CN109438332A - A kind of Acrivastine novel crystal forms A and the preparation method and application thereof - Google Patents
A kind of Acrivastine novel crystal forms A and the preparation method and application thereof Download PDFInfo
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- CN109438332A CN109438332A CN201811100316.2A CN201811100316A CN109438332A CN 109438332 A CN109438332 A CN 109438332A CN 201811100316 A CN201811100316 A CN 201811100316A CN 109438332 A CN109438332 A CN 109438332A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- 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
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Abstract
The invention discloses a kind of Acrivastine novel crystal forms A and the preparation method and application thereof, the crystal of the novel crystal forms A carries out X-ray powder diffraction, with (± 0.20 °) of 2 θ of diffraction maximum position for spectrogram characteristic parameter, 2 θ of diffraction maximum position is successively are as follows: 8.49 °, 9.21 °, 10.04 °, 12.52 °, 16.99 °, 17.55 °, 18.41 °, 19.33 °, 19.96 °, 21.34 °, 23.30 °.Preparation method are as follows: add to Acrivastine in solvent, heat up dissolved clarification, obtains Acrivastine solution, carries out crystallization using temperature differential method, is separated by solid-liquid separation simultaneously drying solid, obtains the novel crystal forms A of Acrivastine.Acrivastine novel crystal forms A provided by the invention has not only filled up the vacancy of this research field, but also have the characteristics that chemical stability is high, bioavilability is high, Acrivastine shoulder to shoulder Acrivastine bulk pharmaceutical chemicals, its dosage form or industrialized production are further developed to the country and are all of great significance.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of Acrivastine novel crystal forms A and the preparation method and application thereof.
Background technique
Acrivastine chemical structural formula is shown below, chemical name are as follows: (E, E) -3- [6- [1- (4- aminomethyl phenyl) -3-
(1- pyrrolidinyl) -1- acrylic] -2- pyridyl group] -2- acrylic acid Acrivastine be white or off-white powder, in three chloromethanes
It is dissolved in alkane, it is slightly molten in 0.1mol/L hydrochloric acid, in ethanol, and slightly soluble, soluble,very slightly in water, in ethyl acetate hardly
It is molten.
Acrivastine is the second generation antihistamine drug of hygron class formation, is competitive histamine H 1 receptor antagonist,
It is to be developed by Glaxo-Wellcome company, Britain, capsule preparations are in August, 1988 in Britain's Initial Public Offering, trade name
Semprex, wherein literary trade name Acrivastine, this product is without obvious cholinolytic effect, and the permeability of central nervous system is low, to urgency
The allergic diseases such as chronic urticaria and allergic rhinitis all have a better effect, and can also alleviate itch and hay fever, no
Good reaction is low, rare drowsiness；Occasionally there is fash；Have no or only slight condition symptoms (gastrointestinal disturbance, headache and drowsiness).
Solid exists in nature with crystal form or amorphous form.Crystal is the structure for the inside being made of crystalline material
Make the solid that particle (such as atom, molecule) is in translation cycle aligned transfer.Crystal form refers to the row of molecule in crystalline material lattice
Column form, the difference between crystal form are substantially the difference in the basic unit-structure cell microstructure crystallized.Same substance
Molecule is capable of forming the phenomenon that a variety of crystal forms and becomes polytropism.Research shows that the different crystal forms form of substance of the same race exists
May be different in terms of one or more physical properties, for example, dissolubility and degree of dissociation, tightness, crystal shape, heap density,
Mobile performance and solid stable state.The different crystal forms of same drug molecule, in crystal structure, stability, productibility and biology
The properties such as availability might have significant difference, to directly affect the curative effect and exploitability of drug, and stablize
Property advantageously ensures that the curative effect of drug in clinical application does not change.
Contain in Acrivastine molecular structure there are two double bond, the degradable multiple cis-trans-isomers of generation under illumination condition,
Chemical stability is lower, which there are no the report of its crystal structure and corresponding data since listing in 1988.Therefore,
In order to fill up the vacancy of this research field, Acrivastine bulk pharmaceutical chemicals crystal form is studied, it is high, raw to develop chemical stability
Object availability is high, the Acrivastine bulk pharmaceutical chemicals novel crystal forms of Acrivastine are a urgent problems to be solved shoulder to shoulder, to domestic further
It develops its dosage form or industrialized production is all of great significance.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of novel crystal forms of Acrivastine.
To achieve the goals above, the technical solution of the present invention is as follows:
The crystal of the novel crystal forms A, the novel crystal forms A of Acrivastine carry out X-ray powder diffraction, which is characterized in that spread out
(± 0.20 °) of 2 θ of peak position is penetrated as spectrogram characteristic parameter, 2 θ of diffraction maximum position is successively are as follows: 8.49 °, 9.21 °,
10.04°、12.52°、16.99°、17.55°、18.41°、19.33°、19.96°、21.34°、23.30°。
Further, 2 θ of diffraction maximum position by intensity from large to small successively are as follows: 17.55 °, 21.34 °, 19.96 °,
9.21°、19.33°、23.30°、18.41°、12.52°、8.49°、10.04°、16.99°。
Further, the X-ray powder diffraction figure of the novel crystal forms A is as shown in figure.
Above-mentioned X-ray powder diffraction figure is obtained by following condition:
Instrument: PANalytical X ' Pert3 Powder；Test condition: CuK α radiation, graphite monochromator, tube voltage
40kV, tube current 40mA, 2 4-60 ° of θ scanning ranges, speed are 3 °/point, and scanning step is 0.02 °.
As those skilled in the art, in X-ray powder diffraction spectrum, enumerates the A type crystalline substance intensity and rank preceding 5-10
Diffraction maximum have error range in identical peak position and peak intensity, the fingerprint of the novel crystal forms A can be represented.
Further, the heat absorption (224.39 DEG C~228.81 of single dominance is shown in the range of 40~500 DEG C
DEG C), by being measured per minute by differential scanning calorimetry (DSC) (DSC) with 10 DEG C of sweep speed.
Further, differential scanning calorimetry (DSC) (DSC) Thermogram is as shown in Figure 2.Differential scanning calorimetry (DSC
Differential scanning calorimetry), refer to during temperature programmed control, remains sample and reference substance
Temperature is identical: keeping the side R with given temperature programmed control, has the function that compensation by changing the additional amount of the side S.Record hot-fluid
DSC curve just can be obtained to the relation curve of T in amount.It is mainly used for drug quality analysis, measures pharmaceutical purity.
Further, thermogravimetric analysis (TGA) figure is as shown in Figure 3.Refer to the matter that sample to be tested is measured under programed temperature
A kind of thermoanalysis technology of amount and temperature change relationship, for the thermal stability and component of research material.TGA is in research and development and quality
Control aspect is all more commonly used detection means.Thermogravimetric analysis often joins with other analysis methods in actual material analysis
With, progress Thermal Synthetic Analysis, comprehensive accurate analysis of material.The important feature of thermogravimetry be it is quantitative strong, object can be accurately measured
The mass change of matter and the rate of variation.
The problem to be solved in the present invention, which also resides in, provides the preparation method of novel crystal forms A, simple process, and method is stablized, easily
In production.
To achieve the above object, the technical solution of the present invention is as follows:
The novel crystal forms A of Acrivastine, preparation method are prepared according to the following steps:
1) it dissolves
Acrivastine is added in solvent, heat up dissolved clarification, obtains Acrivastine solution；
2) crystallization
The obtained Acrivastine solution of step 1) is subjected to crystallization using temperature differential method, simultaneously drying solid is separated by solid-liquid separation, obtains
To the novel crystal forms A of Acrivastine.
Further, in step 1), the solvent is alcohols and water.
As a preferred option, the solvent includes methanol or ethyl alcohol or isopropanol.
Further, in step 1), the mass volume ratio of Acrivastine and solvent are as follows: 1:75~1:10g/ml.
As a preferred option, in step 1), the mass volume ratio of Acrivastine and solvent are as follows: 1:14.
Further, in step 1), the temperature that the Acrivastine dissolves in the solvent is 60~100 DEG C.
As a preferred option, in step 1), the temperature that the Acrivastine dissolves in the solvent is 70~75 DEG C.
Further, in step 2), the temperature of the crystallization is -15~15 DEG C.
As a preferred option, in step 2), the temperature of the crystallization is -15~-5 DEG C.
Further, in step 2), the time of the crystallization is 30 minutes~2 hours.
As a preferred option, in step 2), the time of the crystallization is 1.5 hours.
Further, in step 2), the temperature of the drying is 65~85 DEG C.
As a preferred option, in step 2), the temperature of the drying is 75~85 DEG C.
Further, in step 2), the time of the drying is 5~8 hours.
As a preferred option, in step 2), the time of the drying is 8 hours.
Further, in step 2), the mode of the drying is vacuum drying.
Further, in step 2), the pressure of the drying is -0.07MPa~-0.10MPa.
As a preferred option, in step 2), the pressure of the drying is -0.09MPa~-0.10MPa.
3rd purpose of the invention, which also resides in, provides the application of the novel crystal forms A of Acrivastine a kind of: described Ah
The novel crystal forms A for cutting down sting is preparing the application in H1 receptor antagonist pharmaceuticals.
To achieve the above object, the technical solution of the present invention is as follows:
The novel crystal forms A of the Acrivastine is preparing the application in H1 receptor antagonist pharmaceuticals.
The beneficial effects of the present invention are: the novel crystal forms A chemical stability of Acrivastine provided by the invention is high, biology is sharp
Expenditure is high, and compared with reference preparation (the Acrivastine capsule Acrivastine of Glaxo Wellcome production) 16mg, no significant difference, and two
Person has bioequivalence.Moreover, the method for the novel crystal forms A provided by the invention for preparing Acrivastine also has technique step
Suddenly briefly, the characteristics of being easy to the production of technique.Between the drug since listing in 1988, its crystal structure and corresponding there are no
The report of data and less than it is relevant reference and beneficial to help.Therefore, this problem of very good solution of the present invention, develops chemistry
Stability is high, bioavilability is high, Acrivastine shoulder to shoulder Acrivastine bulk pharmaceutical chemicals novel crystal forms, further develops its dosage form to the country
Or industrialized production is all of great significance.
The novel crystal forms A of Acrivastine provided by the invention has the advantages that following conspicuousness:
1. physical stability is good, commercially produces 70 DEG C of batch (batch 100Kg) and be dried under reduced pressure 10 hours, product purity is not
See significant change, there are levels to have no increase for specific impurities, meet medicinal standard, and in preparing Acrivastine micelle,
Crystal form does not change.
2. meeting medication requirement, medicinal requirements are met by Acrivastine capsule dissolubility prepared by Acrivastine novel crystal forms A,
Studies have shown that the outer dissolved corrosion of the Acrivastine capsule body of different batches is almost the same, sample after 10~20min, main ingredient at
Divide and substantially completely dissolves out.
3. bioequivalence shows single oral dose by Acrivastine capsule clinical research prepared by Acrivastine A crystal form
Acrivastine capsule is compared with reference preparation (the Acrivastine capsule Acrivastine of Glaxo Wellcome production), and pharmacokinetic parameters are through uniting
Credit analysis, no significant difference are counted, the two has bioequivalence.
To sum up, a kind of Acrivastine novel crystal forms of the present invention and the preparation method and application thereof, and obtained a kind of chemical stabilization
Property it is high, bioavilability is high, Acrivastine shoulder to shoulder Acrivastine bulk pharmaceutical chemicals novel crystal forms A, fill up Acrivastine crystal form research field
Vacancy, the country is further developed by its dosage form or industrialized production is all of great significance.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of Acrivastine crystal form A of the invention.
Fig. 2 is differential scanning calorimetry (DSC) spectrogram of middle Acrivastine crystal form A of the invention.
Fig. 3 is thermogravimetric analysis (TGA) figure of middle Acrivastine crystal form A of the invention.
Specific embodiment
Illustrated embodiment is in order to which preferably the present invention will be described, but is not that the contents of the present invention are limited only to institute
For embodiment.So those skilled in the art according to foregoing invention content to embodiment carry out it is nonessential improvement and
Adjustment, still falls within protection scope of the present invention.
Embodiment 1
2g Formulas I sample is taken to add in 20ml methanol, temperature rising reflux 20 minutes, gradually dissolved clarification, stirring 10 minutes cooled down system
To 10~15 DEG C, a large amount of solids are precipitated, and are stirred 30 minutes, filtering, filter cake in 75~85 DEG C, vacuum pressure be -0.09Mpa~-
0.10MPa is dried under reduced pressure 5 hours to obtain 1.2g solid, and yield 60% turns out to be crystal form A through X-ray powder diffraction, makes of this raw material
At preparation and Acrivastine bioequivalence.
Embodiment 2
2g Formulas I sample is taken to add in 20ml isopropanol, temperature rising reflux 20 minutes, non-dissolved clarification added 20ml isopropanol, stirring
20 minutes, fraction solids dissolution was added 20ml isopropanol, is stirred 10 minutes, system dissolved clarification, continues stirring 10 minutes, be cooled to 0
~10 DEG C are stirred 30 minutes, are had no that solid is precipitated, are continued to be cooled to -15 DEG C, there is solid precipitation, continue stirring 30 minutes, filter,
Filter cake is in 75~85 DEG C, and vacuum pressure is dried under reduced pressure for -0.09Mpa~-0.10MPa obtains 1.6g solid for 5 hours, yield 80%,
Crystal form A is turned out to be through X-ray powder diffraction, the preparation and Acrivastine bioequivalence being made into this raw material.
Embodiment 3
It taking 200g Formulas I sample to add in 2800ml ethyl alcohol, is warming up to 75 DEG C of stirrings, system gradually dissolved clarification stirs 10 minutes,
35~40 DEG C are naturally cooling to, system gradually becomes cloudy, and continues to be cooled to 10~15 DEG C, and a large amount of solids are precipitated, continue to be cooled to-
5~-15 DEG C are stirred 1.5 hours, filtering, and for filter cake in 75~85 DEG C, vacuum pressure is that -0.09Mpa~-0.10MPa is dried under reduced pressure 8
Hour obtains 170g solid, and yield 85% turns out to be crystal form A through X-ray powder diffraction, the preparation and Acrivastine being made into this raw material
Bioequivalence.
Embodiment 4
It takes 2g Formulas I sample to add in 100ml water, is warming up to 96 DEG C, stir 20 minutes, non-dissolved clarification adds 50ml water, stirring
20 minutes, system dissolved clarification continued stirring 10 minutes, is naturally cooling to 65~70 DEG C, system gradually becomes cloudy, and continues to be cooled to 10
~20 DEG C are stirred 1 hour, filtering, and for filter cake in 75~85 DEG C, vacuum pressure is that -0.09Mpa~-0.10MPa is dried under reduced pressure 8 hours
1.4g solid is obtained, yield 70% turns out to be crystal form A through X-ray powder diffraction, preparation and the Acrivastine biology being made into this raw material
It is equivalent.
Embodiment 5
By 20 subject's single oral dose Acrivastine capsules and the reference preparation (Acrivastine of Glaxo Wellcome production
Capsule Acrivastine) after 16mg, the internal drug-time curve of the two is almost the same, and tmax is respectively (1.0 ± 0.4) h and (1.1 ± 0.4)
H, Cmax are respectively (220 ± 74) μ g ˙ L-1 and (220 ± 82) μ gL~(- 1)；AUC 0~1 is respectively (630 ± 276) μ
GhL-1 and (640 ± 271) μ ghL-1, the main pharmacokinetic parameters of 2 kinds of preparations without significant difference (P > 0.05), by
The relative bioavailability of test preparation is (97 ± 12) %.Pharmacokinetic parameters have through statistical analysis, no significant difference, the two
Bioequivalence.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (14)
1. the crystal of the novel crystal forms A, the novel crystal forms A of Acrivastine carry out X-ray powder diffraction, which is characterized in that with diffraction
2 θ of peak position is spectrogram characteristic parameter, and 2 θ of diffraction maximum position is successively are as follows: 8.49 ± 0.20 °, 9.21 ± 0.20 °, 10.04
±0.20°、12.52±0.20°、16.99±0.20°、17.55±0.20°、18.41±0.20°、19.33±0.20°、
19.96±0.20°、21.34±0.20°、23.30±0.20°。
2. the novel crystal forms A of Acrivastine according to claim 1, which is characterized in that 2 θ of diffraction maximum position presses intensity
From large to small successively are as follows: 17.55 ± 0.20 °, 21.34 ± 0.20 °, 19.96 ± 0.20 °, 9.21 ± 0.20 °, 19.33 ±
0.20°、23.30±0.20°、18.41±0.20°、12.52±0.20°、8.49±0.20°、10.04±0.20°、16.99±
0.20°。
3. the novel crystal forms A of Acrivastine according to claim 1, which is characterized in that the x-ray powder of the novel crystal forms A
Diffraction pattern is as shown in figure.
4. the preparation method of the novel crystal forms A of Acrivastine described in any one of claims 1 to 3, which is characterized in that including
Step:
1) it dissolves
Acrivastine is added in solvent, heat up dissolved clarification, obtains Acrivastine solution, the mass body of the Acrivastine and solvent
Product ratio are as follows: 1:(75~10) g/ml；
2) crystallization
The obtained Acrivastine solution of step 1) is subjected to crystallization using temperature differential method, simultaneously drying solid is separated by solid-liquid separation, obtains Ah
The novel crystal forms A of sting is cut down, the mode of the drying is vacuum drying.
5. the preparation method according to claim 4, which is characterized in that in step 1), the solvent is alcohols and water.
6. preparation method according to claim 5, which is characterized in that the alcohols includes methanol or ethyl alcohol or isopropanol.
7. the preparation method according to claim 4, which is characterized in that in step 1), the mass volume ratio are as follows: 1:14g/
ml。
8. the preparation method according to claim 4, which is characterized in that in step 1), the Acrivastine is in the solvent
The temperature of middle dissolution is 60~100 DEG C.
9. the preparation method according to claim 4, which is characterized in that in step 2), the temperature of the crystallization is -15~15
℃。
10. preparation method according to claim 9, which is characterized in that in step 2), the time of the crystallization is 0.5 small
When~2 hours.
11. the preparation method according to claim 4, which is characterized in that in step 2), the temperature of the drying is 65~85
℃。
12. preparation method according to claim 11, which is characterized in that in step 2), the time of the drying is 5~8
Hour.
13. the preparation method according to claim 4, which is characterized in that in step 2), the vacuum drying pressure be-
0.07MPa~-0.10MPa.
14. the novel crystal forms A of Acrivastine described in claim 1 is preparing the application in H1 receptor antagonist pharmaceuticals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543076A (en) * | 2015-09-18 | 2017-03-29 | 重庆华邦胜凯制药有限公司 | The method for preparing Acrivastine |
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2018
- 2018-09-20 CN CN201811100316.2A patent/CN109438332A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543076A (en) * | 2015-09-18 | 2017-03-29 | 重庆华邦胜凯制药有限公司 | The method for preparing Acrivastine |
Non-Patent Citations (1)
| Title |
|---|
| 焦万田: "《新编简明药物手册》", 31 December 2017 * |
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