生物科技有限公司 | Refining method of 20,23-dipiperidinyl-5-O-mycaminose-tylonolide bulk drug |
| CN106046086A (en) * | 2016-06-02 | 2016-10-26 | 天津大学 | Method for preparing amorphous tildipirosin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981926A (en) * | 2019-12-12 | 2020-04-10 | 河北远征药业有限公司 | Purification method of crude tildipirosin product |
| CN110981926B (en) * | 2019-12-12 | 2023-05-16 | 河北远征药业有限公司 | Purification method of crude product of tylosin |
| CN113201033A (en) * | 2020-12-21 | 2021-08-03 | 湖北龙翔药业科技股份有限公司 | Method for purifying tildipirosin |
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Application publication date: 20190507 |