CN107033094A - A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition - Google Patents
A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition Download PDFInfo
- Publication number
- CN107033094A CN107033094A CN201610084946.XA CN201610084946A CN107033094A CN 107033094 A CN107033094 A CN 107033094A CN 201610084946 A CN201610084946 A CN 201610084946A CN 107033094 A CN107033094 A CN 107033094A
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- ahu
- stirred
- ahu377
- pentahydrate
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses the crystal formation of a kind of crystal formation of pharmaceutical co-crystals, i.e. the pentahydrate eutectic of AHU377 Valsartans trisodium half.In addition, the invention also discloses preparation method of above-mentioned eutectic crystal formation and combinations thereof.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, be related to a kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and
Pharmaceutical composition.
Background technology
Chinese patent CN101098689A discloses the eutectic compound (LCZ696) of a kind of AHU-377 and Valsartan, changes
Scientific name is [3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxy carbonyl -1- butylcarbamoyls) propionic acid-(S) -3 '-first
Base -2 '-(valeryl { 2 "-(tetrazolium -5- bases) biphenyl -4 '-ylmethyl } amino) butyric acid] half pentahydrate of trisodium, it is simultaneously open
The crystal formation and amorphous substance of the compound, and disclose the preparation method (needing to add crystal seed and obtain) of the eutectic.
In addition, Chinese patent application CN201510384430.2 discloses a kind of preparation method of LCZ696 eutectics, by essence
1: 1 mixed number is obtained the Valsartan of system in molar ratio with the pentahydrate of five sodium of AHU377 half.
Chinese patent application CN201510317119.6 also discloses that a kind of preparation method of LCZ696 eutectics, by AHU377
Valsartan is added in acetonitrile and 15ml isopropyl alcohol mixed solvents and is warming up to 50~55 DEG C, stirring to dissolved clarification；Protect under gentle agitation
Sodium hydrate aqueous solution is instilled, acetone is added and mixes crystallization through being dried to obtain LCZ696 white powdery solids again through n-butanol and neighbour
Xylene mixture solvent, activated carbon are heated to reflux, crystallization, and LCZ696 sterlings are produced after drying.
For LCZ696, this area has such demand：Suitable for industrial-scale production, high specific surface area
Novel crystal forms.
The content of the invention
The present inventor have surprisingly been discovered that a kind of novel crystal forms of the pentahydrate eutectic of AHU377 Valsartans trisodium half, into
Overcome the deficiency of prior art presence work(.
It is an object of the invention to provide a kind of crystal formation of the pentahydrate eutectic of AHU377 Valsartans trisodium half.
It is a further object to provide the preparation method of above-mentioned crystal formation.
Third object of the present invention is to provide the pharmaceutical composition for including above-mentioned crystal formation.
Specifically, the invention provides a kind of crystal formation of the pentahydrate eutectic of AHU377 Valsartans trisodium half, Cu- is used
Ka is radiated, in its X-ray diffraction (XRPD) figure, with spend 2 θ ± 0.1 represented 4.20,5.20,8.36,9.94,12.52,
14.98th, there is diffraction maximum at 16.98,17.82,18.10,18.82,19.42,20.04,20.82,22.68,25.20 and 27.12.
In one embodiment of the present invention, it is common the invention provides a kind of pentahydrate of AHU377 Valsartans trisodium half
Brilliant crystal formation, is radiated using Cu-Ka, in its X-ray diffraction (XRPD) figure, d values be 21.0,17.0,10.6,8.9,7.1,
5.9th, there is diffraction maximum at 5.2,5.0,4.9,4.7,4.6,4.4,4.3,3.9,3.5 and 3.3.
In one embodiment of the present invention, it is common the invention provides a kind of pentahydrate of AHU377 Valsartans trisodium half
Brilliant crystal formation, is radiated, its X-ray diffraction (XRPD) figure has following diffraction maximum using Cu-Ka：
。
On the other hand, the invention provides the preparation side of the above-mentioned pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half
Method, comprises the following steps：
(1) AHU-377 calcium salts are added in ethyl acetate and hydrochloric acid, 20-30 DEG C of stirring to complete molten, insulated and stirred, split-phase,
It is post-treated to obtain AHU-377 free acids；
(2) the AHU-377 free acids for obtaining step (1) are added in acetone, are added Valsartan, are stirred at room temperature；It is added dropwise
Sodium hydrate aqueous solution, insulated and stirred.
In one embodiment of the present invention, the pentahydrate eutectic of AHU377 Valsartans trisodium half that the present invention is provided is new
The preparation method of crystal formation, wherein, the mol ratio of AHU-377 calcium salts and Valsartan in step (2) is 2: 1 in step (1).
The third aspect, the invention provides the medicine for including the above-mentioned pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half
Compositions and pharmaceutic adjuvant.Here, described pharmaceutic adjuvant may be selected from excipient, adhesive, disintegrant, glidant and profit
It is one or more in lubrication prescription.
In embodiments of the invention, the pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half that the present invention is provided
Pharmaceutical composition, wherein, the excipient includes but is not limited to：Microcrystalline cellulose, starch, pregelatinized starch, sucrose, lactose,
Mannitol, calcium monohydrogen phosphate, xylitol；Preferably microcrystalline cellulose, pregelatinized starch, mannitol, amount ranges 10%~80%.
In embodiments of the invention, the pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half that the present invention is provided
Pharmaceutical composition, wherein, described adhesive includes but is not limited to：Polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl are fine
Tie up element, xanthans, sodium alginate；It is preferred that polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, amount ranges 2%~
20%.
In embodiments of the invention, the pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half that the present invention is provided
Pharmaceutical composition, wherein, the disintegrant includes but is not limited to：Sodium carboxymethyl starch, Ac-Di-Sol, low substitution
Hydroxypropyl cellulose, PVPP；It is preferred that low-substituted hydroxypropyl cellulose, Ac-Di-Sol, amount ranges 1%
~30%.
In embodiments of the invention, the pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half that the present invention is provided
Pharmaceutical composition, wherein, the glidant and lubricant include but is not limited to：Silica, talcum powder, magnesium stearate, poly- second
Glycol, hydrogenated vegetable oil, fumaric acid odium stearate, lauryl sodium sulfate, calcium stearate, stearic acid；Amount ranges 0.1%~
10%.
The pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half of Examples 1 and 2 are wanted with above-mentioned in the present invention
Tablet made from the capsule or use vertical compression being mixed with auxiliary material with certain proportion has 30 under the conditions of pH6.8 buffer salt
It is more than more than 85% good dissolution rate in minute.
The pentahydrate eutectic novel crystal forms of AHU377 Valsartans trisodium half of Examples 1 and 2 are wanted with above-mentioned in the present invention
The capsule or the tablet of compacting being mixed with auxiliary material with certain proportion, are investigated 3 months under 40 degree of acceleration environments, scan its X-
RPD collection of illustrative plates is consistent.
In the present invention, X- powder diffractions tester involved in the present invention and test condition are：Anode turns target X- and penetrated
Line diffractometer D/max-2500/PC types (Rigaku)；Copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, diverging
Slit and antiscatter slits are 1 °, receptions slit is 0.3mm, 5 °/min of sweep speed, 3~40 ° of scanning range.
Embodiment
Embodiments of the present invention are illustrated below by example, it is for a person skilled in the art, following
Embodiment does not constitute limiting the scope of the present invention, while according to the teachings of the present invention, changed and obtained using equivalent substitution
To technical scheme still fall within protection scope of the present invention.
Embodiment 1
1 will add ethyl acetate 40mL, 1N hydrochloric acid 40mL in AHU-377 calcium salts 4.3g, 20-30 DEG C of stirring is protected to complete molten
Temperature stirring 10min, split-phase, organic phase is washed with water 50mL*3, and anhydrous sodium sulfate drying, suction filtration is dense dry, is obtained AHU-377 and is dissociated
Acid.
2 add acetone 60mL into AHU-377 free acids, and are made marks outside bottle, continuously add acetone 20mL, and mark
Note, adds Valsartan 4.35g, 5min is stirred at room temperature, the 2mL aqueous solution of 1.18g sodium hydroxides, insulated and stirred 0.5h is slowly added into
(a large amount of white solid precipitations).
Reaction solution is warming up to 40-45 DEG C by 3, adds ethyl acetate 40mL, insulated and stirred 0.5h, 40 DEG C of volumes that are concentrated under reduced pressure
To about 80mL, ethyl acetate 60mL is added in 40-45 DEG C again, insulated and stirred 0.5h, the volume that is concentrated under reduced pressure to about 60mL, again
In adding ethyl acetate 80mL, insulated and stirred 0.5h at 40-45 DEG C, volume about 60mL, insulated and stirred 0.5h are concentrated under reduced pressure into, is dropped
Temperature is to 25-30 DEG C, and insulated and stirred 1h, suction filtration, ethyl acetate elution, filter cake is dried under vacuum to constant weight in 35 DEG C, obtains white solid
8.5g, yield 88%.Cattell method measures moisture：5.3%；
Embodiment 2
1 will add ethyl acetate 65mL, 1N hydrochloric acid 65mL in AHU-377 calcium salts 13.9g, 20-30 DEG C of stirring is protected to complete molten
Temperature stirring 10min, split-phase, organic phase is washed with water 50mL*3, and anhydrous sodium sulfate drying, suction filtration is dense dry, is obtained AHU-377 and is dissociated
Acid.
2 add acetone 140mL, Valsartan 14g into AHU-377 free acids, and 5min is stirred at room temperature, 3.8g hydrogen is slowly added into
The 24.5mL aqueous solution of sodium oxide molybdena, insulated and stirred 0.5h.
3 are concentrated under reduced pressure into above-mentioned 40 DEG C of reaction solution dry, obtain glassy dope, and acetone 140mL, room temperature are added again
Lower stirring and crystallizing (a large amount of white solid precipitations), insulated and stirred 1h, suction filtration, acetone elution, 35 DEG C are dried under reduced pressure to constant weight, obtain
White solid 25.7g, yield 83%.Cattell method measures moisture：5.1%.
Claims (6)
1. a kind of crystal formation of the pentahydrate eutectic of AHU377 Valsartans trisodium half, is radiated, its X-ray diffraction using Cu-Ka
(XRPD) in figure, with spend 2 θ ± 0.1 represented 4.20,5.20,8.36,9.94,12.52,14.98,16.98,17.82,
18.10th, there is diffraction maximum at 18.82,19.42,20.04,20.82,22.68,25.20 and 27.12.
2. a kind of crystal formation of the pentahydrate eutectic of AHU377 Valsartans trisodium half, is radiated, its X-ray diffraction using Cu-Ka
(XRPD) in figure, d values be 21.0,17.0,10.6,8.9,7.1,5.9,5.2,5.0,4.9,4.7,4.6,4.4,4.3,3.9,
There is diffraction maximum at 3.5 and 3.3.
3. crystal formation as claimed in claim 1 or 2, is radiated using Cu-Ka, its X-ray diffraction (XRPD) figure has following spread out
Penetrate peak：
。
4. the preparation method of crystal formation, comprises the following steps as any one of claim 1-3：
(1) AHU-377 calcium salts are added in ethyl acetate and hydrochloric acid, 20-30 DEG C of stirring to complete molten, insulated and stirred, split-phase, after
Handle to obtain AHU-377 free acids；
(2) the AHU-377 free acids for obtaining step (1) are added in acetone, are added Valsartan, are stirred at room temperature；Hydrogen-oxygen is added dropwise
Change sodium water solution, insulated and stirred.
5. preparation method as claimed in claim 4, wherein, AHU-377 calcium salts and Valsartan in step (2) in step (1)
Mol ratio is 2: 1.
6. include the pharmaceutical composition of crystal formation any one of claim 1-3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610084946.XA CN107033094A (en) | 2016-02-04 | 2016-02-04 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610084946.XA CN107033094A (en) | 2016-02-04 | 2016-02-04 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107033094A true CN107033094A (en) | 2017-08-11 |
Family
ID=59532804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610084946.XA Pending CN107033094A (en) | 2016-02-04 | 2016-02-04 | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107033094A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109265406A (en) * | 2018-09-03 | 2019-01-25 | 石药集团中奇制药技术（石家庄）有限公司 | One seed sand library Ba Qu Valsartan sodium novel crystal form and its preparation method and application |
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
| CN112574132A (en) * | 2019-09-30 | 2021-03-30 | 广东东阳光药业有限公司 | Preparation method of shakubiqu valsartan sodium |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN104860894A (en) * | 2015-06-10 | 2015-08-26 | 北京博全健医药科技有限公司 | Method for preparing cardiotonic drug LCZ696 |
| CN105001173A (en) * | 2015-06-30 | 2015-10-28 | 浙江天顺生物科技有限公司 | Preparation method of LZ969 |
| CN105037289A (en) * | 2015-07-17 | 2015-11-11 | 华东理工大学 | Novel crystalline form of angiotensin receptor antagonist and neutral endopeptidase inhibitor supramolecular complex |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
-
2016
- 2016-02-04 CN CN201610084946.XA patent/CN107033094A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN104860894A (en) * | 2015-06-10 | 2015-08-26 | 北京博全健医药科技有限公司 | Method for preparing cardiotonic drug LCZ696 |
| CN105001173A (en) * | 2015-06-30 | 2015-10-28 | 浙江天顺生物科技有限公司 | Preparation method of LZ969 |
| CN105037289A (en) * | 2015-07-17 | 2015-11-11 | 华东理工大学 | Novel crystalline form of angiotensin receptor antagonist and neutral endopeptidase inhibitor supramolecular complex |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020039386A1 (en) | 2018-08-23 | 2020-02-27 | Novartis Ag | New pharmaceutical use for the treatment of heart failure |
| WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
| CN109265406A (en) * | 2018-09-03 | 2019-01-25 | 石药集团中奇制药技术（石家庄）有限公司 | One seed sand library Ba Qu Valsartan sodium novel crystal form and its preparation method and application |
| CN109265406B (en) * | 2018-09-03 | 2020-09-22 | 石药集团中奇制药技术（石家庄）有限公司 | New crystal form of Sacubitril valsartan sodium and preparation method and application thereof |
| CN112574132A (en) * | 2019-09-30 | 2021-03-30 | 广东东阳光药业有限公司 | Preparation method of shakubiqu valsartan sodium |
| CN112574132B (en) * | 2019-09-30 | 2024-02-27 | 广东东阳光药业股份有限公司 | Preparation method of sarcandra/valsartan sodium |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1720853B1 (en) | Novel polymorphic form of imatinib mesylate and a process for its preparation | |
| US20230183235A1 (en) | Solid state forms of amg-510 and process for preparation thereof | |
| US10314819B2 (en) | Solid state forms of Eluxadoline | |
| JP5160892B2 (en) | A novel crystal form of (3-cyano-1H-indol-7-yl)-[4- (4-fluorophenethyl) piperazin-1-yl] methanone hydrochloride | |
| CN107033094A (en) | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition | |
| US9856270B2 (en) | Dolutegravir salts | |
| US20180237438A1 (en) | Crystal form of bisulfate of jak inhibitor and preparation method therefor | |
| US20120289701A1 (en) | Forms of lapatinib ditosylate and processes for preparation thereof | |
| WO2006050921A2 (en) | Preparation of telmisartan salts with improved solubility | |
| WO2016107289A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
| US10377712B2 (en) | Process for preparation of apremilast and novel polymorphs thereof | |
| KR102657147B1 (en) | Crystalline form of bilastin and method for producing the same | |
| JP2004513106A (en) | Crystal form of venlafaxine hydrochloride | |
| US10738013B2 (en) | Eluxadoline crystalline forms and processes for their preparation | |
| US10233144B2 (en) | Crystalline form of AHU377, preparation method and use thereof | |
| WO2018229704A1 (en) | Novel polymorphs of eluxadoline and its solvates, process for its preparation and pharmaceutical composition thereof | |
| JP2020517674A (en) | Method for producing vortioxetine HBr α form | |
| WO2022177927A1 (en) | Unhydrous crystalline form of omecamtiv mecarbil dihydrobromide salt | |
| CA2452253C (en) | Novel crystal of arylethenesulfonamide derivative and preparation process thereof | |
| US10913721B2 (en) | Crystalline form of aripiprazole | |
| KR102128883B1 (en) | Novel polymorphic form of high purity aripiprazole and preparation method thereof | |
| WO2016127962A1 (en) | An amorphous solid form of suvorexant with sulphuric acid | |
| US20220009893A1 (en) | Solid state forms of reproxalap | |
| CN117425651A (en) | Hydrate crystal form of Lazertinib mesylate as well as preparation method and application thereof | |
| JP2016534047A (en) | Tenofovir Disoproxil Dihydrogen Phosphate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170811 |