CN102584637B - 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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Abstract
The invention provides a peramivir 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 shown in the description.
Description
Technical field
The invention belongs to pharmaceutical chemistry field.Particularly, hydrate crystal, preparation method, medicinal compositions and this crystal that the present invention relates to a kind of Peramivir is in the application for the preparation of suppressing in the medicine of influenza neuraminidase.
Background technology
The Main Function of neuraminidase (NA) in influenza virus is to promote the new virus particle forming from cells infected, to separate and diffusion, promotes the diffusion that virus particle is organized towards periphery from the respiratory mucosa infecting.In addition NA also has the toxicity of enhanced virus strain and causes apoptosis, causes the function such as flu-like symptom and respiratory inflammation.NA inhibitor class medicine can suppress copying of influenza virus, reduces that it is pathogenic, symptom while alleviating influenza morbidity, shortens the course of disease, reduces complication.The Peramivir that NA inhibitor has zanamivir, Oseltamivir and the present invention relates at present, zanamivir is one and sucks preparation, after use, can reach higher concentration at the upper respiratory tract, suppress virus replication and release, and without systemic adverse reactions, be approved for treatment uncomplicated, the influenza patient that the age is greater than 7 years old, be preferably in morbidity 2 days in application.But this medicine needs to be investigated to infant's security, and only for influenza initial stage and light disease patient.Oseltamivir is oral preparations, but this medicine at present can only be semi-synthetic, and its output is little, and price is also very expensive.
Peramivir is an influenza virus NA inhibitor of up-to-date listing.Peramivir (English peramivir by name, has another name called RWJ2270201 or BCX-1812) is a kind of neuraminidase influenza inhibitor, can kill efficiently the multiple influenza virus including H5N1 avian influenza virus.Its chemistry (1S, 2S, 3R, 4R)-3-[(R by name)-1-acetamido-2-ethyl-butyl]-4-guanidine radicals-2-hydroxy-cyclopentane carboxylic acid, structural formula is shown in following formula (1).It can kill highly pathogenic H5N1 avian influenza virus.Clinical study result shows that it can effectively act on multiple influenza virus, and it is Tamiflu in the Novel ring pentane taking influenza virus surface glycoprotein neuraminidase as action target spot.The test result in laboratory shows, Peramivir can effectively be resisted each known H5N1 influenza virus, and lethality is strong especially, and is not easy to produce resistance strain.
Formula (1)
Peramivir 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 is at air drying by Peramivir product, and be placed in the system that liquid water exists, allow the trihydrate obtaining after the abundant moisture absorption of Peramivir.This method is had relatively high expectations to the relative humidity of air.Just cannot efficient drying product if relative humidity is too large in air, may make in product, with too much planar water, water-content to be increased.But when relative air humidity too hour, the dry product water content obtaining again can be lower than three crystal water content.This makes the disclosed two kinds of trihydrate crystal A of CN1367776A and B, and preparation method cannot stdn, and the amount of water is wayward.We find A and the B crystal of trihydrate by research, its three crystal water are not all very stable.
The patent of publication number CN101314579A discloses a kind of Peramivir anhydride crystal in addition.But Peramivir water absorbability is stronger, there is certain difficulty in the storage of anhydride.
Summary of the invention
In view of some shortcomings of existing crystal.Therefore, an object of the present invention is to provide a kind of Peramivir hydrate crystal of good stability.
The inventor attentively studies, and is surprised to find that in the time that Peramivir forms 2.5 hydrate crystal, and its stability significantly increases.It should be noted that, Peramivir 2.5 hydrate crystals are different from the disclosed A of CN1367776A and two kinds of crystal of B, i.e. trihydrate crystal is also different from the disclosed anhydride crystal of CN101314579A, their X-ray powder diffraction is strivied for survival in difference, and diffraction peak also exists difference.
Another object of the present invention is to provide a kind of preparation method of above-mentioned Peramivir hydrate crystal.
The inventor studies with keen determination, from Peramivir crude product refining condition and drying conditions, has done great many of experiments, has investigated multiple refining solvent and water, and between different ratios; Investigate multiple drying conditions, thereby found and prepared Peramivir 2.5 hydrate crystals.The excellent storage stability of this crystal.
A further object of the present invention is to provide a kind of medicinal compositions of above-mentioned Peramivir hydrate crystal.
Of the present invention also have an object to be to provide a kind of above-mentioned Peramivir hydrate crystal in the application of preparing in anti-influenza virus medicament.
According to Peramivir hydrate crystal of the present invention, it is characterized in that containing 2.5 crystal water.
According to Peramivir hydrate crystal of the present invention, use Cu-K α radiation,
measure, the X-ray powder diffraction spectral signature representing with 2 θ is as follows:
| Peak |
2 θ angles | Peak relative intensity | Peak |
2 θ angles | 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 |
| Peak |
2 θ angles | Peak relative intensity | Peak |
2 θ angles | 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 substantially as shown in Figure 5.
2 θ angles of X-ray powder diffraction spectrum and peak relative intensity may be due to reason deviations to some extent such as sample batch and testing tools, 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 Peramivir hydrate crystal of the present invention, its by heat poor-thermogravimetric TG-DTA analyzes, at the weightless 11.9wt%-12.5wt% of 25-150 DEG C of scope, its endothermic transition peak is at 267 DEG C ± 5 DEG C; And/or TG-DTA collection of illustrative plates roughly as shown in Figure 2.Described endothermic transition peak temperature refers to the corresponding temperature in summit of endotherm(ic)peak in DTA curve.
According to Peramivir hydrate crystal of the present invention, its infrared spectra wave number is as follows, with cm
-1for 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.Infrared spectra wave number may be due to reason deviations to some extent such as sample batch and testing tools, and deviation is ± 5, all within the scope of the invention.
According to the preparation method of Peramivir hydrate crystal of the present invention, comprise the steps:
(1) Peramivir crude product recrystallization in alcoholic solvent and water is obtained to white solid;
(2), by described white solid vacuum-drying, obtain described Peramivir hydrate crystal.
According to the preferred embodiment of the invention, described vacuum drying vacuum tightness is greater than 0, preferably 0.08-0.1MPa.
The further preferred embodiment according to the present invention, specifically comprises the steps:
(1) Peramivir crude product is added in alcoholic solvent and water, heating for dissolving, air distillation is steamed to 98 DEG C of boiling points, and cooling crystallization, filters, and obtains white solid;
(2) described white solid is placed in to vacuum drier, adds desiccant dryness, system vacuumizes, dry more than 2 days.
The vacuum tightness that described system vacuumizes is greater than 0, preferably 0.08-0.1MPa.
According to the preferred embodiment of the invention, the weight ratio of Peramivir crude product, 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 is methyl alcohol; And/or described water is distilled water; And/or described siccative is Calcium Chloride Powder Anhydrous or Vanadium Pentoxide in FLAKES.
The preferred embodiment according to the present invention, the weight ratio of Peramivir crude product, methyl alcohol, distilled water is 1: 1-5: 3-10, is preferably 1: 2: 4.5.
The invention provides a kind of pharmaceutical composition, said composition contains the described Peramivir hydrate crystal for the treatment of significant quantity, and pharmaceutically acceptable one or more pharmaceutical excipients.
According to the preferred embodiment of the invention, described composition is tablet, capsule, injection liquid or freeze-dried powder.
The preferred embodiment according to the present invention, described composition is tablet, capsule, injection liquid or the freeze-dried powder that contains 5-1000mg Peramivir hydrate crystal.
The invention still further relates to the application in the medicine for the preparation of inhibition influenza neuraminidase as one of unique activeconstituents or activeconstituents of described Peramivir hydrate crystal.Suppress the medicine of H5N1 avian influenza virus in particular for preparation.
Brief description of the drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 is according to the Peramivir trihydrate TG-DTA collection of illustrative plates of comparative example 1.
Fig. 2 is according to the Peramivir 2.5 hydrate TG-DTA collection of illustrative plates of embodiment 1.
Fig. 3 is according to the Peramivir 2.5 hydrate organic solvent residual gas chromatograms of embodiment 1.
Fig. 4 methyl alcohol, ethanol, ethyl acetate and toluene standardized solution gas chromatogram.
Fig. 5 is according to the Peramivir 2.5 hydrate X-ray crystal powder diffractograms of embodiment 1.
Fig. 6 is according to the Peramivir 2.5 hydrate infrared spectrograms of embodiment 1.
Embodiment
According to Peramivir hydrate crystal of the present invention, it contains 2.5 crystal water.Described crystal water quantity is a statistical value.Its preferred preparation method is as follows: (1) purification step: Peramivir crude product is added in methyl alcohol, in distilled water, be heated to 80 DEG C of dissolvings, heat filtering, filtrate air distillation, steams to 98 DEG C of boiling points, stops distillation, being cooled to 25 DEG C stirs 5 hours, filter, washing, obtains white solid on a small quantity; (2) vacuum drying step: white solid is placed in to vacuum drier, adds desiccant dryness, system vacuumizes, dry more than 2 days, obtain Peramivir 2.5 hydrates.
The further preferred embodiment according to the present invention, the weight ratio of described Peramivir crude product, methyl alcohol and distilled water is 1: 2: 4.5.
The preferred embodiment according to the present invention, described siccative comprises Calcium Chloride Powder Anhydrous, the conventional siccative such as Vanadium Pentoxide in FLAKES.
The vacuum tightness that described system vacuumizes preferably requires to be greater than 0.08Mpa, and this vacuum tightness is 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 greater than 0.04MPa and refer to 0.04 to perfect vacuum 0.1MPa scope.
Crystal of the present invention characterizes by the following method.
1. thermogravimetric-heating differential analysis
Instrument title: Rigaku standard type TG-DTA analyser
TG range: 7.0mg
Temperature range: room temperature-400 DEG C
Temperature rise rate: 10 DEG C/min
DTA range: ± 100 μ V
Reference substance: Al
2o
3.
2.X ray powder diffraction
Instrument model: Rigaku D/MAX-2500X x ray diffractometer x
Target: Cu-Ka radiation,
2 θ=2-40 °
Pipe is pressed: 40KV
Guan Liu: 100mA
Filter disc: the monochromatic sheet of graphite.
3. infrared spectra
Testing tool: the ALPHA-T type infrared spectrometer that German BRUKER company produces
Pressing potassium bromide troche.
4. the stability test of pair light:
This product, under 4500Lx ± 500Lx illumination, respectively at sampling in 5,10 days, is investigated to variation and the data comparison with batch sample in 0 day of sample appearance, total impurities, content.
It is to adopt HPLC method that total impurities detects, and selects C18 post, 0.01mol/L KH
2pO
4regulating PH6-methyl alcohol (68: 32) with the NaOH of 1mol/L is moving phase, detects wavelength 205nm.
Assay nonaqueous titrations, taking Glacial acetic acid as solvent, Viola crystallina instruction, extremely becomes blueness from purple with 0.05mol/L perchloric acid titration.
5. pair hot stability test:
Sample is put in 60 DEG C of constant temperature ovens, respectively at sampling in 5,10 days, investigated sample appearance, measure total impurities, content and the divided data comparison with batch sample in 0 day.
6. the influence factor of relative humidity 92.5% test:
Sample is placed in to RH92.5% ± 5% (containing saturated KNO
3the aqueous solution) moisture eliminator in, put under 25 DEG C of conditions, respectively at sampling in 5,10 days, observe outward appearance, measure total impurities and content.
the preparation of comparative example 1, Peramivir A crystal:
In 500 milliliters of there-necked flasks, add 75.5 grams of Peramivir crude products, 258 milliliters of distilled water, 64 milliliters of methyl alcohol.Heated and stirred, is heated to 90 DEG C, return stirring half an hour.Heat filtering, filtrate proceeds in 500 milliliters of there-necked flasks, and air distillation, to boiling point 99-100 DEG C, is cooled to 70-80 DEG C of stirring and spends the night.Next day, suspension was cooled to 0-5 DEG C, and solid collected by filtration, with 0-5 DEG C of distilled water wash.Dry air (relative air humidity 30%-60%), but thereunder place a uncovered beaker adding water, obtain granular trihydrate A crystal.
Fig. 1 is the Peramivir trihydrate TG-DTA collection of illustrative plates according to comparative example 1, has had weightlessness before 50 DEG C, shows that its thermostability is poor.In addition, under dry environment, place also can be weightless for this trihydrate.
the preparation of comparative example 2, Peramivir B crystal:
In 100 ml flasks, add 18.26 grams of Peramivir crude products, 55 milliliters of methyl alcohol, 24 milliliters of distilled water, are heated to reflux temperature and dissolve, heat filtering.Filtrate proceeds in 100 ml flasks, is cooled to 25 DEG C, stirs solid collected by filtration, a small amount of distillation washing 3 hours.Dry air (relative air humidity 30%-60%), a uncovered beaker adding water is placed in its below, obtains the trihydrate B crystal of needle-like.
TG-DTA analyzes and shows, this crystal had had weightlessness before 50 DEG C, showed that its thermostability is poor.
the preparation of embodiment 1, the new crystal of Peramivir 2.5 hydrate:
In 5 liters of there-necked flasks, add Peramivir crude product (by the method for publication number CN101538228A taking (±) 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone as initiator, be prepared into according to 3,9,12,14,16 methods of embodiment in CN101538228A) 600 grams, 1500 milliliters of methyl alcohol (chemically pure reagent), 2700 milliliters, water.Be heated to reflux temperature, stirring and dissolving, heat filtering.Filtrate air distillation, to 98 DEG C of boiling points, stops distillation, is cooled to 25 DEG C and stirs 5 hours, filters, and washing, obtains white solid on a small quantity.White solid is placed in to vacuum drier, adds Calcium Chloride Powder Anhydrous dry, system vacuumizes (vacuum tightness 0.08MPa), and 25 DEG C of temperature are dry more than 2 days.Obtain 579 grams of Peramivir 2.5 hydrate crystals.
In the present embodiment and subsequent embodiment, the instrument of gas-chromatography and test condition are as follows:
Instrument: Agilent Technologies 6890N gas chromatograph; Agilent7694E head-space sampler; Chromatographic column: Agilent db-624 capillary column; 250 DEG C of vaporizer temperature; Column compartment temperature 50 C, keeps 7 minutes, then is warming up to 200 DEG C with 40 DEG C of per minutes, keeps 3 minutes; Detector: FID flame ionization ditector, temperature: 250 DEG C; Constant pressure 3psi, 80 DEG C of headspace sampling temperature, 1 milliliter of sample size.
Being prepared as follows of dehydrated alcohol, methyl alcohol, toluene and ethyl acetate standardized solution in the present embodiment and subsequent embodiment:
Precision measures dehydrated alcohol 15.8 μ L respectively, methyl alcohol 9.5 μ L, and toluene 2.6 μ L, ethyl acetate 13.9 μ L are placed in 100 milliliters of measuring bottles, are diluted with water to scale, shake up to obtain standardized solution.
Being determined as follows of new crystal prototype in the present embodiment and subsequent embodiment:
50 milligrams of precision steelyard sample thiefs, put in headspace sampling bottle, add after 2 milliliters of dissolvings of water, and headspace sampling is measured, and calculate the residual quantity of solvent with external standard method. and measurement result is shown in Fig. 3, and conclusion is that ethanol, methyl alcohol, toluene and ethyl acetate residual quantity all do not detect.
Part of test results as shown in drawings, wherein:
Fig. 2 is the Peramivir 2.5 hydrate TG-DTA collection of illustrative plates according to embodiment 1.Thermogravimetric-heating differential analysis shows: this product is 25-150 DEG C of weightlessness 12.2%.
Fig. 3 is the Peramivir 2.5 hydrate organic solvent residual gas chromatograms according to embodiment 1.
Fig. 4 is methyl alcohol, ethanol, ethyl 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 may exist, and comprises the methyl alcohol that possibility is residual, ethanol, ethyl acetate, toluene etc.
Therefore, 12.2% weightlessness can only be water, and 2.5 water weight accurate Theory percentage composition in Peramivir 2.5 hydrates is 12.05%, shows to contain 2.5 crystal water in product, and dehydration endotherm(ic)peak is two peaks, respectively at 84 DEG C and 110 DEG C.Crystallization is decomposed endothermic transition peak at 267 DEG C.As shown in Figure 5, specific features peak is as shown in table 1 below for the collection of illustrative plates of the X-ray powder diffraction of this product.
the X-ray powder diffraction spectral signature that table 1 represents with 2 θ
| |
2 θ angles | Peak relative | Peak number | 2 θ angles | 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 Peramivir 2.5 hydrate infrared spectrograms according to embodiment 1.Infrared 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.
the stability test result of table 2 Peramivir 2.5 hydrates to light
| Storage period | Outward appearance | Content (%) | |
| 0 day | Off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | Off-white color crystalline powder | 99.98 | 0.25 |
| 10 days | Off-white color crystalline powder | 100.2 | 0.23 |
This product the results are shown in Table 2 to the stability test of light.This product was through illumination 10 days, and sample total impurities does not increase, content warp is more basically identical with the data of the same batch sample of 0 day, and outward appearance does not become, and every inspection data all, within acceptability limit, illustrate that this product is stable to light.
60 DEG C, table 3 Peramivir 2.5 hydrate adds heat stability test result
| Storage period | Outward appearance | Content (%) | |
| 0 day | Off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | Off-white color crystalline powder | 100.2 | 0.25 |
| 10 days | Off-white color crystalline powder | 100.1 | 0.23 |
The product of embodiment 1 adds heat stability test at 60 DEG C and the results are shown in Table 3.Result shows, this product is through 60 DEG C of heating 10 days, sample appearance, total impurities, content and 0 day more basically identical with the analytical data of batch sample, illustrate that this product is to thermally-stabilised.
the stability test result of table 4 Peramivir 2.5 hydrate relative humidity 92.5%
| Storage period | Outward appearance | Content (%) | |
| 0 day | Off-white color crystalline powder | 100.1 | 0.26 |
| 5 days | Off-white color crystalline powder | 100.2 | 0.26 |
| 10 days | Off-white color crystalline powder | 100.0 | 0.23 |
The stability test of the product of embodiment 1 under relative humidity 92.5% condition the results are shown in Table 4.Result shows, through the placement of relative humidity 92.5% 10 days, outward appearance, total impurities and content with within 0 day, compare basically identically with the analytical data of batch sample, illustrate that this product is to wet stable.
the preparation of embodiment 2, the new crystal of Peramivir 2.5 hydrate:
In 2 liters of there-necked flasks, add 200 grams of Peramivir crude products, 485 milliliters of methyl alcohol, 900 milliliters, water.Be heated to reflux temperature, stirring and dissolving, heat filtering.Filtrate air distillation, to 98 DEG C of boiling points, stops distillation, is cooled to 25 DEG C and stirs 5 hours, filters, and washing, obtains white solid on a small quantity.White solid is placed in to vacuum drier, adds without Vanadium Pentoxide in FLAKES and be dried, 30 DEG C of temperature, system vacuumizes (vacuum tightness 0.09MPa), dry more than 2 days.Obtain 174 grams of Peramivir 2.5 hydrate crystals.
the preparation of embodiment 3, the new crystal water injection of Peramivir 2.5 hydrate:
34.1 grams, Peramivir 2.5 hydrate
Water for injection adds to 10 liters.
Make 100 of injections according to regular injection agent preparation method.
the preparation of embodiment 4, the new crystal tablet of Peramivir 2.5 hydrate:
34.1 grams, Peramivir 2.5 hydrate
10 grams of Microcrystalline Celluloses
22 grams of lactose
5% sodium carboxymethyl cellulose solution is appropriate
2 grams of Magnesium Stearates.
Method for preparing tablet thereof makes 100, tablet routinely.
the preparation of embodiment 5, the new crystal lyophilized injectable powder of Peramivir 2.5 hydrate:
34.1 grams, Peramivir 2.5 hydrate
3 kilograms of waters for injection.
After dissolving, make 100, powder pin by conventional freeze-dried powder preparation method.
Claims (11)
1. a Peramivir hydrate crystal, is characterized in that, each Peramivir hydrate contains 2.5 crystal water, and its X-ray powder diffraction figure substantially as shown in Figure 5.
2. Peramivir hydrate crystal according to claim 1, is characterized in that, its by heat poor-thermogravimetric TG-DTA analyzes, at the weightless 11.9wt%-12.5wt% of 25-150 DEG C of scope, its endothermic transition peak is at 267 DEG C.
3. Peramivir hydrate crystal according to claim 2, is characterized in that, its TG-DTA collection of illustrative plates substantially as shown in Figure 2.
4. according to the Peramivir hydrate crystal described in any one in claim 1-3, it is characterized in that, its infrared spectra wave number comprises, with cm
-1for 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. a preparation method for Peramivir hydrate crystal described in any one in claim 1 to 4, is characterized in that, described method comprises the steps:
(1) Peramivir crude product is added in alcoholic solvent and water, heating for dissolving, air distillation is steamed to 98 DEG C of boiling points, and cooling crystallization, filters, and obtains white solid, and wherein said alcoholic solvent is methyl alcohol; And the weight ratio of described Peramivir crude product, alcoholic solvent, water is 1:1-5:3-10;
(2) described white solid is placed in to vacuum drier, add desiccant dryness, system vacuumizes, dry more than 2 days, obtain described Peramivir hydrate crystal, described vacuum drying vacuum tightness be greater than 0 and described siccative be Calcium Chloride Powder Anhydrous or Vanadium Pentoxide in FLAKES.
6. method according to claim 5, is characterized in that, described water is distilled water.
7. according to the method described in claim 5 or 6, it is characterized in that, described vacuum drying vacuum tightness is greater than 0.08MPa.
8. a pharmaceutical composition, is characterized in that, said composition contains the Peramivir hydrate crystal described in any one in the claim 1 to 4 for the treatment of significant quantity, and pharmaceutically acceptable one or more pharmaceutical excipients.
9. composition according to claim 8, is characterized in that, described composition is tablet, capsule, injection liquid or freeze-dried powder.
10. composition according to claim 8 or claim 9, is characterized in that, described treatment significant quantity is 5-1000mg Peramivir hydrate crystal.
11. according to the application in the medicine for the preparation of inhibition influenza neuraminidase as one of unique activeconstituents or activeconstituents of the Peramivir hydrate crystal described in any one in claim 1 to 4.
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| CN109771398B (en) * | 2019-02-25 | 2019-09-20 | 广州南鑫药业有限公司 | A kind of Peramivir solution-type inhalant and preparation method thereof |
| KR102077838B1 (en) * | 2019-07-03 | 2020-02-14 | 주식회사 종근당바이오 | New method for manufacturing Peramivir trihydrate and water-system drying thereof |
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| CA2258217C (en) * | 1996-06-14 | 2005-08-09 | Biocryst Pharmaceuticals Inc. | Substituted cyclopentane compounds useful as neuraminidase inhibitors |
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| HUP0202097A2 (en) * | 1999-06-28 | 2002-10-28 | Biocryst Pharm Inc | Process for preparing substituted cyclopentane derivatives and novel crystalline form of these derivatives |
| AR024600A1 (en) * | 1999-06-28 | 2002-10-16 | Biocryst Pharm Inc | PREPARATION OF CYCLOPENTANE AND CYCLOPENTENE COMPOUNDS SUBSTITUTED AND CERTAIN INTERMEDIARIES |
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| CN100432047C (en) * | 2006-07-03 | 2008-11-12 | 华南农业大学 | Synthesis process of peramivir as medicine for antagonizing influenza and bird flu virus |
| CN101367750B (en) * | 2007-08-14 | 2012-05-23 | 中国人民解放军军事医学科学院毒物药物研究所 | (1S,2S,3S,4R)-3-[(1S)-1-acet-ammonia-2-ethyl-butyl]-4- guanidino-2-hydroxyl-cyclopentyl-1-carboxylic acid aqua compound and medical uses thereof |
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