CN109369546A - A kind of methylpyrazine derivative theophylline semihydrate - Google Patents
A kind of methylpyrazine derivative theophylline semihydrate 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
- 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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- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
The invention belongs to pharmaceutical technology field, specifically provide a kind of methylpyrazine derivative theophylline semihydrate, preparation method and its preparing the purposes in hypolipidemic.Methylpyrazine derivative theophylline semihydrate prepared by the present invention is radiated using Cu-K α, and the X-ray diffraction spectrogram indicated with 2 θ exists: having characteristic peak at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 26.9 ± 0.2 °.Methylpyrazine derivative theophylline semihydrate stability prepared by the present invention is high, dissolved state and solid state are placed purity and are basically unchanged, its solubility in different media is 2.5 times of existing crystal form, and bioavilability with higher, 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 methylpyrazine derivative theophylline half is hydrated
Object.
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 form eutectic structure is less, 103508963 A of patent US2005239803A1, CN
Deng the preparation method for reporting Acipimox, patent CN86103304-2 obtains the Acipimox sediment of crystal character, is
It is hydrated Acipimox, yield is lower.Less for Acipimox crystal eutectic report in report before, Acipimox is total
Brilliant crystallography characterization parameter does not refer to.
Summary of the invention
In view of the deficiencies in the prior art, the one side of the application provides a kind of half hydration of methylpyrazine derivative theophylline
Object.
Signified methylpyrazine derivative theophylline semihydrate is Acipimox theophylline semihydrate, methyl pyrrole in the application
Oxazine derivatives are Acipimoxs.
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, the present invention
Selected in eutectic formation be theophylline, molecular formula C7H8N4O2, its structural formula is shown as b.
According to the first aspect of the invention, methylpyrazine derivative theophylline semihydrate crystal form is provided.In the crystal,
Methylpyrazine derivative: theophylline: the molar ratio of water is 1:1:0.5.
The methylpyrazine derivative theophylline semihydrate crystal form, is radiated using Cu-K α, is spread out with the X-ray that 2 θ are indicated
Penetrating spectrogram has characteristic peak at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 26.9 ± 0.2 °.
Preferably, the methylpyrazine derivative theophylline semihydrate crystal form, is radiated, the X indicated with 2 θ using Cu-K α
X ray diffraction spectrogram at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 20.4 ± 0.2 °, 25.8 ± 0.2 °, 26.9 ±
There is characteristic peak at 0.2 °, 29.2 ± 0.2 °, 32.3 ± 0.2 °.
Preferably, the methylpyrazine derivative theophylline semihydrate crystal form, is radiated using Cu-K α, characteristic peak symbol
Close X-ray powder diffraction pattern as shown in Figure 1.
Preferably, the methylpyrazine derivative theophylline semihydrate crystal form, in differential scanning calorimetric curve (DSC)
There are two endothermic peak, respectively 76.92 DEG C, 220.99 DEG C.
Preferably, the methylpyrazine derivative theophylline semihydrate crystal form, crystallographic parameter is: monoclinic system,
Space group is C2/c；Cell parameter are as follows:α=
90.00 °, β=105.926 (2) °, γ=90.00 °, unit cell volume
The second aspect of the application provides a kind of preparation method of methylpyrazine derivative theophylline semihydrate crystal form, specifically
Preparation step includes: that methylpyrazine derivative and theophylline are added in the mixed solution of organic solvent and water, is dissolved by heating, stirring
Reaction, cool down crystallization, and filtration drying obtains methylpyrazine derivative theophylline semihydrate.
The organic solvent is selected from one of acetonitrile, acetone, tetrahydrofuran, methanol, ethyl alcohol, isopropanol and tert-butyl alcohol
Or it is several.
It is further preferred that organic solvent is selected from one or more of acetonitrile, acetone and tetrahydrofuran.
The molar ratio of the methylpyrazine derivative and theophylline is 1:1.5~2.5.
Preferably, the molar ratio of methylpyrazine derivative and theophylline is 1:1.8~2.2.
The mass volume ratio of methylpyrazine derivative and organic solvent is 3~9:1 in the system, and wherein quality is with mg
Meter, volume is in terms of ml.
Preferably, the mass volume ratio of methylpyrazine derivative and organic solvent is 5~7:1, and wherein quality is in terms of mg, body
Product is in terms of ml.
The mass volume ratio of methylpyrazine derivative and water is 10~55:1 in the system, and wherein quality is in terms of mg, body
Product is in terms of ml.
Preferably, the mass volume ratio of methylpyrazine derivative and water be 25~50:1, wherein quality in terms of mg, volume with
Ml meter.
The temperature of the dissolution heating is 45~75 DEG C.
The cooling crystallization temperature is 0~15 DEG C.
The crystallization time is 40~62 hours.
The preparation method of crystal form of the present invention is described in detail in the following contents:
Methylpyrazine derivative and theophylline are added in organic solvent and the mixed solution of purified water, 45~75 DEG C of heating are molten
Solution, is stirred to react 8~14 hours, is cooled to 0~15 DEG C of crystallization 40~62 hours, filters, and washs filter cake, dry methylpyrazine
Derivative theophylline semihydrate.
The solvent of the washing filter cake is selected from one of acetonitrile, methanol, ethyl alcohol and ethyl acetate.
Preferably, cooling crystallization temperature is 5~10 DEG C.
The drying temperature is 50~70 DEG C, and drying time is 8~12 hours.
The third aspect of the application provides a kind of pharmaceutical composition, and the composition is derivative containing methylpyrazine of the present invention
Object theophylline hemi-hydrate crystalline, 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 methylpyrazine derivative theophylline hemi-hydrate crystalline as active constituent system
Application in standby treatment 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 with CuKa, data are collected with ω scanning mode and carries out Lp correction.ShelXT program of the crystal structure in olex2 software
It is calculated, and atomic species by least square refinement structural parameters and is differentiated using ShelXL program, use geometry meter
Algorithm and difference Fourier method obtain whole hydrogen atoms position, and the goodness of fit (GooF value) 1.057 close to 1.0, shows to weigh
Double recipe case is suitable, structure is accurate.
Testing and parse crystallographic data obtained by methylpyrazine derivative theophylline solvate crystal prepared by the present invention is (table 1):
Its crystallographic parameter is: monoclinic system, space group C2/c；Cell parameter are as follows: α=90.00 °, β=105.926 (2) °, γ=90.00 °, unit cell volumePoint
Minor is: [C6H6N2O3·C7H8N4O2·0.5H2O], molecular weight is: 343.31.Methylpyrazine derivative theophylline of the invention half
The ORTEP chart of hydrate crystal is bright, and methylpyrazine derivative and theophylline are linked together by intramolecular hydrogen bond, wherein methyl
The carboxyl H3 of pyrazines derivatives and the N3 on theophylline form hydrogen bond, and the H6A of O5 and hydrone on theophylline form intramolecular hydrogen bond,
The hydrone is located on symmetry axis, is two eutectic units shareds, therefore there are the water of 0.5 molecule for crystal, as shown in Fig. 3.
The hydrogen bond figure of methylpyrazine derivative theophylline semihydrate of the invention, as shown in Fig. 2.
1 methylpyrazine derivative theophylline semihydrate crystal form predominant crystal data 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 crystallographic data, characteristic peak is detailed in attached drawing 1 and table 2 in corresponding X-ray powder diffraction figure (Cu-K α).
The peak PXRD of 2 methylpyrazine derivative theophylline semihydrate crystal form 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: 30~300 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 of the method for the invention preparation, DSC
There are two endothermic peaks for testing result, and respectively corresponding temperature is 76.92 DEG C and 220.99 DEG C.It can be seen that according to TGA testing result
There are two weightless steps to show calculation shows that theophylline eutectic is not semihydrate to the Ah former times in conjunction with DSC/TGA testing result
Crystal form prepared by the present invention is methylpyrazine derivative theophylline semihydrate crystal form.
The methylpyrazine derivative theophylline semihydrate crystal form of herein described method preparation is relative to the first reported at present
Base pyrazines derivatives crystal form has the advantage that
(1) stability is high.Methylpyrazine derivative theophylline semihydrate is either equal in solid state or dissolved state
Stability with higher.When in solution state, with the extension of dissolution time, impurity 5-Methylpyrazine-2-carboxylic acid contains
Amount is lower than 0.15%, and total impurities content is lower than 0.25%.When in solid state, by illumination, high temperature, high humidity test, HPLC
Purity is still higher than 99.2%, higher than the purity of existing crystal form.
(2) solubility is good.The solubility of methylpyrazine derivative theophylline semihydrate is 2.5 times of existing crystal form solubility
Left and right, the solubility of methylpyrazine derivative theophylline semihydrate in different media are above the solubility of existing crystal form.
(3) bioavilability is high.Rats with Fatty Liver serum can be effectively reduced in methylpyrazine derivative theophylline semihydrate
In cholesterol, triglycerides, low-density lipoprotein concentration.
Detailed description of the invention
Fig. 1: the PXRD figure of methylpyrazine derivative theophylline semihydrate crystal form.
Fig. 2: the hydrogen bond figure of methylpyrazine derivative theophylline semihydrate crystal form.
Fig. 3: the ORTEP figure of methylpyrazine derivative theophylline semihydrate crystal form.
Fig. 4: the TGA/DSC figure of methylpyrazine derivative theophylline semihydrate crystal form.
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:
It is molten that 61.6mg (0.4mmol) methylpyrazine derivative and 144.0mg (0.8mmol) theophylline are added to 12ml mixing
It in agent (10ml acetonitrile+2ml purified water), is heated to 60 DEG C and is stirred to react 10 hours, for slow cooling to after 5~10 DEG C, temperature control is quiet
It sets crystallization 48 hours, filters, elute filter cake with acetonitrile, be dried in vacuo 10h at 50 DEG C, obtain methylpyrazine derivative theophylline half and be hydrated
Object, yield 96.45%, purity 99.95%, impurity I:0.03%.
Embodiment 2:
61.6mg (0.4mmol) methylpyrazine derivative and 129.6mg (0.72mmol) theophylline are added to 15ml to mix
It in solvent (12.5ml acetone+2.5ml purified water), is heated to 50 DEG C and is stirred to react 12 hours, slow cooling is to after 0~5 DEG C, control
Temperature stands crystallization 40 hours, filtering, with ethanol rinse filter cake, is dried in vacuo 8h at 60 DEG C, obtains methylpyrazine derivative theophylline half
Hydrate, yield 95.21%, purity 99.92%, impurity I:0.04%.
Embodiment 3:
61.6mg (0.4mmol) methylpyrazine derivative and 158.4mg (0.88mmol) theophylline are added to 10ml to mix
In solvent (8.8ml tetrahydrofuran+1.2ml purified water), it is heated to 70 DEG C and is stirred to react 8 hours, slow cooling is to 10~15 DEG C
Afterwards, temperature control stands crystallization 60 hours, filtering, elutes filter cake with ethyl acetate, is dried in vacuo 12h at 55 DEG C, obtains methylpyrazine and spread out
Biological theophylline semihydrate, yield 94.36%, purity 99.90%, impurity I:0.06%.
Embodiment 4:
It is molten that 61.6mg (0.4mmol) methylpyrazine derivative and 108.0mg (0.6mmol) theophylline are added to 13ml mixing
In agent (6.8ml ethyl alcohol+6.2ml purified water), it is heated to 45 DEG C and is stirred to react 14 hours, after extremely -5~0 DEG C of slow cooling, temperature control
Crystallization 35 hours are stood, filtering elutes filter cake with acetonitrile, is dried in vacuo 15h at 45 DEG C, obtains half water of methylpyrazine derivative theophylline
Close object, yield 93.15%, purity 99.87%, impurity I:0.07%.
Embodiment 5:
61.6mg (0.4mmol) methylpyrazine derivative and 154.1mg (1.0mmol) theophylline are added to 21.6ml to mix
In solvent (20.5ml acetonitrile+1.1ml purified water), be heated to 75 DEG C and be stirred to react 8 hours, slow cooling to after 15~20 DEG C,
Temperature control stands crystallization 60 hours, filtering, elutes filter cake with methanol, is dried in vacuo 6h at 70 DEG C, obtains methylpyrazine derivative theophylline
Semihydrate, yield 92.61%, purity 99.85%, impurity I:0.09%.
Embodiment 6:
It is molten that 61.6mg (0.4mmol) methylpyrazine derivative and 86.5mg (0.48mmol) theophylline are added to 32ml mixing
In agent (31ml isopropanol+1ml purified water), it is heated to 40 DEG C and is stirred to react 16 hours, after extremely -10~-5 DEG C of slow cooling, control
Temperature stands crystallization 50 hours, filtering, with ethanol rinse filter cake, is dried in vacuo 10h at 50 DEG C, obtains methylpyrazine derivative theophylline half
Hydrate, yield 92.26%, purity 99.83%, impurity I:0.11%.
Embodiment 7:
It is molten that 61.6mg (0.4mmol) methylpyrazine derivative and 216.2mg (1.2mmol) theophylline are added to 13ml mixing
It in agent (5.0ml acetonitrile+8ml purified water), is heated to 80 DEG C and is stirred to react 6 hours, for slow cooling to after 5~10 DEG C, temperature control is quiet
It sets crystallization 48 hours, filters, be dried in vacuo 10h at 45 DEG C, obtain methylpyrazine derivative theophylline semihydrate, yield 92.13%,
Purity 99.80%, 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 4.68g of hydrate form (2.83%), be equivalent to 4.54g without aquatic products.Yield is
73%.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 3.02g 2- carboxyl -5- methylpyrazine -4-
Monohydrate (the experiment value H of oxide2O-11.35%；The calculated value H of monohydrate product2O-11.3%), yield 63%.
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, study on the stability of the methylpyrazine derivative theophylline semihydrate in solution state
The methylpyrazine derivative sample that Example 1-7 and comparative example 1-6 are prepared is dissolved in the water, by methyl pyrrole
Oxazine derivatives solution is placed in 25 DEG C of environment, investigates stability of the methylpyrazine derivative crystal form under solution state, often
Every the content of two hours sampling and testings wherein impurity, test result is shown in Table 3.
Stability test result of the 3 methylpyrazine derivative crystal form of table under solution state
Through test it is found that the present invention program preparation all methylpyrazine derivative theophylline semihydrates can reach it is close
Stabilizing effect.Existing methylpyrazine derivative crystal form its impurity I (5-Methylpyrazine-2-carboxylic acid) and total as known to table 3
Miscellaneous content is high, and impurity I content and the content of total impurities all increase with the extension of dissolution time.It is learnt through test, this hair
The methylpyrazine derivative theophylline semihydrate of bright preparation, the content and total impurities content of sample purity and impurity I do not occur
It substantially change；And 1 crystal form of comparative example to 6 crystal form of comparative example under identical condition, the content of impurity I and the content of total impurities
Constantly increasing, it can be seen that, compared to existing methylpyrazine derivative crystal form, methylpyrazine prepared by the present invention is derivative
Object theophylline semihydrate has preferable stability under solution state.
2, 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 4.
Stability test result of the 4 methylpyrazine derivative crystal form of table under illumination, high temperature and super-humid conditions
It is learnt through test, all methylpyrazine derivative theophylline semihydrates of the present invention program preparation can reach close
Stabilizing effect.By table 4 as it can be seen that the methylpyrazine derivative theophylline semihydrate that is prepared of the present invention is in illumination, high temperature
And obvious variation do not occur for its purity, appearance under conditions of high humidity, and comparative example 1 to 6 crystal form of comparative example identical
Experiment condition under its purity be greatly reduced, impurity content has obvious raising, that is, rotten situation occurs, it is seen that
Methylpyrazine derivative theophylline semihydrate prepared by the present invention has preferable chemical stability compared to existing crystal form.
2, solubility experiment
Specific dissolubility test refers to Chinese Pharmacopoeia 2015.Accurate embodiment 1-7 and the comparative example of weighing respectively
Methylpyrazine derivative crystal is excessive, is placed in small cillin bottle, and it is slow to be separately added into water, 0.1mol/L hydrochloric acid, the phosphate of pH7.4
Solution is rushed, methylpyrazine derivative saturated solution is configured to, shakes up dissolution, is filtered, according to UV-VIS spectrophotometry (general rule
0401) absorbance is measured at the wavelength of 270nm, to calculate its solubility.
The solubility of 5 methylpyrazine derivative crystal form of table in different media
It is learnt through test, all methylpyrazine derivative theophylline semihydrates of the present invention program preparation can reach close
Dissolubility effect.By table 5 as it can be seen that the methylpyrazine derivative theophylline semihydrate of the present invention program preparation is in different pH solution
In solubility be above the crystal form of comparative example 1 to comparative example 6, methylpyrazine derivative crystal form prepared by the present invention is relative to existing
There are crystal form, dissolubility with higher.
Bioavilability experiment: experiment of the methylpyrazine derivative theophylline semihydrate to Rats with Fatty Liver therapeutic effect
(1) material
1. drug
I, Acipimox Capsules (pleasure knows apple), product batch number: Z210A.
II, methylpyrazine derivative theophylline semihydrate
2. reagent: total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein level
White cholesterol (HDL-C), alanine aminotransferase (ALT), aspartic transaminase (AST), alkaline phosphatase (ALP) and blood
Sugared kit.Liver superoxide dismutase (SOD) and malonaldehyde (MDA) kit.
3. instrument: 2400 type full-automation Biochemical Analyzer of ADVIA, Axioskop-plus type optical microscopy, tissue
Embedding machine, Automation-tissue-dehydrating machine, paraffin slicing machine, Pathologic image analysis system etc..
(2) animal
Male Wistar rat after adaptive feeding 1 week, is randomly divided into Normal group, model group, pleasure and knows apple group and first
Base pyrazines derivatives theophylline semihydrate group, every group 5.Every group of rat freely takes the photograph water, and Normal group gives basal feed,
Remaining 3 groups are given high lipid food (containing 88.8% basal feed, 10% lard, 1% cholesterol, 0.2% methylthiouracil), even
Continuous feeding 5 weeks.From testing for the 6th weekend, each group rat is still fed such as preceding method, Normal group and model group physiological saline
1mL stomach-filling；Pleasure knows that apple group and methylpyrazine derivative theophylline semihydrate group give methylpyrazine derivative 0.06/ (kgd)
Stomach-filling 1mL.The equal continuous gavage of 4 groups of rats 4 weeks, puts to death for 24 hours after last stomach-filling, takes blood to take liver and carries out corresponding index detection.
(3) it detects
Observe mental status, measurement Triglycerides in Serum (TG) of rat, cholesterol (TC), low-density lipoprotein
(LDL-C), high-density lipoprotein cholesterol (HDL-C) is horizontal, observes different groups of hepatic tissue sections variations.
(4) result
Rat mental status: high lipid food feeds appetite rat early period and is greater than Normal group, and weight increases comparatively fast, after
Phase appetite reduces, and activity is reduced.Happy rat appetite, the activity for knowing apple group and methylpyrazine derivative theophylline semihydrate group
It is significantly better than that control group.Methylpyrazine derivative theophylline semihydrate group rat weight is obviously lighter than control group.
Hepatic tissue section situation of change: taking hepatic tissue to visually observe after putting to death rat, finds Normal group hepatic tissue color
It is damp normal, it is in kermesinus, section is without greasy feeling；Model group rats liver is loose, surface is turned to be yellow, and section is greasy.It is happy know apple group and
Methylpyrazine derivative theophylline semihydrate group hepatic tissue is slightly biased big, and most of color is dark red, close to Normal appearances.
Each group serum lipids compare: compared with model group, pleasure knows apple group and methylpyrazine derivative theophylline semihydrate group
TG, TC, LDL-C, level are decreased obviously.It the results are shown in Table 6.
The comparison of 6 each group serum lipids of table
This result of study display, methylpyrazine derivative theophylline semihydrate can reduce Rats with Fatty Liver serum TC, TG and
LDL-C is horizontal, removes liver cell inner part lipid accumulation；Show that Histopathologic changes are obviously improved under mirror, methylpyrazine spreads out
Biological theophylline semihydrate group liver tissues of rats only has a small amount of fat drips accumulation, Minimal fatty denaturation, and liver cell form tends to be normal
Cells show, methylpyrazine derivative theophylline semihydrate group have preferable therapeutic effect to Rats with Fatty Liver.
Claims (10)
1. a kind of methylpyrazine derivative theophylline semihydrate, which is characterized in that be by methylpyrazine derivative: theophylline: water is pressed
Molar ratio 1:1:0.5 is combined and is formed.
2. methylpyrazine derivative theophylline semihydrate as described in claim 1, which is characterized in that it is radiated using Cu-K α, with
The X-ray diffraction spectrogram that 2 θ are indicated exists: having characteristic peak at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 26.9 ± 0.2 °.
3. methylpyrazine derivative theophylline semihydrate as claimed in claim 2, which is characterized in that it is radiated using Cu-K α, with
2 θ indicate X-ray diffraction spectrogram at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 20.4 ± 0.2 °, 25.8 ± 0.2 °,
There is characteristic peak at 26.9 ± 0.2 °, 29.2 ± 0.2 °, 32.3 ± 0.2 °.
4. methylpyrazine derivative theophylline semihydrate as claimed in claim 3, 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.
5. methylpyrazine derivative theophylline semihydrate as described in claim 1, which is characterized in that it is in differential scanning calorimetry
There are two endothermic peaks, respectively 76.92 DEG C, 220.99 DEG C in curve (DSC).
6. methylpyrazine derivative theophylline semihydrate as described in any one in claim 1-5, which is characterized in that its crystallography
Parameter is: monoclinic system, space group C2/c；Cell parameter are as follows: α=90.00 °, β=105.926 (2) °, γ=90.00 °, unit cell volume
7. a kind of preparation method of methylpyrazine derivative theophylline semihydrate, which is characterized in that specific preparation step include: by
Methylpyrazine derivative and theophylline are added in the mixed solution of organic solvent and water, dissolve by heating, are stirred to react, and cool down crystallization,
Filtration drying obtains methylpyrazine derivative theophylline semihydrate.
8. the preparation method of methylpyrazine derivative theophylline semihydrate as claimed in claim 7, which is characterized in that You Jirong
Agent is selected from one or more of acetonitrile, acetone, tetrahydrofuran, methanol, ethyl alcohol, isopropanol and tert-butyl alcohol, preferably acetonitrile, third
One or more of ketone and tetrahydrofuran；The molar ratio of methylpyrazine derivative and theophylline is 1:1.5~2.5.
9. a kind of pharmaceutical composition, it includes methylpyrazine derivative theophylline of any of claims 1-5 half to be hydrated
Object, and include other pharmaceutically acceptable auxiliary material components.
10. methylpyrazine derivative theophylline semihydrate of any of claims 1-5 is used for hypolipidemic in preparation
In application.
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| 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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| 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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