CN107163065A - A kind of preparation method of rifampin II crystal formations - Google Patents
A kind of preparation method of rifampin II crystal formations Download PDFInfo
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of preparation method of rifampin II crystal formations.At 25~45 DEG C, under stirring action, I crystal rifampin crude product is added into organic solvent, suspension is formed, stirred 1~6 hour, carried out solvent mediation and turn crystalline substance；By the separation of gained suspension, dry, obtain rifampin II crystal formation products.In order to further improve yield, before suspension is separated, suspension can be cooled down, temperature is reduced to 5~15 DEG C.The application mediates rotating crystal method that rifampin II crystal formations are made by solvent, and particle mean size reaches 130 μm or so, and heap density is more than 0.65g/mL, and even particle size distribution, crystal habit is regular, it is easy to filter.Good product mobility, angle of repose is 40.4 ° or so, and purity is higher than 99.0%, and process yield is higher than 90.0%.The application method is simple to operate, time-consuming short, consumes energy low.
Description
Technical field
The invention belongs to Chemical Engineering industrial crystallization technical field, more particularly to a kind of preparation side of rifampin II crystal formations
Method.
Background technology
The chemical name of rifampin (Rifampicin) is 3- [[(4- methyl isophthalic acids-piperazinyl) imino group] methyl]-Li Fu
Mycin.Molecular formula is：C43H58N4O12, molecular weight：822.95, No. CAS：13292-46-1, outward appearance is cerise or kermesinus knot
Crystalline flour end.Structural formula is shown below：
Rifampin is a kind of semi-synthetic broad spectrum antibiotic of rifomycins, has antibacterial activity to multiple pathogenic microorganisms.
The mechanism of action of rifampin is by the β subunits strong bonded with RNA polymerases, to suppress the synthesis of bacteria RNA, finally
Terminate the synthesis of DNA and protein in bacterium.1966, Italian Leptit companies Maggi et al. successfully developed profit first
Good fortune is put down；1972, China trial-produceed successfully.This invention is great to therapeutic potential lungy.
Rifampin has a variety of crystal formations.The recrystallisation solvent of use is different or changes crystallization condition, and products obtained therefrom crystal formation is to have change
Change, have more than ten and plant crystal formation.It is most common to have：I types, II types, SV types and unformed four kinds.Wherein I types and II types are medicinal crystalline substance
Type, I types are recrystallized to give in n-butanol solvent, and II types are recrystallized to give in acetone solvent.The decomposition temperature of I crystal rifampin
The height compared with II crystal formations is spent, I crystal is heated to 260 DEG C or so and decomposed, II crystal formations are heated to 200 DEG C or so decomposition.In isolation
Under conditions of air, II crystal formation rifampins, which are heated to 190 DEG C or so, can be transformed into I crystal, and the transition process is heat absorption,
It is change crystal formation to illustrate both.At 35 DEG C, in acetone solvent, the solubility of rifampin II crystal formations for 0.0161g/mL (solute/
Solvent), the solubility of I crystal is 0.0183g/mL (solute/solvent), and the solubility of II crystal formations is less than the solubility of I crystal；And
Bioavilability of the II crystal formation rifampins in human body is slightly below I crystal, shows that II crystal formations are stable crystal forms at normal temperatures.With I
Crystal formation is compared, and II crystal formations have certain advantage in heap density, and the heap density of II crystal formations is 0.5g/mL or so, the heap of I crystal
Density is 0.4g/mL or so.
In recent years, in order to optimize Product Process, the physical and chemical performances such as the heap density of rifampin are improved, so as to improve biological utilisation
Degree, prepared by crystallization of the researcher to II crystal formation rifampins has carried out substantial amounts of experimental study.Patent CN103772413A is proposed
I crystal or II crystal formation rifampin raw materials are dissolved in acetone, matched proportion density is rifampin：Acetone=0.08~0.24g/mL, and
The water of acetone volume 1~6% is added, 50~57 DEG C of dissolvings are warming up to, then using evaporation-crystallisation by cooling combination, is finally down to
0-10 DEG C, obtain II crystal formation rifampin products.This method first dissolves by heating raw material, again cooling down crystallization, and it has the disadvantage power consumption
It is higher.Patent CN102079749A propose rifampin crude product acetone is dissolved under agitation, solution temperature be maintained at 51 DEG C~
Between 55 DEG C, solution concentration is between 18%~22%, and system moisture must not be higher than 4%；After dissolving completely, stainless steel cylinder is used
Cooled, cooling rate is 2 DEG C~3 DEG C/h, and -10 DEG C of brine ice fast coolings are used instead to less than 5 DEG C to 30 DEG C or so.Clearly
The crystal adhered on reason stainless steel cylinder, centrifuges to obtain wet product, the vacuum dried II crystal formations for obtaining heap density >=0.8g/mL
Rifampin bulk drug product.The shortcoming of this method is that stationary crystallization, operating time are long, takes more than 17h, product crystal crystal formation
Difference, manual cleaning labor intensity is big.United States Patent (USP) US4174320 is proposed under 20~80 DEG C of temperature ranges, by rifamycin-S
With 1, the hexahydro of 3,5 one tri-tert one, 1,3,5 one three prolixity and paraformaldehyde reaction, in the process with second acid for adjusting pH be 5~
7,20~60min is reacted, separation product evaporates, is dried to obtain crude product, then crude product is dissolved in acetoneand ethyl acetate, tied
Crystalline substance obtains II crystal formation rifampin products.Crystallization mode and operating condition are not described in detail for this method, and it has the disadvantage that crystallization process is in acid
Under the conditions of property, waste acid liquor can be produced, and crystal product granularity is small.
Prior art prepares the production technology of II crystal formation rifampins, and they use high-temperature digestion raw material in acetone, so
Afterwards by evaporation/cooling crystallization mode, II crystal formation rifampin products are obtained, it is small to there is product heap density, 0.5g/mL is left
The right side, particle mean size is smaller, 60 μm or so, skewness, as shown in figure 1, the problems such as power consumption is high, the time, time-consuming.Therefore, open
It is very necessary to send out simple, the with low cost II crystal formation rifampin production technologies of production process a kind of.
The content of the invention
The method for preparing rifampin II crystal formations for the high-temperature digestion, the evaporation/crystallisation by cooling that overcome prior art to be used
Deficiency, the invention provides a kind of solvent mediation rotating crystal method method for preparing rifampin II crystal formations, preparation method has operation
Simply, the advantage such as time cycle short, energy-conservation.
A kind of preparation method of rifampin II crystal formations of the present invention, its step includes：
At 25~45 DEG C, under stirring action, I crystal rifampin crude product is added into organic solvent, suspension, stirring is formed
1~6 hour, carry out solvent mediation and turn crystalline substance；By the separation of gained suspension, dry, obtain rifampin II crystal formation products.
In described method, the temperature that rifampin crude product is suspended in organic solvent is preferably 30~40 DEG C.
One or more mixing of the described organic solvent in methanol, ethanol, acetonitrile, ethyl acetate or acetone is molten
Agent；Suspension concentration is rifampin crude product：Organic solvent=0.04~0.25g/mL；The mother liquor obtained after suspension is separated can
Recycle.
In described method, in order to further improve yield, before suspension is separated, suspension can be carried out cold
But, temperature is reduced to 5~15 DEG C.
In described method, drying temperature be 20~60 DEG C, vacuum 0.01MPa~0.1MPa, drying time be 1~
10h。
The rifampin II crystal formations prepared using the inventive method, its powder x-ray diffraction collection of illustrative plates the θ of the angle of diffraction 2=
4.9 ± 0.2,6.9 ± 0.2,7.7 ± 0.2,8.7 ± 0.2,9.9 ± 0.2,11.0 ± 0.2,12.5 ± 0.2,13.4 ± 0.2,
14.1 ± 0.2,15.6 ± 0.2,16.5 ± 0.2,17.9 ± 0.2,19.9 ± 0.2,21.5 ± 0.2,22.9 ± 0.2,25.0 ±
There is characteristic peak at 0.2,25.9 ± 0.2,26.9 ± 0.2,29.9 ± 0.2 degree, as shown in Figure 2
The rifampin II crystal formations prepared using the inventive method, its TGA collection of illustrative plates is had without weightlessness at 195 ± 2 DEG C
Characteristic peak, as shown in Figure 3.
Polymorphic transformation mechanism is generally divided into solvent mediation and turns brilliant and brilliant two class of solid phase turn.Wherein, solvent mediation, which turns crystalline substance, is
Refer in certain specific solvent, the larger metastable crystal formation dissolving of solubility, while with the less stable crystal form nucleation of solubility
The process of growth.Its motive force is the difference in chemical potential or poor solubility of different crystal forms in the solution.Solvent mediation turns brilliant process can
It is divided into three steps：(1) dissolving of metastable crystal formation.At this moment the concentration of solution reaches the solubility of metastable crystal formation, hence it is evident that more than steady
Determine the solubility of crystal formation, because the solubility of stable crystal form is less than the solubility of metastable crystal formation, solution concentration now relative to
Stable crystal form is oversaturated, the nucleation for having trend (2) stable crystal form of generation stable crystal form nucleus.With metastable crystal formation after
Continuous dissolving, after the nucleation energy barrier of stable crystal form is broken through, stable crystal form starts the solute molecule in nucleation, solution more to stablize
Lattice mode arrange the growth of (3) stable crystal form.Persistently consume degree of supersaturation, metastable crystal formation continued dissolution, stable crystal form is not
It is broken into core and growth.
Described herein, using I crystal rifampin as raw material, it is exactly typical case that rifampin II crystal formations are generated in organic solvent
Solvent mediation turn a brilliant process.The inventive method adds I crystal rifampin crude product into organic solvent, and stirring mixing forms outstanding
The endless fully dissolved of supernatant liquid, i.e. raw material, there is the solid of suspension all the time.In 25~45 DEG C of temperature ranges, described herein specific have
Under machine dicyandiamide solution, I crystal rifampin is metastable crystal formation, and II crystal formation rifampins are stable crystal form, the solubility of I crystal rifampin
More than the solubility of II crystal formations, constant temperature is stirred 1~6 hour, in this process, there occurs that solvent mediation turns crystalline substance：The Li Fu of metastable type
Flat I crystal gradually dissolves, gradually nucleation, the growth of simultaneous stable crystal form rifampin II crystal formations.Stirring 1~6 hour
In resuspension procedure, rifampicin I crystal form will be completely converted into rifampin II crystal formations, and this is a dynamic fade process.
Prior art is to prepare rifampin II crystal formations using evaporation/crystallisation by cooling method, at 50~57 DEG C by I crystal rifampin
It is dissolved completely in solvent acetone, treats that solution is clarified, then cool/evaporation solvent makes solution supersaturation and precipitation is crystallized, crystallized
The journey cycle is long, and process passes through rising temperature for dissolving, again decrease temperature crystalline, its height that consumes energy, and obtained crystal particle mean size is smaller, average
60 μm or so, skewness, as shown in Figure 1.Heap density 0.5g/mL, crystallization process once through yield 70% or so.
The present invention turns a brilliant method using constant temperature suspension and prepares II crystal formation rifampins, has the advantages that：Behaviour
Make that step is simple, time-consuming short, power consumption is few, cost is low, it is easier to the implementation of industrialized scale.Gained II crystal formation rifampin products
Crystallinity is high, and particle mean size reaches 130 μm or so, and heap density is more than 0.65g/mL, and even particle size distribution, crystal habit is regular,
It is easy to filtering, sees Fig. 4.Good product mobility, characterizes 40 ° or so of the angle of repose of mobility, and purity is higher than 99.0%, process yield
More than 90.0%, hence it is evident that higher than 70% yield of existing crystallisation by cooling technology of preparing.
Brief description of the drawings
Fig. 1：Commercially available II crystal formations rifampin stereoscan photograph (500 times of amplification)；
Fig. 2：The X-ray powder diffraction figure of the application II crystal formation rifampin products；
Fig. 3：The thermogravimetric collection of illustrative plates of the application II crystal formation rifampin products；
Fig. 4：The application II crystal formation rifampin products stereoscan photograph (300 times of amplification).
Embodiment
The present invention is explained by following examples, but is not limited thereto：
Embodiment 1：
Ethanol 100mL is taken, stirring is lower to add I crystal rifampin 4g, forms suspension, carried out in constant temperature stirring 2h at 40 DEG C
Solvent mediation turns crystalline substance, filters suspension, and products obtained therefrom dries 10h in the case where 20 DEG C, vacuum are 0.1MPa, obtains II crystal formations profit
The flat 3.65g of good fortune, raw material give money as a gift after yield 91.25%, product crystallinity is high, purity 99.3%, main 138 μm of granularity, heap density
0.68g/mL, epigranular, good fluidity, 40 ° of angle of repose.
The powder x-ray diffraction collection of illustrative plates of product is as shown in Fig. 2 in the θ=4.9,7.0 of the angle of diffraction 2, and 7.8,8.8,9.9,
Have at 11.1,12.6,13.4,14.1,15.7,16.7,17.9,19.9,21.5,23.1,25.1,25.8,26.9,30.0 degree
Characteristic peak；Its TGA is analyzed as shown in figure 3, without weightlessness, having characteristic peak at 194 DEG C.
Embodiment 2：
Methanol 100mL is taken, stirring is lower to add I crystal rifampin 15g, forms suspension, entered in constant temperature stirring 4h at 30 DEG C
The mediation of row solvent turns crystalline substance, filters suspension, and products obtained therefrom dries 8h in the case where 30 DEG C, vacuum are 0.05MPa, obtains II crystal formations
Rifampin 13.6g, raw material give money as a gift after yield 90.67%, product crystallinity is high, purity 99.1%, main 137 μm of granularity, and heap is close
Spend 0.68g/mL, epigranular, good fluidity, 40.3 ° of angle of repose.
The powder x-ray diffraction collection of illustrative plates of product is in the θ=4.9,6.9 of the angle of diffraction 2, and 7.8,8.9,9.9,11.1,12.4,
13.5,14.2,15.7, there is characteristic peak at 16.7,18.0,19.9,21.5,22.8,25.1,25.8,26.9,30.1 degree；Its
TGA analysis displays, no weightlessness has characteristic peak at 195 DEG C.
Embodiment 3：
Acetonitrile 100mL is taken, stirring is lower to add I crystal rifampin 25g, forms suspension, entered in constant temperature stirring 1h at 45 DEG C
The mediation of row solvent turns crystalline substance, filters suspension, and products obtained therefrom dries 1h in the case where 50 DEG C, vacuum are 0.09MPa, obtains II crystal formations
Rifampin 22.7g, raw material give money as a gift after yield 90.8%, product crystallinity is high, purity 99.0%, main 110 μm of granularity, heap density
0.64g/mL, epigranular, good fluidity, 40.7 ° of angle of repose.
The powder x-ray diffraction collection of illustrative plates of product is in the θ=4.9,6.9 of the angle of diffraction 2, and 7.9,8.9,9.9,11.1,12.5,
There is characteristic peak at 13.3,14.3,15.7,16.7,18.1,19.9,21.6,22.9,25.1,25.7,26.8,30.0 degree；Its
TGA analysis displays, no weightlessness melts (decomposition) at 194 DEG C.
Embodiment 4：
Ethyl acetate 100mL is taken, stirring is lower to add I crystal rifampin 20g, forms suspension, is stirred in constant temperature at 40 DEG C
4h carries out solvent mediation and turns crystalline substance, is then cooled down suspension, temperature is reduced to 15 DEG C.Suspension is filtered, products obtained therefrom exists
45 DEG C, vacuum be to dry 5h under 0.01MPa, obtain II crystal formation rifampin 18.5g, raw material give money as a gift after yield 92.5%, production
Product crystallinity is high, purity 99.1%, main 128 μm of granularity, heap density 0.66g/mL, epigranular, good fluidity, angle of repose
40.5°。
The powder x-ray diffraction collection of illustrative plates of product is in the θ=4.7,6.9 of the angle of diffraction 2, and 7.6,8.9,10.0,11.1,12.5,
There is characteristic peak at 13.3,14.3,15.6,16.6,18.1,19.9,21.5,22.7,25.1,25.7,26.8,30.1 degree；Its
TGA analysis displays, no weightlessness melts (decomposition) at 196 DEG C.
Embodiment 5：
Acetone 100mL is taken, stirring is lower to add I crystal rifampin 5g, forms suspension, carried out in constant temperature stirring 6h at 25 DEG C
Solvent mediation turns crystalline substance, filters suspension, and products obtained therefrom dries 2h in the case where 60 DEG C, vacuum are 0.07MPa, obtains II crystal formations profit
The flat 4.51g of good fortune, raw material give money as a gift after yield 90.2%, product crystallinity is high, purity 99.2%, main 103 μm of granularity, heap density
0.65g/mL, epigranular, good fluidity, 40.2 ° of angle of repose.
The powder x-ray diffraction collection of illustrative plates of product is in the θ=4.9,6.9 of the angle of diffraction 2, and 7.9,8.6,9.8,11.1,12.6,
There is characteristic peak at 13.3,14.0,15.7,16.6,18.1,19.9,21.6,22.9,25.1,25.7,26.9,30.0 degree；Its
TGA analysis displays, no weightlessness melts (decomposition) at 193 DEG C.
Embodiment 6：
Acetone 70mL ethyl acetate 30mL are taken, stirring is lower to add I crystal rifampin 10g, suspension is formed, in permanent at 40 DEG C
Temperature stirring 2h carries out solvent mediation and turns crystalline substance, is then cooled down suspension, temperature is reduced to 10 DEG C.Filter suspension, gained
Product dries 5h in the case where 45 DEG C, vacuum are 0.01MPa, obtains II crystal formation rifampin 9.1g, raw material give money as a gift after yield
91%, product crystallinity is high, purity 99.1%, main 120 μm of granularity, heap density 0.67g/mL, epigranular, good fluidity, stops
41.2 ° of angle till.
The powder x-ray diffraction collection of illustrative plates of product is in the θ=4.8,6.9 of the angle of diffraction 2, and 7.6,8.9,10.1,11.1,12.5,
There is characteristic peak at 13.4,14.3,15.5,16.6,18.1,19.8,21.5,22.6,25.1,25.7,26.7,30.2 degree；Its
TGA analysis displays, no weightlessness melts (decomposition) at 195 DEG C.
Embodiment 7：
Methanol and each 50mL of acetone are taken, stirring is lower to add I crystal rifampin 15g, suspension is formed, in constant temperature at 30 DEG C
Stir 4.5h and carry out solvent mediation turn crystalline substance, then cooled down suspension, temperature is reduced to 5 DEG C.Filter suspension, gained
Product dries 4h in the case where 30 DEG C, vacuum are 0.02MPa, obtains II crystal formation rifampin 13.9g, raw material give money as a gift after yield
92.67%, product crystallinity is high, purity 99.3%, main 132 μm of granularity, heap density 0.70g/mL, epigranular, good fluidity,
40.1 ° of angle of repose.
The powder x-ray diffraction collection of illustrative plates of product is in the θ=5.0,6.9 of the angle of diffraction 2, and 7.9,8.6,9.9,11.0,12.3,
There is characteristic peak at 13.3,14.0,15.5,16.7,18.1,19.9,21.4,22.9,25.1,25.7,26.8,29.8 degree；Its
TGA analysis displays, no weightlessness melts (decomposition) at 195 DEG C.
A kind of preparation method for rifampin II crystal formations that the present invention is disclosed and proposed, those skilled in the art can be by using for reference
Present disclosure, appropriate feed change, the experiment of the link such as technological parameter.The method of the present invention is entered by preferred embodiments with product
Gone description, person skilled substantially can not departing from present invention, in spirit and scope to method described herein and
Product is modified or appropriate change is with combining, to realize the technology of the present invention.In particular, it is all similar to replace
Change and change for this technology personnel is it will be apparent that they are considered as being included in the spirit of the present invention, scope and interior
Rong Zhong.
Claims (6)
1. a kind of preparation method of rifampin II crystal formations, it is characterized in that, at 25~45 DEG C, under stirring action, to organic molten
I crystal rifampin crude product is added in agent, suspension is formed, stirred 1~6 hour, solvent mediation is carried out and turns crystalline substance；By gained suspension
Separate, dry, obtain rifampin II crystal formation products.
2. preparation method as claimed in claim 1, it is characterized in that, rifampin crude product be suspended in the temperature of organic solvent for 30~
40℃。
3. preparation method as claimed in claim 1, it is characterized in that, described organic solvent is selected from methanol, ethanol, acetonitrile, second
One or more of mixed solvents in acetoacetic ester or acetone.
4. preparation method as claimed in claim 1, it is characterized in that, suspension concentration is rifampin crude product：Organic solvent=
0.04~0.25g/mL.
5. preparation method as claimed in claim 1, it is characterized in that, before suspension is separated, suspension is cooled down,
Temperature is reduced to 5~15 DEG C.
6. preparation method as claimed in claim 1, it is characterized in that, drying temperature is 20~60 DEG C, vacuum 0.01MPa~
0.1MPa, drying time is 1~10h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108101927A (en) * | 2017-12-18 | 2018-06-01 | 天圣制药集团股份有限公司 | A kind of method for preparing rifampin crystal form II |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358724A (en) * | 2001-12-26 | 2002-07-17 | 杨伟业 | Improved process for rifa high-density raw powder I type crystal |
| CN103755723A (en) * | 2014-02-07 | 2014-04-30 | 天津大学 | Method for preparing rifampicin I crystal form |
| CN103772413A (en) * | 2014-02-07 | 2014-05-07 | 天津大学 | Preparation method of rifampicin II crystal form |
| CN103819487A (en) * | 2014-02-07 | 2014-05-28 | 天津大学 | Novel rifampin crystal form and preparing method thereof |
-
2017
- 2017-07-06 CN CN201710546509.XA patent/CN107163065B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358724A (en) * | 2001-12-26 | 2002-07-17 | 杨伟业 | Improved process for rifa high-density raw powder I type crystal |
| CN103755723A (en) * | 2014-02-07 | 2014-04-30 | 天津大学 | Method for preparing rifampicin I crystal form |
| CN103772413A (en) * | 2014-02-07 | 2014-05-07 | 天津大学 | Preparation method of rifampicin II crystal form |
| CN103819487A (en) * | 2014-02-07 | 2014-05-28 | 天津大学 | Novel rifampin crystal form and preparing method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108101927A (en) * | 2017-12-18 | 2018-06-01 | 天圣制药集团股份有限公司 | A kind of method for preparing rifampin crystal form II |
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