CN102690236B - Four types of sulfuric acid nepresol organic drug eutectics and preparation method thereof - Google Patents
Four types of sulfuric acid nepresol organic drug eutectics and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic drug eutectics, in particular to four types of sulfuric acid nepresol organic drug eutectics and a preparation method thereof. According to the invention, the method comprises the following steps that API (Active Pharmaceutical Ingredient) sulfuric acid nepresol is adopted to serve as the API, 2,3-dihydroxy-benzoic acid, 2,4-dihydroxy-benzoic acid, 2,5-dihydroxy-benzoic acid, and 2,6-dihydroxy-benzoic acid are adopted to serve as precursors, the ethanol and tetrahydrofuran serve as solvent, and a solvent evaporation method is adopted. According to the invention, as the organic solvent which has a low boiling point, is adopted, crystals can be separated out during the solvent evaporation, so as to obtain the four organic drug eutectics with novel structures. The organic drug eutectics prepared by the invention not only cures cardiovascular disease by a traditional API, but also has dramatic improvement in solubility, stability and bioavailability.
Description
Technical field
The invention belongs to organic drug eutectic technical field, be specifically related to four kinds of Dihydrallazinie sulphate organic drug eutectics and preparation method thereof.
Background technology
1894, the thought of German E.Fischer based on " intermolecular selectivity effect " proposed " lock-key " model, is the blank of modern supramolecule scientific theory.Nineteen thirty-seven, Germany K.L.Wolf etc. has created " supramolecule " word, and the entity of the high-sequential forming in order to describe molecular association, from universal significance, all there is interaction in the set of any molecule, so people are usually called " supramolecule " by this layer of structure of material aggregation state.Until 1978, the J.M.Lehn professor of France has just finally proposed the complete concept of " supramolecular chemistry " based on traditional guest-host system research being planted in organic chemistry.Supramolecular chemistry be research molecular interaction conclude and the complexity that forms in order and there is the science of the molecule aggregates of ad hoc structure and function, it is " chemistry that surmounts point subcategory ", and this molecule aggregates abbreviation supramolecule.So the basis of supramolecular chemistry is noncovalent intermolecular interactions, by studying the science of the ergasia that multiple noncovalent intermolecular interactions not of the same race form.There is the molecule of ad hoc structure and group according to specifically can being spontaneously assembled into by way of expectations the supramolecular structure with specific function.Understanding to molecule, supramolecule self-assembly and manipulation ability are just constantly progressive, and by design and preparation to functional materials and molecule etc., molecule, supramolecule, self-assembly field are just continuing to bring out new model.The molecular recognition of being undertaken by the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.
According to crystal engineering, it is guidance, take intermolecular hydrogen bonding or non-covalent interaction as basis, form the supramolecular chemistry of molecule aggregates, with the mixing together of Materials science, physical science, bio-science, life science, environmental science, information technology science, medicine and pharmacology, nano science and other each subjects in, progressively develop into 21 century new ideas and one of the important source of new technology.Crystal engineering is applied to the principle of supramolecular chemistry and method design and the growth of crystal, and by the acting in conjunction of molecular recognition and self assembling process, obtaining structure can regulate and control, and has the new crystal of specific physico-chemical property.The widespread use of crystal engineering by non-covalent interaction, is controlled and is handled functional materials and molecule from molecular level, to prepare and to assemble, has the macromolecular architecture of predetermined structure and further reaches expectation function and application.It is feasible using the approach of the Design Theory pharmaceutical co-crystals of crystal engineering, utilizes the principle of crystal engineering by hydrogen bond, to be connected to form new crystal by active constituents of medicine and other eutectic precursor.
For drug crystal forms research and the solid-state pharmacy industry that is characterized in of medicine, there is very important meaning.On the one hand, the same medicine of different crystal forms, may there were significant differences aspect the biochemical properties such as stability, solubleness and bioavailability, thereby affect the curative effect of medicine.If do not have well assessment to select best drug crystal forms to research and develop, may produce in the clinical later stage variation of crystal formation, thereby cause the extension of medicine listing and produce huge financial loss.Thereby new crystal how to develop medicine can be broken the patent protection of original medicine company to crystal formation, ahead of time imitation medicine is introduced to the market, be a vital problem in recent years, will directly have influence on market and the international competitiveness of imitation medicine and bulk drug company.It has been comparative maturity dark valued field that drug crystal forms research and medicine solid-state is characterized in American-European pharmaceutical industry, but pharmaceutical industry still belongs to the starting stage at home.Due to hydrogen bond, there is the character such as selectivity, directivity and moderate strength, so when changing extraneous solvent or hydrogen bond number, can well control the intensity of hydrogen bond.This handiness has a wide range of applications it in crystal engineering, can be used for controlling molecular orientation.Simultaneously hydrogen bond or other non covalent bond are present in molecular structure, and the properties of molecule itself can not change, covalent linkage that also can saboteur inside.When we are applied in connection drug molecule by these superior character of hydrogen bond, just can reach the object of modified medicaments molecular property, can form to a greater extent new crystalline phase simultaneously.Being formed on when retaining the pharmacological properties of medicine itself of hydrogen bond, has reached the object of the physicochemical property of modified medicaments.The crystallized form of API has a great impact its physical and chemical properties of drugs, comprises solvability, stability, dispersion rate, metabolic stability and bioavailability etc.
Why organic drug eutectic has very large magnetism to be that it provides one not need to destroy and generation covalent linkage just can reach the physics of modified medicaments activeconstituents (API) or the chance of chemical property to pharmaceutical industry.By studying in great detail of the physical properties to organic drug eutectic, show afterwards, there is difference to a certain extent in the character of its certain and pure active constituents of medicine, for API, due to a lot of all with the functional group that can form hydrogen bond, there is the ability of the non covalent bond of very strong formation hydrogen bond or directivity, most of drug molecule or ion also have the foreign molecules of comprising recognizing site, mean that they tend to form polymorphic and solvate, exactly because but the also existence of these functional groups makes them become the ideal chose that forms organic pharmaceutical co-crystals.
Summary of the invention
The object of the present invention is to provide Dihydrallazinie sulphate organic drug eutectic of four kinds of novel textures and preparation method thereof, and its crystalline structure is tested, its performance is characterized.
The selected bulk drug Dihydrallazinie sulphate of the present invention is as active constituents of medicine (API), with 2,3-resorcylic acid, 2,4-resorcylic acid, 2,5-resorcylic acid and 2,6-resorcylic acid is presoma (cocrystal former), thereby obtains the organic drug eutectic of four kinds of novel textures.The molecular formula of Dihydrallazinie sulphate is C
8h
10n
6h
2sO
4, its structural formula as shown in a, precursor 2,3-resorcylic acid, 2,4-resorcylic acid, DHB and 2,6-DHBA, molecular formula is C
7h
6o
4, its structural formula is as shown in b, c, d and e.
Its crystalline structure simplified summary is as follows:
New crystal 4 is the basic structural units that consist of nepresol organic drug eutectic two nepresol molecules (1), four 2,6-DHBA molecules (42) and two water moleculess (5).On directions X, the phenyl ring in nepresol molecule (1) in benzo six-ring and the phenyl ring in 2,6-DHBA molecule (42) are along piling up on directions X; In Y-direction, N atom in nepresol molecule (1) on amino is as hydrogen-bond donor and 2, O atom on 6-resorcylic acid molecule (42) carboxyl forms hydrogen bond as hydrogen bond receptor, H atom in 2,6-DHBA molecule (42) on carboxyl as the N atom on imino-in hydrogen-bond donor and nepresol molecule (1) and amino as hydrogen bond receptor and the dual hydrogen bond of formation; In Z direction, the H atom in water molecules (5) forms hydrogen bond as the O on hydroxyl in hydrogen-bond donor and 2,6-DHBA molecule (42) as hydrogen bond receptor; H atom in nepresol molecule (1) on amino forms hydrogen bond as the O atom in hydrogen-bond donor and water molecules (5) as hydrogen bond receptor; 2,6-DHBA molecule (42) thus in phenyl ring along piling up in Z direction, form the three-dimensional net structure of new crystal 4.
The spacer of the nepresol new crystal 1 that the present invention prepares is triclinic(crystalline)system, its axial length
shaft angle α=99.57 °～99.67 °, β=99.07 °～99.17 °, γ=101.14 °～101.24 °.
The spacer of the nepresol new crystal 2 that the present invention prepares is oblique system, its axial length
shaft angle α=89.95 °～90.05 °, β=90.95 °～91.05 °, γ=89.95 °～90.05 °.
The spacer of the nepresol new crystal 3 that the present invention prepares is oblique system, its axial length
shaft angle α=89.95 °～90.05 °, β=105.98 °～106.08, γ=89.95 °～90.05 °.
The spacer of the nepresol new crystal 4 that the present invention prepares is triclinic(crystalline)system, its axial length
shaft angle α=65.16 °～65.26 °, β=85.57 °～85.67 °, γ=74.79 °～74.89 °.
Dihydrallazinie sulphate organic drug eutectic of the present invention, take ethanol and tetrahydrofuran (THF) as solvent, adopts the method for solvent evaporates to prepare.Because the boiling point of selected organic solvent is lower, therefore there is crystal to separate out in the process of solvent evaporates.Concrete steps are as follows:
The preparation process of Dihydrallazinie sulphate organic drug eutectic 1:
(1) take 0.1～0.3mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 3～5ml of 2～4mol/L, beaker is placed on agitator and is stirred 30～60 minutes, NaOH is fully reacted with sulfuric acid, then reaction solution is poured into centrifuge washing to solution in centrifuge tube and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, remaining solid is put into vacuum drying oven and be dried;
(2) with analytical balance, accurately take dried nepresol 0.1～0.3mmol in transparent glass bottle, accurately measure respectively the each 2ml of ethanol and tetrahydrofuran solution in above-mentioned bottle with liquid-transfering gun, stir, obtain white suspension liquid, accurately take 2,3-resorcylic acid 0.3mmol～0.5mmol in above-mentioned bottle, again stir 30～50min, filter, filtrate room temperature is placed;
(3) with masking foil, seal vial mouth, the standing volatilization of room temperature had or not look tabular crystal to separate out in vial bottom after 12～24 hours, was nepresol organic drug eutectic 1.
The preparation process of Dihydrallazinie sulphate organic drug eutectic 2:
(1) take 0.1～0.3mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 3～5ml of 2～4mol/L, beaker is placed on agitator and is stirred 30～60 minutes, NaOH is fully reacted with sulfuric acid, then reaction solution is poured into centrifuge washing to solution in centrifuge tube and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, remaining solid is put into vacuum drying oven and be dried;
(2) with analytical balance, accurately take dried nepresol 0.1～0.3mmol in transparent glass bottle, accurately measure respectively ethanol and tetrahydrofuran solution 1ml and tetrahydrofuran (THF) 3ml in above-mentioned bottle with liquid-transfering gun, stir, obtain white suspension liquid, accurately take 2,4-resorcylic acid 0.3mmol～0.5mmol in above-mentioned bottle, again stir 30～50min, filter, filtrate room temperature is placed;
(3) with masking foil, seal vial mouth, the standing volatilization of room temperature had red shuttle shape crystal to separate out in vial bottom after 12～24 hours, was nepresol organic drug eutectic 2.
The preparation process of Dihydrallazinie sulphate organic drug eutectic 3:
(1) take 0.1～0.3mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 3～5ml of 2～4mol/L, beaker is placed on agitator and is stirred 30～60 minutes, NaOH is fully reacted with sulfuric acid, then reaction solution is poured into centrifuge washing to solution in centrifuge tube and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, remaining solid is put into vacuum drying oven and be dried;
(2) with analytical balance, accurately take dried nepresol 0.1～0.3mmol in transparent glass bottle, accurately measure respectively the each 2ml of ethanol and tetrahydrofuran solution in above-mentioned bottle with liquid-transfering gun, stir, obtain white suspension liquid, accurately take DHB 0.3mmol～0.5mmol in above-mentioned bottle, again stir 30～50 minutes, filter, filtrate room temperature is placed;
(3) with masking foil, seal vial mouth, the standing volatilization of room temperature had or not look tabular crystal to separate out in vial bottom after 12～24 hours, was nepresol organic drug eutectic 3.
The preparation process of Dihydrallazinie sulphate organic drug eutectic 4:
(1) take 0.1～0.3mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 3～5ml of 2～4mol/L, beaker is placed on agitator and is stirred 30～60 minutes, NaOH is fully reacted with sulfuric acid, then reaction solution is poured into centrifuge washing to solution in centrifuge tube and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, remaining solid is put into vacuum drying oven and be dried;
(2) with analytical balance, accurately take dried nepresol 0.1～0.3mmol in transparent glass bottle, accurately measure respectively the each 2ml of ethanol and tetrahydrofuran solution in above-mentioned bottle with liquid-transfering gun, stir, obtain white suspension liquid, accurately take 2,6-DHBA 0.3mmol～0.5mmol in above-mentioned bottle, again stir 30～50 minutes, filter, filtrate room temperature is placed;
(3) with masking foil, seal vial mouth, the standing volatilization of room temperature had garnet bulk crystals to separate out in vial bottom after 12～24 hours, was nepresol organic drug eutectic 4.
In the present invention, the instrument of detection of drugs eutectic structure and performance is as follows:
1, eutectic structure is measured by Brooker Apex II CCD X-ray single crystal diffractometer, full name Bruker SMART-APEX CCD Diffractometer;
2, X-Ray DIFFRACTOMETER Japan Shimadzu company produces, and model is XRD-6000, Cu-K α (
), tube voltage 40kV, tube current 30mA, 8 °/min of sweep velocity.
Dihydrallazinie sulphate is mainly used in treating hypertension or heart failure.And hypertension is modal cardiovascular diseases, it is one of great public health problem in global range.In addition, elevation of blood pressure or the safety fuse of various diseases, can make the onset risk of the diseases such as coronary heart disease, heart failure and kidney disease increase.Because patient is often asymptomatic in early days, or only there are symptoms such as dizziness, headache, palpitaition, tinnitus, independently disease of one outwardly, be actually important Hazard Factor that cause the heart, the cerebrovascular and nephropathy, if malpractice will pathology become these common hypertension complications such as more serious cerebral apoplexy, myocardial infarction and renal failure, therefore hypertension has " the invisible killer " that be called as human health.Therefore improve the understanding to essential hypertension, early prevention, treatment are in time had to extremely important meaning.Dihydrallazinie sulphate pharmaceutical co-crystals prepared by the present invention, having inherited traditional raw material medicine outside treatment cardiovascular diseases, has obvious change in its solvability, stability and bioavailability!
As shown in Figure 1, new crystal 1 is that 3-resorcylic acid molecule (12), two ethanol molecules (3), two tetrahydrofuran (THF) molecules (4) and two water moleculess (5) form the basic structural unit of nepresol organic drug eutectic by two nepresol molecules (1), four 2; In Z direction, one 2, the O atom in 3-resorcylic acid molecule (12) on hydroxyl is as hydrogen-bond donor and adjacent another 2, and the O atom in 3-resorcylic acid molecule (12) on carboxyl is as a chain of hydrogen bond receptor formation; On directions X, the O atom in water molecules (5) forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule (1) as hydrogen bond receptor; H atom in water molecules (5) forms dual hydrogen bond as two O atoms adjacent in hydrogen-bond donor and 2,3-resorcylic acid molecule (12) as hydrogen bond receptor; H atom in 2,3-resorcylic acid molecule (12) on carboxyl forms hydrogen bond as the N atom on benzo six-ring in hydrogen-bond donor and nepresol molecule (1) as hydrogen bond receptor, thereby forms the two-dimensional network structure of new crystal 1.The unit cell parameters of organic drug eutectic prepared by embodiment 1 is as follows: axial length
shaft angle α=99.62 °, β=99.12 °, γ=101.19 °.
As shown in Figure 2, new crystal 2 is four nepresol molecules (1) and four 2, and 4-resorcylic acid molecule (22) forms the basic structural unit of nepresol organic drug eutectic.In Z direction, one 2, the H atom in 4-resorcylic acid molecule (22) on hydroxyl as hydrogen-bond donor with another 2, the O atom in 4-resorcylic acid molecule (22) on carboxyl is as hydrogen bond receptor formation hydrogen bond and form a undaform chain; On directions X, the N atom in adjacent two nepresol molecules (1) on amino and H atom form dual hydrogen bond as hydrogen-bond donor and acceptor respectively; In Y-direction, the H atom in nepresol molecule (1) on imino-forms hydrogen bond as the O atom on carboxyl in hydrogen-bond donor and 2,4-resorcylic acid molecule (22) as hydrogen bond receptor, thereby forms the three-dimensional net structure of new crystal 2.The unit cell parameters of organic drug eutectic prepared by embodiment 2 is as follows:
shaft angle α=90.00 °, β=91.00 °, γ=90.00 °.
As shown in Figure 3, new crystal 3 is the basic structural units that consist of nepresol organic drug eutectic eight nepresol molecules (1), eight DHB molecules (32) and eight water moleculess (5).In Z direction, adjacent two DHB molecules (32) by pi-pi accumulation effect along piling up in Z direction; In XY plane, the O atom in DHB molecule (32) on hydroxyl forms hydrogen bond as the N atom on amino in hydrogen bond receptor and nepresol molecule (1) as hydrogen-bond donor; In water molecules (5), H atom forms hydrogen bond as the O Sauerstoffatom on carboxyl in hydrogen-bond donor and DHB molecule (32) as hydrogen bond receptor; H atom in water molecules (5) forms hydrogen bond as the N atom on amino in hydrogen-bond donor and nepresol molecule (1) as hydrogen bond receptor, thereby forms the three-dimensional net structure of new crystal 3.The unit cell parameters of organic drug eutectic prepared by embodiment 3 is as follows:
shaft angle α=90.00 °, β=106.03 °, γ=90.00 °.
As shown in Figure 4, new crystal 4 is the basic structural units that consist of nepresol organic drug eutectic two nepresol molecules (1), four 2,6-DHBA molecules (42) and two water moleculess (5).On directions X, the phenyl ring in nepresol molecule (1) in benzo six-ring and the phenyl ring in 2,6-DHBA molecule (42) are along piling up on directions X; In Y-direction, N atom in nepresol molecule (1) on amino is as hydrogen-bond donor and 2, O atom on 6-resorcylic acid molecule (42) carboxyl forms hydrogen bond as hydrogen bond receptor, H atom in 2,6-DHBA molecule (42) on carboxyl as the N atom on imino-in hydrogen-bond donor and nepresol molecule (1) and amino as hydrogen bond receptor and the dual hydrogen bond of formation; In Z direction, the H atom in water molecules (5) forms hydrogen bond as the O on hydroxyl in hydrogen-bond donor and 2,6-DHBA molecule (42) as hydrogen bond receptor; H atom in nepresol molecule (1) on amino forms hydrogen bond as the O atom in hydrogen-bond donor and water molecules (5) as hydrogen bond receptor; 2,6-DHBA molecule (42) thus in phenyl ring along piling up in Z direction, form the three-dimensional net structure of new crystal 4.The unit cell parameters of organic drug eutectic prepared by embodiment 4 is as follows:
shaft angle α=65.21 °, β=85.62 °, γ=74.84 °.
Fig. 5: the computer theory of nepresol organic drug eutectic 1 is simulated the crystal XRD spectra obtaining;
As shown in Figure 5, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out 8.12 °, 12.47 °, 16.12 ° and 25.43 ° of positions and occur series of features peak (curve 1), these characteristic peaks conform to the characteristic peak (curve 2) of the pharmaceutical co-crystals of simulating out according to crystalline structure data and by Materials Studio software.
Fig. 6: the computer theory of nepresol organic drug eutectic 2 is simulated the crystal XRD spectra obtaining;
As shown in Figure 6, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out 12.88 °, 14.80 °, 15.82 °, 16.83 °, 21.78 ° and 24.53 ° of positions and occur series of features peak (curve 1), these characteristic peaks conform to the characteristic peak (curve 2) of the pharmaceutical co-crystals of simulating out according to crystalline structure data and by Materials Studio software.
Fig. 7: the computer theory of nepresol organic drug eutectic 3 is simulated the crystal XRD spectra obtaining;
As shown in Figure 7, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out 10.15 °, 11.77 °, 15.10 °, 17.83 ° and 27.65 ° of positions and occur series of features peak (curve 1), these characteristic peaks conform to the characteristic peak (curve 2) of the pharmaceutical co-crystals of simulating out according to crystalline structure data and by Materials Studio software.
Fig. 8: the computer theory of nepresol organic drug eutectic 4 is simulated the crystal XRD spectra obtaining;
As shown in Figure 8, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out 7.38 °, 7.96 °, 12.87 °, 14.43 °, 19.43 ° and 23.93 ° of positions and occur series of features peak (curve 1), these characteristic peaks conform to the characteristic peak (curve 2) of the pharmaceutical co-crystals of simulating out according to crystalline structure data and by Materials Studio software.
Embodiment
The transparent glass bottle using in invention is foreign import, and capacity is 20ml, has very strong stopping property, and can keep its stopping property good 120 ° of following temperature of C.
The invention will be further elaborated for Application Example below, Dihydrallazinie sulphate and 2,3-resorcylic acid, 2, and experiment detailed process prepared by 4-resorcylic acid, DHB and 2,6-DHBA organic drug eutectic is as follows:
Embodiment 1:
Use Dihydrallazinie sulphate and 2,3-resorcylic acid synthetic organics eutectic 1:
Bulk drug processing:
Accurately take 0.2mmol Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 30 minutes, again this turbid solution is packed in 5ml centrifuge tube, with the speed of 12000r/min centrifugal 3 minutes, remove supernatant liquor, water repetitive scrubbing 3 times, puts into vacuum drying oven and is dried.
Weigh:
Reactant is pressed nepresol: the amount of substance ratio of 2,3-resorcylic acid=1:2 feeds intake, and accurately takes 0.2mmol nepresol and 0.4mmol2 with analytical balance, and 3-resorcylic acid, is all placed in transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 2ml ethanol and 2ml tetrahydrofuran (THF) in this vial with 5ml liquid-transfering gun, stir 30 minutes, the solution turbid solution state that is white in color, filters.
The solvent room temperature hot method of volatilizing:
Seal the little bottleneck of water white transparency with masking foil, filtrate room temperature is placed, volatilization, after approximately 20 hours, a bottle end, has or not look tabular crystal to separate out.
Embodiment 2:
Use Dihydrallazinie sulphate and 2,4-resorcylic acid synthetic organics eutectic 2:
Bulk drug processing:
Accurately take 0.2mmol Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 30 minutes, again this turbid solution is packed in 5ml centrifuge tube, with the speed of 12000r/min centrifugal 3 minutes, remove supernatant liquor, water repetitive scrubbing 3 times, puts into vacuum drying oven and is dried.
Weigh:
Reactant is pressed nepresol: the amount of substance ratio of 2,4-resorcylic acid=1:2 feeds intake, and accurately takes 0.2mmol nepresol and 0.4mmol2 with analytical balance, and 4-resorcylic acid, all in transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 1ml ethanol and 3ml tetrahydrofuran (THF) in this vial with 5ml liquid-transfering gun, stir 30 minutes, the solution turbid solution state that is white in color, filters.
The solvent room temperature hot method of volatilizing:
Seal the little bottleneck of water white transparency with masking foil, filtrate room temperature is placed, volatilization, after approximately 20 hours, a bottle end, has red shuttle shape crystal to separate out.
Embodiment 3:
Use Dihydrallazinie sulphate and DHB synthetic organics eutectic 3:
Bulk drug processing:
Accurately take 0.2mmol Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 30 minutes, again this turbid solution is packed in 5ml centrifuge tube, with the speed of 12000r/min centrifugal 3 minutes, remove supernatant liquor, water repetitive scrubbing 3 times, puts into vacuum drying oven and is dried.
Weigh:
Reactant feeds intake by the amount of substance ratio of nepresol: DHB=1:2, accurately takes 0.2mmol nepresol and 0.4mmol2 with analytical balance, and 5-resorcylic acid, all in transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 2ml ethanol and 2ml tetrahydrofuran (THF) in this vial with 5ml liquid-transfering gun, stir 30 minutes, the solution turbid solution state that is white in color, filters.
The solvent room temperature hot method of volatilizing:
Seal the little bottleneck of water white transparency with masking foil, filtrate room temperature is placed, volatilization, after approximately 20 hours, a bottle end, has or not look tabular crystal to separate out.
Embodiment 4:
Use Dihydrallazinie sulphate and 2,6-DHBA synthetic organics eutectic 4:
Bulk drug processing:
Accurately take 0.2mmol Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 30 minutes, again this turbid solution is packed in 5ml centrifuge tube, with the speed of 12000r/min centrifugal 3 minutes, remove supernatant liquor, water repetitive scrubbing 3 times, puts into vacuum drying oven and is dried.
Weigh:
Reactant feeds intake by the amount of substance ratio of nepresol: 2,6-DHBA=1:2, accurately takes 0.2mmol nepresol and 0.4mmol2 with analytical balance, and 6-resorcylic acid, all in transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 2ml ethanol and 2ml tetrahydrofuran (THF) in this bottle with 5ml liquid-transfering gun, stir 30 minutes, the solution turbid solution state that is white in color, filters.
The solvent room temperature hot method of volatilizing:
Seal the little bottleneck of water white transparency with masking foil, filtrate room temperature is placed, volatilization, after approximately 20 hours, a bottle end, has dark red color lump crystal to separate out.
Claims (2)
1. a Dihydrallazinie sulphate organic drug eutectic, it is characterized in that: pharmaceutical co-crystals is using Dihydrallazinie sulphate as active constituents of medicine, with 2,3-resorcylic acid is presoma, two nepresol molecules, four 2,3-resorcylic acid molecule, two ethanol molecules, two tetrahydrofuran (THF) molecules and two water moleculess form the basic structural unit of nepresol organic drug eutectics; In Z direction, one 2, the O atom in 3-resorcylic acid molecule on hydroxyl is as hydrogen-bond donor and adjacent another 2, and the O atom in 3-resorcylic acid molecule on carboxyl forms a chain as hydrogen bond receptor; On directions X, the O atom in water molecules forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen bond receptor; H atom in water molecules forms dual hydrogen bond as two O atoms adjacent in hydrogen-bond donor and 2,3-resorcylic acid molecule as hydrogen bond receptor; H atom in 2,3-resorcylic acid molecule on carboxyl forms hydrogen bond as the N atom on benzo six-ring in hydrogen-bond donor and nepresol molecule as hydrogen bond receptor; The spacer of this pharmaceutical co-crystals is triclinic(crystalline)system, its axial length
shaft angle α=99.57 °～99.67 °, β=99.07 °～99.17 °, γ=101.14 °～101.24 °.
2. the preparation method of a kind of Dihydrallazinie sulphate organic drug eutectic claimed in claim 1, its step is as follows:
(1) take 0.1～0.3mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 3～5ml of 2～4mol/L, beaker is placed on agitator and is stirred 30～60 minutes, NaOH is fully reacted with sulfuric acid, then reaction solution is poured into centrifuge washing to solution in centrifuge tube and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, remaining solid is put into vacuum drying oven and be dried;
(2) with analytical balance, accurately take dried nepresol 0.1～0.3mmol in transparent glass bottle, accurately measure respectively the each 2ml of ethanol and tetrahydrofuran solution in above-mentioned bottle with liquid-transfering gun, stir, obtain white suspension liquid, accurately take 2,3-resorcylic acid 0.3mmol～0.5mmol in above-mentioned bottle, again stir 30～50min, filter, filtrate room temperature is placed;
(3) with masking foil, seal vial mouth, the standing volatilization of room temperature had or not look tabular crystal to separate out in vial bottom after 12～24 hours, was Dihydrallazinie sulphate organic drug eutectic.
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| Title |
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| 刘利爽.药物共晶的制备与性能表征.《工程科技I辑》.2010, |
| 药物共晶的制备与性能表征;刘利爽;《工程科技I辑》;20100930 * |
| 超分子化学在药物共晶中的应用;陈嘉媚等;《高等学校化学学报》;20110930;第32卷(第9期);1996-2009 * |
| 陈嘉媚等.超分子化学在药物共晶中的应用.《高等学校化学学报》.2011,第32卷(第9期),1996-2009. |
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