CN109206463A - A kind of roxithromycin crystal-form compound and preparation method thereof - Google Patents
A kind of roxithromycin crystal-form compound and preparation method thereof Download PDFInfo
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- CN109206463A CN109206463A CN201810628200.XA CN201810628200A CN109206463A CN 109206463 A CN109206463 A CN 109206463A CN 201810628200 A CN201810628200 A CN 201810628200A CN 109206463 A CN109206463 A CN 109206463A
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- roxithromycin
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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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- 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
Abstract
The present invention relates to a kind of roxithromycin crystal-form compounds and preparation method thereof, and position is successively for the angle of diffraction (2 θ) of the x-ray diffractogram of powder of the novel roxithromycin crystal-form compound are as follows: 7.287,9.521,13.863 14.263,14.618,16.770,19.405 19.910,21.486,22.395,25.299 29.566,37.058.The roxithromycin of this crystal form increases rate of dissolution relative to general crystal form, is conducive to increase absorption rate in vivo, to enhance preventive and therapeutic effect of the drug in clinic.
Description
Technical field
The invention belongs to medical compounds fields, are related to a kind of novel roxithromycin crystal-form compound and its preparation side
Method.
Background technique
Roxithromycin (9- { O- [(2- methoxy ethoxy)-methyl] oximido } erythromycin), structural formula are as follows:
Molecular formula: C41H76N2O15
Molecular weight: 837.03
Roxithromycin is macrolide antibiotics of new generation, mainly acts on gram-positive bacteria, anaerobic bacteria, Chlamydia
With mycoplasma etc..Its vitro antibacterial activity is similar with erythromycin, and vivo bacteria corrosion action is 1-4 times stronger than erythromycin.
Most of existing Chinese patent is to protect to the dosage form of roxithromycin:
The Liu Fengming invention recorded in Chinese patent CN 1939273A (publication number) " is sucked containing roxithromycin and is made
Agent and preparation method thereof ".The invention relates to one kind and contains roxithromycin buccal lozenge and preparation method.
" the Luo Hong for the Guangdong Qingfa Pharmaceutical Co., Ltd's invention recorded in Chinese patent CN 1336176A (publication number)
Mycin bolt and preparation method ".The present invention relates to a kind of Roxoithromycin suppostory and preparation method.
" the one kind for Bei's Pharmaceutical Co., Ltd, Guangzhou's invention recorded in Chinese patent CN 1452975A (publication number)
Roxithromycin injection ".The present invention relates to a kind of roxithromycin dripping pill and preparation method.
The emphasis point of above-mentioned patent is all the patent protection to the different dosage forms of roxithromycin, and point of penetration of the invention with
Above-mentioned patent is essentially different, i.e. the state existing for the roxithromycin solid matter-crystal form research is started with, and obtains best
Crystal form, to play better clinical prevention effect.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of novel roxithromycin crystal-form compound.Crystal form Luo Hong
The preparation high income of mycin compound, crystal form are good, dissolubility is good, are conducive to increase absorption rate in vivo, to increase
Strong preventive and therapeutic effect of the drug in clinic.
The present invention is achieved through the following technical solutions:
The roxithromycin compound is crystal, the 2- θ Angle Position in x-ray diffractogram of powder are as follows: 7.287,
9.521,13.863,14.263,14.618,16.770,19.405,19.910,21.486,22.395,25.299,29.566,
37.058。
Preferably, the X-ray diffractogram of roxithromycin crystal-form compound is as shown in Fig. 1.
Roxithromycin crystal-form compound, characteristic morphology be using infrared spectroscopy KBr tabletting analyze when
3477.45,2966.31,2941.24,1728.10,1635.52,1465.80,1400.22,1377.08,1344.29,
1282.57,1168.78,1074.28,1063.06,1010.63,559.32,514.96,459.03.cm-1Place has absorption peak to deposit
?.
Preferably, the infrared absorption spectrum of novel roxithromycin crystal-form compound is as shown in Fig. 2.
In addition, the present invention also provides a kind of preparation methods of roxithromycin crystal-form compound.
The preparation method of roxithromycin crystal-form compound, includes the following steps:
Step a: being added reaction flask for roxithromycin crude product 50g and good solvent, and stirring heats up 45 ± 2 DEG C, after being completely dissolved,
Stop heating, purified water is instilled into reaction solution, rate of addition 70ml/ hours, after being added dropwise, it is small that 3.5 are stirred at 20 ± 2 DEG C
When, filtering is filtered dry with purifying water washing.
Step b: being added reaction flask for above-mentioned wet feed and acetone, and stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, and is added
2.5g active carbon stirs 30 minutes, filtering, instills purified water in filtrate, and rate of addition 50ml/ hour, after change is muddy, growing the grain, so
Certain speed drips off purified water again afterwards, after being added dropwise, stirs 3~4 hours at 20 ± 2 DEG C, filtering, with purifying water washing,
It is filtered dry, dry roxithromycin crystal.
Preferably, good solvent is methanol, ethyl alcohol, isopropanol, normal propyl alcohol etc. in the step a.
Good solvent is methanol, ethyl alcohol, isopropanol or normal propyl alcohol in step a；Wherein roxithromycin crude product weight: good solvent body
Product=1g:3~5ml.
Good solvent volume in step a: purifying water volume=1:1~3.
Wet feed weight in step b: acetone volume=1g:2~4ml.
Acetone volume in step b: purifying water volume=1:1~3.
Preferably, continuing that water is added dropwise using the growing the grain 10 after crystallization that drips~after sixty minutes in the step b, continuing to drip
Acceleration is 30~100ml/ hours.
Wherein, in above-mentioned steps a, b, water speed is added dropwise and increases by roxithromycin crude product inventory equal proportion.
Specifically, described method includes following steps:
Step a: being added reaction flask for roxithromycin crude product 50g and good solvent, and stirring heats up 45 ± 2 DEG C, after being completely dissolved,
Stop heating, purified water is instilled into reaction solution, rate of addition 70ml/ hours, after being added dropwise, it is small that 3.5 are stirred at 20 ± 2 DEG C
When, filtering is filtered dry with purifying water washing；
Step b: being added reaction flask for above-mentioned wet feed and acetone, and stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, and is added
2.5g active carbon stirs 30 minutes, filtering, instills purified water in filtrate, and rate of addition 50ml/ hour, after change is muddy, growing the grain, so
Certain speed drips off purified water again afterwards, after being added dropwise, stirs 3~4 hours at 20 ± 2 DEG C, filtering, with purifying water washing,
It is filtered dry, dry roxithromycin crystal.
In addition, the present invention also provides a kind of hydrates of roxithromycin crystal-form compound.
It is to influence the deliquescent key factor of roxithromycin solid drugs present invention finds crystal form, so that affecting it has
The absorption of ingredient in vivo is imitated, and has increased or decreased biological intracorporal haemoconcentration, so that solid drugs be caused to exist
Curative effect difference between the effects in clinical disease control and application.Novel roxithromycin crystal-form compound of the invention is easier to pass through gastrointestinal tract
It absorbs, to play better clinical prevention effect.Solvent used in preparation method of the present invention is mainly alcohols, acetone and water,
These solvents are all more soluble easily in water, and environmental pollution is relatively low, be easy waste water is handled, reduce subsequent processing at
This.The hydrate dissolution rate and solubility of roxithromycin crystal-form compound of the invention all greatly improve.
Detailed description of the invention
The X-ray diffractogram of the novel roxithromycin crystal-form compound of Fig. 1.
The infrared absorption spectrum of the novel roxithromycin crystal-form compound of Fig. 2.
Fig. 3 roxithromycin hydrate dissolution rate curve.
Specific embodiment
Using embodiment, the present invention will be further described below, it should be understood that the present invention is not limited only to following embodiment
Range.
Embodiment 1
Step a: reaction flask is added in roxithromycin crude product 50g and methanol 200ml, 45 ± 2 DEG C of stirring heating is completely dissolved
Afterwards, stop heating, by purified water 400ml instill reaction solution, rate of addition 70ml/ hours, after being added dropwise, at 20 ± 2 DEG C
Stirring 3.5 hours, filtering are filtered dry with purifying water washing.
Step b: reaction flask is added in above-mentioned wet feed and acetone 150ml, stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, adds
Enter 2.5g active carbon, stir 30 minutes, filters, instillation purified water 300ml in filtrate, rate of addition 50ml/ hours, after becoming muddy,
Growing the grain 40 minutes, purified water then was dripped off with 30ml/ hours, after being added dropwise, is stirred 3~4 hours at 20 ± 2 DEG C, is filtered,
It with purifying water washing, is filtered dry, dry roxithromycin crystal.Sample 1 is obtained, yield 97.2% is refined.
Embodiment 2
Step a: reaction flask is added in roxithromycin crude product 100g and ethyl alcohol 400ml, 45 ± 2 DEG C of stirring heating is completely molten
Xie Hou, stop heating, by purified water 800ml instill reaction solution, rate of addition 70ml/ hours, after being added dropwise, in 20 ± 2 DEG C
Lower stirring 3.5 hours, filtering are filtered dry with purifying water washing.
Step b: reaction flask is added in above-mentioned wet feed and acetone 300ml, stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, adds
Enter 5g active carbon, stir 30 minutes, filter, purified water 600ml is instilled in filtrate, rate of addition 50ml/ hours, after becoming muddy, is supported
It is 40 minutes brilliant, purified water then was dripped off with 30ml/ hours, after being added dropwise, is stirred 3~4 hours at 20 ± 2 DEG C, is filtered, is used
Water washing is purified, is filtered dry, dry roxithromycin crystal.Sample 2 is obtained, yield 96.5% is refined.
Embodiment 3
Step a: reaction flask is added in roxithromycin crude product 50g and methanol 200ml, 45 ± 2 DEG C of stirring heating is completely dissolved
Afterwards, stop heating, by purified water 400ml instill reaction solution, rate of addition 70ml/ hours, after being added dropwise, at 20 ± 2 DEG C
Stirring 3.5 hours, filtering are filtered dry with purifying water washing.
Step b: reaction flask is added in above-mentioned wet feed and acetone 90ml, stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, adds
Enter 2.5g active carbon, stir 30 minutes, filters, instillation purified water 180ml in filtrate, rate of addition 50ml/ hours, after becoming muddy,
Growing the grain 40 minutes, purified water then was dripped off with 30ml/ hours, after being added dropwise, is stirred 3~4 hours at 20 ± 2 DEG C, is filtered,
It with purifying water washing, is filtered dry, dry roxithromycin crystal.Sample 1 is obtained, yield 92.2% is refined.
Embodiment 4
Step a: reaction flask is added in roxithromycin crude product 50g and methanol 200ml, 45 ± 2 DEG C of stirring heating is completely dissolved
Afterwards, stop heating, by purified water 400ml instill reaction solution, rate of addition 70ml/ hours, after being added dropwise, at 20 ± 2 DEG C
Stirring 3.5 hours, filtering are filtered dry with purifying water washing.
Step b: reaction flask is added in above-mentioned wet feed and DMF150ml, stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, adds
Enter 2.5g active carbon, stir 30 minutes, filters, instillation purified water 300ml in filtrate, rate of addition 50ml/ hours, after becoming muddy,
Growing the grain 40 minutes, purified water then was dripped off with 30ml/ hours, after being added dropwise, is stirred 3~4 hours at 20 ± 2 DEG C, is filtered,
It with purifying water washing, is filtered dry, dry roxithromycin crystal.Sample 3 is obtained, yield 87.2% is refined.
Three samples prepared by above three embodiments are respectively prepared to the hydrate of roxithromycin crystal-form compound: sample
1-1, sample 2-1, sample 3-1 and sample 4-1.Specific implementation step is as follows:
Roxithromycin crystal-form compound 10g and purified water 200ml is added in reaction flask, stirring is warming up to 90 ± 5 DEG C, directly
To compound dissolved clarification, it is then slowly stirred cooling, until the hydrate of roxithromycin crystal-form compound is precipitated, is filtered, drying.?
To four hydrate samples.
It can be found that four roxithromycin crystal-form compounds are made after hydrate, rate of dissolution and dissolution in water
Degree, which has, to be greatly improved, but since the ratio of solvent acetone has been changed to wet-milling in sample 3: acetone=1:1.8, so that brilliant
Type is varied, and solvent acetone has been changed to DMF in sample 4, crystal form difference is resulted in, so that sample 1-1's and sample 2-1 is molten
Solution rate and solubility all go with 4-1 than sample 3-1, and sample 3-1 is better than sample 4-1 again.Illustrate the different crystalline substance of roxithromycin
Type plays the role of conclusive (no matter be formed into complex and be also formed into preparation) for subsequent preparation.
Rate of dissolution measuring method:
Roxithromycin hydrate dissolution rate determination uses paddle method, and the rate of dissolution measurement result of three samples in water is such as
Shown in Fig. 3, specific data are as follows:
Specific data:
Claims (9)
1. a kind of roxithromycin crystal-form compound, which is characterized in that 2 θ angles of the crystal-form compound in x-ray diffractogram of powder
Position are as follows:
7.287,9.521,13.863,14.263,14.618,16.770,19.405,19.910,21.486,22.395,
25.299,29.566,37.058。
2. roxithromycin crystal-form compound according to claim 1, which is characterized in that infrared spectroscopy exists
3477.45,2966.31,2941.24,1728.10,1635.52,1465.80,1400.22,1377.08,1344.29,
1282.57,1168.78,1074.28,1063.06,1010.63,559.32,514.96,459.03cm-1Place has absorption peak to deposit
?.
3. a kind of method for preparing roxithromycin crystal-form compound of any of claims 1 or 2, which is characterized in that steps are as follows:
Step a: reaction flask is added in roxithromycin crude product and good solvent, 45 ± 2 DEG C of stirring heating after being completely dissolved, stops adding
Purified water is instilled reaction solution by heat, after being added dropwise, is stirred 3.5 hours at 20 ± 2 DEG C, filtering, with purifying water washing, filter
Do to obtain wet feed；
Step b: being added reaction flask for wet feed obtained by step a and acetone, and stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, and is added and lives
Property charcoal, stir 30 minutes, filtering, purified water instilled in filtrate, after becoming muddy, then growing the grain drips off purified water again, be added dropwise
Afterwards, it stirs 3~4 hours, filters at 20 ± 2 DEG C, with purifying water washing, be filtered dry, dry roxithromycin crystal.
4. according to the method described in claim 3, it is characterized in that, good solvent is methanol, ethyl alcohol, isopropanol or just in step a
Propyl alcohol；Wherein roxithromycin crude product weight: good solvent volume=1g:3~5ml.
5. according to the method described in claim 3, it is characterized in that, good solvent volume in step a: purifying water volume=1:1~
3。
6. according to the method described in claim 3, it is characterized in that, wet feed weight in step b: acetone volume=1g:2~4ml.
7. according to the method described in claim 3, it is characterized in that, acetone volume in step b: purifying water volume=1:1~3.
8. according to the method described in claim 3, it is characterized in that, using growing the grain 10~60 minutes after the crystallization that drips in step b
Afterwards, continue that water is added dropwise.
9. according to the method described in claim 3, it is characterized in that, specifically comprising the following steps:
Step a: reaction flask is added in roxithromycin crude product 50g and good solvent, 45 ± 2 DEG C of stirring heating after being completely dissolved, stops
Heating, instills reaction solution for purified water, rate of addition 70ml/ hours, after being added dropwise, stirs 3.5 hours at 20 ± 2 DEG C,
Filtering is filtered dry with purifying water washing；
Step b: being added reaction flask for above-mentioned wet feed and acetone, and stirring is warming up to 30 ± 2 DEG C, after being completely dissolved, and it is living that 2.5g is added
Property charcoal, stir 30 minutes, filtering, instill purified water in filtrate, rate of addition 50ml/ hour, after change is muddy, growing the grain, then further
Constant speed degree drips off purified water, after being added dropwise, stirs 3~4 hours at 20 ± 2 DEG C, filtering, with purifying water washing, is filtered dry, does
It is dry to obtain roxithromycin crystal.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112250723A (en) * | 2020-10-27 | 2021-01-22 | 黄石世星药业有限责任公司 | Method for converting roxithromycin crystal form B into crystal form A |
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| CN102286045A (en) * | 2011-09-07 | 2011-12-21 | 山东罗欣药业股份有限公司 | Roxithromycin monohydrate crystal, preparation method thereof and compound dry suspension containing roxithromycin monohydrate crystal and ambroxol hydrochloride composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112250723A (en) * | 2020-10-27 | 2021-01-22 | 黄石世星药业有限责任公司 | Method for converting roxithromycin crystal form B into crystal form A |
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