CN101347412B - Amifostine trihydrate crystal lyophilized preparation and method of preparing the same - Google Patents
Amifostine trihydrate crystal lyophilized preparation and method of preparing the same Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations and discloses a sterile lyophilized crystalline amifostine trihydrate preparation and a preparation method thereof. The sterile lyophilized crystalline amifostine trihydrate preparation is prepared by the mixed solution consisting of the mixing solvent of amifostine, acetone, ethanol and water after the steps of removing pyrogen, filtering and sterilizing by a 0.22mum membrane, filling, pre-freezing, lyophilizing, sublimation and analysis drying, aerating and stopper pressing. The lyophilized crystalline amifostine trihydrate preparation has the advantages of stable performance, convenient preparation process, short process time with the lyophilization process time less than 35 hours, energy saving, high efficiency, being suitable for large-scale production and being easy for transport and storage.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more specifically, relate to a kind of aseptic amifostine trihydrate crystal lyophilized preparation and preparation method thereof.
Background technology
The amifostine chemical name is S-2-(3-aminopropyl amine) ethyl phosphorothioic acid, is also referred to as WR-2721.Ethyol (amifostine) the lyophilizing injection powder pin of U.S. FDA (food and medicine Surveillance Authority) approval U.S. Bioscience company in 1996, first the approval China big pharmaceutical factory of Dalian Metro amikacin srlfate inj (trade name: freeze-dried powder listing amifostine) of calendar year 2001 China SFDA (food and medicine Surveillance Authority).The amifostine chemical structural formula is H
2N-(CH
2)
3-NH-(CH
2)
2-SPO
3H
2, be a kind of organic sulfide phosphate cpd.It in tissue by with the bonded alkaline phosphatase enzyme hydrolysis of cell membrane dephosphorylation after, become and have active metabolite WR-1065, its chemical structural formula is H
2N-(CH
2)
3-NH-(CH
2)
2-SH.Because of sulfydryl has the effect of removing free radical in the tissue, so can lower the toxicity of cisplatin, cyclophosphamide and mitomycin etc.Amifostine is a normal cell protective agent, is mainly used in the auxiliary treatment of various cancers.Before being carried out chemotherapy, multiple cancer patients such as pulmonary carcinoma, ovarian cancer, breast carcinoma, nasopharyngeal carcinoma, bone tumor, digestive tract tumor, hematological system tumor use amifostine, kidney, bone marrow, heart, ear and the neural toxicity that can obviously alleviate chemotherapeutics and produced, and do not reduce the drug effect of chemotherapeutics.Use amifostine before the radiotherapy and can significantly reduce xerostomia and catarrhal generation.Amifostine is used to protect the infected patient of HIV to use efabirenz Qi Duofuting (AZT) and avoids harmful side effect.
Be unsettled under the aqueous solution of amifostine or the desiccation, study at present stable, contain three crystalline hydrate amifostines report and have:
1. Chinese patent ZL00119038.5 discloses and need not lyophilizing, and is by regulating pH, freezing under aseptic condition, obtains containing the amifostine crystal of three water of crystallization, just can be distributed into injectable powder after the amifostine that crystallization goes out must sieve, but need not pass through freeze-drying process.
2. Chinese patent ZL93117436.8 discloses the C that contains amifostine
1-C
5The solution of alcohol and water carries out the lyophilizing crystallization, and prepares stable crystallized pirimiphos-methyl composite.Though this method public use contains the solution of C1-C5 alcohol and water, cryodesiccated process need be annealed, and temperature range is wide, has only the embodiment of ethanol as solvent among the embodiment, and sublimation drying is long above 50 hours.
3. Chinese patent ZL200410037763.X discloses the acetone of amifostine and the solution of water carries out the lyophilizing crystallization, prepare stable crystallized pirimiphos-methyl preparation, this method public use acetone solvent, cryodesiccated process need be annealed, temperature range is wide, and sublimation drying was above 50 hours.
Though aforementioned patent discloses three kinds of methods that prepare the stable crystalline amifostine, because the amifostine huge market demand, people need work out the method convenient, energy-conservation more, that efficient production is stablized amifostine.
Summary of the invention
Therefore, the object of the present invention is to provide a kind of aseptic amifostine trihydrate crystal lyophilized preparation that improves.The inventor adopts freeze drying process to prepare aseptic amifostine trihydrate crystal lyophilized preparation; its preparation process process conditions and preparation stability are carried out a large amount of research; obtain convenient preparation process; process time is short, energy-conservation, efficient; be fit to large-scale production; said preparation stable performance simultaneously is easy to transportation and storage.
The invention provides a kind of aseptic amifostine trihydrate crystal lyophilized preparation, it is characterized in that,,, make after the lyophilizing through removing pyrogen, 0.22 μ m membrane filtration degerming by containing the mixed solution that amifostine, acetone and alcohol mixed solvent and water are formed.
Described amifostine is amifostine or its hydrate according to the conventional or known method preparation in this area, and is preferably the amifostine trihydrate crystal, the amifostine trihydrate crystal that most preferably obtains as follows:
Step 1: with reactant N-(2-bromoethyl)-1, two hydrobromates of 3-propane diamine and sodium thiophosphate are dissolved in the water by the molar ratio of 1.01～1.2:1.0, add polar non-solute as promoter, 10～40 ℃ of reactions; After the reaction, reactant solution need not be analysed by alcohol, and directly thick product amifostine trihydrate crude product is separated out in cooling;
Step 2: the amifostine trihydrate crude product that step 1 is obtained carries out the recrystallization purification first time, is about to the amifostine trihydrate dissolving crude product in water, separates out with methanol then, obtains not having the water of crystallization amifostine;
Step 3: the no water of crystallization amifostine that step 2 is obtained carries out the recrystallization purification second time, being about to not have the water of crystallization amifostine is dissolved in the water, and with 0.1～1.50% activated carbon decolorizing of no water of crystallization amifostine weight, separate out the amifostine trihydrate crystal with ethanol then, its purity 〉=99.5%, mercaptans content≤0.1%, other its related substances≤0.1% (by U.S. USP29).
In above-mentioned preparation method, institute's water is pure water or deionized water.
More specifically:
In described step 1, reactant N-(2-bromoethyl)-1, two hydrobromates of 3-propane diamine and sodium thiophosphate place the water stirring and dissolving by the molar ratio of 1.01～1.20:1.0, and preferred 1.03～1.10:1.0; Dissolving used water weight is N-(2-bromoethyl)-1,1.3～3.8 times of the two hydrobromate additions of 3-propane diamine, and preferred 1.7～2.5 times; 10～40 ℃ of solution temperature scopes; Described polar non-solute is a dimethyl sulfoxide, and the addition of dimethyl sulfoxide is N-(2-bromoethyl)-1, and the two hydrobromates of 3-propane diamine add 1.0～2.8 times of weight; Reaction temperature is controlled at 10～40 ℃, and preferred 15～25 ℃; Check reaction solution with silver nitrate solution in the course of reaction, do not separate out to there being black precipitate; After reaction finishes, with reaction product solution directly cooling be cooled to-15 ℃～10 ℃, preferred-10 ℃～5 ℃, kept 2～24 hours, filter three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystal crude product.
In described step 2, promptly recrystallization is purified for the first time: with the amifostine trihydrate crude product of pure water dissolving step 1 preparation, the pure water consumption is 1.0～6.0 times of amifostine trihydrate crude product weight, and preferred 2.5～4.5 times; 15～45 ℃ of solution temperatures; After the dissolving, add methanol, it is to add 0.1～0.8 times of pure water amount that methanol adds weight, and preferred 0.2～0.6 times; Be cooled to 20 ℃～-15 ℃, the temperature range of preferably lowering the temperature is 8 ℃～-5 ℃, separates out no water of crystallization amifostine.
In described step 3, promptly recrystallization is purified for the second time: with the no water of crystallization amifostine of pure water dissolving step 2 preparations, water consumption is 1.0～6.0 times of the no water of crystallization amifostine weight of adding, and preferred 2.5～4.5 times; 15～45 ℃ of solution temperatures; And preferred 0.1～1.5% the active carbon that adds no water of crystallization amifostine weight decolours, and stirs more than 15 minutes, then filtration; In gained filtrate, add ethanol, ethanol add weight be add 0.05～0.4 times of pure water amount, and preferred 0.1～0.3 times; Be cooled to 20 ℃～-15 ℃, the temperature range of preferably lowering the temperature is 8 ℃～-5 ℃, separates out the amifostine crystal that contains three water of crystallization.
Filter according to a conventional method then, drying.After the filtration, use the alcoholic solution washing crystal, vacuum drying, three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystalline compounds of high purity stable.
Three hydration 3-aminopropyl amine ethyl phosphorothioic acid (amifostine) crystal that obtain as stated above, yield are greater than 65%, purity〉99.5%, mercaptans content≤0.1%, other impurity≤0.1%, its stability improves greatly, thereby side effect significantly reduces, and can be used for useful in preparing drug formulations and uses.
In amifostine trihydrate crystal lyophilized preparation provided by the invention, described acetone and ethanol mixed solvent, acetone and ethanol proportioning are 0.2～4.0:1 (by volume), and preferred acetone and alcoholic acid proportioning are 0.5～2.0:1 (by volume).
Of the present invention containing in the mixed solution that amifostine, acetone and alcohol mixed solvent and water forms, contain: amifostine 50～400mg/ml, preferably contain amifostine 80～200mg/ml; 1～30% (percent by volume) acetone and alcohol mixed solvent, the acetone of preferred 6～15% (percents by volume) and alcohol mixed solvent; The water of 65～99% (percents by volume), the water of preferred 85～94% (percents by volume).
More specifically, aseptic amifostine trihydrate crystal lyophilized preparation provided by the invention makes as follows, and this method may further comprise the steps:
(1) preparation contains the mixed solution of amifostine, acetone and alcohol mixed solvent and water composition: relation preparation according to the above ratio contains the mixed solution of amifostine, pharmaceutically acceptable acetone and alcohol mixed solvent and water;
(2) depyrogenation, degerming:, remove pyrogen, filtration sterilization to the solution activated carbon decolorizing that (1) step prepares;
(3) fill: under 100 grades of clean area conditions, solution after fill (2) step process is in lyophilizing control injection bottle, and fill contains amifostine 80～900mg/ bottle, its solution amount 0.5～6.0ml/ bottle, preferably contain amifostine 100～700mg/ bottle, its solution amount 1.0～6.0ml/ bottle;
(4) pre-freeze: the control injection bottle that fill is contained aseptic amifostine solution is placed on the flaggy of freeze dryer, undertaken freezing by the flaggy temperature is set, the flaggy temperature reaches-16 ℃～-45 ℃, preferably-20 ℃～-30 ℃, cooling rate 20 minutes/℃～1 minute/℃, preferred 15 minutes/℃～3 minutes/℃, held time preferred 4～8 hours 2～16 hours;
(5) sublimation drying: carry out sublimation drying-45 ℃～-10 ℃ scopes, will be on (4) step basis, start freeze dryer condensation chamber cryogenic temperature and be lower than-47 ℃, starting vacuum pump rises to more than the 300mTorr the interior vacuum of freeze dryer, slowly heat by flaggy, the flaggy temperature is risen in-25～-10 ℃ of scopes carry out sublimation drying, 16～48 hours time;
(6) parsing-desiccation: after (5) step finishes, be warming up to-5 ℃～25 ℃ and carry out parsing-desiccation, 2～10 hours time;
(7) inflation, tamponade: finish in (6) step, introduce aseptic noble gas in 2 ℃～25 ℃ scopes, tamponade again obtains aseptic amifostine trihydrate crystal lyophilized preparation;
And the above-mentioned whole freeze-drying process time can be controlled in 35 hours finishes, and the time is short, and is energy-conservation.
In described (1) step, also can in gained solution, add the material of one or more in the acceptable adjuvant on the conventional pharmaceutical, as excipient, analgesics and buffer agent etc.
In described (2) step, described activated carbon dosage can be 0.05%～5% (percentage by weight) of amifostine consumption, preferred 0.1%～2.0%.After adding active carbon, stirred 15～30 minutes down, filter decarburization at 20 ℃～25 ℃.Described filtration sterilization can be with 0.22 μ m filtering with microporous membrane.
Described (4) step cryogenic temperature reaches-25 ℃, and freezing 2～10 hours, preferred 3～5 hours.
Described (5) step sublimation drying when preferred temperature is chilled in-25 ℃, rises to freeze dryer vacuum more than the 300mTorr, slowly heating, and the flaggy temperature slowly rises to-20～-10 ℃ by-25 ℃, and scope was carried out sublimation drying 16～24 hours.
Described (6) parsing-desiccation step, the control freeze dryer gets the flaggy temperature at-5 ℃～25 ℃, preferred-5 ℃～15 ℃, keeps 5-10 hour.
The aseptic amifostine trihydrate crystal lyophilized preparation of the present invention is a normal cell protective agent, is mainly used in the auxiliary treatment of various cancers, alleviate put, chemotherapy is to the toxic and side effects of human normal tissue.Use the general each using dosage of freeze-dried powder of the present invention in 200～900mg scope, freeze-dried powder is dissolved in water for injection or other injection, described injection is conventional injection, as 5% glucose injection or 0.9% sodium chloride injection.But administering mode intravenous, intramuscular, subcutaneous, intracavity and intrathecal drug delivery.
The aseptic amifostine trihydrate crystal lyophilized preparation stable performance that contains of the present invention is dissolved during use fully rapidly, its convenient preparation process, and the process time is short, energy-conservation, efficient, is fit to large-scale production, is easy to transportation and storage.
Description of drawings
Figure 1A and Figure 1B are that the present invention prepares crystalline XRPD spectrogram of amifostine trihydrate and the data that embodiment 1 obtains.
Fig. 2 is that the present invention prepares the crystalline X ray single crystal diffraction of the amifostine trihydrate figure that embodiment 1 obtains.
Fig. 3 is that the present invention prepares the crystalline ultramicroscope photograph of amifostine trihydrate that embodiment 1 obtains
Sheet clearlys show that from figure amifostine trihydrate is to exist with crystal form, and is the flat crystal.
The specific embodiment:
Following embodiment is that the present invention is further described and describes that these explanations and description are not the further restriction to content of the present invention.
One. the crystalline preparation of the amifostine trihydrate of high purity stable
Step 1: synthetic
In the 50L stainless steel cauldron, add pure water 13.6kg, 12 water sodium thiophosphate 19.2mol (7.6kg), stir and add N-(2-bromoethyl)-1 down, the two hydrobromate 19.8mol (6.8kg of 3-propane diamine, 3% is excessive), slowly add 11.0kgDMSO, keep reaction temperature simultaneously and be no more than 25 ℃.After dripping DMSO, with silver nitrate solution monitoring reaction solution, do not separate out to there being black precipitate, reaction finishes, and reaction solution is cooled to 0 ℃, per hour stirs 5 minutes, keeps 18 hours.Centrifugal filtration gets three hydration 3-aminopropyl amine ethyl phosphorothioic acid crude product 6.1kg.
Step 2: recrystallization is purified for the first time
In 50L rustless steel crystallization kettle, add the 22.0kg pure water, the 3-aminopropyl amine ethyl phosphorothioic acid crude product 6.1kg of step preparation in the adding, dissolving at room temperature adds active carbon 95.0g, stirs 15 minutes under the room temperature, filter, add methanol 8.7kg in the mother solution, logical cooling water temperature to 0 ℃ was kept 18 hours, centrifugal filtration, getting a recrystallizing and refining does not have water of crystallization 3-aminopropyl amine ethyl phosphorothioic acid 4.8kg.
Step 3: recrystallization is purified for the second time
In 50L rustless steel crystallization kettle, add the 20.0kg pure water, add the no water of crystallization 3-aminopropyl amine ethyl phosphorothioic acid 4.8kg that the first time, recrystallization obtained, at room temperature stirring and dissolving adds active carbon 75.0g, stirred 15 minutes under the room temperature, filter, add ethanol 3.2kg in the mother solution, logical cooling water temperature to 0 ℃, kept 18 hours, centrifugal filtration, 30 ℃ of vacuum dryings get three hydration 3-aminopropyl amine ethyl phosphorothioic acid 3.6kg.Adopt HPLC method (by 29 editions official methods of the U.S.) to analyze purity 99.81%, mercaptans content 0.021%, other related substances 0.078%.
Table 1 has provided the contrast of amifostine content and its related substances on three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal of above-mentioned preparation and the market:
As can be seen from Table 1, the crystalline content of amifostine trihydrate of the present invention's preparation will be higher than the amifostine trihydrate that market is purchased, and related substance mercaptan, disulfide and other related substance all are significantly less than the product that existing market is purchased simultaneously.
Adopt the D/MAX-2400X x ray diffractometer x, press 40KV at pipe, pipe flow 100mA, Cu target K a, test angle 4-60 °, 6 °/min, 1 ° of non-proliferation slit, anti-diffuse-reflectance slit: 1 °, receive slit 0.15mm, record this crystal X-ray powder diffraction pattern shown in Figure 1A and Figure 1B.
Fig. 3 is this crystalline electron micrograph, clearlys show that from figure amifostine trihydrate exists with crystal form, and is the flat sheet-like crystal.
The amifostine trihydrate crystal structure determination
The crystalline crystal structure of amifostine trihydrate is determined.At room temperature finish crystal measurement, the mensuration of unit cell and the collection of data with the molybdenum radiation.
Structure is found the solution by direct method and is accurate through complete matrix method of least square and Fourier calculus of finite differences.All non-hydrogen atoms are anisotropically accurate, and the hydrogen atom that is connected to the oxygen atom of nitrogen and water is located also isotropically accurate by the Fourier difference diagram.
Crystallization among the chirality space group P2:2:2 of chemical compound, three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal structure figure as shown in Figure 2.Used instrument CCDX ray single crystal diffractometer, model Bruker Smart APEXII type.
Table 2. three hydration 3-aminopropyl amine ethyl phosphorothioic acid crystal X-single crystal diffraction data
Table 3. location parameter and temperature factor parameter
Bond distance and the bond angle of table 4.DS1
Two, the preparation of amifostine trihydrate crystal lyophilized preparation
The solution preparation: with 100.0g three crystalline hydrate amifostines (the big pharmaceutical factory of Dalian Metro), add 600ml water for injection, after the stirring at room dissolving, stirring adds 95% ethanol of 42.1ml and the mixed solvent of 40ml acetone down, adds the injection water and is settled to 800ml;
Depyrogenation, degerming: add the needle-use activated carbon of 0.1g under the room temperature, stirred 15 minutes, decarburization is filtered, and filtrate is by the extremely clarification of 0.22 μ m filtering with microporous membrane;
Fill: under 100 grades of clean area conditions, with above-mentioned settled solution fill in the control injection bottle of cleaning sterile, every bottle of 4.0ml (containing amifostine 400mg) in anhydride;
Pre-freeze: the control injection bottle that fill is contained aseptic amifostine solution is placed on the flaggy of freeze dryer, is undertaken freezingly by the flaggy temperature is set, and Da Wendu-25 ℃, keeps 4 hours;
Sublimation drying: after pre-freeze is finished, start freeze dryer condensation chamber cryogenic temperature and be lower than-47 ℃, start vacuum pump the interior vacuum of freeze dryer is risen to more than the 300mTorr, slowly heat by flaggy, make the flaggy temperature rise to-16 ℃ and carry out sublimation drying, sublimation drying 24 hours from-25 ℃;
Parsing-desiccation: behind sublimation drying, be warming up to 4 ℃ from-16 ℃, kept 4 hours by the flaggy temperature is set;
Inflation, tamponade: finish in the parsing-desiccation step, introduce aseptic nitrogen at 4 ℃, tamponade more promptly obtains aseptic amifostine trihydrate crystal lyophilized preparation A.
Method according to embodiment 1 prepares amifostine trihydrate crystal lyophilized preparation B of the present invention, just adopts the amifostine trihydrate crystal 120.0g of the above-mentioned preparation of the present invention; The ethanol 33.7ml of adding 95% and the mixed solvent of 40ml acetone.
Method according to embodiment 1 prepares amifostine trihydrate crystal lyophilized preparation C of the present invention, just adopts the amifostine trihydrate crystal 6 0.0g of the above-mentioned preparation of the present invention, the ethanol 63.2ml of adding 95% and the mixed solvent of 60ml acetone.
Method according to embodiment 1 prepares amifostine trihydrate crystal lyophilized preparation D of the present invention, just adds excipient mannitol 80.0g in the solution preparation; Pre-freeze: the control injection bottle that fill is contained aseptic amifostine solution is placed on the flaggy of freeze dryer, is undertaken freezingly by the flaggy temperature is set, and Da Wendu-30 ℃, keeps 4 hours; Sublimation drying: after pre-freeze is finished, start freeze dryer condensation chamber cryogenic temperature and be lower than-47 ℃, start vacuum pump the interior vacuum of freeze dryer is risen to more than the 300mTorr, slowly heat by flaggy, make the flaggy temperature rise to-20 ℃ and carry out sublimation drying, sublimation drying 24 hours from-30 ℃; Parsing-desiccation: behind sublimation drying, be warming up to 5 ℃ from-20 ℃, kept 6 hours by the flaggy temperature is set.
With amifostine trihydrate crystal lyophilized preparation A of the present invention, B, C, it is 25 ℃ ± 2 ℃ that D places temperature, and relative humidity is 60% ± 5% condition, respectively 0,1, its character of sample analysis, pH value, clarity of solution and color, moisture, related substance and assay (pressing the USP29 method) in the time of 3,6,12 months.The results are shown in Table 5.Embodiment 10 data with Chinese patent ZL200410037763.X contrast simultaneously, see Table 5.
Table 5 the present invention prepares the injection amifostine trihydrate crystal lyophilized preparation and is compared with the prior art the room temperature stability result of the test
Annotate 1: data among the Chinese patent ZL200410037763.X, amifostine content and related substances Determination on content method among the Chinese patent ZL200410037763.X are unexposed.
Annotate 2: Chinese patent ZL200410037763.X moisture is to measure with dry weight-loss method.
Find that from table 5 its related substances (＜0.10%) that the invention provides high-purity amifostine trihydrate crystal preparation is lower than Chinese ZL200410037763.X disclosed (0.35～0.39%) level, amifostine trihydrate crystal lyophilized preparation of the present invention was room temperature state 1 year, other related substance does not change, but mercaptan and disulfide slightly increase, and meet the requirement of USP29 version.
With preparation A of the present invention, it is 40 ℃ ± 2 ℃ that B, C, D place temperature, and relative humidity is 75% ± 5% condition, respectively 0,1, and its character of sample analysis, pH value, clarity of solution and color, moisture, related substance and assay in the time of 2,3,6 months.The results are shown in Table 6.
Table 6 the present invention prepares injection amifostine trihydrate crystal lyophilized preparation accelerated test result
To impinging upon among the Chinese patent ZL93117436.8, three water amifostines are at 50 ℃, 35 days and accelerated test result's (table 7) of 28 days of amorphism amifostine.
The accelerated test result of table 7 Chinese patent ZL93117436.8
Find out that from table 6, table 7 stability of amifostine trihydrate crystal lyophilized preparation of the present invention is more stable than three water amifostine crystallizations of open method preparation among the Chinese patent ZL93117436.8.And the freeze-drying process time of the present invention is short, energy-conservation.
Claims (7)
1. an aseptic amifostine trihydrate crystal lyophilized preparation is characterized in that, by containing the mixed solution that amifostine, acetone and alcohol mixed solvent and water are formed,, make after the lyophilizing through removing pyrogen, filtration sterilization, wherein:
In the described mixed solution, contain: amifostine 50～400mg/ml, the water of the acetone of 1～30% percent by volume and alcohol mixed solvent and 65～99% percents by volume, and in described acetone and the ethanol mixed solvent, acetone and ethanol proportioning by volume percentage ratio count 0.2～4.0: 1;
Amifostine in the described mixed solution is that employing amifostine trihydrate crystal is a raw material, and described amifostine trihydrate crystal is for obtaining as follows:
Step 1: with reactant N-(2-bromoethyl)-1, two hydrobromates of 3-propane diamine and sodium thiophosphate are by 1.01～1.2: 1.0 molar ratio is dissolved in the water, and adds the polar non-solute dimethyl sulfoxide as promoter, 10～40 ℃ of reactions; After the reaction, reactant solution need not be analysed by alcohol, and directly thick product amifostine trihydrate crude product is separated out in cooling;
Step 2: the amifostine trihydrate crude product that step 1 is obtained carries out the recrystallization purification first time, and the amifostine trihydrate dissolving crude product in water, is separated out with methanol then, obtains not having the water of crystallization amifostine;
Step 3: the no water of crystallization amifostine that step 2 is obtained carries out the recrystallization purification second time, to not have the water of crystallization amifostine is dissolved in the water, and, separate out the amifostine trihydrate crystal with ethanol then with 0.1～1.50% activated carbon decolorizing of no water of crystallization amifostine weight;
In above-mentioned preparation method, institute's water is pure water or deionized water.
2. amifostine trihydrate crystal lyophilized preparation according to claim 1, it is characterized in that, described containing in the mixed solution that amifostine, acetone and alcohol mixed solvent and water forms, contain: amifostine 80～200mg/ml, the water of the acetone of 6～15% percents by volume and alcohol mixed solvent and 85～94% percents by volume.
3. amifostine trihydrate crystal lyophilized preparation according to claim 1 and 2 is characterized in that, in described acetone and the ethanol mixed solvent, acetone and ethanol proportioning are 0.5～2.0: 1, by volume the percentage ratio meter.
4. amifostine trihydrate crystal lyophilized preparation according to claim 1 and 2 is characterized in that, described containing in the mixed solution that amifostine, acetone and alcohol mixed solvent and water forms further comprises excipient mannitol.
5. preparation method according to each described amifostine trihydrate crystal lyophilized preparation among the claim 1-3 is characterized in that this method may further comprise the steps:
(1) preparation contains the mixed solution of amifostine, acetone and alcohol mixed solvent and water composition: preparation contains the mixed solution of amifostine, acetone and alcohol mixed solvent and water;
(2) depyrogenation, degerming:, remove pyrogen, filtration sterilization to the solution activated carbon decolorizing that (1) step prepares;
(3) fill: under 100 grades of clean area conditions, the solution after fill (2) step process is in lyophilizing control injection bottle, and fill contains amifostine 80～900mg/ bottle, its solution amount 0.5～6.0ml/ bottle;
(4) pre-freeze: the control injection bottle that fill is contained aseptic amifostine solution is placed on the flaggy of freeze dryer, undertaken freezing by the flaggy temperature is set, the flaggy temperature reaches-16 ℃～-45 ℃, and cooling rate 20 minutes/℃～1 minute/℃ was held time 2～16 hours;
(5) sublimation drying: carry out sublimation drying-45 ℃～-10 ℃ scopes, will be on (4) step basis, start freeze dryer condensation chamber cryogenic temperature and be lower than-47 ℃, starting vacuum pump rises to more than the 300mTorr the interior vacuum of freeze dryer, slowly heat by flaggy, the flaggy temperature is risen in-25～-10 ℃ of scopes carry out sublimation drying, 16～48 hours time;
(6) parsing-desiccation: after (5) step finishes, be warming up to-5 ℃～25 ℃ and carry out parsing-desiccation, 2～10 hours time;
(7) inflation, tamponade: finish in (6) step, introduce aseptic noble gas in 2 ℃～25 ℃ scopes, tamponade again obtains aseptic amifostine trihydrate crystal lyophilized preparation.
6. the preparation method of amifostine trihydrate crystal lyophilized preparation according to claim 5 is characterized in that,
In described (1) step, add water for injection in the amifostine trihydrate crystal, after the stirring at room dissolving, stirring adds acetone and ethanol mixed solvent down, add injection water standardize solution, obtain containing the mixed solution of amifostine, acetone and alcohol mixed solvent and water;
In described (3) step fill, under 100 grades of clean area conditions, the solution after fill (2) step process contains amifostine 100～700mg/ bottle in lyophilizing control injection bottle, its solution amount 1.0～6.0ml/ bottle;
In described (4) step pre-freeze, the control injection bottle that fill is contained aseptic amifostine solution is placed on the flaggy of freeze dryer, is undertaken freezingly by the flaggy temperature is set, and the flaggy temperature reaches-20 ℃～-30 ℃, cooling rate 15 minutes/℃～3 minutes/℃ was held time 4～8 hours;
And the whole freeze-drying process time was controlled in 35 hours finishes.
7. the preparation method of amifostine trihydrate crystal lyophilized preparation according to claim 5 is characterized in that, described containing in the mixed solution that amifostine, acetone and alcohol mixed solvent and water forms further comprises excipient mannitol.
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| CN102286019B (en) * | 2011-07-11 | 2014-02-05 | 大连美罗大药厂 | Method for preparing dihydrate 3-amino propyl amine ethyl phosphorothioic acid |
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