CN102627612B - Two novel dihydralazine sulphate pharmaceutical co-crystals and preparation method thereof - Google Patents
Two novel dihydralazine sulphate pharmaceutical co-crystals and preparation method thereof Download PDFInfo
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- CN102627612B CN102627612B CN201210115130.0A CN201210115130A CN102627612B CN 102627612 B CN102627612 B CN 102627612B CN 201210115130 A CN201210115130 A CN 201210115130A CN 102627612 B CN102627612 B CN 102627612B
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Abstract
The invention belongs to the technical field of pharmaceutical co-crystal, and particularly relates to two novel dihydralazine sulphate pharmaceutical co-crystals and a preparation method thereof. According to the pharmaceutical co-crystal, dihydralazine sulphate is used as an active pharmaceutical ingredient (API), and the selected precursor is saccharin. A dihydralazine sulphate molecule, a saccharin molecule and a water molecule are combined together through hydrogen bonds and an accumulation effect to form a basic structural unit of the dihydralazine pharmaceutical co-crystal. In a preparation process of the pharmaceutical co-crystal, the selected solvent is ethanol and sodium hydroxide solution, the adopted method is a solvent room-temperature volatilization method; and since the boiling point of the selected organic solvent is relatively low, crystals are separated in a solvent volatilization process. The dihydralazine sulphate pharmaceutical co-crystal prepared by the invention has obvious improvement on all dissolution, stability and bioavailability apart from the inheritance of the advantage of the conventional raw material medicine for treating cardiovascular diseases.
Description
Technical field
The invention belongs to pharmaceutical co-crystals technical field, be specifically related to two kinds of nepresol pharmaceutical co-crystals 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.The strong bonding force that supramolecular chemistry has following notable feature: a. formation super molecular compound is weak interaction force stack and collaborative result between differing molecular, is the general performance of multi-acting force; B. the super molecular compound that differing molecular self-assembly forms demonstrates and the diverse new function of former self assembly molecule.And the molecular recognition of being undertaken by the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.
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.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.
The active constituents of medicine (API) existing with crystalline form is confined to salt, polymorph and solvate (comprising hydrate) traditionally always.From intellecture property and bioavailability, API itself has very high utility value, and wherein structure and composition composition is most important integral part.Britain Camb structural database (CSD) is the main source about the structure of matter microscopic information of molecular designing and design of material.
Drug crystal forms research and the solid-state pharmacy industry that is characterized in of medicine have 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.
For imitation medicine company; 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 being introduced to the market, is 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.
Summary of the invention
The object of the present invention is to provide nepresol pharmaceutical co-crystals of two kinds of novel textures and preparation method thereof, and its crystalline structure is tested, its performance is characterized.
The selected bulk drug nepresol of the present invention is as active constituents of medicine (API), and the presoma of selecting is asccharin, obtains the pharmaceutical co-crystals of two kinds of novel textures.
The active constituents of medicine (API) of using in invention is nepresol, and molecular formula is C
8h
10n
6, its structural formula is as shown in a.The eutectic precursor (cocrystal former) of using in invention is asccharin, and molecular formula is C
7h
5nO
3s, its structural formula is shown as b.
New crystal 1(CC-1) be that a nepresol molecule, an asccharin molecule and a water molecules are by the basic structural unit of hydrogen bond and accumulation formation nepresol pharmaceutical co-crystals, between asccharin molecule, by C-H... π effect, along directions X, pile up, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that forms nepresol eutectic at YZ face by hydrogen bond; Wherein, in asccharin molecule, the O atom on sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and water molecules as hydrogen-bond donor; O atom in water molecules as hydrogen-bond donor respectively with asccharin molecule in O atom and N atom on carbonyl as hydrogen bond receptor, form hydrogen bond, this kind of hydrogen bond belongs to dual hydrogen bond; O atom in water molecules forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen-bond donor; H atom in nepresol molecule on imino-forms hydrogen bond as the N atom in hydrogen-bond donor and asccharin molecule as hydrogen bond receptor.The spacer of the nepresol pharmaceutical co-crystals that the present invention prepares is rhombic system, its axial length a=10.9716～11.0716
b=14.2733～14.3733
c=21.8905～21.9905
shaft angle α=89.95 °～90.05 °, β=89.95 °～90.05 °, γ=89.95 °～90.05 °; Its XRD spectrum signature peak value appears at 7.983 °～8.083 °, and 10.804 °～10.904 °, 12.836 °～12.936 °, 16.072 °～16.172 °, 17.991 °～18.091 °, 18.913 °～19.013 °, 23.465 °～23.565 °.
New crystal 2(CC-2) be that a nepresol molecule, two asccharin molecules and a water molecules are by the basic structural unit of hydrogen bond and the two hydrazine pyridazine pharmaceutical co-crystals of accumulation formation, between asccharin molecule, pass through π ... π dislocation accumulation is stretched along directions X, nepresol molecule, asccharin molecule and water molecules stretch by hydrogen bond and accumulation the three-dimensional network structure that forms nepresol eutectic at YZ face; Wherein, asccharin molecule is with the π-π accumulation that misplaces in the x-direction of mode end to end, Y-direction asccharin molecule is so that mode is along pi-pi accumulation end to end, and the O atom in Z direction asccharin molecule on carbonyl forms hydrogen bond as the H atom on amino in hydrogen bond receptor and nepresol molecule and imino-as hydrogen-bond donor; In asccharin molecule, N atom forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen-bond donor; O atom in asccharin molecule on sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and water molecules as hydrogen-bond donor; H atom in water molecules forms hydrogen bond as the N atom on amino in hydrogen-bond donor and nepresol molecule as hydrogen bond receptor.The spacer of the nepresol pharmaceutical co-crystals that the present invention prepares is triclinic(crystalline)system, its axial length a=10.0847～10.1847
b=10.2265～10.3265
c=12.0126～12.1126
shaft angle α=77.751 °～77.851 °, β=82.955 °～83.055 °, γ=88.734 °～88.834 °; Its XRD spectrum signature peak value appears at 7.567 °～7.667 °, and 12.109 °～12.209 °, 15.015 °～15.115 °, 17.103 °～17.203 °, 20.602 °～20.702 °, 26.667 °～26.767 °.
The selected solvent of the present invention is ethanol and sodium hydroxide solution, and employing method is solvent evaporation method, because the boiling point of selected organic solvent is relatively low, therefore there is crystal to separate out in the process of solvent evaporates.
The preparation method of nepresol pharmaceutical co-crystals CC-1 of the present invention is solvent evaporation method, and concrete steps are as follows:
(1) take 0.3～0.5mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 2～5ml of 2～2.5mol/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 after centrifugal in centrifuge tube and washed to solution and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, solid is put into vacuum drying oven and be dried;
(2) take dried nepresol 0.3～0.5mmol and asccharin 0.3～0.5mmol and put into vial, then in vial, pipette 8～12ml ethanolic soln with transfer pipet, rock vial and make asccharin dissolution of solid;
(3) with masking foil, seal vial mouth, after the standing volatilization 24～48h of room temperature, vial bottom has colourless diamond platy crystal to separate out, and is nepresol pharmaceutical co-crystals.
The preparation method of nepresol pharmaceutical co-crystals CC-2 of the present invention is room temperature volatilization method, and concrete steps are as follows:
(1) take 0.3～0.5mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 2～5ml of 2～2.5mol/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 after centrifugal in centrifuge tube and washed to solution and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, solid is put into vacuum drying oven and be dried;
(2) take dried nepresol 0.3～0.5mmol and asccharin 1.4～1.8mmol and put into vial, then in vial, pipette 8～12ml ethanolic soln with transfer pipet, rock vial and make asccharin dissolution of solid;
(3) with masking foil, seal vial mouth, after the standing volatilization 12～36h of room temperature, vial bottom has colourless transparent cake crystal to separate out, and is nepresol pharmaceutical co-crystals.
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.
Nepresol 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.Nepresol 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!
Accompanying drawing explanation
Fig. 1: nepresol pharmaceutical co-crystals CC-1 structural unit schematic diagram;
As shown in Figure 1, a nepresol molecule (1), an asccharin molecule (2) and a water molecules (3) consist of the basic structural unit of nepresol pharmaceutical co-crystals hydrogen bond and accumulation, between asccharin molecule, by C-H... π effect, along directions X, pile up, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that forms nepresol eutectic at YZ face by hydrogen bond; Wherein, in asccharin molecule, the O atom on sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and water molecules as hydrogen-bond donor; O atom in water molecules as hydrogen-bond donor respectively with asccharin molecule in O atom and N atom on carbonyl as hydrogen bond receptor, form hydrogen bond, this kind of hydrogen bond belongs to dual hydrogen bond; O atom in water molecules forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen-bond donor; H atom in nepresol molecule on imino-forms hydrogen bond as the N atom in hydrogen-bond donor and asccharin molecule as hydrogen bond receptor.This pharmaceutical co-crystals spacer is rhombic system, and its unit cell parameters is as follows: axial length a=11.0216
b=14.3233
c=21.9405
shaft angle α=90.000 °, β=90.000 °, γ=90.000 °.
Fig. 2: nepresol pharmaceutical co-crystals CC-2 structural unit schematic diagram;
As shown in Figure 2, a nepresol molecule (1), two asccharin molecules (2) and a water molecules (3) consist of the basic structural unit of two hydrazine pyridazine pharmaceutical co-crystals hydrogen bond and accumulation, between asccharin molecule, pass through π ... π dislocation accumulation is stretched along directions X, nepresol molecule, asccharin molecule and water molecules stretch by hydrogen bond and accumulation the three-dimensional network structure that forms nepresol eutectic at YZ face; Wherein, asccharin molecule is with the π-π accumulation that misplaces in the x-direction of mode end to end, Y-direction asccharin molecule is so that mode is along pi-pi accumulation end to end, and the O atom in Z direction asccharin molecule on carbonyl forms hydrogen bond as the H atom on amino in hydrogen bond receptor and nepresol molecule and imino-as hydrogen-bond donor; In asccharin molecule, N atom forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen-bond donor; O atom in asccharin molecule on sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and water molecules as hydrogen-bond donor; H atom in water molecules forms hydrogen bond as the N atom on amino in hydrogen-bond donor and nepresol molecule as hydrogen bond receptor.This pharmaceutical co-crystals spacer is triclinic(crystalline)system, and its unit cell parameters is as follows: axial length a=10.1347
b=10.2796
c=12.0626
shaft angle α=77.801 °, β=83.005 °, γ=88.784 °.
Fig. 3: the computer theory of nepresol pharmaceutical co-crystals CC-1 is simulated the crystal XRD spectrum obtaining;
As shown in Figure 3, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out at 8.033 °, 10.854 °, 12.886 °, 16.122 °, 18.041 °, 18.963 ° and 23.515 ° and occur series of features peak.These characteristic peaks conform to the characteristic peak of the pharmaceutical co-crystals of simulating out according to crystalline structure data and by Materials Studio software.
Fig. 4: the computer theory of nepresol pharmaceutical co-crystals CC-2 is simulated the crystal XRD spectrum obtaining;
As shown in Figure 4, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out at 7.617 °, 12.159 °, 15.065 °, 17.153 °, 20.652 ° and 26.717 ° and occur series of features peak.These characteristic peaks conform to the characteristic peak 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.
The invention will be further elaborated for Application Example below, and experiment detailed process prepared by nepresol and asccharin eutectic is as follows:
Embodiment 1:
Use the synthetic eutectic CC-1 of Dihydrallazinie sulphate and asccharin:
Bulk drug processing:
Accurately take 0.134g Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 0.5h, again this turbid solution is packed in 5ml centrifuge tube, with the centrifugal 3min of speed of 12000r/min, 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: asccharin=1:1.Accurately taking 0.134g(0.4 mole with analytical balance) asccharin of dried nepresol and 0.073g is in transparent glass bottle.
The dissolving of bulk drug:
With 10ml transfer pipet, accurately pipette 8ml ethanol and add in transparent glass small bottle container, rock a little, make dissolution of solid even.
The hot method of solvent evaporates:
After solid dissolves completely, seal bottleneck, the standing volatilization of room temperature with masking foil.After about 36h, the bottle end, has diamond platy crystal to separate out, and the crystal mass of weighing is 0.052g.
Embodiment 2:
Use the synthetic eutectic CC-2 of Dihydrallazinie sulphate and asccharin:
Bulk drug processing:
Accurately take 0.134g Dihydrallazinie sulphate with analytical balance, add the NaOH solution 3ml of 2mol/L, stir 0.5h, again this turbid solution is packed in 5ml centrifuge tube, with the centrifugal 3min of speed of 12000r/min, 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: asccharin=1:4.The asccharin that accurately takes the dried nepresol of 0.134g and 0.304g with analytical balance is in transparent glass bottle.
The dissolving of bulk drug:
With 10ml transfer pipet, accurately pipette 8ml ethanol and add in transparent glass small bottle container, rock a little, make dissolution of solid even.
The hot method of solvent evaporates:
After solid dissolves completely, seal bottleneck, the standing volatilization of room temperature with masking foil.After about 24h, the bottle end, has or not look bulk crystals to separate out, and the crystal mass of weighing is 0.067g.
Claims (2)
1. a nepresol pharmaceutical co-crystals, is characterized in that: using nepresol as active constituents of medicine, take asccharin as presoma; A nepresol molecule, an asccharin molecule and a water molecules are by the basic structural unit of hydrogen bond and accumulation formation nepresol pharmaceutical co-crystals, between asccharin molecule, by C-H... π effect, along directions X, pile up, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that forms nepresol eutectic at YZ face by hydrogen bond; Wherein, in asccharin molecule, the O atom on sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and water molecules as hydrogen-bond donor; O atom in water molecules as hydrogen-bond donor respectively with asccharin molecule in O atom and N atom on carbonyl as hydrogen bond receptor, form hydrogen bond, this kind of hydrogen bond belongs to dual hydrogen bond; O atom in water molecules forms hydrogen bond as the H atom on imino-in hydrogen bond receptor and nepresol molecule as hydrogen-bond donor; H atom in nepresol molecule on imino-forms hydrogen bond as the N atom in hydrogen-bond donor and asccharin molecule as hydrogen bond receptor; The spacer of this pharmaceutical co-crystals is rhombic system, its axial length a=10.9716～11.0716
b=14.2733～14.3733
c=21.8905～21.9905
shaft angle α=89.95 °～90.05 °, β=89.95 °～90.05 °, γ=89.95 °～90.05 °.
2. the preparation method of a kind of nepresol pharmaceutical co-crystals claimed in claim 1, its step is as follows:
(1) take 0.3～0.5mmol Dihydrallazinie sulphate in beaker, then add NaOH solution 2～5ml of 2～2.5mol/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 after centrifugal in centrifuge tube and washed to solution and be neutral, now the color of solution is yellow-green colour, removes supernatant liquor, solid is put into vacuum drying oven and be dried;
(2) take dried nepresol 0.3～0.5mmol and asccharin 0.3～0.5mmol and put into vial, then in vial, pipette 8～12ml ethanolic soln with transfer pipet, rock vial and make asccharin dissolution of solid;
(3) with masking foil, seal vial mouth, after the standing volatilization 24～48h of room temperature, vial bottom has colourless diamond platy crystal to separate out, and is nepresol pharmaceutical co-crystals.
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Non-Patent Citations (4)
| Title |
|---|
| Norfloxacin saccharinate–saccharin dihydrate cocrystal – A new pharmaceutical cocrystal with an organic counter ion;S.P. Velaga et al.;《Journal of Molecular Structure》;20080208;第889卷;150-153 * |
| S.P. Velaga et al..Norfloxacin saccharinate–saccharin dihydrate cocrystal – A new pharmaceutical cocrystal with an organic counter ion.《Journal of Molecular Structure》.2008,第889卷150-153. |
| 弋东旭等.药物共晶技术应用.《第三届中国晶型药物研发技术学术研讨会》.2011,103-110. |
| 药物共晶技术应用;弋东旭等;《第三届中国晶型药物研发技术学术研讨会》;20111023;103-110 * |
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