CN106892900A - A kind of Vonoprazan fumarate and preparation method thereof - Google Patents
A kind of Vonoprazan fumarate and preparation method thereof Download PDFInfo
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- CN106892900A CN106892900A CN201710228875.0A CN201710228875A CN106892900A CN 106892900 A CN106892900 A CN 106892900A CN 201710228875 A CN201710228875 A CN 201710228875A CN 106892900 A CN106892900 A CN 106892900A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to pharmaceutical technology field, a kind of Vonoprazan fumarate and preparation method thereof is disclosed.The Vonoprazan fumarate purity that the present invention is provided is high,Good stability,The X ray powder diffractions that it is represented with the 2 θ ± 0.2 ° angles of diffraction are at 7.0981 °,11.3820°,13.0325°,16.1547°,17.8743°,18.9326°,19.6142°,21.3245°,22.8746°,24.0231°,24.7301°,25.8304°,26.5415°,28.3646°,28.4541°,29.4729°,31.5671°,34.3426°,36.4821 characteristic diffraction peak is shown at °,The X ray powder diffractograms obtained using Cu K alpha ray measurements are as shown in Figure 1,It is entirely different with prior art,Surprisingly find that the Vonoprazan fumarate dissolubility that the present invention is obtained is significantly improved through experiment.The invention also discloses the preparation method of Vonoprazan fumarate, the preparation method is simple to operation, and reaction condition is gentle, is adapted to large-scale production.The composition tablet dissolution rate and stability that Vonoprazan fumarate of the invention is made are significantly improved, and are especially suitable for clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of Vonoprazan fumarate and preparation method thereof.
Background technology
Vonoprazan fumarate, chemical entitled 1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Base]-N- methyl methylamine fumarates, its molecular formula is：C17H16FN3O2S·C4H4O4, molecular weight：461.46, chemical constitution is such as
Shown in Formulas I.Vonoprazan fumarate is a kind of new proton pump inhibitor, can be used as acid secretion inhibitors, neoplastic disease or from
The medicine of body immunity disease.Omeprazole etc. as proton pump inhibitor can effective gastric acid secretion inhibiting, but in acidity
Under the conditions of unstability and because metabolism enzyme polymorphism and the effect that causes of drug interaction are disperseed, Vonoprazan fumarate
Excellent in stability, more excellent therapeutic effect is shown with to peptic ulcer, reflux esophagitis etc. in acid condition.
One different crystal forms of bulk drug can have different chemically and physically characteristics, including fusing point, chemical reactivity, table
See solubility, optically and mechanically rate of dissolution, property, vapour pressure and density.These characteristics can directly affect bulk drug and system
The treatment and/or production of agent, and stability, solubility and the bioavilability of preparation can be influenceed.When compound has polycrystalline
During type, because specific polymorph has specific macroscopic property and stability, therefore during preparation, understand
The crystal formation of the compound applied in each formulation is important, to ensure the pharmaceutical activity chemical combination of process application same modality
Thing.Therefore, it is that the known mixture of single crystal formation or some crystal formations is necessary to keep pharmaceutical active compounds.
The A of patent CN 105315258 disclose Vonoprazan fumarate new crystal formation A, B and suitable industrialized production
Preparation method, the present invention prepares crystal formation preparation process is simple, and good stability meets medicinal requirements.Crystal formation A its preparation methods are：
Vonoprazan fumarate free alkali is dissolved in ethyl acetate, fumaric acid methanol solution is added, reaction is stirred at room temperature, filtered,
Obtain Vonoprazan fumarate A crystal formations after filter cake drying, crystal formation A is 15.290,20.403,20.704,21.572,25.182,
There is characteristic diffraction peak at 25.559, differential scanning calorimetric collection of illustrative plates has absworption peak at 204.8 DEG C.Crystal formation B its preparation methods are：By richness
Horse acid Wo Nuolazan A crystal formations are dissolved in the ketone aqueous solution of the aqueous solution of the alkylol of C1~C4 or below C4, heating stirring
Dissolving, stirring lets cool；Filtering, Vonoprazan fumarate B crystal form is obtained after filter cake drying, crystal formation B is 12.253,13.559,
15.259th, there is characteristic diffraction peak at 16.889,17.422,20.399,20.764,22.478,25.198,28.077.Differential thermal is swept
Retouch calorimetric collection of illustrative plates has absworption peak at 209.0 DEG C.
CN 106478597A disclose a kind of Vonoprazan fumarate monocrystalline and its production and use, and the present invention is rich
Horse acid Wo Nuolazan is easy to be separated with other impurities, and the Vonoprazan fumarate single crystal forms for obtaining are good, and HPLC purity can be high
Up to more than 99.5%, and the reappearance of the method is very good.Additionally, being irrigated using the fumaric acid that the method for the present invention is prepared
Nola praises monocrystalline, it is easy to the absolute structure of product is determined by the X-ray diffraction analysis of monocrystalline, and then, using when ensure that
The accuracy of the medicine containing Vonoprazan fumarate monocrystalline.The preparation method of this monocrystalline is：To Vonoprazan fumarate crude product
Middle addition recrystallisation solvent first alcohol and water (0.25-4:1, preferably 1:1)；And under predetermined temperature (20-30 degrees Celsius), slowly
Volatilization recrystallisation solvent, and culture 5-10 days is carried out, to obtain crystalline product, the crystalline product constitutes the fertile promise of the fumaric acid
Monocrystalline is praised in drawing.Monocrystalline of the present invention in θ=11.4 of the angle of diffraction 2,12.3,13.5,15.1,15.3,16.9,18.6,20.4,20.7,
There is characteristic peak at 22.4 and 25.1.
The A of CN 106317020 disclose a kind of Vonoprazan fumarate crystal formation α and preparation method thereof, and the crystal form purity is high,
And with good chemical stability and stability of crystal form, it is easy to prepare with scale, simple to operate, low cost, with wide
Application prospect.The preparation method of crystal formation α is：Will Vonoprazan fumarate crude product add glycol monoethyl ether in, heating 60 DEG C~
Backflow dissolving, is subsequently adding purified water, reaction is stirred at room temperature 1~2 hour, filters, and purifies water washing filter cake, dries, and obtains richness
Horse acid Wo Nuolazan crystal formations α.Determined through differential scanning calorimetric analysis (DSC), Vonoprazan fumarate crystal formation α of the invention, with 2
The X-ray powder diffraction (X-RPD) that θ angles are represented at 8.6 ± 0.2 °, 10.2 ± 0.2 °, 12.7 ± 0.2 °, 17.4 ± 0.2 °,
18.1 ± 0.2 °, 19.6 ± 0.2 °, 20.3 ± 0.2 °, 23.2 ± 0.2 °, 24.5 ± 0.2 °, there is diffraction maximum at 27.8 ± 0.2 °；
There is endothermic peak in the range of 166~204 DEG C in its DSC collection of illustrative plates；Preferably, the peak value of the endothermic peak of its DSC collection of illustrative plates appears in 194
At ± 2 DEG C.
CN106478601A discloses a kind of Vonoprazan fumarate novel crystal forms, its preparation method with ethyl acetate, methyl alcohol,
Purified water is mixed crystallization solvent, obtains the new crystal formation of Vonoprazan fumarate.In its powder x-ray diffraction collection of illustrative plates, spreading out
The θ of firing angle 2 is have characteristic peak at 12.18 ± 0.5,13.43 ± 0.5,22.35 ± 0.5,37.06 ± 0.5,38.25 ± 0.5.This hair
Bright described novel crystal forms have good stability, and can be prevented effectively from the increase of impurity of the drug, reduce the high cost that storage brings, to produce
The security of product and ensure that clinical efficacy brings effective guarantee.
The A of CN 104327051 disclose a kind of crystal form of the fumarate of azole derivatives, crystal form A purity
Height, good stability is adapted to preparation technical process and long term storage, also has superiority in industrial production.Its preparation method is：
1) by 1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3 base]-N- methyl methylamine list fumarates, or
Person adds 1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3 base]-N- methyl methylamines and fumaric acid respectively
In appropriate organic solvent, cooling, crystallization, the organic solvent are selected from alcohols, ketone of the carbon number less than or equal to 3 for heat of solution
Any one or a few mixed solvent of class, esters；Or their mixed solvents with water；Described organic solvent may be selected from
Methyl alcohol, ethanol, isopropanol, isobutanol, tert-pentyl alcohol, acetone, butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2- methyl
Tetrahydrofuran, isopropyl ether, methyl tertiary butyl ether(MTBE), methylcyclopentyl ether, acetonitrile, N,N-dimethylformamide, N, N- dimethyl second
Acid amides.2) filtering for crystallizing and wash, dry.Wherein about 5.1 (17.3), 10.1 (8.7), 11.4 (7.7), 11.5 (7.6),
12.2 (7.3), 13.4 (6.6), 13.9 (6.4), 15.2 (5.8), 16.1 (5.5), 16.6 (5.3), 16.9 (5.3) 17.3
(5.1), 17.8 (5.0), 18.5 (4.8), 19.1 (4.7), 20.0 (4.4), 20.3 (4.4), 20.6 (4.3), 21.0 (4.2),
21.5 (4.1), 22.4 (4.0), 23.0 (3.9), 23.5 (3.8), 24.3 (3.7), 25.1 (3.5), 25.5 (3.5) 26.0
(3.4) there is feature at, 26.7 (3.3), 27.6 (3.2), 27.9 (3.2), 28.8 (3.1), 29.1 (3.1), and 29.9 (3.0) places
Peak.Its fusing point is about 203 DEG C.
, in crystallization, if using different solvent and process conditions, its molecule is in each crystal formation for Vonoprazan fumarate
The number of permutations of structure cell and position and latticed form are different, form different crystal structures, Vonoprazan fumarate polymorphic
Change can change its property, quality and drug effect.Therefore, the stable crystalline of Vonoprazan fumarate, should for further research
The physicochemical properties of compound, study its drug regimen and clinical practice, and tool is of great significance.
Vonoprazan fumarate belongs to insoluble drug, typically applies in solid form in the formulation, the biology of its preparation
Availability quality directly affects its curative effect, and it is more sensitive to illumination, therefore research to its crystal formation has highly important meaning
Justice.In addition, impurity present in medicine influences larger thus appropriate impurity-removing method very necessary the quality of product.Due to
Troublesome impurity is more in Vonoprazan fumarate, and prior art does not provide efficient Vonoprazan fumarate purification process,
It is difficult to take into account yield and purity.
The present invention, using new method for crystallising, has obtained a kind of new fumaric acid Wo Nuola by substantial amounts of experimental study
Crystal formation is praised, the Vonoprazan fumarate purity that the present invention is provided is high, good stability, surprisingly find what the present invention was obtained through experiment
Vonoprazan fumarate dissolubility is significantly improved.The invention also discloses the preparation method of Vonoprazan fumarate, the preparation side
Method is simple to operation, and reaction condition is gentle, is adapted to large-scale production.The composition piece that Vonoprazan fumarate of the invention is made
Agent dissolution rate and stability are significantly improved, and are especially suitable for clinical practice.
The content of the invention
Goal of the invention of the invention is to propose a kind of Vonoprazan fumarate of good stability and preparation method thereof.
In order to realize the purpose of the present invention, the technical scheme for using for：
The present invention provides a kind of Vonoprazan fumarate compound, its X-ray powder represented with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum 7.0981 °, 11.3820 °, 13.0325 °, 16.1547 °, 17.8743 °, 18.9326 °, 19.6142 °,
21.3245°、22.8746°、24.0231°、24.7301°、25.8304°、26.5415°、28.3646°、28.4541°、
29.4729 °, 31.5671 °, 34.3426 °, show characteristic diffraction peak at 36.4821 °.
The X-ray powder diffraction that the Vonoprazan fumarate compound that the present invention is provided is obtained using Cu-K alpha ray measurements
Figure is as shown in Figure 1.
Present invention also offers a kind of preparation method of Vonoprazan fumarate compound, concretely comprise the following steps：
(1) Vonoprazan fumarate crude product is taken, the mixed solution of acetonitrile/tetramethylethylenediamine is added, is heated with stirring to complete
Portion dissolves, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol is added dropwise, continue crystallization of lowering the temperature；
(3) insulated and stirred is complete to crystallization, growing the grain, suction filtration, and washing is dried, and obtains white crystalline powder.
Preferably, in the acetonitrile described in step (1)/tetramethylethylenediamine mixed solution, acetonitrile and tetramethylethylenediamine
Volume ratio is 2~3:1；Step (1) the Vonoprazan fumarate crude product is 1g with the mass volume ratio of mixed solution:20ml~
30ml；Mixing speed described in step (1) is 30-50 revs/min.
Preferably, in the acetonitrile described in step (1)/tetramethylethylenediamine mixed solution, acetonitrile and tetramethylethylenediamine
Volume ratio is 2.5:1；Step (1) the Vonoprazan fumarate crude product is 1g with the mass volume ratio of mixed solution:25ml, step
Suddenly the mixing speed described in (1) is 40 revs/min.
Preferably, the volume ratio 0.5~1 of step (2) isopropanol and step (1) described mixed solution:1；Step (2)
The rate of addition be 1.0~2.0mL/min, the cooling extent be every 10 minutes 1 DEG C~3 DEG C；Step (2) the cooling analysis
Crystalline substance is to be cooled to -10 DEG C~-5 DEG C crystallizations.
Preferably, the volume ratio 0.8 of step (2) isopropanol and step (1) described mixed solution:1；Step (2) institute
Rate of addition is stated for 1.5mL/min, the cooling extent be every 10 minutes 2 DEG C；Step (2) the cooling crystallization is to be cooled to -8
DEG C crystallization.
Preferably, step (3) described rearing crystal time is 1h~4h；Step (3) described drying temperature is 40 DEG C~50 DEG C.
Preferably, step (3) described rearing crystal time is 2h；Step (3) described drying temperature is 45 DEG C.
In the present invention, described Vonoprazan fumarate crude product can be that Vonoprazan fumarate to be further purified is consolidated
Body mixture, or marketable material is prepared by art methods, the crystal formation result of gained is in error model
In enclosing, novel crystal forms of the present invention are.
Present invention also offers a kind of pharmaceutical composition containing Vonoprazan fumarate of the present invention, the pharmaceutical composition is
Tablet containing Vonoprazan fumarate.
The formation mechenism of crystal is very complicated, and the acquisition of a new crystal also has very big contingency, and sometimes different is molten
Agent, identical crystal structure can be produced under different crystallization conditions.Some specific crystal formations also can not necessarily obtain more added with
The physicochemical property of profit.The properties such as stability, hygroscopicity, dissolubility, bioactivity, the toxicity of medicine can be produced because of the difference of crystal formation
The huge difference of life.
The present invention is dissolved and different solvent crystallizations by substantial amounts of experiment sieving by selecting different solvents, is obtained
Preparation method of the invention, by the control to mixing speed, solvent load, temperature and rearing crystal time, unexpectedly obtains
A kind of Vonoprazan fumarate novel crystal forms.The Vonoprazan fumarate purity for providing of the invention is high, good stability, pleasantly surprised through testing
Ground finds that the Vonoprazan fumarate dissolubility that the present invention is obtained is significantly improved.The invention also discloses Vonoprazan fumarate
Preparation method, the preparation method is simple to operation, and reaction condition is gentle, is adapted to large-scale production.Fumaric acid of the invention irrigates promise
The composition tablet dissolution rate and stability that La Zan is made are significantly improved, and are especially suitable for clinical practice.
Research shows, in the X-ray powder diffraction pattern, the diffraction spectrogram obtained by novel crystal forms is for specific crystal formation
Often characteristic, the wherein relative intensity of bands of a spectrum (especially in low angle) may because of crystallization condition, particle diameter and its
The difference of its condition determination and the advantage orientation effect that produces and change.Therefore, the relative intensity of diffraction maximum is to targeted crystalline substance
Type is not characteristic, when judging whether identical with known crystal formation, it should be noted that the relative position at peak rather than
Their relative intensity.Vonoprazan fumarate provided by the present invention crystallizes its X-ray powder diffraction collection and prior art
Relative position with visibly different peak, it is seen that it is a kind of novel crystal forms unlike the prior art.
Studied to explain and illustrate skill of the present invention below by the Vonoprazan fumarate crystal formation that the present invention is provided
Art scheme：
1st, crystal formation detection
Take the Vonoprazan fumarate crystallization that the present invention is prepared, the X-ray powder obtained using Cu-K alpha ray measurements
Last diffraction pattern as shown in figure 1, its X-ray powder diffraction figure for being represented with 2 θ ± 0.2 angles of diffraction 7.0981 °, 11.3820 °,
13.0325°、16.1547°、17.8743°、18.9326°、19.6142°、21.3245°、22.8746°、24.0231°、
24.7301°、25.8304°、26.5415°、28.3646°、28.4541°、29.4729°、31.5671°、34.3426°、
Characteristic peak is shown at 36.4821 °.
2nd, differential thermal analysis and thermogravimetric analysis
Differential thermal and thermogravimetric analysis are carried out to Vonoprazan fumarate crystal prepared by the present invention, as a result as shown in Figure 2；Knot
Fruit shows that this product does not have absworption peak or without transition before 150 DEG C, illustrates nodeless mesh water or recrystallisation solvent in sample；This product
There is endothermic peak at about 216.3 DEG C.
3rd, water analysis
Determined using cassette moisture teller, the water content of Vonoprazan fumarate crystal of the present invention is 0.06%.
4th, purity detecting
Through HPLC purity detectings, the purity of the crystallization of vildagliptin that the present invention is prepared can reach 99.98~
99.99%.
Compared with prior art, the invention has the advantages that：
(1) Vonoprazan fumarate provided by the present invention is a kind of novel crystal forms different from prior art；Institute of the present invention
The preparation method of the Vonoprazan fumarate of offer is simple to operation, and reaction condition is gentle, is adapted to large-scale production.
(2) present invention provide Vonoprazan fumarate purity is high, good stability, surprisingly found through experiment of the invention
To Vonoprazan fumarate dissolubility significantly improve.The composition tablet dissolution rate that Vonoprazan fumarate of the invention is made
And stability is significantly improved, clinical practice is especially suitable for.
Brief description of the drawings
The present invention is further illustrated below in conjunction with the accompanying drawings：
Fig. 1 is the X-ray powder diffraction collection of Vonoprazan fumarate compound prepared by the embodiment of the present invention 1.
Fig. 2 is the TG-DSC collection of illustrative plates of Vonoprazan fumarate compound prepared by the embodiment of the present invention 1.
Specific embodiment
Technical scheme is described in detail with embodiment below, it will help to technical scheme
Advantage, effect have and further understand, embodiment does not limit protection scope of the present invention, and protection scope of the present invention is by weighing
Profit requires to determine.
Embodiment 1：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 2 to add acetonitrile/tetramethylethylenediamine:1) mixing
Solution 2000ml, stirring (50 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 1000ml is added dropwise with the speed of 1.0mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 3 DEG C) to -10 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 1h, suction filtration, washing, 45 DEG C of dryings obtain white crystalline powder.
Obtained white crystalline powder is shown in Fig. 1 using the X-ray powder diffraction spectrogram that Cu-K alpha ray measurements are obtained.
Embodiment 2：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 3 to add acetonitrile/tetramethylethylenediamine:1) mixing
Solution 2500ml, stirring (40 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 2500ml is added dropwise with the speed of 1.5mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 2 DEG C) to -8 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 2h, suction filtration, washing, 50 DEG C of dryings obtain white crystalline powder.
X-ray powder diffraction spectrogram and implementation that obtained white crystalline powder is obtained using Cu-K alpha ray measurements
Example 1 is similar.
Embodiment 3：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 2.5 to add acetonitrile/tetramethylethylenediamine:1) mixed
Solution 3000ml is closed, stirring (30 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 2400ml is added dropwise with the speed of 2.0mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 2 DEG C) to -5 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 3h, suction filtration, washing, 40 DEG C of dryings obtain white crystalline powder.
X-ray powder diffraction spectrogram and implementation that obtained white crystalline powder is obtained using Cu-K alpha ray measurements
Example 1 is similar.
Embodiment 4：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 3 to add acetonitrile/tetramethylethylenediamine:1) mixing
Solution 2500ml, stirring (40 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 1250ml is added dropwise with the speed of 1.5mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 1 DEG C) to -5 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 2h, suction filtration, washing, 45 DEG C of dryings obtain white crystalline powder.
X-ray powder diffraction spectrogram and implementation that obtained white crystalline powder is obtained using Cu-K alpha ray measurements
Example 1 is similar.
Embodiment 5：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 2.5 to add acetonitrile/tetramethylethylenediamine:1) mixed
Solution 2000ml is closed, stirring (30 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 1500ml is added dropwise with the speed of 2.0mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 2 DEG C) to -8 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 4h, suction filtration, washing, 40 DEG C of dryings obtain white crystalline powder.
X-ray powder diffraction spectrogram and implementation that obtained white crystalline powder is obtained using Cu-K alpha ray measurements
Example 1 is similar.
Embodiment 6：The preparation of fumaric acid Wo Nuola compounds
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 2 to add acetonitrile/tetramethylethylenediamine:1) mixing
Solution 3000ml, stirring (50 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol 3000ml is added dropwise with the speed of 1.0mL/min, continue (drop of lowering the temperature
Warm amplitude be every 10 minutes 3 DEG C) to -5 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 1h, suction filtration, washing, 50 DEG C of dryings obtain white crystalline powder.
X-ray powder diffraction spectrogram and implementation that obtained white crystalline powder is obtained using Cu-K alpha ray measurements
Example 1 is similar.
The present invention is further illustrated below by experimental example：
Experimental example 1：Solubility test
Trial target：Sample prepared by embodiment of the present invention 1-3；
Reference substance 1：With reference to Vonoprazan fumarate crystal form A prepared by 104327051 A embodiments of patent CN 1.
Reference substance 2：With reference to Vonoprazan fumarate crystal formation A prepared by 105315258 A embodiments of patent CN 1.
Reference substance 3：With reference to Vonoprazan fumarate crystal formation B prepared by 105315258 A embodiments of patent CN 2.
Reference substance 4：With reference to Vonoprazan fumarate crystal formation α prepared by 106317020 A embodiments of patent CN 1.
Reference substance 5：With reference to Vonoprazan fumarate monocrystalline prepared by patent CN 106478597A embodiments 2.
Reference substance 6：With reference to Vonoprazan fumarate crystal formation prepared by patent CN106478601A embodiments.
Reference substance 7：With reference to Vonoprazan fumarate prepared by 105085484 A embodiments of patent CN 1.
Reference substance 8：With reference to Vonoprazan fumarate crystal prepared by 105130955 A embodiments of patent CN one.
Reference substance 9：With reference to Vonoprazan fumarate crystal prepared by 105294653 A embodiments of patent CN 13.
Reference substance 10：With reference to Vonoprazan fumarate crystal prepared by patent CN106366071A embodiments 10.
Reference substance 11：With reference to Vonoprazan fumarate crystal prepared by 104860926 A embodiments of patent CN 1.
Reference substance 12：With reference to Vonoprazan fumarate crystal prepared by patent 101300229A embodiments 8.
Its dissolubility, method are determined with reference to Chinese Pharmacopoeia two notes on the use of version in 2015：Take this product appropriate, be separately added into water,
Every strength shaking in 5 minutes 30 seconds, the dissolving situation in 30 minutes is observed, obtained final product, the results are shown in Table 1.
The crystal formation of the invention of table 1 and reference substance the dissolubility test result in water
The aqueous sample that above-described embodiment 1-6 is dissolved is stirred 72 hours in 25 DEG C of constant temperature, samples 5ml.Sample is passed through
0.45 μm of filtering with microporous membrane, discards just filtrate, takes the μ L of subsequent filtrate 20 and determines solubility (mg/ml) in medicament contg as water.
The results are shown in Table 2：
Solubility contrast of the crystal formation of the present invention of table 2 with prior art crystal formation in water
As can be seen from the above table, at 25 DEG C, the solubility in water of Vonoprazan fumarate novel crystal forms of the present invention with it is existing
There is technology to compare, be significantly increased, achieve unexpected technique effect.
Embodiment 2：Solvent screening is tested
Operated using preparation method of the invention, it is specific as follows：
(1) Vonoprazan fumarate crude product 100g is taken, (volume ratio is 2~3 to add solvent orange 2 A:1) mixed solution
2000ml-3000ml, stirring (30-50 revs/min) is heated to whole dissolvings, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, solvent B (isopropanol and step is added dropwise with the speed of 1.0~2.0mL/min
(1) volume ratio 0.5~1 of the mixed solution:1), continue to lower the temperature (cooling extent be every 10 minutes 1 DEG C~3 DEG C) to -10 DEG C
~-5 DEG C of crystallizations；
(3) insulated and stirred is complete to crystallization, and growing the grain 1h~4h, suction filtration, washing, 40 DEG C~50 DEG C dryings obtain white crystals
Property powder.
The solvent screening experimental result of table 3
Experimental example 4：Stability test
Experimental example investigates the stabilization of the Vonoprazan fumarate crystallization that the present invention is provided by accelerated test and long term test
Property.
1st, accelerated test
Sample prepared by Example 1-3, places 6 months under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%,
Proterties, relevant material, content is measured by sampling respectively at 0,1,2,3,6 the end of month, 4 are the results are shown in Table.
Table 4：Accelerated test result (40 ± 2 DEG C of temperature, relative humidity 75 ± 5%)
As seen from Table 4, Vonoprazan fumarate crystallization of the present invention is in 40 ± 2 DEG C of temperature, the condition of relative humidity 75 ± 5%
Lower to place 6 months, relevant content of material does not have significantly raised, and each index has no significant change, and illustrates this product good stability.
2nd, long term test
Sample prepared by Example 1-3, places 6 months under conditions of 25 ± 2 DEG C of temperature, relative humidity 60 ± 5%,
Proterties, relevant material, content is measured by sampling respectively at 0,3,6,9,12,18,24 the end of month, 5 are the results are shown in Table.
Table 5：Long-term test results (25 ± 2 DEG C of temperature, relative humidity 60 ± 5%)
As seen from Table 5, Vonoprazan fumarate crystallization of the present invention is in 25 ± 2 DEG C of temperature, the condition of relative humidity 60 ± 5%
Lower to place 24 months stabilizations, each index has no significant change.Illustrate that chemical stability is good, be adapted to manufacture and the length of pharmaceutical preparation
Phase stores.
Claims (10)
1. a kind of Vonoprazan fumarate compound, it is characterised in that：Its X-ray powder represented with the 2 θ ± 0.2 ° angles of diffraction
Diffracting spectrum 7.0981 °, 11.3820 °, 13.0325 °, 16.1547 °, 17.8743 °, 18.9326 °, 19.6142 °,
21.3245°、22.8746°、24.0231°、24.7301°、25.8304°、26.5415°、28.3646°、28.4541°、
29.4729 °, 31.5671 °, 34.3426 °, show characteristic diffraction peak at 36.4821 °.
2. a kind of Vonoprazan fumarate compound as claimed in claim 1, it is characterised in that measured using Cu-K alpha rays
The X-ray powder diffraction figure for obtaining is as shown in Figure 1.
3. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 1 or 2, it is characterised in that including such as
Lower step：
(1) Vonoprazan fumarate crude product is taken, the mixed solution of acetonitrile/tetramethylethylenediamine is added, is heated with stirring to all molten
Solution, activated carbon decolorizing, filtering；
(2) step (1) filtrate is down to 0 DEG C, isopropanol is added dropwise, continue crystallization of lowering the temperature；
(3) insulated and stirred is complete to crystallization, growing the grain, suction filtration, and washing is dried, and obtains white crystalline powder.
4. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 3, it is characterised in that step (1)
In described acetonitrile/tetramethylethylenediamine mixed solution, acetonitrile is 2~3 with the volume ratio of tetramethylethylenediamine:1；Step (1)
The Vonoprazan fumarate crude product is 1g with the mass volume ratio of mixed solution:20ml~30ml；Stirring described in step (1)
Speed is 30-50 revs/min.
5. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 4, it is characterised in that step (1)
In described acetonitrile/tetramethylethylenediamine mixed solution, acetonitrile is 2.5 with the volume ratio of tetramethylethylenediamine:1；Step (1) institute
It is 1g that Vonoprazan fumarate crude product is stated with the mass volume ratio of mixed solution:25ml；Mixing speed described in step (1) is 40
Rev/min.
6. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 4, it is characterised in that step (2)
The volume ratio 0.5~1 of the isopropanol and step (1) described mixed solution:1；Step (2) described rate of addition be 1.0~
2.0mL/min, the cooling extent be every 10 minutes 1 DEG C~3 DEG C；Step (2) the cooling crystallization is to be cooled to -10 DEG C~-5
DEG C crystallization.
7. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 4, it is characterised in that step (2)
The volume ratio 0.8 of the isopropanol and step (1) described mixed solution:1；Step (2) described rate of addition is 1.5mL/min,
The cooling extent be every 10 minutes 2 DEG C；Step (2) the cooling crystallization is to be cooled to -8 DEG C of crystallizations.
8. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 4, it is characterised in that step (3)
The rearing crystal time is 1h~4h；Step (3) described drying temperature is 40 DEG C~50 DEG C.
9. a kind of preparation method of Vonoprazan fumarate compound as claimed in claim 4, it is characterised in that step (3)
The rearing crystal time is 2h；Step (3) described drying temperature is 45 DEG C.
10. a kind of pharmaceutical composition containing any described Vonoprazan fumarate compound of claim 1~2, its feature
It is that described pharmaceutical composition is the tablet containing Vonoprazan fumarate.
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| CN114989138A (en) * | 2021-03-02 | 2022-09-02 | 天地恒一制药股份有限公司 | Vonoprazan salt and crystal form, preparation method and application thereof |
| WO2023221419A1 (en) * | 2022-05-20 | 2023-11-23 | 山东道合药业有限公司 | Crystal form of vonoprazan pyroglutamate and preparation method therefor |
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Application publication date: 20170627 |