CN103382179A - Ingavirin polymorph and its preparation method - Google Patents
Ingavirin polymorph and its preparation method Download PDFInfo
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- CN103382179A CN103382179A CN2013102198794A CN201310219879A CN103382179A CN 103382179 A CN103382179 A CN 103382179A CN 2013102198794 A CN2013102198794 A CN 2013102198794A CN 201310219879 A CN201310219879 A CN 201310219879A CN 103382179 A CN103382179 A CN 103382179A
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Abstract
The invention belongs to the field of chemical pharmaceutical technology and relates to an ingavirin polymorph and its preparation method. The invention aims to provide the ingavirin polymorph in allusion to insufficiencies existing in the prior art. The invention provides ingavirin polymorphs A and B which have excellent physicochemical properties and good stability and are used in the research on in vivo study of ingavirin. Meanwhile, the invention provides a preparation method of the polymorphs A and B.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to polymorphic form of a kind of ingavirin and preparation method thereof.
Background technology
Influenza virus; be called for short influenza virus; that a kind of mankind of causing and animal suffer from grippal RNA viruses; on taxonomy; influenza virus belongs to Orthomyxoviridae family; it can cause acute upper respiratory tract infection, and propagates rapidly by air, often has periodically all over the world and is very popular.The human influenza virus is divided into first (A), second (B), third (C) three types, is the pathogenic agent of influenza (influenza).Wherein influenza A virus antigen easily morphs, and repeatedly causes worldwide being very popular.
Ingavirin (ingavirin, chemical name: 5-((2-(1 hydrogen-imidazol-4 yl) ethyl) amino)-5-oxopentanoic acid) is for influenza virus, the active drug of adenovirus infection.Ingavirin is a kind of nontoxic, broad-spectrum antiviral medicament with complexing action mechanism, and arbidol and the Oseltamivir sold than existing market have obvious advantage.
Pharmaceuticals2011,
4,1518-1534Reported the comparison of ingavirin and Tamiflu and ribavirin, can find out that ingavirin has restraining effect preferably to virus.
Application number be WO2003072124 Patent Application Publication the structure of ingavirin, ingavirin can be used for the treatment of the oncology disease as the cytodifferentiation inducible factor, and is stable especially for the melanoma growth, increase the efficient of melanoma immunotherapy, reduce the haematics toxicity of chemotherapy.
The polymorphic of medicine is all significant to quality and the technique of physico-chemical property, bioavailability and the preparation of medicine, for example between the medicine different crystal forms, the stability of the differentia influence medicine of physico-chemical property, same drug crystal forms is different, may there be larger difference in bioavailability, larger on preparation impact, also have a strong impact on the activity of medicine.Affect the solubility rate of medicine due to different crystal formations, and the difference of different crystal forms surface free energy, cause the bonding force between crystalline particle different, affect mobility and compressing tablet hardness, tablet weight variation, content homogeneity and the physical stability of medicine.At present, ingavirin goes on the market as tablet, is therefore necessary to its crystal formation research, is also necessary.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, the polymorphic form of new ingavirin is provided.
Another object of the present invention is to provide the preparation method of above-mentioned ingavirin polymorphic form.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
The crystalline polymorph A of ingavirin uses Cu-K α radiation, 35KV, and 30mA, precision ± 0.0001 °, the X-ray powder diffraction figure of its feature, 2 θ that show with kilsyth basalt are 16.25388; 17.5537; 18.19366; 18.74863; 19.78359; 20.20446; 22.27632; 24.14684; 24.38282; 24.93973; 25.34327; 26.41213; 26.93823; 27.06627; 28.01838; 28.62621; 28.94396; 29.92034; 32.30439; 33.21582; 34.69475; 37.98252; 38.51969; 39.85372; 42.54231 located diffraction peak.
The d-value of table 1 polymorphic A and 2 θ angles
| The d- |
2 θ angles | Relative intensity |
| 5.44881 | 16.25388 | 4.57 |
| 5.04767 | 17.5537 | 11.74 |
| 4.87200 | 18.19366 | 71.57 |
| 4.72902 | 18.74863 | 11.11 |
| 4.48390 | 19.78359 | 21.79 |
| 4.39143 | 20.20446 | 21.60 |
| 3.98746 | 22.27632 | 16.08 |
| 3.68264 | 24.14684 | 87.79 |
| 3.64753 | 24.38282 | 100.00 |
| 3.56733 | 24.93973 | 41.68 |
| 3.51144 | 25.34327 | 87.44 |
| 3.37171 | 26.41213 | 5.14 |
| 3.30704 | 26.93823 | 20.58 |
| 3.29169 | 27.06627 | 19.15 |
| 3.18196 | 28.01838 | 4.73 |
| 3.11576 | 28.62621 | 9.48 |
| 3.08227 | 28.94396 | 6.00 |
| 2.98388 | 29.92034 | 3.41 |
| 2.76890 | 32.30439 | 10.00 |
| 2.69498 | 33.21582 | 7.83 |
| 2.58341 | 34.69475 | 9.49 |
| 2.36700 | 37.98252 | 6.03 |
| 2.33522 | 38.51969 | 5.88 |
| 2.26008 | 39.85372 | 6.87 |
| 2.12326 | 42.54231 | 6.24 |
Its X-ray powder diffraction figure basically as shown in Figure 1.
Ingavirin crystalline polymorph A has one or more approximately 3232cm that are selected from the infrared spectra that Potassium Bromide records
-1, 3163cm
-1, 3100cm
-1, 3007cm
-1, 2868cm
-1, 2005cm
-1, 1463cm
-1, 1269cm
-1, 1200cm
-1, 1138cm
-1Or 948cm
-1Characteristic peak.
Its infrared spectrogram basically as shown in Figure 3.
The preparation method of ingavirin crystalline polymorph A comprises the following steps:
A, at-40 ℃ of-180 ℃ of temperature, with the ingavirin dissolution of solid in solvent (ingavirin quality/solvent volume=1g:1 ~ 50mL);
B, at-40 ℃ of-50 ℃ of temperature, the cooling ingavirin crystal of separating out;
C, filtration;
D, dry under 30 ℃ ~ 100 ℃ namely gets ingavirin polymorphic form A.
As preferably, in described steps A, solvent is selected from water, acetone, butanone, hexone, acetonitrile, ethyl acetate, triethylamine, diethylamine, di-isopropyl methylamine, diisopropyl ethyl amine, diisopropylamine, dioxane, benzene, toluene, DMF, dimethyl sulfoxide (DMSO), isopropyl ether, ether, tetrahydrofuran (THF), in methyl alcohol, ethanol, n-propyl alcohol or Virahol one or more.
The crystalline polymorph B of ingavirin uses Cu-K α radiation, 35KV, and 30mA, the X-ray powder diffraction figure of precision ± 0.0001 ° its feature, 2 θ that show with kilsyth basalt are 15.48400; 17.03720; 17.64442; 17.83801; 19.08664; 20.24814; 21.25388; 21.83913; 23.93256; 24.27171; 25.48872; 26.98308; 29.09590; 30.12190; 41.31897 located diffraction peak.
The d-value of table 2 polymorph b and 2 θ angles
| The d- |
2 θ angles | Relative intensity |
| 5.71795 | 15.48400 | 9.68 |
| 5.20001 | 17.03720 | 11.56 |
| 5.02240 | 17.64442 | 7.22 |
| 4.96833 | 17.83801 | 5.13 |
| 4.64603 | 19.08664 | 5.34 |
| 4.38206 | 20.24814 | 30.34 |
| 4.17692 | 21.25388 | 53.01 |
| 4.06629 | 21.83913 | 7.79 |
| 3.71513 | 23.93256 | 100.00 |
| 3.66398 | 24.27171 | 41.06 |
| 3.49173 | 25.48872 | 7.32 |
| 3.30165 | 26.98308 | 6.97 |
| 3.06652 | 29.09590 | 7.93 |
| 2.96437 | 30.12190 | 10.42 |
| 2.18325 | 41.31897 | 5.55 |
Its X-ray powder diffraction figure basically as shown in Figure 2.
Ingavirin crystalline polymorph B has one or more approximately 3244cm that are selected from the infrared spectra that Potassium Bromide records
-1, 3066cm
-1, 2971 cm
-1, 2932cm
-1, 2857cm
-1, 2802cm
-1, 2005cm
-1, 1777cm
-1, 1300cm
-1, 1234cm
-1, 1216cm
-1, 1196cm
-1, 1129cm
-1, 1086cm
-1, 1051cm
-1, 1033cm
-1, 933cm
-1, 811cm
-1, 740cm
-1Or 588cm
-1Characteristic peak.
Its infrared spectrogram basically as shown in Figure 4.
The preparation method of ingavirin crystalline polymorph B comprises the following steps:
A, at-40 ℃ of-180 ℃ of temperature, with the ingavirin dissolution of solid in solvent (ingavirin quality/solvent volume=1g:1 ~ 50mL);
B, under-40 ℃-50 ℃, the cooling ingavirin crystal of separating out;
C, filtration;
D, dry under 30 ℃ ~ 100 ℃ namely gets the ingavirin polymorph b.
As optimal way, in described step (1), solvent is selected from water, acetone, butanone, hexone, acetonitrile, ethyl acetate, triethylamine, dioxane, benzene, toluene, DMF, dimethyl sulfoxide (DMSO), isopropyl ether, ether, tetrahydrofuran (THF), in methyl alcohol, ethanol, n-propyl alcohol or Virahol one or more.
The X powder diffraction test condition is as follows: (instrument model: X ' Pert Pro MPD, measuring unit: Institute of Analysis of Sichuan University)
K-Alpha1 wavelength(dust): 1.5405600
K-Alpha2 wavelength(dust): 1.5443900
K-Alpha2/?K-Alpha1?intensity?ratio:?0.5000
K-Alpha wavelength(dust): 1.5405600
K-Beta wavelength(dust): 1.3922200
Peak?positions?defined?by:?Minimum?of?2
nd?derivative
Minimum?peak?tip?width(2Theta):0.00
Minimum?peak?tip?width(2Theta):1.00
Peak?base?width(2Theta):2.00
Minimum?significance:0.60
The test condition of IR: KBr compressing tablet, scope (cm
-1) 4000.28 ~ 399.256.
Table 3 ingavirin crystalline polymorph A solubility test result
Table 4 ingavirin crystalline polymorph B solubility test result
Beneficial effect of the present invention is: the invention provides ingavirin polymorphic A, polymorph b, possess excellent physico-chemical property, good stability is used for the interior research of body of research ingavirin.The preparation method of polymorphic A, polymorph b is provided simultaneously.
Description of drawings
The collection of illustrative plates of the X-ray powder diffraction of Fig. 1 ingavirin polymorphic A;
The collection of illustrative plates of the X-ray powder diffraction of Fig. 2 ingavirin polymorph b;
The infrared spectra collection of illustrative plates of Fig. 3 ingavirin polymorphic A;
The infrared spectra collection of illustrative plates of Fig. 4 ingavirin polymorph b.
Embodiment
Disclosed all features in this specification sheets, or the step in disclosed all methods or process except mutually exclusive feature and/or step, all can make up by any way.
Embodiment 1: the preparation of ingavirin crystal form A
With 2g ingavirin solid, after the 14mL water dissolution, add acetone 60mL, the adularescent solid is separated out, and stirs 2h under ice bath, filters, and filter cake washing with acetone 2 times get ingavirin crystal form A 1.4g.Yield: 70%.
Embodiment 2: the preparation of ingavirin crystal form A
2.98g ingavirin crude product, 50mL methyl alcohol are joined in reactor, stir the lower 25mL of dropping triethylamine to dissolution of solid, then slowly add the 360mL ethyl acetate, be cooled to 0 ℃ of stirring and crystallizing 2h, filter, filter cake is collected filter cake with the washing of 100mL ethyl acetate, drying under reduced pressure gets white solid 1.94g, is the ingavirin crystal form A.
Embodiment 3: the preparation of ingavirin crystal form B
With 2g ingavirin solid, after 28mL water/ethanol (1:1) dissolving, stir 24h under room temperature, to filter, filter cake washing with alcohol 2 times get ingavirin crystal form B 1.2g.Yield: 60%.
Embodiment 4: the preparation of ingavirin crystal form B
With 2g ingavirin solid, after the mixed system dissolving with hexone/DMSO, stir 24h under room temperature, filter, filter cake gets ingavirin crystal form B 1.5g with hexone washing 2 times.Yield: 75%.
Embodiment 5: the stability study of ingavirin crystal form A
" Chinese pharmacopoeia appendix XI X C " medicine stability test governing principle " regulation for pharmaceutical preparation, was carried out necessary influence factor test according to main character according to two ones of versions in 2010.
For investigating ingavirin to the susceptibility of each influence factor, this test is adopted high temperature, high humidity and three kinds of conditions of illumination to carry out the influence factor test and is investigated.
High temperature test: get the ingavirin crystal form A, be placed in electric heating constant-temperature blowing drying box, placed 10 days at 60 ℃ of temperature, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, and result and 0 day sample data are compared, test-results sees Table 5.
High humidity test: get the ingavirin crystal form A, be placed in the encloses container interior (stratification saturated potassium chloride solution under container) of constant temperature, be to place 10 days under 92.5% condition in relative humidity, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, and result and 0 day sample data are compared, test-results sees Table 6.
Strong illumination test: getting the ingavirin crystal form A, be placed in lighting box, is to place 10 days under the condition of 5000lx in illumination, in the 5th day and sampling in the 10th day, detect by stable high spot reviews project, and result and 0 day sample data are compared, test-results sees Table 7.
Table 5 ingavirin crystal form A influence factor test-results (high temperature test)
Table 6 ingavirin crystal form A influence factor test-results (high humidity test)
Table 7 ingavirin crystal form A influence factor test-results (strong illumination test)
Can find out from above-mentioned experimental result, ingavirin crystal form A character is relatively stable.
Embodiment 6: ingavirin crystal form A capsule and commercially available product
(lot number: 30110)Every assay relatively
The every assay of table 8 ingavirin crystal form A capsule and commercially available product relatively
Can find out from above-mentioned experimental result, ingavirin crystal form A of the present invention is compared with commercially available ingavirin capsule after making capsule, and every qualitative data has been obtained good technique effect all significantly better than commercially available product.
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature or any new combination that discloses in this manual, and the arbitrary new method that discloses or step or any new combination of process.
Claims (12)
1. the crystalline polymorph A of ingavirin uses Cu-K α radiation, the X-ray powder diffraction figure of its feature, and 2 θ that show with kilsyth basalt are 16.25388; 17.55537; 18.19366; 18.74863; 19.78359; 20.20446; 22.27632; 24.14684; 24.38282; 24.93973; 25.34327; 26.41213; 26.93823; 27.06627; 28.01838; 28.62621; 28.94396; 29.92034; 32.30439; 33.21582; 34.69475; 37.98252; 38.51969; 39.85372; 42.54231 located diffraction peak.
2. ingavirin crystalline polymorph A according to claim 1, its X-ray powder diffraction figure basically as shown in Figure 1.
3. a kind of ingavirin crystalline polymorph A according to claim 1 and 2, is characterized in that: have one or more approximately 3232cm that are selected from the infrared spectra that Potassium Bromide records
-1, 3163cm
-1, 3100cm
-1, 3007cm
-1, 2868cm
-1, 2005cm
-1, 1463cm
-1, 1269cm
-1, 1200cm
-1, 1138cm
-1Or 948cm
-1Characteristic peak.
4. a kind of ingavirin crystalline polymorph A according to claim 1 and 2, its infrared spectrogram basically as shown in Figure 3.
5. the preparation method of the arbitrary described a kind of ingavirin crystalline polymorph A of claim 1-4 comprises the following steps:
A, at-40 ℃ of-180 ℃ of temperature, in solvent, the ingavirin solid masses with the solvent volume ratio is with the ingavirin dissolution of solid: 1g:1 ~ 50mL);
B, at-40 ℃ of-50 ℃ of temperature, the cooling ingavirin crystal of separating out;
C, filtration;
D, dry under 30 ℃ ~ 100 ℃ namely gets ingavirin polymorphic form A.
6. the preparation method of a kind of ingavirin crystalline polymorph A according to claim 5, it is characterized in that: in described steps A, solvent is selected from water, acetone, butanone, hexone, acetonitrile, ethyl acetate, triethylamine, diethylamine, di-isopropyl methylamine, diisopropyl ethyl amine, diisopropylamine, dioxane, benzene, toluene, DMF, dimethyl sulfoxide (DMSO), isopropyl ether, ether, tetrahydrofuran (THF), in methyl alcohol, ethanol, n-propyl alcohol or Virahol one or more.
7. the crystalline polymorph B of ingavirin uses Cu-K α radiation, the X-ray powder diffraction figure of its feature, and 2 θ that show with kilsyth basalt are 15.48400; 17.03720; 17.64442; 17.83801; 19.08664; 20.24814; 21.25388; 21.83913; 23.93256; 24.27171; 25.48872; 26.98308; 29.09590; 30.12190; 41.31897 located diffraction peak.
8. the crystalline polymorph B of a kind of ingavirin according to claim 7, its X-ray powder diffraction figure basically as shown in Figure 2.
9. according to claim 7 or 8 described a kind of ingavirin crystalline polymorph B, is characterized in that: have one or more approximately 3244cm that are selected from the infrared spectra that Potassium Bromide records
-1, 3066cm
-1, 2971 cm
-1, 2932cm
-1, 2857cm
-1, 2802cm
-1, 2005cm
-1, 1777cm
-1, 1300cm
-1, 1234cm
-1, 1216cm
-1, 1196cm
-1, 1129cm
-1, 1086cm
-1, 1051cm
-1, 1033cm
-1, 933cm
-1, 811cm
-1, 740cm
-1Or 588cm
-1Characteristic peak.
10. according to claim 7 or 8 described a kind of ingavirin crystalline polymorph B, its infrared spectrogram basically as shown in Figure 4.
11. the preparation method of the arbitrary described a kind of ingavirin crystalline polymorph B of claim 7-10 comprises the following steps:
A, at-40 ℃ of-180 ℃ of temperature, in solvent, the ingavirin solid masses with the solvent volume ratio is with the ingavirin dissolution of solid: 1g:1 ~ 50mL);
B, under-40 ℃-50 ℃, the cooling ingavirin crystal of separating out;
C, filtration;
D, dry under 30 ℃ ~ 100 ℃ namely gets the ingavirin polymorph b.
12. the preparation method of a kind of ingavirin crystalline polymorph B according to claim 11, it is characterized in that: in described steps A, solvent is selected from water, acetone, butanone, hexone, acetonitrile, ethyl acetate, triethylamine, dioxane, benzene, toluene, DMF, dimethyl sulfoxide (DMSO), isopropyl ether, ether, tetrahydrofuran (THF), in methyl alcohol, ethanol, n-propyl alcohol or Virahol one or more.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418512A (en) * | 2014-09-19 | 2016-03-23 | 江苏正大丰海制药有限公司 | Single crystal of ingavirin, preparation method and pharmaceutical composition of ingavirin |
| CN106257276A (en) * | 2015-06-19 | 2016-12-28 | 江苏正大丰海制药有限公司 | A kind of ingavirin and the method for detecting impurities of preparation thereof |
| RU2801042C2 (en) * | 2021-11-18 | 2023-08-01 | Общество с ограниченной ответственностью "Гелеспон" | Crystalline form of 4-[2-(1h-imidazol-4-yl)-ethylcarbamoyl]-butanoic acid, a method of its production, pharmaceutical compositions based on it, its use as an antiviral agent, a method of its identification in pharmaceutical products |
| WO2023204729A1 (en) * | 2022-04-19 | 2023-10-26 | Общество с ограниченной ответственностью "Гелеспон" | Pharmaceutical compositions based on a novel substance of 4-[2-(1н-imidazol-4-yl)-ethylcarbamoyl]-butanoic acid and method for producing said substance |
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| WO2023204729A1 (en) * | 2022-04-19 | 2023-10-26 | Общество с ограниченной ответственностью "Гелеспон" | Pharmaceutical compositions based on a novel substance of 4-[2-(1н-imidazol-4-yl)-ethylcarbamoyl]-butanoic acid and method for producing said substance |
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Application publication date: 20131106 |