CN109400540A - A kind of niacinamide methylpyrazine derivative eutectic A - Google Patents
A kind of niacinamide methylpyrazine derivative eutectic A Download PDFInfo
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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
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- 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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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/78—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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Abstract
The invention belongs to pharmaceutical technology field, specifically provide a kind of niacinamide methylpyrazine derivative eutectic A, preparation method and its preparing the purposes in hypolipidemic.The present invention is prepared niacinamide methylpyrazine derivative eutectic A and is radiated using Cu-K α, and the X-ray diffraction spectrogram indicated with 2 θ exists: having characteristic peak at 10.3 ± 0.2 °, 13.6 ± 0.2 °, 17.8 ± 0.2 °, 26.3 ± 0.2 °.Solubility is high in the medium for niacinamide methylpyrazine derivative eutectic prepared by the present invention, and preparation process is simple, has preferable prospects for commercial application.
Description
Technical field
The invention belongs to technical field of organic pharmaceutical co-crystal, in particular to a kind of niacinamide methylpyrazine derivative eutectic A.
Background technique
Pharmaceutical co-crystals are to pass through the molecular recognition of intermolecular mutual synergistic effect progress based on supramolecular chemistry principle
And Supramolecular self assembly.Active pharmaceutical ingredient (API) and suitable eutectic formation (cocrystal former, CCF) pass through
H-bonding self-assembly, or non-covalent bond (Van der Waals force of such as aromatic hydrocarbons or phenyl ring, the pi-conjugated work of π-with saturability and directionality
With with halogen key) a kind of new structure for being formed of assembling, i.e. pharmaceutical co-crystals.It neither needs to form new be total to based on hydrogen bond
Valence link, and do not need to destroy existing covalent bond, while retaining the pharmacological action of drug itself, and the object of energy modified medicaments
Physicochemical property, such as improve the stability of drug, reduce its draw it is moist, improve dissolubility, improve bioavilability, it is total for drug
Application of the crystalline substance in terms of pharmaceuticals industry provides vast potential for future development.In recent years, pharmaceutical co-crystals research was increasingly by people
Concern.At this stage, external that the research of pharmaceutical co-crystals is started gradually to increase and be goed deep into；And the country is studied it also relatively
It is few.For imitation medicine, the research of pharmaceutical co-crystals can also break patent protection of the Yuan Yan medicine company to drug crystal forms, be conducive to
Imitation medicine is introduced to the market.Therefore, obtain more has important reality meaning with novel, practical and creative pharmaceutical co-crystals
Justice, especially some water-insoluble drugs.
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.
Pharmaceutical co-crystals will affect the physicochemical property of drug, directly affect dissolution and suction of the drug under the conditions of physiological pH 7.4
It produces effects rate, and then influences the bioavilability of drug, clinical efficacy etc..By way of pharmaceutical co-crystals, it can be very good to apply
Eutectic advantage, this has very important work for the spatial arrangement and physicochemical property that understand and grasp the effective molecule of drug
With.
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 eutectic structure is less, patent US2005239803A1, CN 103508963A
Deng the preparation method for reporting Acipimox, patent US2005239803A1, CN 103508963A etc. reports Ah former times not
The preparation method of department, patent CN86103304-2 obtain the Acipimox sediment of crystal character, are Acipimox hydrate, produce
Rate is lower.In report before, less, Acipimox eutectic crystallography characterization parameter is reported for Acipimox crystal eutectic
It does not refer to.
Summary of the invention
In view of the deficiencies in the prior art, on the one hand the application provides a kind of niacinamide methylpyrazine derivative eutectic A.
Signified methylpyrazine derivative is Acipimox in the present invention, signified niacinamide methylpyrazine derivative eutectic A
It is that Jingjing type A meaning is identical together by niacinamide Acipimox eutectic A, eutectic A.
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 as indicated at a, the present invention
Selected in eutectic formation be niacinamide, molecular formula C6H6N2O, its structural formula is shown as b.
According to the first aspect of the invention, niacinamide methylpyrazine derivative eutectic crystal form A is provided.The eutectic
In, the molar ratio of methylpyrazine derivative and niacinamide is 1:1.
Preferably, the niacinamide methylpyrazine derivative eutectic crystal form A, is radiated, the X indicated with 2 θ using Cu-K α
X ray diffraction spectrogram has characteristic peak at 10.3 ± 0.2 °, 13.6 ± 0.2 °, 17.8 ± 0.2 °, 26.3 ° ± 0.2 °.
Preferably, the niacinamide methylpyrazine derivative eutectic crystal form A, is radiated, the X indicated with 2 θ using Cu-K α
X ray diffraction spectrogram at 10.3 ± 0.2 °, 13.6 ± 0.2 °, 14.9 ± 0.2 °, 17.8 ± 0.2 °, 20.5 ± 0.2 °, 26.3 ±
There is characteristic peak at 0.2 °, 28.1 ± 0.2 °.
Preferably, the niacinamide methylpyrazine derivative eutectic crystal form A, is radiated, characteristic peak meets using Cu-K α
X-ray powder diffraction pattern as shown in Figure 1.
Preferably, the niacinamide methylpyrazine derivative eutectic crystal form A, at differential scanning calorimetric curve (DSC)
In there are endothermic peak, be 195.79 DEG C.
Preferably, the niacinamide methylpyrazine derivative eutectic crystal form A, crystallographic parameter is: monoclinic system, hand
Property space group be P21/c；Cell parameter are as follows:α=
90.00 °, β=103.494 (5) °, γ=90.00 °, unit cell volume
The second aspect of the application provides the preparation method of niacinamide methylpyrazine derivative eutectic crystal form A a kind of, specifically
Preparation step includes: that methylpyrazine derivative and niacinamide are dissolved in organic solvent, is dissolved by heating, after solution clarification, cooling
Crystallization, filtration drying obtain niacinamide methylpyrazine derivative eutectic crystal form A.
The organic solvent is selected from methanol, ethyl alcohol, isopropanol, methyl formate, ethyl acetate, Ethyl formate, acetic acid first
The one or more of ester, butyl acetate.
Preferably, organic solvent is selected from one or both of methanol, ethyl acetate.
The molar ratio of the methylpyrazine derivative and niacinamide is 1:0.8~2.
Preferably, the molar ratio of methylpyrazine derivative and niacinamide is 1:1.0~1.5.
In the system mass volume ratio of methylpyrazine derivative and organic solvent be 40~200:1, wherein quality with
Mg meter, volume is in terms of ml.
The mass volume ratio of niacinamide and organic solvent is 25~320:1 in the system, and wherein quality is in terms of mg, volume
In terms of ml.
The temperature of the dissolution heating is 45~85 DEG C.
The cooling crystallization temperature is 0~30 DEG C.
Preferably, cooling crystallization temperature is 5~20 DEG C.
The crystallization time is 10~72 hours.
It is further preferred that the preparation method comprises the following steps:
Methylpyrazine derivative and niacinamide are dissolved in organic solvent, 45~85 DEG C of heating for dissolving, after solution clarification, drop
Temperature to 0~30 DEG C crystallization 10~72 hours, filter cake, dry niacinamide methylpyrazine derivative eutectic crystal form A are washed in filtering.
The solvent of the washing filter cake is selected from one of methanol, ethyl alcohol and ethyl acetate.
The drying temperature is 50~80 DEG C, and drying time is 8~12 hours.
The present invention also provides another preparation methods of niacinamide methylpyrazine derivative crystal form A, specifically include as follows
Step:
After mixing by methylpyrazine derivative and niacinamide, organic solvent is added dropwise, starts to grind, grinding finishes, and does
It is dry to obtain niacinamide methylpyrazine derivative eutectic crystal form A.
Preferably, the organic solvent be selected from one of methanol, ethyl alcohol, the tert-butyl alcohol, methyl formate and ethyl acetate or
It is several.
Preferably, the molar ratio of the methylpyrazine derivative and niacinamide is 1:1~1.5.
Preferably, the mass volume ratio of the methylpyrazine derivative and solvent is 2~8:1, wherein quality is in terms of g, body
Product is in terms of ml.
Preferably, the mass volume ratio of the niacinamide and solvent is 2~12:1, wherein quality is in terms of g, and volume is with ml
Meter.
Preferably, milling time is 5~30min.
The third aspect of the application provides a kind of pharmaceutical composition, and the composition contains niacinamide methyl pyrrole of the present invention
Oxazine derivatives eutectic crystal form A, 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 application provides a kind of niacinamide methylpyrazine derivative eutectic crystal form A and prepares as active constituent
Treat the application in hypolipidemic.
The confirmation of crystal structure
X-ray crystal data is collected on Rigaku XtaLAB Synergy model instrument, test temperature 293 (2) K,
It is radiated, is gone forward side by side with ω scanning mode collection data, row Lp correction with CuKa.With direct method analytic structure, difference Fourier method is looked for
Whole non-hydrogen atoms out, the hydrogen atom on all carbon and nitrogen are obtained using theoretical plus hydrogen, are carried out using least square method to structure
Refine.
The crystallographic data for testing and parsing niacinamide methylpyrazine derivative eutectic crystal form A prepared by the present invention is (table
1): its crystallographic parameter: monoclinic, chiral space group: P21/c；Cell parameter are as follows: α=90.00 °, β=103.494 (5) °, γ=
90.00 °, unit cell volumeMolecular formula is: C12H12N4O4, molecular weight is: 276.26.Nicotinoyl of the invention
The ORTEP chart of amine methylpyrazine derivative eutectic crystal form A is bright, and a molecule methylpyrazine derivative and one point are contained in the eutectic
Sub- niacinamide solvent is not present in eutectic, as shown in Fig. 2.Niacinamide methylpyrazine derivative eutectic crystal form A's of the invention
Hydrogen bond figure, as shown in Fig. 3.
1 niacinamide methylpyrazine derivative eutectic crystal form A predominant crystal data of table
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 niacinamide methylpyrazine derivative eutectic crystal form A of table
Prepared all samples crystallographic parameter all having the same and X-ray powder diffraction spectrogram in embodiment.
The niacinamide methylpyrazine derivative eutectic crystal form A of the method for the invention preparation, differential scanning calorimetric curve
(DSC) result is nicotinoyl as shown in figure 4,210.47 ± 1 DEG C of only one endothermic peak in differential scanning calorimetric curve (DSC)
The fusing point of amine methylpyrazine derivative eutectic crystal form A；Its thermogravimetric analysis (TGA) only exists a weightless step, shows the nicotinoyl
Solvent, and stable structure is not present in amine methylpyrazine derivative eutectic crystal form A.The niacinamide methylpyrazine derivative eutectic is brilliant
TGA/DSC map type A as shown in Figure 4.
The niacinamide methylpyrazine derivative eutectic crystal form A of the method for the invention preparation is relative to the methyl reported at present
The solubility of pyrazines derivatives crystal form is good.The solubility of niacinamide methylpyrazine derivative eutectic crystal form A is existing crystal form dissolution
2 times or so of degree, the solubility of niacinamide methylpyrazine derivative eutectic crystal form A in different media is above existing crystal form
Solubility.
Detailed description of the invention
Fig. 1: the PXRD map of niacinamide methylpyrazine derivative eutectic crystal form A.
Fig. 2: niacinamide methylpyrazine derivative eutectic crystal form A ORTEP figure.
Fig. 3: the hydrogen bond figure of niacinamide methylpyrazine derivative eutectic crystal form A.
Fig. 4: niacinamide methylpyrazine derivative eutectic crystal form A TGA/DSC figure.
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:
5.0g (32.4mmol) methylpyrazine derivative and 4.0g (32.4mmol) niacinamide are dissolved in 50ml methanol, added
Heat after solution clarification, is cooled to 20 DEG C, static crystallization 52 hours filters, and filter cake is eluted with methanol, and 60 DEG C true to 60 DEG C of dissolutions
The dry 10h of sky, obtains niacinamide methylpyrazine derivative eutectic crystal form A 8.5g, yield 95.80%, HPLC:99.95%, impurity
I:0.03%.
Embodiment 2:
5.0g (32.4mmol) methylpyrazine derivative and 6.0g (48.6mmol) niacinamide are dissolved in 50ml ethyl acetate
In, 77 DEG C of dissolutions are heated to, after solution clarification, are cooled to 15 DEG C, static crystallization 48 hours filters, and filter cake is drenched with ethyl acetate
It washes, 65 DEG C of vacuum drying 9h, obtains niacinamide methylpyrazine derivative eutectic crystal form A 8.7g, yield 97.20%, HPLC:
99.92%, impurity I:0.05%.
Embodiment 3:
10.0g (64.8mmol) methylpyrazine derivative and 9.6g (77.8mmol) niacinamide are dissolved in 50ml methanol,
65 DEG C of dissolutions are heated to, after solution clarification, are cooled to 10 DEG C, static crystallization 36 hours filters, and filter cake is eluted with methanol, and 50 DEG C
It is dried in vacuo 12h, obtains niacinamide methylpyrazine derivative eutectic crystal form A 17.1g, yield 95.70%, HPLC:99.90% is miscellaneous
Matter I:0.07%.
Embodiment 4:
2.0g (13.0mmol) methylpyrazine derivative and 3.2g niacinamide (26.0mmol) are dissolved in 50ml ethyl alcohol, added
Heat after solution clarification, is cooled to 0 DEG C, static crystallization 24 hours filters, and filter cake is eluted with methanol, 70 DEG C of vacuum to 70 DEG C of dissolutions
Dry 8h, dry niacinamide methylpyrazine derivative eutectic crystal form A 3.4g, yield 93.20%, HPLC:99.87%, impurity
I:0.09%.
Embodiment 5:
8.0g (51.9mmol) methylpyrazine derivative and 4.0g niacinamide (41.5mmol) are dissolved in 50ml isopropanol,
80 DEG C of dissolutions are heated to, after solution clarification, are cooled to 30 DEG C, static crystallization 48 hours filters, filter cake ethanol rinse, 80 DEG C
It is dried in vacuo 12h, obtains niacinamide methylpyrazine derivative eutectic crystal form A 10.7g, yield 93.3%, HPLC:99.85% is miscellaneous
Matter I:0.10%.
Embodiment 6:
5.0g (32.4mmol) methylpyrazine derivative and 6.0g niacinamide (48.6mmol) are dissolved in 50ml Ethyl formate
In, 45 DEG C of dissolutions are heated to, after solution clarification, are cooled to -5 DEG C, static crystallization 12 hours filters, and filter cake is drenched with ethyl acetate
It washes, 60 DEG C of vacuum drying 12h, dry niacinamide methylpyrazine derivative eutectic crystal form A 8.2g, yield 91.3%, HPLC:
99.83%, impurity I:0.10%.
Embodiment 7:
5.0g (32.4mmol) methylpyrazine derivative and 6.0g niacinamide (48.6mmol) are dissolved in 20ml methyl acetate
In, 55 DEG C of dissolutions are heated to, after solution clarification, are cooled to 35 DEG C, static crystallization 8 hours filters, and filter cake is drenched with ethyl acetate
It washes, 85 DEG C of vacuum drying 7h, dry niacinamide methylpyrazine derivative eutectic crystal form A 8.0g, yield 90.0%, HPLC:
99.81%, impurity I:0.11%.
Embodiment 8:
After mixing by 5.0g (32.4mmol) methylpyrazine derivative and 4.0g niacinamide (32.4mmol), it is added dropwise
1ml methanol starts to grind 5min, finish, and filter cake is eluted with methanol, 60 DEG C of vacuum drying 12h, and it is derivative to obtain niacinamide methylpyrazine
Object eutectic crystal form A8.6g, yield 94.7%, HPLC:99.80%, impurity I:0.11%.
Embodiment 9:
5.0g (32.4mmol) methylpyrazine derivative and 6.0g niacinamide (48.6mmol) are added in ball mill, stirring
After uniformly, 1.5ml Ethyl formate is added dropwise, starts to grind 5min, finish, filter cake is eluted with methanol, and 70 DEG C of vacuum drying 10h are obtained
Niacinamide methylpyrazine derivative eutectic crystal form A8.8g, yield 97.0%, HPLC:99.78%, impurity I:0.12%.
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%.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 dissolubility test refers to Chinese Pharmacopoeia 2015.Precision weighs embodiment 1-9 and comparative example 1-6 respectively
Methylpyrazine derivative crystal it is excessive, be placed in small cillin bottle, be 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 solubility of 3 methylpyrazine derivative crystal form of table in different media
Through testing, all niacinamide methylpyrazine derivative eutectics of the present invention program preparation can reach similar dissolution
Spend effect.By solubility test result it is found that the niacinamide methylpyrazine derivative eutectic crystal form A of the present invention program preparation is not
The crystal form of comparative example 1 to comparative example 6, methylpyrazine derivative crystal form prepared by the present invention are above with the solubility in pH solution
Relative to existing crystal form, dissolubility with higher.
Claims (10)
1. a kind of niacinamide methylpyrazine derivative eutectic A, which is characterized in that massaged by methylpyrazine derivative and niacinamide
You combine than 1:1 and are formed, and are radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ exists: 10.3 ± 0.2 °, 13.6 ±
There is characteristic peak at 0.2 °, 17.8 ± 0.2 °, 26.3 ± 0.2 °.
2. niacinamide methylpyrazine derivative eutectic A as described in claim 1, which is characterized in that radiated using Cu-K α, with 2
θ indicate X-ray diffraction spectrogram at 10.3 ± 0.2 °, 13.6 ± 0.2 °, 14.9 ± 0.2 °, 17.8 ± 0.2 °, 20.5 ± 0.2 °,
There is characteristic peak at 26.3 ± 0.2 °, 28.1 ± 0.2 °.
3. niacinamide methylpyrazine derivative eutectic A as claimed in claim 2, which is characterized in that it is radiated using Cu-K α,
Characteristic peak meets X-ray powder diffraction pattern as shown in Figure 1.
4. niacinamide methylpyrazine derivative eutectic A as described in claim 1, which is characterized in that it is in differential scanning calorimetry
There are endothermic peaks in curve (DSC), are 195.79 DEG C.
5. niacinamide methylpyrazine derivative eutectic A according to any one of claims 1-4, which is characterized in that its crystallography
Parameter is: monoclinic system, chiral space group P21/c；Cell parameter are as follows: α=90.00 °, β=103.494 (5) °, γ=90.00 °, unit cell volume
6. a kind of preparation method of niacinamide methylpyrazine derivative eutectic A, which is characterized in that specific preparation step includes: first
Base pyrazines derivatives and niacinamide are dissolved in organic solvent, are dissolved by heating, and after solution clarification, cool down crystallization, and filtration drying obtains cigarette
Amide methylpyrazine derivative eutectic A.
7. the preparation method of niacinamide methylpyrazine derivative eutectic A as claimed in claim 6, which is characterized in that methyl pyrrole
The molar ratio of oxazine derivatives and niacinamide is 1:0.8~2, preferably 1:1.0~1.5.
8. a kind of preparation method of niacinamide methylpyrazine derivative eutectic A, which is characterized in that specific preparation step include: by
Methylpyrazine derivative and niacinamide after mixing, are added dropwise organic solvent, start to grind, and grinding finishes, dry niacinamide
Methylpyrazine derivative eutectic A.
9. a kind of pharmaceutical composition, it includes niacinamide methylpyrazine derivative eutectics of any of claims 1-4
A, and include other pharmaceutically acceptable auxiliary material components.
10. niacinamide methylpyrazine derivative eutectic A of any of claims 1-4 is in preparation in hypolipidemic
Application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112110865A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Isonicotinamide acipimox cocrystal II and preparation method thereof |
| CN113121456A (en) * | 2020-01-15 | 2021-07-16 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| WO2021203572A1 (en) * | 2020-04-08 | 2021-10-14 | 山东新时代药业有限公司 | 1,2-bis(4-pyridyl)ethane-acipimox co-crystal |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103923024A (en) * | 2014-04-25 | 2014-07-16 | 山东新时代药业有限公司 | Refining method of acipimox |
| CN108440405A (en) * | 2018-03-29 | 2018-08-24 | 东华理工大学 | A kind of the eutectic product and method for crystallising of niacinamide and benzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103923024A (en) * | 2014-04-25 | 2014-07-16 | 山东新时代药业有限公司 | Refining method of acipimox |
| CN108440405A (en) * | 2018-03-29 | 2018-08-24 | 东华理工大学 | A kind of the eutectic product and method for crystallising of niacinamide and benzoic acid |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112110865A (en) * | 2019-06-20 | 2020-12-22 | 鲁南制药集团股份有限公司 | Isonicotinamide acipimox cocrystal II and preparation method thereof |
| CN112110865B (en) * | 2019-06-20 | 2023-02-24 | 鲁南制药集团股份有限公司 | Isonicotinamide acipimox cocrystal II and preparation method thereof |
| 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 |
| WO2021203572A1 (en) * | 2020-04-08 | 2021-10-14 | 山东新时代药业有限公司 | 1,2-bis(4-pyridyl)ethane-acipimox co-crystal |
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