CN110372575A - A kind of dihydropyridine calcium antagonist eutectic and its preparation method and application - Google Patents
A kind of dihydropyridine calcium antagonist eutectic and its preparation method and application Download PDFInfo
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- CN110372575A CN110372575A CN201910620005.7A CN201910620005A CN110372575A CN 110372575 A CN110372575 A CN 110372575A CN 201910620005 A CN201910620005 A CN 201910620005A CN 110372575 A CN110372575 A CN 110372575A
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- eutectic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention relates to a kind of dihydropyridine calcium antagonist eutectic and its preparation method and application, eutectic molecular formula is (C20H25ClN2O5)·(C6H5COOH)·(Y)n, wherein Y is any one of hydrone, ethanol molecule or isopropanol molecule, 0≤n≤3, and eutectic crystallization is in anorthic system, P1 chiral space group, unit cell dimension: α=97.1~97.5 °, β=92.2~92.6 °, γ=111.5~112.1 °,The present invention improves the dissolubility and stability of existing levamlodipine eutectic crystal form, potentially, is conducive to the promotion of depressor tablet stability and the improvement of bioavilability in large-scale production tablet.
Description
Technical field
The present invention relates to crystal form technical field of pharmaceuticals, and in particular to a kind of dihydropyridine calcium antagonist eutectic and its preparation
Methods and applications.
Background technique
Crystal form drug due to stability, reproducibility, bioavilability and operability etc. advantage, it is excellent in patent medicine
First select.Crystal form drug includes the types such as polymorphic, hydrate, solvate and the salt of drug molecule.The crystal form of drug is not
Together, physicochemical property difference is significant, will have a direct impact on its dissolution and absorption efficiency in physiological conditions, and then influence drug
Bioavilability and clinical efficacy etc..
Forth generation dihydropyridine calcium ion antagonist depressor of the levamlodipine as treatment hypertension, due to treating
Effect height, Small side effects, the deep trust by numerous doctors patient are treatment hypertension common drugs.Levamlodipine is a kind of
Free alkali compound need to be crystallized at salt.Currently, domestic commercially available levamlodipine is mainly the left-handed ammonia of benzene sulfonic acid at salt drug
Flordipine and maleic acid levo amido chloro diping (structural formula is as follows).
The left-handed ammonia chlorine of benzene sulfonic acid, though good effect, few side effects, the deep trust by patient, Levamlodipine besylate
Eutectic crystal form, especially hydration eutectic crystal form, stability is unsatisfactory.Benzene sulfonic acid is replaced with into maleic acid, the Malaysia of exploitation
Sour levamlodipine, although eutectic stability of crystal form slightly improves, studies have shown that the treatment of maleic acid levo amido chloro diping
It imitates unsatisfactory.Therefore, around levamlodipine free alkali, new eutectic crystal form is developed, it is two that exploring, which improves the above problem,
One of the important content of pyridinium hydroxide class calcium antagonist new drug development.
Summary of the invention
The purpose of the present invention is to solve the above-mentioned problems and provide a kind of dihydropyridine calcium antagonist eutectic and its
Preparation method and application.
The purpose of the present invention is achieved through the following technical solutions:
A kind of dihydropyridine calcium antagonist eutectic, eutectiferous molecular formula are as follows: (C20H25ClN2O5)·
(C6H5COOH)·(Y)n, wherein Y is any one of hydrone, ethanol molecule or isopropanol molecule, 0≤n≤3,
C20H25ClN2O5It is levamlodipine, C6H5COOH is benzoic acid.
It should be noted that the specific value of n is limited to the type of solvent in salt-forming reaction, temperature condition and subsequent
Product drying condition and have it is a certain range of cash, this variation does not influence eutectic crystal form.
The eutectic is crystallized in anorthic system, P1 chiral space group, unit cell dimension: α=97.1~97.5 °, β=92.2~92.6 °, γ=111.5~112.1 °,
It should be noted that numerical value is to be limited to solvent molecule and a in the bracket of unit cell numerical value, chiral Flack value
The numerical error that number, test equipment and analysis method generate.
Above-mentioned crystallography measurement parameter is obtained by X-ray single crystal diffraction test method, and basic process is as follows:
The crystal of size needed for meeting test is chosen, and the crystal " riveting " is fixed on survey in glass fiber top
On test instrument.X-ray crystal data is collected on German Brooker Apex Duo model instrument, is radiated with MoK αDiffraction data is collected with ω scanning mode and carries out Lp correction.Absorption correction uses SADABS program.
With direct method analytic structure, whole non-hydrogen atoms are found out with difference Fourier method, the hydrogen atom on all carbon and nitrogen is using theoretical
Hydrogen is added to obtain, the hydrogen atom of crystalline water molecules is directly found out from difference Fourier figure, using least square method to structural modifications.
All resolvings are completed using SHELXTL program bag.
The characteristic X-ray powder diffraction data of the eutectic crystal form of the dihydropyridine calcium antagonist and X-ray wave used
Long unrelated interplanar distanceThe main diffraction data reproduced is as follows:
It should be noted that, in conjunction with Prague correlation theory formula, can be calculated as previously described based on given numerical value
The crystallographic system of eutectic crystal form of dihydropyridine calcium antagonist provided by the invention, unit cell numerical value, be not offered as the eutectic crystal form
The number at X-ray powder diffraction peak is only limitted to number listed in table.
The eutectic crystal form of the dihydropyridine calcium antagonist is above-mentioned benzoic acid levamlodipine eutectic crystal form, described
The preparation method of benzoic acid levamlodipine eutectic crystal form the following steps are included:
(1) levamlodipine free alkali is completely dissolved and obtains reaction solution in a solvent；
(2) under the conditions of being stirred at room temperature, a certain amount of salt-forming reagent is added into reaction solution, obtains salt-forming reaction solution；
(3) reaction solution stirring is warming up to target temperature held for some time, is then allowed to stand cooling crystallization, is separated by filtration, i.e.,
?.
Preparation method provided by the present invention is the method that classical free alkali is crystallized at salt, it may be assumed for preparing free alkali first
Then salt-forming reagent is added in solution, crystallized to be prepared.
It should be noted that levamlodipine used herein is commercially available industrial chemicals, if being used for pharmacy, make
It is optimal with the bulk pharmaceutical chemicals for meeting GMP requirement, using crystallization in P212121Levamlodipine free alkali as raw material.This
In the solvent that uses be isopropanol, ethyl alcohol, any one commercially available industrial chemicals in water, if it is for pharmacy, then preferably make
With the coordinative solvent for meeting pharmaceutical requirements.
In step (1), the ratio of the levamlodipine free alkali and the solvent can be according to production need
It was determined that for the purpose of being completely dissolved levamlodipine free alkali, preferably, in the step (1), the left-handed ammonia
The molar ratio of Flordipine free alkali and the solvent is 1:50~200.
In step (2), the salt-forming reagent refers to benzoic acid, and the amount of the benzoic acid of the addition is left-handed to meet
Amlodipine free base completely at salt for the purpose of, preferably, in the step (2), the levamlodipine free alkali
Molar ratio with the benzoic acid is 1:1~2.
In step (2), the specific adding manner that benzoic acid is added can determine according to the needs of production, can be
Solidapowder form is added, and the solution form for being also possible to configure benzoic acid is added, preferably, benzoic acid, which is configured to concentration, is
The solution of 0.5~2M is added.
In step (3), the reaction solution is warming up to target temperature and refers in 50~120 DEG C of temperature ranges, preferably,
80~100 DEG C, the held for some time refers to that the time not less than 2 hours, is less than this numerical value, it is difficult to form crystal phase or yield
Economic benefit it is too low, preferably, 5~24 hours.
In step (3), the insulating process can be determined according to specific production Instrumental appointed condition, and constant temperature can be used
Heating device makes its sealed thermal insulating, is also possible to be heated to reflux device, preferably, being kept the temperature using confined reaction instrument.
It further include standing cooling, cooling temperature in the preparation step (3) of the levamlodipine eutectic product
It is generally lower than insulation reaction temperature, preferably, cooling the temperature to 5-25 DEG C of crystallization in the step (3).
In order to obtain crystalline product, preferably, further including filtering in the step (3), (original crystallization is molten for mother liquor washing
Liquid), drying at room temperature.
The filtering can use any suitable method, preferably, the filtering is decompression in the step (3)
Filtering.
By the above method prepare a kind of eutectic crystal form of dihydropyridine calcium antagonist, be in appearance it is needle-shaped or
Rodlike colourless transparent crystal.
The present invention improves the dissolubility and stability of existing levamlodipine eutectic crystal form, potentially, extensive
Be conducive to the promotion of depressor tablet stability and the improvement of bioavilability in production tablet, have and be different from a benzene sulfonic acid left side
The molecular structural formula of Amlodipine and maleic acid levo amido chloro diping is revolved, there is specific crystal form and atomic space position, it is clear
Crystallography major parameter, potentially, the control of quality suitable for large-scale production.
Beneficial effects of the present invention, or major advantage compared with prior art is:
(1) the eutectic crystal form of a kind of dihydropyridine calcium antagonist provided by the invention, in anorthic system, P1 is chiral empty for crystallization
Between group crystal, have specific crystal form, crystallography major parameter and exact atomic space position, numerical value be different from any one
The eutectic crystal form of kind clinic or commercially available dihydropyridine type calcium antagonists.
(2) a kind of eutectic crystal form of dihydropyridine calcium antagonist provided by the invention is specifically benzoic acid levamlodipine
Crystal, be different from clinical or commercially available Levamlodipine besylate, maleic acid levo amido chloro diping.
(3) preparation method of the eutectic crystal form of a kind of dihydropyridine calcium antagonist provided by the invention, raw material sources are wide, grasp
Make simple, crystal habit rule, particle size is uniform, there are specific X-ray powder diffraction data, answers suitable for large-scale promotion
With.
(4) the eutectic crystal form of a kind of dihydropyridine calcium antagonist of the invention of parameter as characterized above improves existing
There are the dissolubility and stability of levo-amlodipine salt, is conducive to promotion and the biological utilisation of levo-amlodipine agent stability
The improvement of degree.
Detailed description of the invention
Fig. 1 is the crystal structure signal of a specific embodiment of dihydropyridine calcium antagonist eutectic crystal provided by the invention
Figure.
Fig. 2 is the packing of molecules structure of a specific embodiment of dihydropyridine calcium antagonist eutectic crystal provided by the invention
Schematic diagram.
Fig. 3 is the X-ray powder of a specific embodiment of the dihydropyridine calcium antagonist eutectic crystal of offer of the invention
Diffraction spectrogram.
Fig. 4 is the heat analysis spectrum of a specific embodiment of the dihydropyridine calcium antagonist eutectic crystal form of offer of the invention
Figure.
Specific embodiment
The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.
For a kind of dihydropyridine calcium antagonist eutectic crystal form clearly provided by the invention, the present invention is in a large amount of drug knot
It is successfully prepared the crystalline product on the basis of brilliant research experiment, provides specific crystallographic parameter, levamlodipine molecule
The space conformation of middle functional group.In order to be more clearly understood that technology contents of the invention, spy lifts following embodiment specifically
It is bright.
Embodiment 1
The preparation of benzoic acid levamlodipine crystal
1) 2.04 grams of levamlodipine free alkali are weighed, is added it in the aqueous solution of 4.5mL, is stirred at room temperature to complete
Dissolution；
2) room temperature configuration concentration is the benzoic acid aqueous solution of 1M, under the conditions of being stirred at room temperature, by the aqueous solution of 5mL benzoic acid
In being added drop-wise to dropwise in 30 seconds in solution 1)；
3) above-mentioned salt-forming reaction solution is transferred in reaction kettle, increases the temperature of reaction solution to 50 DEG C, keeps the temperature 5 hours,
It is then allowed to stand and is cooled to 5 DEG C, obtain a large amount of needle-shaped or rodlike crystalline products colorless and transparent, pattern is uniform；
4) resulting crystalline product is filtered under diminished pressure, former crystallization solution washing, 5 DEG C of aqueous solvent washs to get Fig. 1 is
Crystal structure schematic diagram, Fig. 2 are packing of molecules structural schematic diagram.
Embodiment 2-8
The preparation method is the same as that of Example 1, and specific technological parameter is shown in Table 1.
1 embodiment 2-8 technological parameter of table
Embodiment 9
The test of X-ray single crystal diffraction
By taking benzoic acid levamlodipine eutectic crystal prepared by embodiment 1 as an example, selects crystal quality and size meets
The crystal that test equipment requires, is tested using the X-ray single crystal diffractometer of German Brooker company Apex Duo model,
Test parameter is carried out according to the strategy that instrument is formulated.Test temperature is 296K, is radiated with Mo-K αWith ω
Scanning mode collects diffraction data and carries out Lp correction.Absorption correction uses SADABS program.With direct method analytic structure, with difference
Value Fourier method finds out whole non-hydrogen atoms, and the hydrogen atom on all carbon and nitrogen is obtained using theoretical plus hydrogen, using least square
Method is to structural modifications.All resolvings are completed using SHELXTL program bag.
In above-mentioned measurement, crystal test can be tested on any X-ray single crystal diffraction instrument, be not limited to Germany
Brooker company Apex Duo model, light source are not limited to Mo target.Resulting crystallographic data is tested independent of analytic method.
Test and parsing gained crystallographic data are as shown in table 2.
2 crystallographic data of table
Embodiment 10
The test of X-ray powder polycrystalline diffraction
Benzoic acid levamlodipine polycrystalline product in Example 1, is penetrated using German Brooker Advance D8X-
Line polycrystalline diffractometer tests it, and test parameter is default standard setting, room temperature tabletting test.In order to guarantee test effect
Fruit has preferable reproducibility, avoids strength difference caused by particle high preferred orientation difference, and sample to be tested need to be ground through tabletting,
300 meshes point, and granulating working procedure is handled again.Copper target K α 1 is radiated Irradiation wavelengths, scanning angle from 1~
50 °, the example spectrogram of test is as shown in figure 3, the sample of the polycrystalline product of embodiment 2-8 has similar X-ray powder polycrystalline
Diffraction spectrogram.
Embodiment 11
The thermogravimetric stability of benzoic acid levamlodipine crystal
The benzoic acid levamlodipine polycrystalline of 1 preparation process of Example production is opened after reproducing grain process
Open up thermal stability research.(TG-DSC) test, test condition: N are carried out using TAQ600 analyzer2Atmosphere, temperature range 25-
500 DEG C, 10 DEG C/min of heating rate.The temperature that compound is thermally decomposed as the result is shown shows offer of the present invention at 150 DEG C or more
Crystal form thermal stability with higher, Thermal Chart as shown in figure 4, embodiment 2-8 sample have similar thermostabilization
Property.
Embodiment 12
The solubility test of benzoic acid levamlodipine crystal
Solubility test tests characterization process according to drug solubility.Specifically, accurately weighing 200 milligrams of sieving sample
Product are placed in vial after being granulated, and being scattered in temperature is 37 DEG C, then closed in the PBS buffer solution that pH is 7.4, are put
It is placed on the shaking table that temperature is 37 DEG C, sets 100rpm for revolving speed.It, will using 200nm filter membrane in t=5 hours taking-up bottles
Solid is separated with filtrate, and the content in filtrate uses the ultraviolet-visible analytical content of 238nm wavelength.Sample is parallel
Measurement 3 times, it is 0.134 ± 0.014mg/mL that measurement, which obtains its solubility, shows crystal form provided by the invention relative to benzene sulfonic acid
Levamlodipine solubility increases.The sample of embodiment 1-8 has similar solubility.
In conclusion the present invention is different from city using the benzoic acid levamlodipine of free alkali eutectic salifying method preparation
The Levamlodipine besylate and maleic acid levo amido chloro diping for selling clinical use are a kind of dihydropyridine type calcium antagonists
New eutectic crystal form, has specific crystallography relevant parameter, the steric configuration and arrangement of unit cell size and eutectic structure.This hair
This dihydropyridine calcium antagonist eutectic crystal form raw material of bright offer is easy to get extensively, and preparation method is simple, obtained crystalline substance
Body crystal form rule, particle size is uniform, can satisfy the requirement of X-ray diffraction test, and correlated quality is easily controllable, is suitable for big
Scale promotes and applies.
It should be understood by those skilled in the art that foregoing description and the embodiment of the present invention shown in the drawings are only used as illustrating
And it is not intended to limit the present invention.
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention.
Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general
Principle is applied in other embodiments without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability
Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be of the invention
Within protection scope.
Claims (10)
1. a kind of dihydropyridine calcium antagonist eutectic, which is characterized in that eutectiferous molecular formula are as follows: (C20H25ClN2O5)·
(C6H5COOH)·(Y)n, wherein Y is any one of hydrone, ethanol molecule or isopropanol molecule, 0≤n≤3,
C20H25ClN2O5It is levamlodipine, C6H5COOH is benzoic acid.
2. a kind of dihydropyridine calcium antagonist eutectic according to claim 1, which is characterized in that the eutectic knot
Crystalline substance is in anorthic system, P1 chiral space group, unit cell dimension:
α=97.1~97.5 °, β=92.2~92.6 °, γ=111.5~112.1 °,
3. a kind of dihydropyridine calcium antagonist eutectic according to claim 2, which is characterized in that described is eutectiferous
The characteristic X-ray powder diffraction data interplanar distance unrelated with X-ray wavelength usedThe main diffraction data reproduced is:
4. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist as described in claim 1, which is characterized in that will be left-handed
Amlodipine free base is completely dissolved obtains reaction solution in a solvent；Under the conditions of being stirred at room temperature, it is added into reaction solution and is tried at salt
Agent obtains salt-forming reaction solution；Reaction solution stirring is warming up to target temperature held for some time, is then allowed to stand cooling crystallization,
Be separated by filtration to get.
5. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist according to claim 4, which is characterized in that described
Solvent is any one in isopropanol, ethyl alcohol or water, and the molar ratio of the levamlodipine free alkali and the solvent is
1:50~200.
6. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist according to claim 4, which is characterized in that described
Salt-forming reagent is benzoic acid, and the mole ratio of the levamlodipine and the benzoic acid is 1:1~2.
7. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist according to claim 4, which is characterized in that described
Target temperature is 50~120 DEG C, and soaking time is 2~24 hours.
8. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist according to claim 4, which is characterized in that described
Standing cooling crystallization is to cool the temperature to 5-25 DEG C of crystallization.
9. a kind of eutectiferous preparation method of dihydropyridine calcium antagonist according to claim 4, which is characterized in that preparation
Obtained eutectic is that appearance is needle-shaped or rodlike colourless transparent crystal.
10. a kind of dihydropyridine calcium antagonist eutectic as described in claim 1 answering in preparation treatment hypertension drug
With.
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| CN201910620005.7A CN110372575A (en) | 2019-07-10 | 2019-07-10 | A kind of dihydropyridine calcium antagonist eutectic and its preparation method and application |
| JP2021546042A JP2022508791A (en) | 2019-07-10 | 2020-06-05 | Dihydropyridine calcium channel blocker co-crystal, its production method and use |
| PCT/CN2020/094643 WO2021004209A1 (en) | 2019-07-10 | 2020-06-05 | Eutectic of calcium dihydropyridine antagonist and preparation method therfor and application thereof |
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| CN111671750A (en) * | 2020-05-17 | 2020-09-18 | 复旦大学 | Levamlodipine maleate eutectic drug crystallized in triclinic system and preparation method and application thereof |
| WO2021004209A1 (en) * | 2019-07-10 | 2021-01-14 | 复旦大学 | Eutectic of calcium dihydropyridine antagonist and preparation method therfor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021004209A1 (en) * | 2019-07-10 | 2021-01-14 | 复旦大学 | Eutectic of calcium dihydropyridine antagonist and preparation method therfor and application thereof |
| CN111671750A (en) * | 2020-05-17 | 2020-09-18 | 复旦大学 | Levamlodipine maleate eutectic drug crystallized in triclinic system and preparation method and application thereof |
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| JP2022508791A (en) | 2022-01-19 |
| WO2021004209A1 (en) | 2021-01-14 |
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