CN102627612A - 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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- CN102627612A CN102627612A CN2012101151300A CN201210115130A CN102627612A CN 102627612 A CN102627612 A CN 102627612A CN 2012101151300 A CN2012101151300 A CN 2012101151300A CN 201210115130 A CN201210115130 A CN 201210115130A CN 102627612 A CN102627612 A CN 102627612A
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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 medicine eutectic technical field, be specifically related to two kinds of novel Dihydrallazinie sulphate medicine eutectics and preparation method thereof.
Background technology
1894, German E.Fischer proposed " lock-key " model based on the thought of " intermolecular selectivity effect ", promptly is the blank of modern supramolecule scientific theory.Nineteen thirty-seven; Germany K.L.Wolf etc. has created " supramolecule " speech, and the entity of the high-sequential that forms in order to describe molecular association is said from universal significance; All there is interaction in the set of any molecule, so people usually are called " supramolecule " with this layer of structure of material aggregation attitude.Up to 1978, the J.M.Lehn professor of France just finally proposed the complete concept of " supramolecular chemistry " based on traditional Subjective and Objective architectural study that is planted in the organic chemistry.Supramolecular chemistry be the research molecular interaction conclude and form complicated in order and have a science of the molecule aggregates of ad hoc structure and function, it is " chemistry that surmounts the branch subcategory " and this molecule aggregates abbreviation supramolecule.So the basis of supramolecular chemistry is intermolecular non-covalent interaction, through studying the science of the ergasia that a plurality of intermolecular non-covalent 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 mol, is the general performance of multiple reactive force; B. the super molecular compound that forms of differing mol self-assembly demonstrates and the diverse new function of former self assembly molecule.And molecular recognition of carrying out through the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.
Crystal engineering is applied to crystalline design and growth with the principle and the method for supramolecular chemistry, through the acting in conjunction of molecular recognition and self assembling process, obtains the Adjustable structure control, has the new crystal of specific physico-chemical property.The approach of the Design Theory medicine eutectic of utilization crystal engineering is feasible, utilizes the principle of crystal engineering to be connected to form new crystal through active constituents of medicine and other eutectic precursor through hydrogen bond.
Active constituents of medicine (API) so that crystalline form exists is confined to salt, polymorph and solvolyte (comprising hydrate) traditionally always.On intellecture property and bioavailability, API itself has very high utility value, and wherein structure and moity are most important component.Britain Camb structural database (CSD) is the main source about the structure of matter microscopic information of molecular designing and material design.
Research of medicine crystal formation 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 biochemical properties such as stability, solubleness and bioavailability, thereby influence the curative effect of medicine.If there is well assessment to select best medicine crystal formation to research and develop, may produces the variation of crystal formation in the clinical later stage, thereby cause the extension of medicine listing and produce enormous economic 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 vital problem in recent years, will directly have influence on imitation medicine and bulk drug company's market and international competitiveness.It has been comparative maturity and dark valued field that medicine crystal formation 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 Dihydrallazinie sulphate medicine eutectic of two kinds of novel textures and preparation method thereof, and its crystalline structure is tested, its performance is characterized.
The present invention selects for use the bulk drug Dihydrallazinie sulphate as active constituents of medicine (API), and the presoma of selecting for use is an asccharin, obtains the medicine eutectic of two kinds of novel textures.
The active constituents of medicine of using in the invention (API) is a Dihydrallazinie sulphate, and molecular formula is C
8H
10N
6H
2SO
4, its structural formula is shown in a.The eutectic precursor of using in the invention (cocrystal former) is an asccharin, and molecular formula is C
7H
5NO
3S, its structural formula is shown in b.
New crystal 1 (CC-1) is a nepresol molecule, asccharin molecule and water molecules constitute nepresol medicine eutectic through hydrogen bond and accumulation a basic structural unit; Pile up along directions X through C-H... π effect between the asccharin molecule, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond at the YZ face; Wherein, the O atom on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor in the asccharin molecule; O atom in the water molecules as hydrogen-bond donor respectively with the asccharin molecule in O atom and N atom on the carbonyl form hydrogen bond as hydrogen bond receptor, this kind hydrogen bond belongs to dual hydrogen bond; O atom in the water molecules forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor; H atom in the nepresol molecule on the imino-forms hydrogen bond as the N atom in hydrogen-bond donor and the asccharin molecule as hydrogen bond receptor.The spacer of the nepresol medicine eutectic that the present invention prepares is a 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) is a nepresol molecule, two asccharin molecules and water molecules constitute two hydrazine pyridazine medicine eutectics through hydrogen bond and accumulation a basic structural unit; Pass through π between the asccharin molecule ... π dislocation accumulation is stretched along directions X, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond and accumulation at the YZ face; Wherein, The asccharin molecule with mode end to end along x direction π-π accumulation that misplaces; Y direction asccharin molecule is so that mode is along pi-pi accumulation end to end, and the O atom in the Z direction asccharin molecule on the carbonyl forms hydrogen bond as the H atom on amino in hydrogen bond receptor and the nepresol molecule and the imino-as hydrogen-bond donor; The N atom forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor in the asccharin molecule; O atom in the asccharin molecule on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the N atom on the amino in hydrogen-bond donor and the nepresol molecule as hydrogen bond receptor.The spacer of the nepresol medicine eutectic that the present invention prepares is a 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 the employing method is a solvent evaporation method, because the boiling point of the organic solvent of being selected for use is relatively low, so in the process of solvent evaporates, promptly there is crystal to separate out.
The preparation method of Dihydrallazinie sulphate medicine eutectic CC-1 of the present invention is a solvent evaporation method, and concrete steps are following:
(1) takes by weighing 0.3～0.5mmol Dihydrallazinie sulphate in beaker; The NaOH solution 2～5ml that adds 2～2.5mol/L then places beaker and stirs 30～60 minutes on the whisking appliance, and NaOH and sulfuric acid are fully reacted; Pour in the centrifuge tube reaction solution into centrifugal after scouring to solution then and be neutral; This moment, the color of solution was a yellow-green colour, removed supernatant, solid is put into vacuum drying oven carry out drying;
(2) take by weighing dried nepresol 0.3～0.5mmol and asccharin 0.3～0.5mmol and put into vial, in vial, pipette 8～12ml ethanolic soln with transfer pipet again, rock vial and make the dissolving of asccharin solid;
(3) seal the vial mouth with masking foil, after room temperature left standstill volatilization 24～48h, the vial bottom had colourless diamond platy crystal to separate out, and is nepresol medicine eutectic.
The preparation method of Dihydrallazinie sulphate medicine eutectic CC-2 of the present invention is the room temperature volatilization method, and concrete steps are following:
(1) takes by weighing 0.3～0.5mmol Dihydrallazinie sulphate in beaker; The NaOH solution 2～5ml that adds 2～2.5mol/L then places beaker and stirs 30～60 minutes on the whisking appliance, and NaOH and sulfuric acid are fully reacted; Pour in the centrifuge tube reaction solution into centrifugal after scouring to solution then and be neutral; This moment, the color of solution was a yellow-green colour, removed supernatant, solid is put into vacuum drying oven carry out drying;
(2) take by weighing dried nepresol 0.3～0.5mmol and asccharin 1.4～1.8mmol and put into vial, in vial, pipette 8～12ml ethanolic soln with transfer pipet again, rock vial and make the dissolving of asccharin solid;
(3) seal the vial mouth with masking foil, after room temperature left standstill volatilization 12～36h, the vial bottom had colourless transparent cake crystal to separate out, and is nepresol medicine eutectic.
The instrument of detection of drugs eutectic structure and performance is following among the present invention:
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 day island proper Tianjin company produces; Model is XRD-6000; Cu-K α
tube voltage 40kV; Tube current 30mA, 8 °/min of sweep velocity.
Dihydrallazinie sulphate is mainly used in treatment hypertension or heart failure.And hypertension is modal cardiovascular diseases, is one of great public health problem in the global range.In addition, elevation of blood pressure still is the safety fuse of multiple disease, and the onset risk of diseases such as coronary heart disease, heart failure and kidney disease is increased.Because the patient is often asymptomatic in early days; Or symptoms such as dizziness, headache, palpitaition, tinnitus are only arranged; Be a kind of independently disease outwardly; Be actually and cause the important risk that the heart, the cerebrovascular and ephrosis become, if malpractice will pathology become these common hypertensive patients diseases such as more serious Stroke, myocardial infarction and renal failure, so hypertension has " the invisible killer " who is called as human health.Therefore improve understanding, early prevention, treatment are in time had extremely important meaning essential hypertension.The Dihydrallazinie sulphate medicine eutectic of the present invention's preparation all has tangible change having inherited the traditional raw material medicine outside the treatment cardiovascular diseases on its solvability, stability and bioavailability!
Description of drawings
Fig. 1: nepresol medicine eutectic CC-1 structural unit synoptic diagram;
As shown in Figure 1; A nepresol molecule (1), an asccharin molecule (2) and a water molecules (3) constitute the basic structural unit of nepresol medicine eutectic through hydrogen bond and accumulation; Pile up along directions X through C-H... π effect between the asccharin molecule, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond at the YZ face; Wherein, the O atom on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor in the asccharin molecule; O atom in the water molecules as hydrogen-bond donor respectively with the asccharin molecule in O atom and N atom on the carbonyl form hydrogen bond as hydrogen bond receptor, this kind hydrogen bond belongs to dual hydrogen bond; O atom in the water molecules forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor; H atom in the nepresol molecule on the imino-forms hydrogen bond as the N atom in hydrogen-bond donor and the asccharin molecule as hydrogen bond receptor.This medicine eutectic spacer is a rhombic system, and its unit cell parameters is following: 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 medicine eutectic CC-2 structural unit synoptic diagram;
As shown in Figure 2; A nepresol molecule (1), two asccharin molecules (2) and a water molecules (3) constitute the basic structural unit of two hydrazine pyridazine medicine eutectics through hydrogen bond and accumulation; Pass through π between the asccharin molecule ... π dislocation accumulation is stretched along directions X, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond and accumulation at the YZ face; Wherein, The asccharin molecule with mode end to end along x direction π-π accumulation that misplaces; Y direction asccharin molecule is so that mode is along pi-pi accumulation end to end, and the O atom in the Z direction asccharin molecule on the carbonyl forms hydrogen bond as the H atom on amino in hydrogen bond receptor and the nepresol molecule and the imino-as hydrogen-bond donor; The N atom forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor in the asccharin molecule; O atom in the asccharin molecule on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the N atom on the amino in hydrogen-bond donor and the nepresol molecule as hydrogen bond receptor.This medicine eutectic spacer is a triclinic(crystalline)system, and its unit cell parameters is following: 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 crystal XRD spectrum that the computer theory simulation of nepresol medicine eutectic CC-1 obtains;
As shown in Figure 3, from the x-ray diffraction pattern peak of this eutectic of synthetic, can find out the series of features peak to occur at 8.033 °, 10.854 °, 12.886 °, 16.122 °, 18.041 °, 18.963 ° and 23.515 °.These characteristic peaks conform to the characteristic peak of the medicine eutectic of simulating out according to the crystalline structure data and through Materials Studio software.
Fig. 4: the crystal XRD spectrum that the computer theory simulation of nepresol medicine eutectic CC-2 obtains;
As shown in Figure 4, from the x-ray diffraction pattern peak of this eutectic of synthetic, can find out the series of features peak to occur at 7.617 °, 12.159 °, 15.065 °, 17.153 °, 20.652 ° and 26.717 °.These characteristic peaks conform to the characteristic peak of the medicine eutectic of simulating out according to the crystalline structure data and through Materials Studio software.
Embodiment
The transparent glass bottle that uses in the invention is foreign import, and capacity is 20ml, has very strong stopping property, and can keep its stopping property good 120 ℃ of following temperature.
Following application implementation example is done further elaboration to the present invention, and the experiment detailed process of Dihydrallazinie sulphate and the preparation of asccharin eutectic is following:
Embodiment 1:
Use the synthetic eutectic CC-1 of Dihydrallazinie sulphate and asccharin:
Bulk drug is handled:
Accurately take by weighing the 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 the 5ml centrifuge tube,, remove supernatant with the centrifugal 3min of the speed of 12000r/min; Water repetitive scrubbing 3 times is put into vacuum drying oven and is carried out drying.
Weighing:
Reactant is by nepresol: the amount of substance ratio of asccharin=1: 1 feeds intake.The asccharin that accurately takes by weighing 0.134g (0.4 mole) dried nepresol and 0.073g with analytical balance is in the transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 8ml ethanol with the 10ml transfer pipet and add in the transparent glass small bottle container, rock a little, make the solid dissolving evenly.
The hot method of solvent evaporates:
After treating that solid dissolves fully, seal bottleneck with masking foil, room temperature leaves standstill volatilization.Behind about 36h, the bottle end, have the 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 is handled:
Accurately take by weighing the 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 the 5ml centrifuge tube,, remove supernatant with the centrifugal 3min of the speed of 12000r/min; Water repetitive scrubbing 3 times is put into vacuum drying oven and is carried out drying.
Weighing:
Reactant is by nepresol: the amount of substance ratio of asccharin=1: 4 feeds intake.The asccharin that accurately takes by weighing dried nepresol of 0.134g and 0.304g with analytical balance is in the transparent glass bottle.
The dissolving of bulk drug:
Accurately pipette 8ml ethanol with the 10ml transfer pipet and add in the transparent glass small bottle container, rock a little, make the solid dissolving evenly.
The hot method of solvent evaporates:
After treating that solid dissolves fully, seal bottleneck with masking foil, room temperature leaves standstill volatilization.Behind about 24h, the bottle end, have or not color lump shape crystal to separate out, and the crystal mass of weighing is 0.067g.
Claims (4)
1. Dihydrallazinie sulphate medicine eutectic, it is characterized in that: as active constituents of medicine, is presoma with the asccharin with Dihydrallazinie sulphate; Nepresol molecule, asccharin molecule and water molecules constitute the basic structural unit of nepresol medicine eutectic through hydrogen bond and accumulation; Pile up along directions X through C-H... π effect between the asccharin molecule, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond at the YZ face; Wherein, the O atom on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor in the asccharin molecule; O atom in the water molecules as hydrogen-bond donor respectively with the asccharin molecule in O atom and N atom on the carbonyl form hydrogen bond as hydrogen bond receptor, this kind hydrogen bond belongs to dual hydrogen bond; O atom in the water molecules forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor; H atom in the nepresol molecule on the imino-forms hydrogen bond as the N atom in hydrogen-bond donor and the asccharin molecule as hydrogen bond receptor; The spacer of this medicine eutectic is a 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 the described a kind of Dihydrallazinie sulphate medicine eutectic of claim 1, its step is following:
(1) takes by weighing 0.3～0.5mmol Dihydrallazinie sulphate in beaker; The NaOH solution 2～5ml that adds 2～2.5mol/L then places beaker and stirs 30～60 minutes on the whisking appliance, and NaOH and sulfuric acid are fully reacted; Pour in the centrifuge tube reaction solution into centrifugal after scouring to solution then and be neutral; This moment, the color of solution was a yellow-green colour, removed supernatant, solid is put into vacuum drying oven carry out drying;
(2) take by weighing dried nepresol 0.3～0.5mmol and asccharin 0.3～0.5mmol and put into vial, in vial, pipette 8～12ml ethanolic soln with transfer pipet again, rock vial and make the dissolving of asccharin solid;
(3) seal the vial mouth with masking foil, after room temperature left standstill volatilization 24～48h, the vial bottom had colourless diamond platy crystal to separate out, and is nepresol medicine eutectic.
3. Dihydrallazinie sulphate medicine eutectic, it is characterized in that: as active constituents of medicine, is presoma with the asccharin with Dihydrallazinie sulphate; Nepresol molecule, two asccharin molecules and water molecules constitute the basic structural unit of two hydrazine pyridazine medicine eutectics through hydrogen bond and accumulation; Pass through π between the asccharin molecule ... π dislocation accumulation is stretched along directions X, nepresol molecule, asccharin molecule and water molecules stretch the three-dimensional network structure that constitutes the nepresol eutectic through hydrogen bond and accumulation at the YZ face; Wherein, The asccharin molecule with mode end to end along x direction π-π accumulation that misplaces; Y direction asccharin molecule is so that mode is along pi-pi accumulation end to end, and the O atom in the Z direction asccharin molecule on the carbonyl forms hydrogen bond as the H atom on amino in hydrogen bond receptor and the nepresol molecule and the imino-as hydrogen-bond donor; The N atom forms hydrogen bond as the H atom on the imino-in hydrogen bond receptor and the nepresol molecule as hydrogen-bond donor in the asccharin molecule; O atom in the asccharin molecule on the sulfonic group forms hydrogen bond as the H atom in hydrogen bond receptor and the water molecules as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the N atom on the amino in hydrogen-bond donor and the nepresol molecule as hydrogen bond receptor; The spacer of this medicine eutectic is a 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 °.
4. the preparation method of the described a kind of Dihydrallazinie sulphate medicine eutectic of claim 3, its step is following:
(1) takes by weighing 0.3～0.5mmol Dihydrallazinie sulphate in beaker; The NaOH solution 2～5ml that adds 2～2.5mol/L then places beaker and stirs 30～60 minutes on the whisking appliance, and NaOH and sulfuric acid are fully reacted; Pour in the centrifuge tube reaction solution into centrifugal after scouring to solution then and be neutral; This moment, the color of solution was a yellow-green colour, removed supernatant, solid is put into vacuum drying oven carry out drying;
(2) take by weighing dried nepresol 0.3～0.5mmol and asccharin 1.4～1.8mmol and put into vial, in vial, pipette 8～12ml ethanolic soln with transfer pipet again, rock vial and make the dissolving of asccharin solid;
(3) seal the vial mouth with masking foil, after room temperature left standstill volatilization 12～36h, the vial bottom had colourless transparent cake crystal to separate out, and is nepresol medicine eutectic.
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| CN112712858A (en) * | 2019-10-25 | 2021-04-27 | 江苏恩华药业股份有限公司 | Prediction method for crystal structure formation of two drugs |
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Non-Patent Citations (2)
| Title |
|---|
| S.P. VELAGA ET AL.: "Norfloxacin saccharinate–saccharin dihydrate cocrystal – A new pharmaceutical cocrystal with an organic counter ion", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
| 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》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112712858A (en) * | 2019-10-25 | 2021-04-27 | 江苏恩华药业股份有限公司 | Prediction method for crystal structure formation of two drugs |
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