CN109400539A - A kind of methylpyrazine derivative semihydrate - Google Patents
A kind of methylpyrazine derivative semihydrate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- A61P3/06—Antihyperlipidemics
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention belongs to pharmaceutical technology field, specifically provide a kind of methylpyrazine derivative semihydrate, preparation method and its preparing the purposes in hypolipidemic.Methylpyrazine derivative hemi-hydrate crystalline prepared by the present invention is radiated using Cu-K α, has characteristic peak at 7.8 ± 0.2 °, 9.3 ± 0.2 ° with the X-ray diffraction spectrogram that 2 θ are indicated.Methylpyrazine derivative semihydrate dissolubility prepared by the present invention is good, is 2.5 times of existing methylpyrazine derivative crystal form solubility.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 semihydrate.
Background technique
Acipimox semihydrate, the entitled Acipimox semihydrate of chemistry, for white or
Off-white color crystalline powder, structural formula are as follows:
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 and its crystal form parameter do not referred to, it is therefore desirable to it provides
A kind of Acipimox crystal form with definite crystallographic parameter, studies the characteristics such as its stability, dissolubility, to be Acipimox
The application of semihydrate provides better foundation.
The present invention provides a kind of method of simple and easily operated preparation high-purity Acipimox semihydrate, 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 semihydrate.
Signified methylpyrazine derivative semihydrate is Acipimox semihydrate, 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 semihydrate crystal form is provided.In the crystal, methyl
The molar ratio of pyrazines derivatives and water is 1:0.5, and structure is shown in formula I:
The methylpyrazine derivative semihydrate crystal form, is radiated, the X-ray diffraction spectrum indicated with 2 θ using Cu-K α
Figure has characteristic peak at 7.8 ± 0.2 °, 9.3 ± 0.2 °.
Preferably, the methylpyrazine derivative semihydrate crystal form, is radiated, the X-ray indicated with 2 θ using Cu-K α
Diffraction spectrogram has characteristic peak at 7.8 ± 0.2 °, 9.3 ± 0.2 °, 15.5 ± 0.2 °, 18.4 ± 0.2 °, 27.8 ± 0.2 °.
Preferably, the methylpyrazine derivative semihydrate crystal form, is radiated using Cu-K α, characteristic peak meet as
X-ray powder diffraction pattern shown in FIG. 1.
Preferably, the methylpyrazine derivative semihydrate crystal form, is deposited in differential scanning calorimetric curve (DSC)
In two endothermic peaks, respectively 103.22 DEG C and 199.21 DEG C.
Preferably, the methylpyrazine derivative semihydrate crystal form, crystallographic parameter is: monoclinic system, space
Group is C2/m；Cell parameter are as follows:α=90.00 °, β=
125.53 (3), γ=90.00 °, unit cell volume
The second aspect of the present invention provides a kind of preparation method of methylpyrazine derivative semihydrate, specific preparation step
Include: that methylpyrazine derivative is suspended in solvent, dissolve by heating, be stirred to react, cool down crystallization, and filtration drying obtains methyl pyrrole
Oxazine derivatives semihydrate.
The mass volume ratio of the methylpyrazine derivative and solvent is 1:2~8, and wherein quality is in terms of g, and volume is with ml
Meter.
The solvent is selected from water or one of water and tetrahydrofuran, acetone, methanol, ethyl alcohol, acetonitrile and isopropanol group
It closes.
Preferably, the volume content of water is 10%~100% in solvent.
Preferably, the mass volume ratio of methylpyrazine derivative and water is 1:2~5 in system, and wherein quality is in terms of g, body
Product is in terms of ml.
The temperature of the heating for dissolving is 40~60 DEG C.
The reaction time is 4~10 hours.
The temperature of the cooling crystallization is 0~15 DEG C.
The concrete mode of the cooling crystallization is program cooling, it is preferable that the speed of cooling is 0.2~0.5 DEG C/min.
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 semihydrate, 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 semihydrate as active constituent and prepares treatment drop
Application in blood lipids.
The confirmation of crystal structure
X-ray crystal form data are collected on Rigaku XtaLAB Synergy model instrument, test temperature 293 (2) K,
It is radiated with CuKa, data are collected with ω scanning mode and carries out Lp correction.With direct method analytic structure, difference Fourier method is found out
Whole non-hydrogen atoms, the hydrogen atom on all carbon and nitrogen are obtained using theoretical plus hydrogen, carry out essence to structure using least square method
It repairs.
Testing and parse crystallographic data obtained by methylpyrazine derivative semihydrate prepared by the present invention is (table 1): its
Crystallographic parameter is: monoclinic system, space group C2/m；Cell parameter are as follows: α=90.00 °, β=125.53 (3), γ=90.00 °, unit cell volumeOf the invention
The ORTEP chart of methylpyrazine derivative crystal form is bright, and the methylpyrazine derivative of two molecules shares a hydrone, can confirm this
Crystal form is methylpyrazine derivative semihydrate.The hydrogen bond figure of methylpyrazine derivative crystal form of the invention, the bright methyl of the chart
Pyrazines derivatives connect into the two-dimensional structure for prolonging cob plane by intermolecular hydrogen bonding (symmetry operation code are as follows: 1-x, y ,-z), such as attached
Shown in Fig. 2.
The predominant crystal data of 1 methylpyrazine derivative semihydrate of table
X-ray powder diffraction test equipment and test condition in the present invention: X-ray powder diffraction instrument: PANalytical
E；Cu-Kα；Sample stage: plate；Input path: BBHD；Optical diffraction: PLXCEL；Voltage 45kv, electric current 40mA；Divergent slit:
1/4；Antiscatter slits: 1；Rope draws slit: 0.04rad；Step-length: 0.5s；Scanning range: 3~50 °.
According to above-mentioned crystallographic data, in corresponding X-ray powder diffraction figure (Cu-K α) characteristic peak be detailed in attached drawing 1 and
Table 2.
The peak PXRD of 2 methylpyrazine derivative semihydrate 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 4 by the TGA/DSC of the methylpyrazine derivative crystal form of the method for the invention preparation, DSC
There are two endothermic peaks for testing result, and respectively corresponding temperature is 103.22 DEG C and 199.21 DEG C.It can be seen that according to TGA testing result
There are two weightless steps, calculation shows that the methylpyrazine derivative crystal is semihydrate, in conjunction with DSC/TGA testing result table
Bright, crystal form prepared by the present invention is methylpyrazine derivative semihydrate crystal form.
The methylpyrazine derivative semihydrate of the method for the invention preparation spreads out relative to the methylpyrazine reported at present
Biological crystal form has the advantage that
(1) with high purity.Methylpyrazine derivative semihydrate purity prepared by the present invention is higher than 99.80%, impurity 5- first
Base pyrazine -2- carboxylic acid is lower than 0.10%.
(2) solubility is high.The solubility of methylpyrazine derivative semihydrate prepared by the present invention in the medium is existing
2.5 times or so of crystal form.
Detailed description of the invention
Fig. 1: the X-ray powder diffraction pattern of methylpyrazine derivative semihydrate.
Fig. 2: the hydrogen bond figure of methylpyrazine derivative semihydrate.
Fig. 3: the ORTEP figure of methylpyrazine derivative semihydrate.
Fig. 4: differential scanning calorimetric curve (DSC) figure of methylpyrazine derivative semihydrate.
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:
1.0g methylpyrazine derivative sample is suspended in 5.0ml purified water, 50 DEG C of stirring and dissolvings is heated to, obtained
Saturated solution, after being stirred to react 6 hours, decrease temperature crystalline (control cooling rate is 0.3 DEG C/min) is cooled to 5~10 DEG C, stands
It crystallization 48 hours, filters, vacuum drying 3h obtains methylpyrazine derivative hemi-hydrate crystalline, yield 97.33%, purity at 40 DEG C
99.95%, impurity I:0.03%.
Embodiment 2:
1.0g methylpyrazine derivative sample is suspended in 4.0ml solvent (purified water 2.0ml+ methanol 2.0ml), is heated
To 40 DEG C of stirring and dissolvings, supersaturated solution is obtained, after being stirred to react 10 hours, decrease temperature crystalline (control cooling rate is 0.5 DEG C/
Min), it is cooled to 0~5 DEG C, stands crystallization 48 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative half and is hydrated at 40 DEG C
Object crystal, yield 96.11%, purity 99.90%, impurity I:0.05%.
Embodiment 3:
1.0g methylpyrazine derivative sample is suspended in 8.0ml solvent (purified water 1.0ml+ tetrahydrofuran 7.5ml),
60 DEG C of stirring and dissolvings are heated to, supersaturated solution is obtained, after being stirred to react 4 hours, (control cooling rate is 0.2 to decrease temperature crystalline
DEG C/min), 10~15 DEG C are cooled to, stands crystallization 36 hours, is filtered, vacuum drying 3h obtains methylpyrazine derivative half at 40 DEG C
Hydrate crystal, yield 94.56%, purity 99.92%, impurity I:0.04%.
Embodiment 4:
1.0g methylpyrazine derivative sample is suspended in 2.0ml solvent (purified water 1.5ml+ ethyl alcohol 0.5ml), is heated
To 60 DEG C of stirring and dissolvings, supersaturated solution is obtained, after being stirred to react 8 hours, decrease temperature crystalline (control cooling rate is 0.4 DEG C/
Min), 10~15 DEG C are cooled to, stands crystallization 42 hours, is filtered, vacuum drying 3h obtains half water of methylpyrazine derivative at 40 DEG C
Solvate crystal, yield 93.25%, purity 99.90%, impurity I:0.05%.
Embodiment 5:
1.0g methylpyrazine derivative sample is suspended in 6.0ml solvent (purified water 4.0ml+ isopropanol 2.0ml), is added
Heat obtains supersaturated solution to 80 DEG C of stirring and dissolvings, after being stirred to react 3 hours, decrease temperature crystalline (control cooling rate is 1.0 DEG C/
Min), 20~25 DEG C are cooled to, stands crystallization 48 hours, is filtered, vacuum drying 3h obtains half water of methylpyrazine derivative at 40 DEG C
Solvate crystal, yield 92.88%, purity 99.85%, impurity I:0.08%.
Embodiment 6:
1.0g methylpyrazine derivative sample is suspended in 10.0ml solvent (purified water 1.0ml+ acetone 9.0ml), is added
Heat obtains supersaturated solution to 35 DEG C of stirring and dissolvings, and after being stirred to react 12 hours, (control cooling rate is 0.1 to decrease temperature crystalline
DEG C/min), it is cooled to 0~5 DEG C, stands crystallization 48 hours, is filtered, vacuum drying 3h obtains half water of methylpyrazine derivative at 40 DEG C
Solvate crystal, yield 91.81%, purity 99.80%, impurity I:0.10%.
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%.
Solubility experiment
Specific solubility test refers to Chinese Pharmacopoeia 2015.The first of embodiment 1-6 and comparative example 1-6 are weighed respectively
Base pyrazines derivatives are excessive, are placed in small cillin bottle, it is molten to be separately added into water, 0.1mol/L hydrochloric acid, the phosphate-buffered of pH7.4
Liquid is configured to methylpyrazine derivative saturated solution, shakes up dissolution, filtering, according to UV-VIS spectrophotometry (general rule
0401) absorbance is measured at the wavelength of 270nm, to calculate its solubility.
The solubility of 3 methylpyrazine derivative of table in different media
Through testing, all methylpyrazine derivative semihydrates of the present invention program preparation can reach similar solubility
Effect.Seen from table 3, solubility of the methylpyrazine derivative semihydrate of the present invention program preparation in different pH solution is equal
Higher than the crystal form of comparative example 1-6, methylpyrazine derivative crystal form prepared by the present invention is with higher molten relative to existing crystal form
Xie Xing.
Claims (10)
1. a kind of methylpyrazine derivative semihydrate, which is characterized in that be by methylpyrazine derivative and water in molar ratio 1:
0.5 combines formation, and structure is shown in formula I:
2. methylpyrazine derivative semihydrate as described in claim 1, which is characterized in that the compound crystallization uses
Cu-K α radiation, has characteristic peak at 7.8 ± 0.2 °, 9.3 ± 0.2 ° with the X-ray diffraction spectrogram that 2 θ are indicated.
3. methylpyrazine derivative semihydrate as claimed in claim 2, which is characterized in that the compound crystallization uses
Cu-K α radiation, the X-ray diffraction spectrogram indicated with 2 θ at 7.8 ± 0.2 °, 9.3 ± 0.2 °, 15.5 ± 0.2 °, 18.4 ± 0.2 °,
There is characteristic peak at 27.8 ± 0.2 °.
4. methylpyrazine derivative semihydrate as claimed in claim 3, 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.
5. methylpyrazine derivative semihydrate as described in claim 1, which is characterized in that it is in differential scanning calorimetric curve
(DSC) there are two endothermic peaks in, respectively 103.22 DEG C and 199.21 DEG C.
6. methylpyrazine derivative semihydrate as described in any one in claim 1-5, which is characterized in that its crystallographic parameter
It is: monoclinic system, space group C2/m；Cell parameter are as follows:
α=90.00 °, β=125.53 (3), γ=90.00 °, unit cell volume
7. a kind of preparation method of methylpyrazine derivative semihydrate, which is characterized in that specific preparation step includes: by methyl
Pyrazines derivatives are suspended in solvent, are dissolved by heating, are stirred to react, and cool down crystallization, and filtration drying obtains methylpyrazine derivative half
Hydrate.
8. the preparation method of methylpyrazine derivative semihydrate as claimed in claim 7, which is characterized in that solvent is selected from water
Or one of water and tetrahydrofuran, acetone, methanol, ethyl alcohol, acetonitrile and isopropanol combine, the volume content of water is in solvent
10%~100%.
9. a kind of pharmaceutical composition, it includes methylpyrazine derivative semihydrates of any of claims 1-5, and
Include other pharmaceutically acceptable auxiliary material components.
10. methylpyrazine derivative semihydrate of any of claims 1-5 is in preparation in hypolipidemic
Using.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| CN103508963A (en) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | Preparation method of acipimox |
| CN103923024A (en) * | 2014-04-25 | 2014-07-16 | 山东新时代药业有限公司 | Refining method of acipimox |
| CN105218464A (en) * | 2014-05-26 | 2016-01-06 | 四川亿明药业股份有限公司 | The synthesis technique of acipimox |
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2018
- 2018-12-30 CN CN201811648329.3A patent/CN109400539A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103508963A (en) * | 2012-06-27 | 2014-01-15 | 威海威太医药技术开发有限公司 | Preparation method of acipimox |
| CN103923024A (en) * | 2014-04-25 | 2014-07-16 | 山东新时代药业有限公司 | Refining method of acipimox |
| CN105218464A (en) * | 2014-05-26 | 2016-01-06 | 四川亿明药业股份有限公司 | The synthesis technique of acipimox |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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