CN102351812B - Methanesulfonic acid cinepazide crystal form III and preparation method thereof - Google Patents
Methanesulfonic acid cinepazide crystal form III and preparation method thereof Download PDFInfo
- Publication number
- CN102351812B CN102351812B CN2011102683841A CN201110268384A CN102351812B CN 102351812 B CN102351812 B CN 102351812B CN 2011102683841 A CN2011102683841 A CN 2011102683841A CN 201110268384 A CN201110268384 A CN 201110268384A CN 102351812 B CN102351812 B CN 102351812B
- Authority
- CN
- China
- Prior art keywords
- methanesulfonic acid
- crystal form
- acid cinepazide
- cinepazide
- form iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 Oc1cc(C=CC(*2CC*(CC(*3CCCC3)=O)CC2)=O)cc(O)c1O Chemical compound Oc1cc(C=CC(*2CC*(CC(*3CCCC3)=O)CC2)=O)cc(O)c1O 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a methanesulfonic acid cinepazide crystal form III and a preparation method thereof, and belongs to the field of chemical pharmaceutics. The water solubility of the prepared methanesulfonic acid cinepazide crystal form III is higher than that of an amorphous material, and the methanesulfonic acid cinepazide crystal form III is particularly suitable for injection, has higher chemical stability than the amorphous material, facilitates production of medicines, and storage and transportation of raw material medicines, improves the safety of the medicines and provides safe guarantee for clinical application of the medicines.
Description
This application is that denomination of invention is " methanesulfonic acid cinepazide crystal form and preparation method thereof ", the dividing an application of the application for a patent for invention that application number is 2008102278637.
Technical field
The invention belongs to medical technical field, be specifically related to methanesulfonic acid cinepazide crystal form and preparation method thereof.
Background technology
Cinepazide Maleate is the maleate of cinepazide, in the formulation of Discussion on Chinese Listed, is mainly injection liquid.Cinepazide Maleate has expansion of cerebral vascular and promotes the dual function of neurocyte Nutrition and Metabolism, nearly treatment that has started to be applied at home cardiovascular and cerebrovascular in 2 years.Cinepazide Maleate is calcium ion channel blocker, by stoping the Ca2+ cross-film to enter in smooth muscle cell, make vascular smooth muscle relaxation, the cerebrovascular, coronary vasodilator and peripheral blood vessel expansion, thereby alleviating vascular spasm, reduce vascular resistance, increase volume of blood flow, can strengthen the effect of adenosine and cyclic monophosphate (cAMP), reduce the oxygen consumption, can suppress the cAMP phosphodiesterase, cAMP quantity is increased, can also improve erythrocytic snappiness and deformability, improve it by the ability of minute blood vessel, reduce the viscosity of blood, improve microcirculation, can be by improving cerebrovascular volume of blood flow, improve the metabolism of brain.
Two keys that one cis-trans isomerism is arranged in the structure of cinepazide, deposit process long-term, its cis isomerism body burden can obviously raise, and this cis-isomeride has larger toxicity, storage and transportation to medicine production, bulk drug have brought great inconvenience, and larger on the drug safety impact, bring certain risk to clinical application.
Patent application " new pharmaceutical salts of cinepazide and preparation method thereof " (application number: obtain a kind of methanesulfonic acid cinepazide 200710096248.2), structural formula is as follows:
Its solubleness in water wants large than Cinepazide Maleate, its stability is also good than Cinepazide Maleate, be particularly suitable for making injection liquid, the drug formulation that meets cinepazide, although the drug safety impact of the mesylate of mentioning above-mentioned has reduced, but the drug safety problem still exists, the raw material methanesulfonic acid cinepazide is amorphous powder, unstable chemcial property, two keys that one cis-trans isomerism is arranged in its structure, deposit process long-term, its cis isomerism body burden can obviously raise, and this cis-isomeride has larger toxicity, bring certain risk to clinical application.Therefore, be necessary further to improve the stability of mesylate, make the drug safety impact drop to bottom line.
Summary of the invention
The present invention is directed to the defect in above-mentioned field, the different crystal forms of methanesulfonic acid cinepazide is provided, its solubleness in water increases, and the raw material good stability, improved drug safety.
The preparation method of methanesulfonic acid cinepazide crystal form is provided simultaneously.
Methanesulfonic acid cinepazide crystal form I is characterized in that: use the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 5.3 ± 0.2, and there is characteristic peak at 9.2 ± 0.2,22.8 ± 0.2 places.
Methanesulfonic acid cinepazide crystal form I is further characterized in that: in its DSC, the fusing endotherm(ic)peak changes at 244 ℃, uses the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 16.9 ± 0.2, and 17.2 ± 0.2,17.7 ± 0.2,20.6 there is characteristic peak at ± 0.2,21.2 ± 0.2 places.
Methanesulfonic acid cinepazide crystal form II is characterized in that: use the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 9.1 ± 0.2, and there is characteristic peak at 17.1 ± 0.2,22.8 ± 0.2 places.
Methanesulfonic acid cinepazide crystal form II is further characterized in that: in its DSC, the fusing endotherm(ic)peak changes at 245 ℃, uses the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 16.7 ± 0.2, and 17.6 ± 0.2,18.6 ± 0.2,19.0 there is characteristic peak at ± 0.2,25.7 ± 0.2 places.
Methanesulfonic acid cinepazide crystal form III is characterized in that: be the methanesulfonic acid cinepazide dihydrate, use the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 5.8 ± 0.2, and there is characteristic peak at 11.5 ± 0.2,17.2 ± 0.2 places.
Methanesulfonic acid cinepazide crystal form III, be further characterized in that: be the methanesulfonic acid cinepazide dihydrate, in its DSC, the fusing endotherm(ic)peak changes at 246 ℃, use the Cu-Ka radiation, the X-ray powder diffraction meaned with 2 θ angles is 16.4 ± 0.2, and 18.0 ± 0.2,20.2 ± 0.2,21.7 there is characteristic peak at ± 0.2,23.6 ± 0.2 places.
The preparation method of methanesulfonic acid cinepazide crystal form I, methanesulfonic acid cinepazide is joined to methylene dichloride, trichloromethane, Nitromethane 99Min., in one or more solvents in DMF, low-grade fever is dissolved, obtain crystal after solvent evaporates, wherein the ratio of solute and solvent is 1g: 40-80mL, perhaps methanesulfonic acid cinepazide is joined to methylene dichloride, trichloromethane, Nitromethane 99Min., DMF, methyl alcohol, in ethylene glycol monomethyl ether, low-grade fever is dissolved, again solution is added drop-wise to ether, methyl tertiary butyl ether, in acetonitrile, crystallize out, wherein the ratio of solute and solvent is 1g: 10-40mL, when solution drips, the ratio of solution and solvent is 1mL: 30-60mL.
The preparation method of methanesulfonic acid cinepazide crystal form II, methanesulfonic acid cinepazide is dissolved in to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, one or more in acetonitrile solvent, standing, obtain crystal after solvent evaporates, wherein the ratio of solute and solvent is 2g: 3-10mL, perhaps methanesulfonic acid cinepazide is dissolved in to Nitromethane 99Min., again solution is added drop-wise in acetonitrile, perhaps methanesulfonic acid cinepazide is dissolved in to the DMSO solvent, again solution is added drop-wise in the mixed solvent of tetracol phenixin and ether, crystallize out, wherein the ratio of solute and solvent is 1g: 5-20mL, when solution drips, the ratio of solution and solvent is 1mL: 10-20mL.
The preparation method of methanesulfonic acid cinepazide crystal form III, be dissolved in the water methanesulfonic acid cinepazide, standing or add after acetone standing, crystallize out, the ratio 1g of solute and water: 4-10mL wherein, the ratio of acetone and water is 1: 5.
Methanesulfonic acid cinepazide crystal form I, II, III treat and/or prevent the application in the medicine of cardiovascular and cerebrovascular diseases in preparation.
The formulation of described medicine is pharmaceutically acceptable arbitrary formulation.
The present invention adopts patent application " new pharmaceutical salts of cinepazide and preparation method thereof ", and (application number: the methanesulfonic acid cinepazide that 200710096248.2) described method prepares, it is carried out to the crystal formation detection is metamict crystals, sees accompanying drawing 1.Cultivate monocrystalline by single solvent and mixed solvent, and adopt the method for liquid liquid and gas-liquid diffusion diffusion to cultivate monocrystalline and powder thereof, by test result analysis such as powder X-ray RD, monocrystalline XRD test, thermogravimetric-heating differential analysis (TGA-DSC), ultimate analyses, discovery makes multiple crystal formation, than metamict crystals stability, crystal formation I, crystal form II and crystal form II I are arranged preferably, wherein crystal form II I is with two solvent molecules.
The present invention is using this product as starting raw material, and the crystallization in methylene chloride, trichloromethane, Nitromethane 99Min., DMF, methanol/ether, methylene dichloride/ether, methyl alcohol/methyl tertiary butyl ether, DMF/ ether, ethylene glycol monomethyl ether/ether, ethylene glycol monomethyl ether/acetonitrile is crystal formation I.The X-ray powder diffraction meaned with 2 θ angles is 5.3 ± 0.2, and 9.2 ± 0.2,16.9 ± 0.2,17.2 ± 0.2,17.7 there is characteristic peak at ± 0.2,20.6 ± 0.2,21.2 ± 0.2,22.8 ± 0.2 places, and 2 θ angles are 5.3 ± 0.2, and the characteristic peak at 9.2 ± 0.2,22.8 ± 0.2 3 places is three strongest ones peaks.Solubleness and study on the stability experiment showed, that the solubleness of crystal formation I is slightly large than raw material, and good stability is in raw material, and its DSC-TGA and ultimate analysis show, this crystal formation does not contain crystal water.
The present invention is using this product as starting raw material, and the crystallization in solvent methanol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, acetonitrile, Nitromethane 99Min./acetonitrile, DMSO/ tetracol phenixin/ether is crystal form II.The X-ray powder diffraction meaned with 2 θ angles is 9.1 ± 0.2,16.7 ± 0.2,17.1 ± 0.2,17.6 ± 0.2,18.6 ± 0.2,19.0 ± 0.2,22.8 ± 0.2,25.7 ± 0.2, there is characteristic peak at place, and 2 θ angles 9.1 ± 0.2,17.1 ± 0.2, the characteristic peak at 22.8 ± 0.2 3 places is three strongest ones peaks.Solubleness and study on the stability experiment showed, that the solubleness of crystal form II is slightly large than raw material, and good stability is in raw material, and its DSC-TGA and ultimate analysis show, this crystal formation does not contain crystal water.
The present invention is using this product as starting raw material, and in aqueous solvent, the crystallization in water/acetone is crystal form II I.The X-ray powder diffraction meaned with 2 θ angles is 5.8 ± 0.2, and 11.5 ± 0.2,16.4 ± 0.2,17.2 ± 0.2,18.0 ± 0.2,20.2 ± 0.2,21.7 ± 0.2,23.6 there is characteristic peak at ± 0.2 place, and 2 θ angles 5.8 ± 0.2,11.5 ± 0.2, the characteristic peak at 17.2 ± 0.2 3 places is three strongest ones peaks, its DSC-TGA and ultimate analysis show, this crystal formation contains two crystal water.Solubleness and study on the stability experiment showed, that the solubleness of crystal form II is slightly large than raw material, and good stability is in raw material.
The crystal formation I that the present invention obtains, crystal form II, crystal form II I, can be used for making all kinds of class preparations, and because the more unformed methanesulfonic acid cinepazide of its solubleness wants large, above-mentioned crystal formation is particularly suitable for preparing freeze-dried formulation, mouth collapses solution dosage etc.
By a large amount of experimental results show that, the chemical stability of methanesulfonic acid cinepazide crystal form I of the present invention, crystal form II and crystal form II I is better than unbodied methanesulfonic acid cinepazide, under high temperature, high humidity, illumination condition, the transformation efficiency of its cis-isomeride is fewer than unbodied methanesulfonic acid cinepazide, the security that has improved medicine is crystal form II especially, cis-isomeride under its high temperature, high humidity also reduces accordingly, for the clinical drug application provides safety control.
The accompanying drawing explanation
Fig. 1 methanesulfonic acid cinepazide raw material XRD-powder diagram,
The XRD-powder diagram of Fig. 2 methanesulfonic acid cinepazide crystal form I (crystallize out in methylene dichloride),
The DSC-TGA figure (crystallize out in methylene dichloride) of Fig. 3 methanesulfonic acid cinepazide crystal form I,
The XRD-powder diagram of Fig. 4 methanesulfonic acid cinepazide crystal form II (crystallize out in methyl alcohol),
The DSC-TGA figure (crystallize out in methyl alcohol) of Fig. 5 methanesulfonic acid cinepazide crystal form II
Fig. 6 methanesulfonic acid cinepazide crystal form II single crystal diffraction figure (crystallize out in methyl alcohol)
The XRD-powder diagram of Fig. 7 methanesulfonic acid cinepazide crystal form III (crystallize out in water),
The DSC-TGA figure (crystallize out in water) of Fig. 8 methanesulfonic acid cinepazide crystal form III
Fig. 9 methanesulfonic acid cinepazide crystal form III single crystal diffraction figure (crystallize out in water)
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Instrument model and test condition
XRD: Cu K α-wire harness for the powder x-ray diffraction figure of various polymorphic forms
by D/MAX-RB type X-ray diffractometer, record.
TG/DSC: Japan leads Tianjin DSC-40M, DTA-40M Thermal Analysis, 10 °/min of temperature rise rate, nitrogen atmosphere, flow 40mL/min.
Ultimate analysis: moral ELEMENTAR VarioELIII.
Single crystal diffractometer: Bruker SMART APEX2
Embodiment 1 methanesulfonic acid cinepazide raw material
1.1 raw material preparation
According to patent application " new pharmaceutical salts of cinepazide and preparation method thereof ", (application number: preparation method 200710096248.2) adopts the type of cooling to separate out from the look crystalline powder.
1.2 XRD-powder diagram
See Fig. 1, show that the raw material prepared by above-mentioned patent is the amorphous powder.
1.3 solubility experiment
The solvent that can dissolve methanesulfonic acid cinepazide has: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, DMF, water, ethylene glycol monomethyl ether, methylene dichloride, chloroform, acetonitrile, Nitromethane 99Min., DMSO.Wherein water, methyl alcohol, Nitromethane 99Min., ethylene glycol monomethyl ether, DMSO solvability are fabulous, and other are general.The solvent that can not dissolve methanesulfonic acid cinepazide has: the trimethyl carbinol, acetone, butanone, ethyl formate, ethyl acetate, benzene, toluene, monochloro-benzene, tetracol phenixin, normal hexane, hexanaphthene, ether, methyl tert-butyl ether, sherwood oil, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
2.1 preparation method
The crystallization of methanesulfonic acid cinepazide in methylene dichloride, trichloromethane, Nitromethane 99Min., DMF, methanol/ether, methylene dichloride/ether, methyl alcohol/methyl tertiary butyl ether, DMF/ ether, ethylene glycol monomethyl ether/ether, ethylene glycol monomethyl ether/acetonitrile is crystal formation I.
Method one (take methylene dichloride as example): under the lucifuge condition, the 0.5g methanesulfonic acid cinepazide is added in the 25mL methylene dichloride, low-grade fever makes its dissolving, stirs 1h, filters, standing preservation, after three days, solvent evaporates is killed, and by the solid crushing, normal temperature is placed dry 6h, collect sample, obtain methanesulfonic acid cinepazide crystal form I.
Method two (take the DMF/ ether as example): under the lucifuge condition, the 0.7g methanesulfonic acid cinepazide is added in 20mL DMF, dissolve, stir 30min, solution is added drop-wise in the 100mL ether, separate out white crystalline solid, suction filtration, drain, and under 55 ℃ of conditions, dries 30min, collect sample, obtain methanesulfonic acid cinepazide crystal form I.
Additive method: in Nitromethane 99Min., DMF, methanol/ether, methyl alcohol/methyl tertiary butyl ether, ethylene glycol monomethyl ether/ether, DMF/ ether, ethylene glycol monomethyl ether/acetonitrile, sample obtains methanesulfonic acid cinepazide crystal form I with reference to above two kinds of methods.
2.2 XRD-powdery diffractometry test:
See Fig. 2.
2-Theta and the I% of methanesulfonic acid cinepazide XRD powdery diffractometry of crystallize out powder in methylene dichloride
| 2-Theta | 5.281 | 9.218 | 12.282 | 16.818 | 17.181 | 17.723 | 19.017 | 20.158 | 20.571 | 21.239 |
| I％ | 89.5 | 81.7 | 19.5 | 61 | 47.4 | 30.3 | 14.8 | 13.9 | 26.8 | 21.7 |
| 2-Theta | 21.723 | 22.769 | 23.4 | 23.936 | 24.395 | 24.962 | 25.711 | 26.524 | 28.324 | 29.08 |
| I％ | 17 | 100 | 7.1 | 7 | 8.6 | 19 | 21.2 | 14.6 | 7.8 | 15.2 |
2.3 DSC-TGA test:
See Fig. 3, DSC: having 244.00 ℃ unimodal, is the fusing endotherm(ic)peak; TGA: before decomposing, nothing is obviously weightless.
2.4 ultimate analysis:
The calculated value of raw material methanesulfonic acid cinepazide: N, 8.18%; H, 6.87%; C, 53.78%; S, 6.24%; Actual measured value: N, 8.21%; H, 6.88%; C, 53.86%; S, 6.74%.The observed value of methanesulfonic acid cinepazide crystallize out powder in methylene dichloride: N, 8.05%; H, 6.84%; C, 53.62%; S, 6.44%.
3.1 preparation method
The crystallization of methanesulfonic acid cinepazide in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, acetonitrile, Nitromethane 99Min./acetonitrile, DMSO/ tetracol phenixin/ether is crystal form II.
Method one (take methyl alcohol as example): under the lucifuge condition, the 2g methanesulfonic acid cinepazide is added in 5mL methyl alcohol, the low-grade fever hydrotropy, stir 0.5h, filters, and standing preservation, place approximately 23 days, and solvent evaporates is killed, and collects sample, obtains methanesulfonic acid cinepazide crystal form II.
Method two (take DMSO/ tetracol phenixin/ether as example): under the lucifuge condition, the 1g methanesulfonic acid cinepazide is added in 15mLDMSO, dissolve, stir 30min, solution is added drop-wise in the mixed solvent of 150mL tetracol phenixin and 100mL ether, separate out white crystalline solid, suction filtration, drain, and under 55 ℃ of conditions, dries 2h, collect sample, obtain methanesulfonic acid cinepazide crystal form II.
Additive method: the sample of ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, acetonitrile, Nitromethane 99Min./acetonitrile obtains methanesulfonic acid cinepazide crystal form II with reference to above two kinds of methods.
3.2 XRD-powdery diffractometry test:
See Fig. 4.
2-Theta and the I% of methanesulfonic acid cinepazide XRD powdery diffractometry of crystallize out powder in methyl alcohol
| 2-Theta | 9.121 | 14.051 | 16.618 | 17.087 | 17.634 | 18.567 | 18.955 | 20.101 | 21.202 |
| I％ | 100 | 9.8 | 40.2 | 52.7 | 32.8 | 28.7 | 39.4 | 18.8 | 11.3 |
| 2-Theta | 21.965 | 22.772 | 24.329 | 24.876 | 25.38 | 25.657 | 27.034 | 28.835 |
| I％ | 11.4 | 44.9 | 21.8 | 18.9 | 14.9 | 25.2 | 11.3 | 10.4 |
3.3 DSC-TGA test:
See Fig. 5, DSC: having 244.59 ℃ unimodal, is the fusing endotherm(ic)peak; TGA: before decomposing, nothing is obviously weightless.
3.4 ultimate analysis:
The observed value of methanesulfonic acid cinepazide crystallize out powder in methyl alcohol: N, 7.97%; H, 6.89%; C, 53.58%; S, 6.25%.
4 monocrystalline (methyl alcohol) diffraction: see Fig. 6.
Embodiment 4 methanesulfonic acid cinepazide crystal form III (two hydrates)
4.1 preparation method
The crystallization of methanesulfonic acid cinepazide in water, water/acetone is the dihydrate of methanesulfonic acid cinepazide.
Method one (take water as example): under the lucifuge condition, the 2g methanesulfonic acid cinepazide is added in 10mL water, dissolves, and add the 5g methanesulfonic acid cinepazide, stir 30min, filter standing preservation 18 days, there is solid to separate out, suction filtration, drain, and normal temperature is placed 6h, collect sample, obtain the dihydrate of methanesulfonic acid cinepazide.
Method two (take water/acetone as example): under the lucifuge condition, the 0.3g methanesulfonic acid cinepazide is added in 2mL water, and adds 10mL acetone, add the 0.6g methanesulfonic acid cinepazide, stirring at normal temperature 0.5h, filter, standing preservation 18 days, separate out solid, suction filtration, drain, normal temperature is placed 6h, obtains methanesulfonic acid cinepazide crystal form III.
4.2 XRD-powdery diffractometry test:
See Fig. 7.
2-Theta and the I% of methanesulfonic acid cinepazide XRD powdery diffractometry of crystallize out powder in water, water/acetone
| 2-Theta | 5.763 | 10.937 | 11.491 | 11.857 | 16.402 | 17.239 |
| I％ | 94.7 | 18.1 | 100 | 21.6 | 29.1 | 52.2 |
| 2-Theta | 20.22 | 20.725 | 21.716 | 22.596 | 23.615 | 26.858 |
| I％ | 36.7 | 18.3 | 48.7 | 21.7 | 30.1 | 13.4 |
4.3 DSC-TGA test:
See Fig. 8.DSC: have 125.01 ℃, 246.08 ℃ two bimodal, and previous peak is the crystal water endotherm(ic)peak of leaving away, and a rear peak is the crystal melting endotherm(ic)peak; TGA: weightlessness 6.502%, calculated value: 6.555%, illustrate that hydrate crystal forms is in conjunction with 2 water moleculess.
4.4 ultimate analysis:
The observed value of methanesulfonic acid cinepazide crystallize out powder in water: N, 7.28%; H, 7.09%; C, 50.35%; S, 5.74%; Calculated value: N, 7.64%; H, 7.15%; C, 50.26%; S, 5.83%.
4.5 monocrystalline (water) diffraction:
See Fig. 9.Contain 2 water moleculess in monocrystalline test chart open fire compound.
Sum up
Obtain three kinds of crystal formations (crystal formation I, crystal form II, crystal form II I) of methanesulfonic acid cinepazide by above-mentioned experiment.It is that about 5.3 ° places have more a diffraction peak that crystal formation I compares with crystal form II at 2-Theta, and crystal form II I is two hydrates of methanesulfonic acid cinepazide, and the XRD-powdery diffractometry is obviously different from crystal formation I, II.
TGA-DSC test, ultimate analysis, monocrystalline test show: crystal formation I, II be not all in conjunction with solvent molecule; Crystal form II I combines 2 water moleculess.
The preparation of example of formulations 1 the compounds of this invention aseptic powder injection
1, prescription
Prescription 1
Methanesulfonic acid cinepazide crystal form I 500g
Prepare altogether 1000
Methanesulfonic acid cinepazide crystal form II 500g
Prepare altogether 1000
Methanesulfonic acid cinepazide crystal form III 100g
Prepare altogether 1000
2, preparation technology:
First will prepare preparation antibiotic glass bottle used and plug etc. and carry out aseptically process; Take raw material (feeding intake after conversion) and auxiliary material by above-mentioned formula again.Gains are placed in to the portioning machine packing, and detect at any time the amount of the gains in the vial of packing into.Jumped a queue on vial and gland, and carry out finished product and entirely examine, subsequently the packing warehouse-in.
The preparation of example of formulations 2 the compounds of this invention dispersible tablets
1, prescription:
Prescription 1:
Prescription 2:
Prescription 3:
2, preparation technology:
Take Microcrystalline Cellulose 100g and starch 100g according to prescription, put into fluid bed granulator and mix, spray into wherein water appropriate, stir 15 minutes, granulation, be placed in pelletizing machine by the gained particle again and carry out whole grain.Take Microcrystalline Cellulose 100g, sodium starch glycolate 25g, main ingredient 125g, mix rear mistake 100 mesh sieves.The learn from else's experience particle of whole grain, the powder after sieving and micropowder silica gel, the Magnesium Stearate of recipe quantity is placed in mixing tank and fully mixes, and the material of getting after mixing carries out content detection; The definite sheet weight sheet according to the assay result; Finished product is examined entirely, the packing warehouse-in.
The preparation that example of formulations 3 the compounds of this invention mouths collapse the solution sheet
1, prescription:
Prescription 1:
Prescription 2:
Prescription 3:
2, preparation technology:
Take main ingredient and Microcrystalline Cellulose, N.F,USP MANNITOL (or sorbyl alcohol), sodium starch glycolate, low-substituted hydroxypropyl cellulose according to prescription, raw material pulverizing is crossed to 100 mesh sieves, add the Magnesium Stearate of recipe quantity to be placed in mixing tank and fully mix, the material of getting after mixing carries out content detection; The definite sheet weight sheet according to the assay result; Finished product is examined entirely, the packing warehouse-in.
The chemical stability experiment of experimental example 1 methanesulfonic acid cinepazide crystal form
1 test sample
Test sample: methanesulfonic acid cinepazide raw material, crystal formation 1, crystal formation 2, crystal formation 3
Source: above-described embodiment 1-4 makes product
2 test conditionss
2.1 high temperature test
Get trial-product appropriate, put temperature and be under 60 ℃ of conditions and place 10 days, in the 10th day sampling and measuring, relatively after outward appearance, test indices by result and comparison in 0 day.
2.2 exposure experiments to light
Get trial-product appropriate, put illumination and be under the 4500LX condition and place 10 days, in the 10th day sampling and measuring, relatively after outward appearance, test indices by result and comparison in 0 day.
2.3 high wet test
Get trial-product appropriate, put relative humidity and be under 75% condition and place 10 days, in the 10th day sampling and measuring, relatively after outward appearance, test indices by result and comparison in 0 day.
3 test-results and evaluation
Chemical stability adopts the condition of influence factor test, inquires into the stability inferior at high temperature, illumination, high humidity part.
The evaluation of 1 high-temperature stability
2 light durability tests
3 high humidity estimation of stabilitys
Each index velocity of variation compares:
Conclusion:
High temperature is investigated: crystal formation I, and II, the III isomer changes all few than amorphous raw material, and indices is without considerable change, and crystal form II presents the trend that isomer oppositely transforms minimizing.
Illumination is investigated: the variation of crystal form II I isomer is more obvious than crystal formation I, crystal form II, and it is obvious that the isomer of crystal formation I, III changes more amorphous raw material, and other indexs are without considerable change.
High humidity is investigated: crystal formation I, and II, the III isomer changes all few than amorphous raw material, and crystal form II presents the trend that isomer oppositely transforms minimizing.Crystal formation I, II moisture absorption approximately 5%, crystal form II I moisture absorption is not obvious, and 3 kinds of crystal formations all have caking phenomenon.
In general, crystal formation I, II, III stability is better than amorphous raw material, crystal form II particularly, the stability performance under high temperature, illumination, super-humid conditions is more excellent.
Experimental example 2 methanesulfonic acid cinepazide crystal form solubleness are estimated
The solubleness of methanesulfonic acid cinepazide raw material and three kinds of crystal formations
| Compound | Water (1mL, 25 ℃) | Ethanol (1mL, 25 ℃) |
| The methanesulfonic acid cinepazide raw material | 1.320g | -- |
| Methanesulfonic acid cinepazide crystal form I | 1.3469g | 0.0042g |
| Methanesulfonic acid cinepazide crystal form II | 1.3683g | 0.0015g |
| Methanesulfonic acid cinepazide crystal form III | 1.3956g | 0.0078g |
Above-mentioned experimental data finds out, three kinds of its solubleness of crystal formation that the present invention obtains all are greater than amorphous raw material.
Claims (5)
1. methanesulfonic acid cinepazide crystal form III is characterized in that: it is the methanesulfonic acid cinepazide dihydrate, and its XRD-powder diagram as shown in Figure 7.
2. methanesulfonic acid cinepazide crystal form III as claimed in claim 1, is characterized in that: melt endotherm(ic)peak in its DSC and change at 246 ℃.
3. the preparation method of the described methanesulfonic acid cinepazide crystal form III of claim 1 or 2, under the lucifuge condition, be added to the 2g methanesulfonic acid cinepazide in 10ml water, dissolve, and add the 5g methanesulfonic acid cinepazide, stir 30min, filter, standing preservation 18 days, have solid to separate out, suction filtration, drain, normal temperature is placed 6h, collects sample, obtains the dihydrate of methanesulfonic acid cinepazide.
4. the described methanesulfonic acid cinepazide crystal form III of claim 1-2 any one treats and/or prevents the application in the medicine of cardiovascular and cerebrovascular diseases in preparation.
5. application according to claim 4, the formulation of described medicine is pharmaceutically acceptable arbitrary formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102683841A CN102351812B (en) | 2008-12-01 | 2008-12-01 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011102683841A CN102351812B (en) | 2008-12-01 | 2008-12-01 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008102278637A Division CN101747295B (en) | 2008-12-01 | 2008-12-01 | Methanesulfonic acid cinepazide crystal form and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102351812A CN102351812A (en) | 2012-02-15 |
| CN102351812B true CN102351812B (en) | 2013-12-18 |
Family
ID=45575482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011102683841A Active CN102351812B (en) | 2008-12-01 | 2008-12-01 | Methanesulfonic acid cinepazide crystal form III and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351812B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397411B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
| CN106397410B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
| CN106397412A (en) * | 2015-07-30 | 2017-02-15 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonists, a preparing method thereof and uses of the receptor agonists |
| CN106397413B (en) * | 2015-07-30 | 2021-03-26 | 四川科瑞德制药股份有限公司 | 5-hydroxytryptamine receptor agonist and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058568A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
| CN101058566A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
-
2008
- 2008-12-01 CN CN2011102683841A patent/CN102351812B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101058568A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
| CN101058566A (en) * | 2006-04-21 | 2007-10-24 | 车冯升 | Novel medicinal salt for cinepazide and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102351812A (en) | 2012-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103641822B (en) | A kind of Ka Gelie purifies compound and pharmaceutical composition thereof | |
| CN104211707B (en) | Nalmefene hydrochloride dihydrate | |
| CN103298819B (en) | Crystalline 6,7-unsaturated-7-carbamoyl morphinane derivative, and method for producing same | |
| CN103221411B (en) | (R) crystal formation of the chloro-N-of-7-(quinuclidine-3-yl) benzo [b] thiophene-2-carboxamide derivatives hydrochloride monohydrate | |
| CN104736538B (en) | A kind of crystal formation of inhibitor and its production and use | |
| CN102351853B (en) | Azilsartan medoxomil compound, preparation method and medicinal composition thereof | |
| CN103965114A (en) | Deuterated phenylamino pyrimidine compound and drug composition containing the same | |
| CN102351812B (en) | Methanesulfonic acid cinepazide crystal form III and preparation method thereof | |
| CN108137516A (en) | Crystal form, preparation method and the pharmaceutical composition of Ao Zhamode | |
| CN104017031A (en) | Hypoglycemic drug and composition | |
| TW202024066A (en) | Crystal form of morpholinyl quinazoline compound, preparation method and applications thereof | |
| CN101597271A (en) | The derivative of Ailamode, its preparation method and medicinal application | |
| CN105130996A (en) | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form | |
| CN102391209B (en) | Mesylate cinepazide crystal form II and preparation method thereof | |
| CN101747295B (en) | Methanesulfonic acid cinepazide crystal form and preparation method | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN108264465B (en) | Dapoxetine hydrochloride monohydrate, preparation method and application thereof | |
| CN101143834B (en) | Polymorphism for N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide sodium salt and preparation method thereof | |
| CN104784146A (en) | Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer | |
| CN105085421B (en) | Bit piperazine fumarate difficult to understand, hydrate, crystal formation and preparation method thereof | |
| CN104610208B (en) | Crystal formation A of (1S) 1,6 dideoxy 1 [4 methoxyl group 3 (trans 4 n-propyl cyclohexyl) aminomethyl phenyl] D glucopyranoses and its preparation method and application | |
| CN103664889B (en) | Lansoprazole compound | |
| CN110845492B (en) | Ipratropium bromide monohydrate | |
| CN110845491B (en) | Ipratropium bromide crystal | |
| CN105030772A (en) | Ilaprazole sodium composition serving as medicine for treating digestive diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20161122 Address after: 101113 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee after: Beijing Sihuan Pharmaceutical Co., Ltd. Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Address before: 101114 Beijing city Tongzhou District three Airport Hospital Patentee before: Beijing Sihuan Pharmaceutical Co., Ltd. |