CN109438370A - A kind of methylpyrazine derivative anhydrous crystal forms - Google Patents
A kind of methylpyrazine derivative anhydrous crystal forms Download PDFInfo
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- CN109438370A CN109438370A CN201811644125.2A CN201811644125A CN109438370A CN 109438370 A CN109438370 A CN 109438370A CN 201811644125 A CN201811644125 A CN 201811644125A CN 109438370 A CN109438370 A CN 109438370A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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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 invention belongs to pharmaceutical technology field, specifically provide a kind of methylpyrazine derivative anhydrous crystal forms, preparation method and its preparing the purposes in hypolipidemic.Methylpyrazine derivative anhydrous crystal forms prepared by the present invention are radiated using Cu-K α, have characteristic peak at 5.4 ± 0.2 °, 6.2 ± 0.2 °, 9.3 ± 0.2 °, 27.3 ± 0.2 ° with the X-ray diffraction spectrogram that 2 θ are indicated.Methylpyrazine derivative anhydrous crystal forms dissolubility prepared by the present invention is good, is 3 times of existing methylpyrazine derivative crystal form solubility.The methylpyrazine derivative anhydrous crystal forms stability of the present patent application preparation is good, is still higher than 99.85% through stability test detection methylpyrazine derivative HPLC purity.Preparation process of the present invention is simple, has preferable prospects for commercial application.
Description
Technical field
The invention belongs to crystal form drug molecule technical field, in particular to a kind of methylpyrazine derivative anhydrous crystal forms.
Background technique
Acipimox anhydrous crystal forms, the entitled Acipimox anhydrous crystal forms of chemistry, for white or
Off-white color crystalline powder, structural formula is as shown in following formula a:
Acipimox is nicotinic acid derivates, is a kind of broad-spectrum long-acting lipid regulating agent, is used for various primary and secondary height
Pionemia mainly acts on adipose tissue, by inhibiting adipose tissue to discharge free fatty acid, reduces plasma low density lipoprotein
And the synthesis of very low density lipoprotein, so that the level of plasma low density lipoprotein and very low density lipoprotein in blood plasma is reduced,
Simultaneously by inhibiting hepatic lipase activity to increase plasma HDL levels.Acipimox is by Italian Farmitalia Carlo
Erba company develops, and listed in 1985 in Italy, then, relies on its higher safety and significant curative effect, phase
It is listed after in multiple countries and regions such as Germany, Chile, Switzerland, Hong-Kong.
The difference of drug crystal forms will affect the physicochemical property of drug, directly affect drug physiological pH 7.4 under the conditions of
Dissolution and absorption efficiency, and then influence the bioavilability of drug, clinical efficacy etc..By way of drug crystallization, on the one hand
The crystallographic parameter of crystal form drug molecule can be specified, on the other hand can determine in crystal form whether contain solvent, this is for reason
The spatial arrangement and physicochemical property of solution and grasp drug molecule have very important effect.
It is more about the relevant report of Acipimox at present, but primarily with regard to its preparation, preparation, physicochemical property and medicine
The report of the properties such as reason, the report about its crystal form is less, and patent US2005239803A1, CN 103508963A etc. is reported
The preparation method of Acipimox, but Acipimox crystal form do not referred to, it is therefore desirable to it is brilliant to provide a kind of Acipimox
Type studies the characteristics such as its stability, dissolubility, so that the application for Acipimox crystal form provides better foundation.
The present invention provides a kind of method of simple and easily operated preparation high-purity Acipimox anhydrous crystal forms, provides one
Kind has the product of the characteristics such as preferable chemical stability and dissolubility, and the application for Acipimox in drug treatment provides more
Good foundation, thus the medical value of more efficient performance Acipimox.
Summary of the invention
In view of the deficiencies in the prior art, on the one hand the application provides a kind of methylpyrazine derivative anhydrous crystal forms.
Signified methylpyrazine derivative anhydrous crystal forms are Acipimox anhydrous crystal forms, methylpyrazine derivative in the application
It is Acipimox.
Acipimox is white as drug ingedient of the invention, the entitled Acipimox of chemistry
Color or off-white color crystalline powder.No. CAS: 51037-30-0, molecular formula C6H6N2O3, structural formula is as shown in a.
According to the first aspect of the invention, methylpyrazine derivative anhydrous crystal forms are provided.The methylpyrazine is derivative
Object anhydrous crystal forms are radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ at 5.4 ± 0.2 °, 6.2 ± 0.2 °, 9.3 ±
There is characteristic peak at 0.2 °, 27.3 ± 0.2 °.
Preferably, the methylpyrazine derivative anhydrous crystal forms, are radiated, the X-ray diffraction indicated with 2 θ using Cu-K α
Spectrogram at 5.4 ± 0.2 °, 6.2 ± 0.2 °, 9.3 ± 0.2 °, 16.8 ± 0.2 °, 19.3 ± 0.2 °, 19.6 ± 0.2 °, 27.3 ±
There is characteristic peak at 0.2 °, 27.9 ± 0.2 °.
Preferably, the methylpyrazine derivative anhydrous crystal forms, are radiated using Cu-K α, and characteristic peak meets such as Fig. 1 institute
The X-ray powder diffraction pattern shown.
Preferably, the methylpyrazine derivative anhydrous crystal forms, there are one in differential scanning calorimetric curve (DSC)
A endothermic peak is 200.97 DEG C.
The second aspect of the present invention provides a kind of preparation method of methylpyrazine derivative anhydrous crystal forms, specific preparation step
Include: that methylpyrazine derivative is suspended in solvent A, dissolve by heating, be stirred to react, cool down crystallization, and filtration drying obtains methyl
Pyrazines derivatives anhydrous crystal forms.
The solvent A is selected from one of the mixed solution of tetrahydrofuran or tetrahydrofuran and solvent B.
Preferably, the volume ratio of tetrahydrofuran and solvent B are preferably 1~10:9~0.
Preferably, solvent B is in methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, ethylene glycol, ethyl acetate, acetone and acetonitrile
One or more.
It is further preferred that solvent B is selected from one or more of methanol, ethyl alcohol, acetone and acetonitrile.
The mass volume ratio of the methylpyrazine derivative and solvent A be 1:5~50, wherein quality in terms of g, volume with
Ml meter.
The temperature of the heating for dissolving is 40~70 DEG C.
The concrete mode of the cooling crystallization is program cooling, and the speed of cooling is 0.1~0.5 DEG C/5min；Crystallization
Temperature is -5~10 DEG C.
The drying mode is vacuum drying, and drying temperature is 40~50 DEG C, and the dry time is 3~5 h.
The preparation step of crystal form of the present invention is described in further detail in the following contents:
Methylpyrazine derivative is suspended in solvent A, it is supersaturated solution that 40~70 DEG C, which dissolve by heating, is stirred to react 2
~6 hours, -5~10 DEG C are cooled to, stands crystallization, filtering, 40~50 DEG C of 3~5 h of vacuum drying obtain methylpyrazine derivative
Anhydrous crystal forms.
The solvent A is selected from one of the mixed solution of tetrahydrofuran or tetrahydrofuran and solvent B.
Preferably, the volume ratio of tetrahydrofuran and solvent B are 1~10:9~0.
It is further preferred that all tetrahydrofurans of solvent A.
Preferably, the mass volume ratio of methylpyrazine derivative and solvent A is 1:8~20, and wherein quality is in terms of g, volume
In terms of ml.
Characteristic peak is detailed in attached drawing 1 and table 1 in the X-ray powder diffraction figure (Cu-K α) of methylpyrazine derivative anhydrous crystal forms.
The peak PXRD of 1 methylpyrazine derivative anhydrous crystal forms of table
Prepared all samples crystallographic parameter all having the same and X-ray powder diffraction spectrogram in embodiment.
TGA/DSC heat analysis tester and test condition in the present invention: TGA/DSC thermal analyzer: METTLER TOLEDO
TGA/DSC3+；Dynamic temperature section: 30~350 DEG C；The rate of heat addition: 10 DEG C/min；Program segment gas N2；Gas flow: 50mL/
min；Crucible: 40 μ l of aluminium crucible.
Test results are shown in figure 2 by the TGA/DSC of the Acipimox crystal of the method for the invention preparation, DSC detection knot
Fruit is only in 200.71 DEG C of appearance, one endothermic fusion peak.It can be seen that according to TGA testing result and only exist a weightless step,
Show that the Acipimox crystal without containing water or other solvents, shows crystal form prepared by the present invention in conjunction with DSC/TGA testing result
For Acipimox anhydrous crystal forms.
The third aspect of the present invention provides a kind of pharmaceutical composition, and the composition is derivative containing methylpyrazine of the present invention
Object anhydrous crystal forms, and include other pharmaceutically acceptable auxiliary material components.
Preferably, pharmaceutical composition of the invention preparation is as follows: using standard and conventional technique, makes the compounds of this invention
In conjunction with solid acceptable on galenic pharmacy or liquid-carrier, and be allowed to arbitrarily with adjuvant acceptable on galenic pharmacy and
Excipient combines and is prepared into available dosage form.
Preferably, other components include other active constituents, excipient, the filler etc. that can be used in combination.
Preferably, the pharmaceutical composition is spray, tablet, capsule, powder-injection, liquid injection agent etc..
The fourth aspect of the present invention provides a kind of methylpyrazine derivative anhydrous crystal forms as active constituent and prepares treatment drop
Application in blood lipids.
The methylpyrazine derivative anhydrous crystal forms of the method for the invention preparation are spread out relative to the methylpyrazine reported at present
Biological crystal form has the advantage that
(1) with high purity.Methylpyrazine derivative anhydrous crystal forms purity prepared by the present invention is higher than 99.87%, impurity 5- first
Base pyrazine -2- carboxylic acid is lower than 0.11%.
(2) solubility is high.The solubility of methylpyrazine derivative anhydrous crystal forms prepared by the present invention in the medium is existing
3 times or so of crystal form.
(3) stability is good.Methylpyrazine derivative anhydrous crystal forms solid prepared by the present invention is through exposure experiments to light, high temperature and humidity
After test, HPLC purity is still higher than 99.7%, much higher than purity of the existing crystal form after stability test.
Detailed description of the invention
Fig. 1: the X-ray powder diffraction pattern of methylpyrazine derivative anhydrous crystal forms.
Fig. 2: differential scanning calorimetric curve (DSC) figure of methylpyrazine derivative anhydrous crystal forms.
Fig. 3: the X-ray powder diffraction pattern of 3 crystal form of comparative example.
Fig. 4: the peak PXRD of 3 crystal form of comparative example.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention, impurity I is 5-Methylpyrazine-2-carboxylic acid, and methylpyrazine derivative is Acipimox.
Embodiment 1:
2.0g methylpyrazine derivative sample is suspended in 20ml tetrahydrofuran, 60 DEG C of stirring and dissolvings are heated to, is obtained
Supersaturated solution, after being stirred to react 3 hours, stirring cooling (control cooling rate is 1 DEG C/5min) is cooled to 5~10 DEG C, stands
It crystallization 48 hours, filters, vacuum drying 3h obtains methylpyrazine derivative anhydrous crystal forms crystal, yield 97.55%, purity at 40 DEG C
99.96%, impurity I:0.03%.
Embodiment 2:
2.0g methylpyrazine derivative sample is suspended in 16ml mixed solution (tetrahydrofuran: methanol=9:1), is heated
To 50 DEG C of stirring and dissolvings, obtain supersaturated solution, after being stirred to react 4 hours, stirring it is cooling (control cooling rate is 2 DEG C/
It 5min) is cooled to 0~5 DEG C, stands crystallization 42 hours, is filtered, vacuum drying 4h obtains methylpyrazine derivative without crystal at 45 DEG C
Type crystal, yield 96.21%, purity 99.94%, impurity I:0.05%.
Embodiment 3:
2.0g methylpyrazine derivative sample is suspended in 40ml mixed solvent (tetrahydrofuran: acetone=2:8), is heated
To 40 DEG C of stirring and dissolvings, obtain supersaturated solution, after being stirred to react 5 hours, stirring it is cooling (control cooling rate is 3 DEG C/
It 5min) is cooled to -5~0 DEG C, stands crystallization 54 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative without crystal at 50 DEG C
Type crystal, yield 95.42%, purity 99.93%, impurity I:0.06%.
Embodiment 4:
2.0g methylpyrazine derivative sample is suspended in 10ml mixed solvent (tetrahydrofuran: ethyl alcohol=7:3), is heated
To 70 DEG C of stirring and dissolvings, obtain supersaturated solution, after being stirred to react 3 hours, stirring it is cooling (control cooling rate is 4 DEG C/
5~10 DEG C 5min) are cooled to, stands crystallization 42 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative without crystal at 50 DEG C
Type crystal, yield 94.18%, purity 99.91%, impurity I:0.08%.
Embodiment 5:
2.0g methylpyrazine derivative sample is suspended in 100ml mixed solvent (tetrahydrofuran: acetonitrile=1:9), is added
Heat obtains supersaturated solution to 60 DEG C of stirring and dissolvings, after being stirred to react 4 hours, stirring it is cooling (control cooling rate is 5 DEG C/
It 5min) is cooled to -5~0 DEG C, stands crystallization 48 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative without crystal at 40 DEG C
Type crystal, yield 93.02%, purity 99.90%, impurity I:0.09%.
Embodiment 6:
2.0g methylpyrazine derivative sample is suspended in 110ml mixed solvent (tetrahydrofuran: ethylene glycol=1:9),
Be heated to 80 DEG C of stirring and dissolvings, obtain supersaturated solution, after being stirred to react 2 hours, stirring it is cooling (control cooling rate is 5 DEG C/
It 5min) is cooled to -5~0 DEG C, stands crystallization 48 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative without crystal at 40 DEG C
Type crystal, yield 91.58%, purity 99.89%, impurity I:0.10%.
Embodiment 7:
2.0g methylpyrazine derivative sample is suspended in 8ml mixed solvent (tetrahydrofuran: isopropanol=5:5), is added
Heat obtains supersaturated solution to 35 DEG C of stirring and dissolvings, after being stirred to react 6 hours, stirring it is cooling (control cooling rate is 3 DEG C/
- 10~-5 DEG C 5min) are cooled to, stands crystallization 48 hours, is filtered, it is anhydrous to obtain methylpyrazine derivative by vacuum drying 3h at 40 DEG C
Crystal form crystal, yield 90.15%, purity 99.87%, impurity I:0.11%.
Comparative example 1:
The concentrated sulfuric acid that 2730ml mass concentration is 98% is added in 10L glass reaction kettle, is added under stirring condition
5- methylpyrazine -2,3- dicarboxylic acids of 910.0g, is heated to 60 DEG C, heating reaction 1h, be then slowly added into 5.5kg water,
164.9g sodium tungstate (Na2WO4·2H2O), the hydrogen peroxide that 623.0g mass concentration is 30% continues heating stirring 8h, ice bath item
Cooling crystallization 4h under part, filters solid, and dry 12h at 100 DEG C prepares product Acipimox 595g.Product is received in the reaction
Rate 77.3%；HPLC purity 96.2%, impurity I:2.8%.
Comparative example 2:
200ml water is added into 100g Acipimox crude product, is heated to 100 DEG C, 3.0g active carbon is added after stirring and dissolving
Continue insulated and stirred 20 minutes, filters；Filtrate is cooled to 60 DEG C with 10 DEG C/h, 220g acetone is then added dropwise thereto, drop finishes,
Be cooled to 5 DEG C of crystallization 7h with 10 DEG C/h, filter, with acetone washing filter cake, dry (0.01MPa, 80 DEG C) up to off-white color Ah
Former times does not take charge of, yield 88.6%.HPLC purity: 98.3%, 5-Methylpyrazine-2-carboxylic acid (impurity I): 0.5%.Comparative example
3:
By the Na of 330mg (1mmol)2WO4·2H2O is placed in 50ml flask, dissolved and be equipped with 16ml water mechanical stirring,
Reflux cooler and thermometer.The hydrogen peroxide of 40% weight/volume of 3.75ml (400g/L) (44mmol) is incorporated in solution
In, with dilute H2SO4Being adjusted to pH value is 1.5, and the 2- carboxyl -5- methylpyrazine of 5.52g (40mmol) is then added.
The suspended matter for reacting the water generated is heated to 70 DEG C under stiring and maintains this temperature 2.5 hours.Thus obtain
Gradually solubilized suspended matter.Finally discovery has portion of product precipitating.Mixture is stood overnight at room temperature, and generates crystal shape
The precipitating of the reaction product of shape.This product is washed through filtering and with ice water, then is placed in drying on porous plate and can be obtained part and be
2- carboxyl -5- methylpyrazine -4- oxide the 4.62g of hydrate form (2.83%), be equivalent to 4.48g without aquatic products.Yield is
72.0%.HPLC purity: 95.1%, impurity I:2.3%.
Comparative example 4:
By the Na of 250mg (0.75mg)2WO4·2H2O is placed in 50ml flask, is dissolved with 13ml water and is equipped with machinery and stirred
It mixes, reflux cooler and thermometer.The hydrogen peroxide of 40% weight/volume of 3.23ml (400g/L) (38mmol) is incorporated in
In solution, with dilute H2SO4Being adjusted to pH value is 2.0, and the 2- carboxyl -5- methylpyrazine of 3.76g 98% (30mmol) is then added.
The suspended matter for reacting the water generated is heated to 80 DEG C under stiring and maintains this temperature 2 hours.And after 45min i.e.
It can get the suspended matter of solubilising completely.Finally, solution stands overnight at room temperature and generates the heavy of the reaction product of crystal shape
It forms sediment.This product is washed through filtering and with ice water, then is placed on porous plate dry acquisition 3.00g 2- carboxyl -5- methylpyrazine -4-
Monohydrate (the experiment value H of oxide2O-11.35%；The calculated value H of monohydrate product2O-11.3%), yield is
62.6%.HPLC purity: 94.2%, impurity I:3.4%.
Comparative example 5:
2- carboxyl -5- methylpyrazine 4- oxide (2.5g) is added to the mixed of methanol (60ml) and ethanol amine (1.1ml)
It closes in solution.Mixture is heated to reflux 20 minutes, is then cooled down and is filtered, 2- carboxyl -5- methyl pyrrole is obtained after methanol crystallization
Piperazine 4- oxide ethanolamine salt (2.1g), mp.177 ° -180 DEG C, yield: 60.17%, HPLC purity: 96.8%, impurity I:
2.1%.
Comparative example 6:
Under nitrogen protection, in the 500mL.x.4 equipped with mechanical agitator, water condenser (having gas access) and thermocouple
It is reacted in neck bottle.Trimethyl silicane sodium alkoxide (3.71g) and THF (90g) are added into reactor, 5- methylpyrazine is then added
Mixture is stirred at room temperature 4 hours carboxylic acid -4- oxide ethyl ester (6.00g), solid is collected by filtration and with THF (3x45g)
It rinses.It is dried in vacuo (25 inches of mercury, 65 DEG C), obtaining 5.38g, (yield: 92.5%) sodium salt, is pale solid, and HPLC is pure
Degree: 96.8%, impurity I:2.4%.
Stability test
1, temperature and humidity and exposure experiments to light
Specific stability testing method is referring to 2015 editions the 4th guidance methods in relation to study on the stability of Chinese Pharmacopoeia
It carries out, purity detecting is detected with HPLC method, and specific test result is shown in Table 2.
Stability test result of the 2 methylpyrazine derivative crystal form of table under illumination, high temperature and super-humid conditions
Through testing, all methylpyrazine derivative anhydrous crystal forms of the present invention program preparation can reach similar stability
Effect.As can be seen from Table 2, condition of the methylpyrazine derivative anhydrous crystal forms that are prepared of the present invention in illumination, high temperature and high humidity
Obvious variation do not occur for its lower purity, appearance, and comparative example 1 to 6 crystal form of comparative example under identical experiment condition
Its purity is greatly reduced, and impurity content has obvious raising, that is, rotten situation occurs, it is seen that prepared by the present invention
Methylpyrazine derivative anhydrous crystal forms have preferable chemical stability compared to existing crystal form.
Solubility experiment
Specific solubility test refers to Chinese Pharmacopoeia 2015.Precision weighs embodiment 1-7 and comparative example 1-6 respectively
The methylpyrazine derivative of preparation is excessive, is placed in small cillin bottle, is separately added into the phosphate of water, 0.1mol/L hydrochloric acid, pH7.4
Buffer solution is configured to methylpyrazine derivative saturated solution, shakes up dissolution, filtering, (logical according to UV-VIS spectrophotometry
Then 0401), absorbance is measured at the wavelength of 270nm to calculate its solubility, the results are shown in Table 3.
The solubility of 3 methylpyrazine derivative crystal form of table in different media
Through testing, all methylpyrazine derivative anhydrous crystal forms of the present invention program preparation can reach similar dissolubility
Effect.Seen from table 3, solubility of the methylpyrazine derivative anhydrous crystal forms of the present invention program preparation in different pH solution is equal
Higher than comparative example 1 to the crystal form of comparative example 6, methylpyrazine derivative crystal form prepared by the present invention has relative to existing crystal form
Higher dissolubility.
Claims (10)
1. a kind of methylpyrazine derivative anhydrous crystal forms, which is characterized in that the compound crystallization is radiated using Cu-K α, with 2 θ
The X-ray diffraction spectrogram of expression has characteristic peak at 5.4 ± 0.2 °, 6.2 ± 0.2 °, 9.3 ± 0.2 °, 27.3 ± 0.2 °.
2. methylpyrazine derivative anhydrous crystal forms as described in claim 1, which is characterized in that the compound crystallization uses
Cu-K α radiation, the X-ray diffraction spectrogram indicated with 2 θ at 5.4 ± 0.2 °, 6.2 ± 0.2 °, 9.3 ± 0.2 °, 16.8 ± 0.2 °,
There is characteristic peak at 19.3 ± 0.2 °, 19.6 ± 0.2 °, 27.3 ± 0.2 °, 27.9 ± 0.2 °.
3. methylpyrazine derivative anhydrous crystal forms as described in claim 1, which is characterized in that the compound crystallization uses
Cu-K α radiation, characteristic peak meet X-ray powder diffraction pattern as shown in Figure 1.
4. methylpyrazine derivative anhydrous crystal forms as described in claim 1, which is characterized in that it is in differential scanning calorimetric curve
(DSC) there are an endothermic peaks in, are 200.71 DEG C.
5. a kind of preparation method of methylpyrazine derivative anhydrous crystal forms, which is characterized in that specific preparation step includes: by methyl
Pyrazines derivatives are suspended in solvent A, dissolve by heating, be stirred to react, cool down crystallization, filtration drying obtain methylpyrazine derivative without
Crystal type.
6. the preparation method of methylpyrazine derivative anhydrous crystal forms as claimed in claim 5, which is characterized in that solvent A is selected from
The volume ratio of one of the mixed solution of tetrahydrofuran or tetrahydrofuran and solvent B, tetrahydrofuran and solvent B are 1~10:9
~0.
7. the preparation method of methylpyrazine derivative anhydrous crystal forms as claimed in claim 6, which is characterized in that solvent B is selected from
One or more of methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, ethylene glycol, ethyl acetate, acetone and acetonitrile, preferably methanol,
One or more of ethyl alcohol, acetone and acetonitrile.
8. the preparation method of methylpyrazine derivative anhydrous crystal forms as claimed in claim 5, which is characterized in that methylpyrazine spreads out
The mass volume ratio of biology and solvent A is 1:5~50, and wherein quality is in terms of g, and volume is in terms of ml.
9. a kind of pharmaceutical composition, it includes methylpyrazine derivative anhydrous crystal forms of any of claims 1-4, and
Include other pharmaceutically acceptable auxiliary material components.
10. methylpyrazine derivative anhydrous crystal forms of any of claims 1-4 are in preparation in hypolipidemic
Using.
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| CN113121456A (en) * | 2020-01-15 | 2021-07-16 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| CN115073384A (en) * | 2021-12-29 | 2022-09-20 | 山东新时代药业有限公司 | Acipimox crystal form and preparation method thereof |
| CN113121456B (en) * | 2020-01-15 | 2024-04-26 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
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| CN113121456A (en) * | 2020-01-15 | 2021-07-16 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| CN113121456B (en) * | 2020-01-15 | 2024-04-26 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| CN115073384A (en) * | 2021-12-29 | 2022-09-20 | 山东新时代药业有限公司 | Acipimox crystal form and preparation method thereof |
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