CN102584637A - Peramivir hydrate crystal, preparation method, medical compound and usage thereof - Google Patents
Peramivir hydrate crystal, preparation method, medical compound and usage thereof Download PDFInfo
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- CN102584637A CN102584637A CN2011100092870A CN201110009287A CN102584637A CN 102584637 A CN102584637 A CN 102584637A CN 2011100092870 A CN2011100092870 A CN 2011100092870A CN 201110009287 A CN201110009287 A CN 201110009287A CN 102584637 A CN102584637 A CN 102584637A
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- 229960001084 peramivir Drugs 0.000 title claims abstract description 80
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 title claims abstract description 78
- 239000013078 crystal Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 239000000843 powder Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 102000005348 Neuraminidase Human genes 0.000 claims description 11
- 108010006232 Neuraminidase Proteins 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 206010022000 influenza Diseases 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 238000009835 boiling Methods 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 230000007704 transition Effects 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
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- 230000005855 radiation Effects 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 241000712461 unidentified influenza virus Species 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 150000004677 hydrates Chemical class 0.000 description 12
- 239000012535 impurity Substances 0.000 description 10
- 238000013112 stability test Methods 0.000 description 8
- 150000004684 trihydrates Chemical class 0.000 description 8
- 241000700605 Viruses Species 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000005070 sampling Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- RFUCJKFZFXNIGB-ZBBHRWOZSA-N (1s,2s,3s,4r)-3-[(1s)-1-acetamido-2-ethylbutyl]-4-(diaminomethylideneamino)-2-hydroxycyclopentane-1-carboxylic acid;trihydrate Chemical compound O.O.O.CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1N=C(N)N RFUCJKFZFXNIGB-ZBBHRWOZSA-N 0.000 description 4
- 206010064097 avian influenza Diseases 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002512 suppressor factor Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 3
- 229940061367 tamiflu Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- 229960001028 zanamivir Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- -1 RWJ 270201 anhydride Chemical class 0.000 description 1
- 241000405217 Viola <butterfly> Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
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- 230000000241 respiratory effect Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
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Images
Abstract
The invention provides a peramivir 2.5 hydrate crystal, a preparation method for the crystal, a medical compound containing the crystal and the application of the crystal in preparing the drugs for resisting influenza virus. The structural formula of the peramivir is as follows.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field.Particularly, hydrate crystal, preparation method, medicinal compsns and this crystal that the present invention relates to a kind of RWJ 270201 is used for suppressing the application of the medicine of influenza neuraminidase in preparation.
Background technology
The main effect of neuraminidase (NA) in influenza virus is to promote the new virus particle that forms from cells infected, to separate and diffusion, promotes the diffusion that virus particle is organized from the respiratory mucosa that infects towards periphery.NA also has the toxicity of enhanced virus strain and causes apoptosis in addition, causes functions such as flu-like symptom and respiratory inflammation.NA suppressor factor class medicine can suppress duplicating of influenza virus, reduces that it is pathogenic, the symptom when alleviating the influenza morbidity, shortens the course of disease, reduces complication.The RWJ 270201 that present NA suppressor factor has zanamivir, Tamiflu and the present invention relates to; Zanamivir is one and sucks preparation, can reach higher concentration at the upper respiratory tract after the use, suppresses virus replication and release; And there is not systemic adverse reactions; It is uncomplicated to be approved for treatment, and the age is greater than 7 years old influenza patient, is preferably in morbidity and uses in 2 days.But this medicine remains to be investigated to infant's security, and only is used for influenza initial stage and light disease patient.Tamiflu is an oral prepns, yet this medicine at present can only be semi-synthetic, and its output is little, and price is also very expensive.
RWJ 270201 is an influenza virus NA suppressor factor of up-to-date listing.RWJ 270201 (English peramivir by name has another name called RWJ2270201 or BCX-1812) is a kind of neuraminidase influenza suppressor factor, can kill the multiple influenza virus that comprises the H5N1 bird flu virus efficiently.Its chemical being called (1S, 2S, 3R, 4R)-3-[(R)-1-acetamido-2-ethyl-butyl]-4-guanidine radicals-2-hydroxy-cyclopentane carboxylic acid, structural formula is formula (1) as follows.It can kill highly pathogenic H5N1 bird flu virus.The clinical study result show it can effective function in multiple influenza virus, it is to be Tamiflu in the novel pentamethylene of action target spot with influenza virus surface glycoprotein neuraminidase.Breadboard test result shows that RWJ 270201 can effectively resist each known H5N1 influenza virus, and lethality is strong especially, and is not easy to produce the resistance strain.
Formula (1)
RWJ 270201 has CN1282316A in the synthetic patent of China's application at present; CN1358170A and CN1367776A; CN1367776A discloses two kinds of trihydrate crystal A and B; Its preparation method be with the RWJ 270201 product at air drying, and the system that places liquid water to exist lets the trihydrate that obtains after the abundant moisture absorption of RWJ 270201.This method is had relatively high expectations to the relative humidity of air.Just cannot the efficient drying product if relative humidity is too big in the air, may make to have too much planar water in the product, water-content is increased.But when relative air humidity too hour, the product water-content that drying obtains can be lower than three crystal water content again.This makes disclosed two kinds of trihydrate crystal A of CN1367776A and B, and the preparation method can't stdn, and the amount of water is wayward.Our A and B crystal through discovering trihydrate, its three crystal water not all are very stable.
The patent of publication number CN101314579A discloses a kind of RWJ 270201 anhydride crystal in addition.But the RWJ 270201 water absorbability is stronger, and there is certain degree of difficulty in the storage of anhydride.
Summary of the invention
In view of existing some shortcomings of crystalline.Therefore, an object of the present invention is to provide a kind of RWJ 270201 hydrate crystal of good stability.
The inventor attentively studies, and is surprised to find that when RWJ 270201 forms 2.5 hydrate crystals, and its stability significantly increases.Need to prove; RWJ 270201 2.5 hydrate crystals are different from the disclosed A of CN1367776A and two kinds of crystal of B, and promptly trihydrate crystal also is different from the disclosed anhydride crystal of CN101314579A; Their X-ray powder diffraction is strivied for survival in difference, and also there is difference in diffraction peak.
Another object of the present invention provides a kind of preparation method of above-mentioned RWJ 270201 hydrate crystal.
The inventor studies with keen determination, from RWJ 270201 crude product refining condition and drying conditions, has done a large amount of experiments, has investigated multiple purified solvent and water, and between different ratios; Investigated multiple drying conditions, thereby found and prepared RWJ 270201 2.5 hydrate crystals.This crystalline excellent storage stability.
A further object of the present invention provides a kind of medicinal compsns of above-mentioned RWJ 270201 hydrate crystal.
Of the present invention also have a purpose to provide the application of a kind of above-mentioned RWJ 270201 hydrate crystal in the preparation anti-influenza virus medicament.
According to RWJ 270201 hydrate crystal of the present invention, it is characterized in that containing 2.5 crystal water.
According to RWJ 270201 hydrate crystal of the present invention; Use Cu-K α radiation,
to measure, the X-ray powder diffraction spectral signature of representing with 2 θ is following:
| |
2 θ angles | The peak relative intensity | Peak |
2 θ angles | The peak relative intensity |
| 1 | 4.680 | 100 | 26 | 22.860 | 23 |
| 2 | 6.020 | 63 | 27 | 23.200 | 23 |
| 3 | 6.560 | 40 | 28 | 24.160 | 47 |
| 4 | 7.600 | 29 | 29 | 24.820 | 19 |
| 5 | 8.920 | 23 | 30 | 25.180 | 17 |
| 6 | 9.320 | 58 | 31 | 26.580 | 27 |
| 7 | 10.080 | 7 | 32 | 27.300 | 16 |
| 8 | 12.020 | 40 | 33 | 27.920 | 24 |
| 9 | 12.320 | 14 | 34 | 28.460 | 15 |
| 10 | 12.900 | 35 | 35 | 29.700 | 18 |
| 11 | 13.980 | 19 | 36 | 30.080 | 22 |
| 12 | 14.760 | 13 | 37 | 30.720 | 23 |
| 13 | 15.340 | 55 | 38 | 31.360 | 15 |
| 14 | 15.920 | 5 | 39 | 31.960 | 11 |
| 15 | 16.660 | 16 | 40 | 33.200 | 10 |
| 16 | 17.160 | 12 | 41 | 33.760 | 13 |
| 17 | 17.420 | 11 | 42 | 34.220 | 9 |
| 18 | 17.840 | 7 | 43 | 35.520 | 11 |
| 19 | 18.680 | 34 | 44 | 36.200 | 11 |
| 20 | 19.620 | 32 | 45 | 40.280 | 9 |
| |
2 θ angles | The peak relative | Peak number | 2 θ angles | The peak relative intensity | |
| 21 | 20.220 | 45 | ||||
| 22 | 20.760 | 35 | ||||
| 23 | 21.200 | 26 | ||||
| 24 | 21.820 | 18 | ||||
| 25 | 22.180 | 14 |
And/or its X-ray powder diffraction figure is as shown in Figure 5 basically.
X-ray powder diffraction spectrographic 2 θ angles and peak relative intensity may be owing to reasons such as sample batch and testing tool deviations to some extent, and the deviation at 2 θ angles is ± 0.05, and the deviation of peak relative intensity is ± 3, all within the scope of the invention.
According to RWJ 270201 hydrate crystal of the present invention, it is analyzed through hot poor-thermogravimetric TG-DTA, and at the weightless 11.9wt%-12.5wt% of 25-150 ℃ of scope, its endothermic transition peak is at 267 ℃ ± 5 ℃; And/or the TG-DTA collection of illustrative plates is roughly as shown in Figure 2.The pairing temperature in summit that described endothermic transition peak temperature is meant endotherm(ic)peak in the DTA curve.
According to RWJ 270201 hydrate crystal of the present invention, its ir spectra wave number is following, with cm
-1Be unit: 3297,2964,2935,2877,1655,1560,1459,1442,1383,1300,1248,1190,1166,1148,1102,1036,963,817,783,754,698,641,596 and 407.The ir spectra wave number may be owing to reasons such as sample batch and testing tool deviation to some extent, and deviation is ± 5, all within the scope of the invention.
Preparing method according to RWJ 270201 hydrate crystal of the present invention comprises the steps:
(1) RWJ 270201 bullion recrystallization in alcoholic solvent and water is obtained white solid;
(2), obtain said RWJ 270201 hydrate crystal with said white solid vacuum-drying.
According to the preferred embodiment of the invention, said vacuum drying vacuum tightness is greater than 0, preferred 0.08-0.1MPa.
The further preferred embodiment according to the present invention specifically comprises the steps:
(1) the RWJ 270201 bullion is added in alcoholic solvent and the water, heating for dissolving, air distillation is steamed to 98 ℃ of boiling points, and the cooling crystallization filters, and gets white solid;
(2) said white solid is placed vacuum drier, add the siccative drying, system vacuumizes, and is dry more than 2 days.
The vacuum tightness that said system vacuumizes is greater than 0, preferred 0.08-0.1MPa.
According to the preferred embodiment of the invention, the weight ratio of RWJ 270201 bullion, alcoholic solvent, water is 1: 1-5: 3-10 is preferably 1: 2: 4.5.
The further preferred embodiment according to the present invention, described alcoholic solvent are methyl alcohol; And/or described water is zero(ppm) water; And/or said siccative is Calcium Chloride Powder Anhydrous or Vanadium Pentoxide in FLAKES.
The preferred embodiment according to the present invention, the weight ratio of RWJ 270201 bullion, methyl alcohol, zero(ppm) water are 1: 1-5: 3-10 is preferably 1: 2: 4.5.
The present invention provides a kind of pharmaceutical composition, and said composition contains said RWJ 270201 hydrate crystal and pharmaceutically acceptable one or more pharmaceutical excipients of treating significant quantity.
According to the preferred embodiment of the invention, said compsn is tablet, capsule, injection liquid or freeze-dried powder.
The preferred embodiment according to the present invention, said compsn are tablet, capsule, injection liquid or the freeze-dried powder that contains 5-1000mg RWJ 270201 hydrate crystal.
The invention still further relates to described RWJ 270201 hydrate crystal and be used for suppressing the application of the medicine of influenza neuraminidase as one of unique activeconstituents or activeconstituents in preparation.The medicine that suppresses the H5N1 bird flu virus in particular for preparation.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is according to the RWJ 270201 trihydrate TG-DTA collection of illustrative plates of comparative example 1.
Fig. 2 is according to the RWJ 270201 2.5 hydrate TG-DTA collection of illustrative plates of embodiment 1.
Fig. 3 is according to the RWJ 270201 2.5 hydrate organic solvent residual gas chromatograms of embodiment 1.
Fig. 4 methyl alcohol, ethanol, ETHYLE ACETATE and toluene standardized solution gas chromatogram.
Fig. 5 is according to the RWJ 270201 2.5 hydrate X-ray crystal powder diffractograms of embodiment 1.
Fig. 6 is according to the RWJ 270201 2.5 hydrate infrared spectrograms of embodiment 1.
Embodiment
According to RWJ 270201 hydrate crystal of the present invention, it contains 2.5 crystal water.Described crystal water quantity is a statistical value.Its preferred manufacturing procedure is following: (1) purification step: the RWJ 270201 bullion is added in the methyl alcohol, be heated to 80 ℃ of dissolvings in the zero(ppm) water, heat filtering, filtrating air distillation; Steam to 98 ℃ of boiling points, stop distillation, be cooled to 25 ℃ and stirred 5 hours; Filter, a small amount of washing gets white solid; (2) vacuum drying step: white solid is placed vacuum drier, add the siccative drying, system vacuumizes, and is dry more than 2 days, gets RWJ 270201 2.5 hydrates.
The further preferred embodiment according to the present invention, the weight ratio of said RWJ 270201 bullion, methyl alcohol and zero(ppm) water is 1: 2: 4.5.
The preferred embodiment according to the present invention, said siccative comprises Calcium Chloride Powder Anhydrous, siccative commonly used such as Vanadium Pentoxide in FLAKES.
The vacuum tightness that said system vacuumizes preferably requires greater than 0.08Mpa, and this vacuum tightness is the vacuum meter reading, is the relative pressure of a relative external atmosphere pressure, and actual is a negative value, and numerical value is between 0 to 0.1MPa.For example, be meant that greater than 0.04MPa 0.04 arrives the scope of perfect vacuum 0.1MPa.
Crystal of the present invention characterizes through following method.
1. thermogravimetric-heating differential analysis
Instrument title: Japanese standard type TG-DTA analyser of science
TG range: 7.0mg
TR: room temperature-400 ℃
Temperature rise rate: 10 ℃/min
DTA range: ± 100 μ V
Reference substance: Al
2O
3
2.X ray powder diffraction
Instrument model: Japanese D/MAX-2500X x ray diffractometer x of science
Target: Cu-Ka radiation,
2 θ=2-40 °
Pipe is pressed: 40KV
Pipe stream: 100mA
Filter disc: the monochromatic sheet of graphite.
3. ir spectra
Testing tool: the ALPHA-T type IR that German BRUKER company produces
Pressing potassium bromide troche.
4. to the stability test of light:
Under 4500Lx ± 500Lx illumination, respectively at sampling in 5,10 days, variation and 0 day data with the lot sample article of investigating sample appearance, total impurities, content compared with these article.
It is to adopt the HPLC method that total impurities detects, and selects the C18 post for use, 0.01mol/L KH
2PO
4NaOH adjusting PH6-methyl alcohol (68: 32) with 1mol/L is moving phase, detects wavelength 205nm.
Assay is used nonaqueous titrations, is solvent with the Glacial acetic acid min. 99.5, and the Viola crystallina indication extremely becomes blueness by purple with the 0.05mol/L perchloric acid titration.
5. to the stability test of heat:
Sample is put in 60 ℃ of constant temperature ovens,, investigated sample appearance, measure total impurities, content and 0 day divided data and compare with the lot sample article respectively at sampling in 5,10 days.
6. the influence factor of relative humidity 92.5% test:
Place RH92.5% ± 5% (to contain saturated KNO in sample
3The aqueous solution) in the moisture eliminator, put under 25 ℃ of conditions,, observe outward appearance, measure total impurities and content respectively at sampling in 5,10 days.
Comparative example 1, the preparation of RWJ 270201 A crystalline:
Add RWJ 270201 bullion 75.5 grams in 500 milliliters of there-necked flasks, 258 milliliters of zero(ppm) water, 64 milliliters of methyl alcohol.Heated and stirred is heated to 90 ℃, refluxing and stirring half a hour.Heat filtering, filtrating changes in 500 milliliters of there-necked flasks, and air distillation to boiling point 99-100 ℃, is cooled to 70-80 ℃ of stirred overnight.Next day, suspension-s was cooled to 0-5 ℃, and solid collected by filtration is with 0-5 ℃ of distilled water wash.Dry air (relative air humidity 30%-60%), but thereunder place a uncovered beaker that adds water, obtain granular trihydrate A crystal.
Fig. 1 is the RWJ 270201 trihydrate TG-DTA collection of illustrative plates according to comparative example 1, before 50 ℃, weightlessness has been arranged, shows that its thermostability is poor.In addition, this trihydrate also can be weightless in exsiccant environment held.
Comparative example 2, the preparation of RWJ 270201 B crystalline:
Add RWJ 270201 bullion 18.26 grams in 100 ml flasks, 55 milliliters of methyl alcohol, 24 milliliters of zero(ppm) water are heated to the reflux temperature dissolving, heat filtering.Filtrating changes in 100 ml flasks, is cooled to 25 ℃, stirs solid collected by filtration, a small amount of distillation washing 3 hours.Dry air (relative air humidity 30%-60%), a uncovered beaker that adds water is placed in its below, obtains acicular trihydrate B crystal.
The TG-DTA analysis revealed, this crystal had had weightlessness before 50 ℃, show that its thermostability is poor.
Embodiment 1, the new crystalline preparation of RWJ 270201 2.5 hydrates:
Add the RWJ 270201 bullion in 5 liters of there-necked flasks (by the method for publication number CN101538228A so that (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone is initiator; Be prepared into according to 3,9,12,14,16 methods of embodiment among the CN101538228A) 600 grams; 1500 milliliters of methyl alcohol (chemically pure reagent), 2700 milliliters in water.Be heated to reflux temperature, stirring and dissolving, heat filtering.The filtrating air distillation to 98 ℃ of boiling points, stops to distill, and is cooled to 25 ℃ and stirs 5 hours, filters, and a small amount of washing gets white solid.White solid is placed vacuum drier, add the Calcium Chloride Powder Anhydrous drying, system vacuumizes (vacuum tightness 0.08MPa), and 25 ℃ of temperature are dry more than 2 days.Get RWJ 270201 2.5 hydrate crystals 579 grams.
The instrument and the test condition of gc are following in present embodiment and the subsequent implementation example:
Instrument: Agilent Technologies 6890N gas chromatograph; The Agilent7694E head-space sampler; Chromatographic column: Agilent db-624 capillary column; 250 ℃ of vaporizer temperature; 50 ℃ of column compartment temperature kept 7 minutes, were warming up to 200 ℃ with 40 ℃ of PMs again, kept 3 minutes; Detector: FID flame ionization ditector, temperature: 250 ℃; CP 3psi, 80 ℃ of headspace sampling temperature, 1 milliliter of sample size.
The preparation of absolute ethyl alcohol, methyl alcohol, toluene and ETHYLE ACETATE standardized solution is following in present embodiment and the subsequent implementation example:
Precision is measured absolute ethyl alcohol 15.8 μ L respectively, methyl alcohol 9.5 μ L, toluene 2.6 μ L, ETHYLE ACETATE 13.9 μ L place 100 milliliters of measuring bottles, are diluted with water to scale, shake up standardized solution.
The mensuration of new crystal prototype is following in present embodiment and the subsequent implementation example:
50 milligrams of precision steelyard sample thiefs are put in the headspace sampling bottle, add 2 milliliters of dissolvings of entry after, headspace sampling is measured, and calculates the residual quantity of solvent with external standard method. measure the result and see Fig. 3, conclusion is that ethanol, methyl alcohol, toluene and ethyl acetate residual quantity all do not detect.
Part of test results is shown in accompanying drawing, wherein:
Fig. 2 is the RWJ 270201 2.5 hydrate TG-DTA collection of illustrative plates according to embodiment 1.Thermogravimetric-heating differential analysis shows: this product is 25-150 ℃ of weightlessness 12.2%.
Fig. 3 is the RWJ 270201 2.5 hydrate organic solvent residual gas chromatograms according to embodiment 1.
Fig. 4 is methyl alcohol, ethanol, ETHYLE ACETATE and toluene standardized solution gas chromatogram.The organic solvent residual vapor detection of product shows that product does not contain any organic solvent that possibly exist, and comprises the methyl alcohol that possibility is residual, ethanol, ETHYLE ACETATE, toluene etc.
Therefore, 12.2% weightlessness can only be water, and the weight accurate Theory percentage composition of 2.5 water in RWJ 270201 2.5 hydrates is 12.05%, shows and contains 2.5 crystal water in the product, and the dehydration endotherm(ic)peak is two peaks, respectively at 84 ℃ and 110 ℃.Crystallization is decomposed the endothermic transition peak at 267 ℃.The collection of illustrative plates of the X-ray powder diffraction of this product is as shown in Figure 5, and concrete characteristic peak is as shown in table 1 below.
The X-ray powder diffraction spectral signature that table 1 is represented with 2 θ
| |
2 θ angles | The peak relative | Peak number | 2 θ angles | The peak relative intensity | |
| 1 | 4.680 | 100 | 26 | 22.860 | 23 | |
| 2 | 6.020 | 63 | 27 | 23.200 | 23 | |
| 3 | 6.560 | 40 | 28 | 24.160 | 47 | |
| 4 | 7.600 | 29 | 29 | 24.820 | 19 | |
| 5 | 8.920 | 23 | 30 | 25.180 | 17 | |
| 6 | 9.320 | 58 | 31 | 26.580 | 27 | |
| 7 | 10.080 | 7 | 32 | 27.300 | 16 | |
| 8 | 12.020 | 40 | 33 | 27.920 | 24 | |
| 9 | 12.320 | 14 | 34 | 28.460 | 15 | |
| 10 | 12.900 | 35 | 35 | 29.700 | 18 | |
| 11 | 13.980 | 19 | 36 | 30.080 | 22 | |
| 12 | 14.760 | 13 | 37 | 30.720 | 23 | |
| 13 | 15.340 | 55 | 38 | 31.360 | 15 | |
| 14 | 15.920 | 5 | 39 | 31.960 | 11 | |
| 15 | 16.660 | 16 | 40 | 33.200 | 10 | |
| 16 | 17.160 | 12 | 41 | 33.760 | 13 | |
| 17 | 17.420 | 11 | 42 | 34.220 | 9 | |
| 18 | 17.840 | 7 | 43 | 35.520 | 11 | |
| 19 | 18.680 | 34 | 44 | 36.200 | 11 | |
| 20 | 19.620 | 32 | 45 | 40.280 | 9 | |
| 21 | 20.220 | 45 | ||||
| 22 | 20.760 | 35 | ||||
| 23 | 21.200 | 26 | ||||
| 24 | 21.820 | 18 | ||||
| 25 | 22.180 | 14 |
Fig. 6 is the RWJ 270201 2.5 hydrate infrared spectrograms according to embodiment 1.Ir spectra wave number (the cm of this product
-1) be: 3297,2964,2935,2877,1655,1560,1459,1442,1383,1300,1248,1190,1166,1148,1102,1036,963,817,783,754,698,641,596,407.
Table 2 RWJ 270201 2.5 hydrates are to the stability test result of light
| Storage period | Outward appearance | Content (%) | |
| 0 day | The off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | The off-white color crystalline powder | 99.98 | 0.25 |
| 10 days | The off-white color crystalline powder | 100.2 | 0.23 |
This product is seen table 2 to the stability test result of light.These article were through illumination 10 days, and the sample total impurities does not increase, the content warp compares basically identical with the data of 0 day same lot sample article, and outward appearance does not become, and each item inspection data all within acceptability limit, explain that these article are stable to light.
Table 3 RWJ 270201 2.5 hydrates add the heat stability test result for 60 ℃
| Storage period | Outward appearance | Content (%) | |
| 0 day | The off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | The off-white color crystalline powder | 100.2 | 0.25 |
| 10 days | The off-white color crystalline powder | 100.1 | 0.23 |
The product of embodiment 1 adds the heat stability test result at 60 ℃ and sees table 3.The result shows that these article were through 60 ℃ of heating 10 days, and sample appearance, total impurities, content and 0 day analytical data with the lot sample article compare basically identical, explain that these article are to thermally-stabilised.
The stability test result of table 4 RWJ 270201 2.5 hydrate relative humidity 92.5%
| Storage period | Outward appearance | Content (%) | |
| 0 day | The off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | The off-white color crystalline powder | 100.2 | 0.26 |
| 10 days | The off-white color crystalline powder | 100.0 | 0.23 |
The stability test result of the product of embodiment 1 under relative humidity 92.5% condition sees table 4.The result shows, through the placement of relative humidity 92.5% 10 days, outward appearance, total impurities and content with 0 day with the analytical data of the lot sample article basically identical of comparing, explain that these article are to wet stable.
Add RWJ 270201 bullion 200 grams in 2 liters of there-necked flasks, 485 milliliters of methyl alcohol, 900 milliliters in water.Be heated to reflux temperature, stirring and dissolving, heat filtering.The filtrating air distillation to 98 ℃ of boiling points, stops to distill, and is cooled to 25 ℃ and stirs 5 hours, filters, and a small amount of washing gets white solid.White solid is placed vacuum drier, and it is dry to add no Vanadium Pentoxide in FLAKES, 30 ℃ of temperature, and system vacuumizes (vacuum tightness 0.09MPa), and is dry more than 2 days.Get RWJ 270201 2.5 hydrate crystals 174 grams.
The preparation of embodiment 3, the new crystal water injection of RWJ 270201 2.5 hydrates:
RWJ 270201 2.5 hydrates 34.1 grams
Water for injection adds to 10 liters.
Make 100 of injections according to conventional injection preparation method.
The preparation of embodiment 4, the new crystal tablet of RWJ 270201 2.5 hydrates:
RWJ 270201 2.5 hydrates 34.1 grams
Lactose 22 grams
5% sodium carboxymethyl cellulose solution is an amount of
Make 100 in tablet by the conventional tablet preparation method.
The preparation of embodiment 5, the new crystal lyophilized injectable powder of RWJ 270201 2.5 hydrates:
RWJ 270201 2.5 hydrates 34.1 grams
3 kilograms of waters for injection.
The dissolving back makes 100 on powder pin with conventional freeze-dried powder preparation method.
Claims (13)
1. a RWJ 270201 hydrate crystal is characterized in that, each RWJ 270201 hydrate contains 2.5 crystal water.
2. RWJ 270201 hydrate crystal according to claim 1; It is characterized in that; Use Cu-K α radiation,
to measure, the X-ray powder diffraction spectrum characteristics peak of representing with 2 θ comprises:
Preferably, its X-ray powder diffraction figure is as shown in Figure 5 basically.
3. RWJ 270201 hydrate crystal according to claim 1 and 2 is characterized in that, it is analyzed through hot poor-thermogravimetric TG-DTA, and at the weightless 11.9wt%-12.5wt% of 25-150 ℃ of scope, its endothermic transition peak is at 267 ℃;
Preferably, its TG-DTA collection of illustrative plates is as shown in Figure 2 basically.
4. according to each described RWJ 270201 hydrate crystal in the claim 1 to 3, it is characterized in that its ir spectra wave number comprises, with cm
-1Be unit: 3297,2964,2935,2877,1655,1560,1459,1442,1383,1300,1248,1190,1166,1148,1102,1036,963,817,783,754,698,641,596 and 407.
5. the preparation method of each said RWJ 270201 hydrate crystal in the claim 1 to 4 is characterized in that said method comprises the steps:
(1) the RWJ 270201 bullion is obtained white solid through recrystallization in alcoholic solvent and water;
(2), obtain said RWJ 270201 hydrate crystal with said white solid vacuum-drying.
6. method according to claim 5 is characterized in that, said vacuum drying vacuum tightness is preferably greater than 0.08MPa greater than 0.
7. method according to claim 5 is characterized in that said method comprises the steps:
(1) the RWJ 270201 bullion is added in alcoholic solvent and the water, heating for dissolving, air distillation is steamed to 98 ℃ of boiling points, and the cooling crystallization filters, and gets white solid;
(2) said white solid is placed vacuum drier, add the siccative drying, system vacuumizes, and is dry more than 2 days.
8. according to each described method in the claim 5 to 7, it is characterized in that the weight ratio of said RWJ 270201 bullion, alcoholic solvent, water is 1: 1-5: 3-10.
9. according to each described method in the claim 5 to 8, it is characterized in that described alcoholic solvent is a methyl alcohol;
And/or described water is zero(ppm) water;
And/or said siccative is Calcium Chloride Powder Anhydrous or Vanadium Pentoxide in FLAKES.
10. a pharmaceutical composition is characterized in that, said composition contains each described RWJ 270201 hydrate crystal of claim 1 to 4 and pharmaceutically acceptable one or more pharmaceutical excipients of treating significant quantity.
11. compsn according to claim 10 is characterized in that, said compsn is tablet, capsule, injection liquid or freeze-dried powder.
12. according to claim 10 or 11 described compsns, described treatment significant quantity is a 5-1000mg RWJ 270201 hydrate crystal.
13. be used for suppressing the application of the medicine of influenza neuraminidase in preparation as one of unique activeconstituents or activeconstituents according to each described RWJ 270201 hydrate crystal in the claim 1 to 4.
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| KR102077838B1 (en) * | 2019-07-03 | 2020-02-14 | 주식회사 종근당바이오 | New method for manufacturing Peramivir trihydrate and water-system drying thereof |
| WO2020173095A1 (en) * | 2019-02-25 | 2020-09-03 | 广州南鑫药业有限公司 | Peramivir solution type inhalant and preparation method therefor |
| CN112724046A (en) * | 2020-10-14 | 2021-04-30 | 天津应天成科技有限公司 | Peramivir impurity F and preparation method and application thereof |
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