CN113527223B - Refining method of gadobutrol - Google Patents
Refining method of gadobutrol Download PDFInfo
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- CN113527223B CN113527223B CN202110690380.6A CN202110690380A CN113527223B CN 113527223 B CN113527223 B CN 113527223B CN 202110690380 A CN202110690380 A CN 202110690380A CN 113527223 B CN113527223 B CN 113527223B
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- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 title claims abstract description 41
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Abstract
The invention provides a process for preparing gadobutrol, which comprises decolorizing gadobutrol crude product, dripping NH4OH solution, placing in dialysis bag for ultrasonic or resin chromatography, adding hydrogen, continuously stirring, displacing pure water in flask, detecting PH and conductivity, freeze drying to obtain pure gadobutrol, regulating mild test operation, obtaining product purity up to 99.9%, free gadolinium content less than 0.01, detecting by using KIM-1 as kidney injury parameter, and the product can reduce contrast agent nephrotoxicity even without nephrotoxicity.
Description
Technical Field
The invention relates to the field of a preparation method of gadobutrol, which comprises a method for refining a gadobutrol crude product to obtain a high-purity product.
Background
Gadobutrol is a gadolinium-containing contrast agent for nuclear spin tomography and is used for contrast enhancement in Magnetic Resonance Tomography (MRT) of the skull and spine. Ginkgol is a nonionic complex composed of gadolinium and the macrocyclic ligand 10- (2, 3 dihydroxy-1- (hydroxymethyl) propyl) -1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid (butrol). Usually sold as a 1 molar aqueous solution, the main methods of preparation at present are:
because the reaction steps of the gadobutrol are more, 4 amino groups on the ring Teng Ning can react, and protection and deprotection are needed, so that more byproducts of the product are caused, wherein the ring-opening reaction conditions are severe, various impurities are easy to generate, and the purity requirement of the contrast agent is extremely high, therefore, the intermediate and the finished product are required to be purified in multiple steps, and the process is extremely complicated.
In order to improve the purity of the gadobutrol, the refining method mainly comprises intermediate purification and product purification modes, wherein the method comprises the steps of adopting ion exchange resin, crystallizing, concentrating and recrystallizing mother liquor, concentrating and dehydrating in the follow-up process, pretreating and activating the needed ion resin, repeating a plurality of resin and crystallization processes, and consuming long energy and time.
For example, CN105037288B discloses a preparation method of high-purity butoxide, which improves the purity of the butoxide to more than 99.5% by purifying the aqueous solution of the crude product of butoxide through ion exchange resin for a plurality of times and then mixing the solvent for recrystallization purification.
CN103547573B prepares high purity gadobutrol by selecting specific water content through specific controlled crystallization conditions, can reduce lipophilic impurities (e.g. D03A) and strongly hydrophilic impurities, and crude product is subjected to acidic-basic-acidic multiple ion column chromatography, and then is crystallized through complex conditions to obtain pure gadobutrol with specific water content.
The purification process is cumbersome and requires strict control of conditions, the prior art needs to be improved in terms of convenience, yield and efficiency of the purification process, and in addition, the more purified compounds can reduce the required dose of paramagnetic contrast agent and possibly shorten the acquisition time of the imaging process.
Because the free quantity of Gd obviously affects the toxic and side effects of the drug, gadolinium as heavy metal can form an injury which is difficult to reverse in the brain of the kidney, so that the imaging time is shortened by reducing the dosage as much as possible while the contrast effect is ensured, and the risk of toxic and side effects can be reduced. In order to increase the chemical relaxation rate, the prior art generally adopts MRI to load on a macromolecular material, and the larger the molecular structure is, the larger the steric hindrance is, and the rotation movement of molecules is delayed, so that the rotation related time is increased, and the R1 is greatly increased.
However, macromolecular Gd 3+ The circulation time of the contrast agent in the body is increased, and Gd is gradually released 3+ Increased probability of (c) may lead to serious toxicity problems such as kidney injury, renal system fibrosis, etc., and brain deposition may seriously affect the nervous system.
Disclosure of Invention
According to the invention, by improving the purification method and combining membrane permeation with a freeze-drying process, the purer gadobutrol is obtained, and the kidney injury and even the non-kidney toxicity can be obviously reduced.
The method comprises the following specific steps:
dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 OH solution, regulating pH to 6-6.8, rotary evaporating the obtained filtrate to remove solvent, adding purified water for redissolving, optionally adding the solution into cationic resin, placing the filtrate into a dialysis bag (SpectrumLabs), immersing the dialysis bag into water in a glass flask, introducing a proper amount of hydrogen, continuously stirring for 1-24h, and monitoring pH change in the water in the beaker at different times by a precise pH monitor. Stirring for 24h until the pH is stable, taking out the dialysis bag, adding a small amount of 50% ethanol, performing ultrasonic treatment, replacing water in the glass flask, continuously stirring overnight, taking out the dialysis bag until the pH in the flask is stable, filtering to obtain an initial precipitate, refrigerating in a refrigerator in a flat chassis, placing in a freeze drying box, and drying for 12-18h.
Or dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 OH solution, adjusting pH to 6-6.8, rotary evaporating the obtained filtrate to remove solvent, adding purified water for dissolving again, placing the filtrate in a dialysis bag (spectrumLabs), immersing the dialysis bag in water of a glass flask, introducing proper amount of hydrogen, continuously stirring for 1-24h, monitoring pH change in the water of the beaker at different time by a precise pH monitor, stirring until pH is stable, replacing water of the glass flask, adding a small amount of ethanol 10-20ml into the dialysis bag, intermittently ultrasonic, continuously stirring, replacing water in the flask again, stirring overnight until pH is stable, conductivity is less than 20 mu s, taking out the dialysis bag, filtering to obtain primary precipitate, and heatingEvaporating solvent, refrigerating in a refrigerator in a flat chassis, and drying in a freeze drying oven for 12-18 hr
Or dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 Adding purified water into OH solution for redissolving after rotary evaporation of the solvent, carrying out resin column SK1B chromatography, carrying out gradient elution, placing filtrate in a dialysis bag, immersing the dialysis bag in water of a glass flask, introducing a proper amount of hydrogen, continuously stirring for 1-24h, monitoring the change of PH in the water of the beaker by a precise PH monitor at different time, stirring for 24h until PH is stable, taking out the dialysis bag, replacing water in the flask, adding ethanol into the dialysis bag, carrying out digital ultrasound, intermittently carrying out ultrasound for 30min, continuously stirring overnight until the water conductivity in the flask is less than 20 mu s, filtering to obtain primary precipitate, and carrying out rotary evaporation to remove the solvent.
Or dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 Adding purified water to dissolve the OH solution again after rotary evaporation of the solvent, regulating pH between 6 and 6.8, carrying out digital ultrasound, introducing a proper amount of hydrogen, continuously stirring for 1 to 24 hours, monitoring the pH change in beaker water to be stable by a precise pH monitor at different times, purifying by using Amberchrome CG161M resin column, carrying out gradient elution by using water and ethanol, continuously stirring and filtering the obtained filtrate to obtain an initial precipitate, evaporating the initial precipitate to be nearly dry by using a heating plate, placing the initial precipitate in a flat chassis, refrigerating by using a refrigerator, and freeze-drying to obtain white powder, wherein the purity of gadobutrol is 99.9% (HPLC) by HPLC, the single impurity content is less than 0.02%, and the free gadolinium content is less than 0.01%.
Or dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 Performing rotary evaporation on the obtained filtrate to remove the solvent, adding purified water for redissolving, purifying by using an Amberchrome CG161M resin column, performing gradient elution by using water and ethanol, placing the obtained filtrate into a dialysis bag, adding a small amount of ethanol, immersing the dialysis bag into the water of a glass flask, intermittently performing ultrasonic treatment, simultaneously introducing a proper amount of hydrogen, continuing stirring, replacing the flask water, stirring overnight, monitoring the pH change in the flask water to be stable by using a precise pH monitor at different times, wherein the water conductivity is less than 20 mu s,filtering to obtain an initial precipitate. The primary precipitate is placed on a heating plate, the solvent is evaporated, and then the primary precipitate is placed in a flat chassis for refrigeration and then is frozen and dried, so that white powder gadobutrol with the purity of 99.9 percent by HPLC detection is obtained.
Wherein the dialysis bag is 500Da in size and 500Da in molecular weight cut-off (MWCO), wherein the hydrogen gas is introduced for preferably 1-2 hours, more preferably 2 hours, wherein the Branson digital ultrasound is preferably carried out by intermittent ultrasound for 20-120min, more preferably 30min after standing for 1min after ultrasound with 10% micro-amplitude for 30 s; the small amount of ethanol is 10-20ml of 50% ethanol.
Preferably, the primary sediment is placed in a flat chassis to be kept at a height of about 2cm, the primary sediment is placed in freeze drying equipment at 40-50 ℃ below zero after being refrigerated for 12 hours, the pressure of a drying box is kept at 10-13Pa, after pre-drying for 2-5 hours, the drying box is depressurized to 1Pa, dried in vacuum for 2 hours, and the temperature is slowly increased to 35 ℃ for continuous drying for 8-10 hours.
More preferably, the primary sediment is placed in a flat chassis to be kept at a height of 2cm, the primary sediment is placed in freeze drying equipment at minus 50 ℃ after being refrigerated for 12 hours, the pressure of a drying box is kept at 12Pa, after pre-drying for 3 hours, the drying box is depressurized to 1Pa, dried in vacuum for 2 hours, and the temperature is slowly increased to 35 ℃ to continue drying for 9 hours.
The purity of the purified gadobutrol is more than or equal to 99.8%, and the content of free gadolinium is less than 0.01%.
The hydrogen gas inlet amount can be selected to be 0.2m < 3 >/h, the ultrasonic frequency can be 40KHZ, and the power is 150W.
The gadobutrol purified by the method of the present invention (examples 1 and 2) was subjected to a comparative test with commercially available gadobutrol and gadobutrol purified by the method of CN105037288B and CN 103547573B.
The invention has the beneficial effects that:
1) The invention tries a non-conventional purification method, improves the purity of the product, degrades organic impurities and reduces the production of byproducts under specific conditions.
2) The steps of purification and the like are simplified, the preparation conditions are mild, and the preparation is easy to repeat.
3) The kidney toxicity of the medicine is obviously reduced.
Drawings
Fig. 1: the prepared gadobutrol LC-MC map
FIG. 2 HPLC chromatogram of refined gadobutrol
Detailed Description
Example 1 (preparation Process of CN 105037288)
Dissolving 700g of gadobutrol crude product in 1kg of water, immersing 717 resin, slowly adding 18kg of pure water, measuring conductivity by a conductivity meter, slowly adding 2M ammonia water to flow through the resin when the conductivity is less than or equal to 30 mu s, decompressing and evaporating the solution containing the product to dryness, adding pure water for dissolving after evaporating to dryness, cooling to 26 ℃, adding cationic resin IR120, regulating the pH to 4, filtering, adding 57g of active carbon into the filtrate, refluxing and decoloring by a temperature rising cutter, and evaporating by hot filtration; adding pure water 5 times the mass of the product obtained by the steps, heating to 30 ℃ to completely dissolve the product to obtain a clear solution, adding isopropanol 10 times the volume of the clear solution, slowly heating to 50 ℃, preserving heat and crystallizing for 10 hours, cooling to 30 ℃, filtering and drying to obtain 460g of gadobutrol, wherein the detected purity is 99.5% (HPLC), the single impurity content is less than 0.037%, and the free gadolinium content is less than 0.02%.
Example 2 (prepared by the preparation Process of CN 103547573B)
120kg of crude gadobutrol was dissolved in 1200kg of water and pumping was started onto a column containing an acidic ion exchanger (AMBERLITE IRC 50). The eluate is pumped directly onto a column of basic ion exchanger (IRA 67) and then the eluate is pumped back onto the acidic ion exchanger (and so on). The solution was repeatedly circulated until a conductivity limit of <20 mus/cm was reached. The solution was transferred to a thin layer evaporator and concentrated carefully at 50 mbar.
And (3) final crystallization: 16kg of activated carbon NORIT SX PLUS was added to 324kg of crude gadobutrol (19.l% -20.9% strength solution in water) (conductivity 20. Mu.S) and the mixture was stirred at 20℃for 60 minutes. The activated carbon was removed by filtration and washed twice with water. The filtrate solution containing the product was then filtered through a sterile filter rod and concentrated under reduced pressure at a jacket temperature of 80 ℃. The jacket temperature was then raised to 75 ℃, and in the first step, the addition of ioozg of alcohol was measured, then the jacket temperature was raised to 98 ℃ (internal temperature >75 ℃) and a further 1360kg of alcohol was added, so that the internal temperature was not lower than 72 ℃ (total time of addition was measured to be about 120 minutes). At this point in time, the water content of the solution was measured according to the Karl-Fischer method. Ideally, this value should be 10% -12%. If this value is too high or too low, it is precisely adjusted to 11% by adding (in small portions) water or alcohol. Once the desired water content was reached, the mixture was heated under reflux for 120 minutes. The mixture was cooled to 20 ℃, the product was separated using a centrifuge or pressure suction filter, and the filter cake was washed with ethanol. The product was then dried under reduced pressure (jacket temperature 55 ℃) until an internal temperature >53 ℃ was reached. The product was then packed into aluminum coated PE bags. Colorless crystalline powder was obtained. The detection purity is 99.7 percent (HPLC), the single impurity content is less than 0.03 percent, and the free gadolinium content is less than 0.01 percent.
Example 3:
taking 80g of crude gadobutrol, adding 800ml of pure water for dissolution, adding 500g of active carbon for decolorization, then dripping 100ml of 0.2% NH4OH solution, adding pure water for redissolving after removing solvent by rotary evaporation, adjusting pH to be between 6 and 6.8, placing in a dialysis bag (SpectrumLabs) with molecular weight cut-off (MWCO) of 500Da, immersing the dialysis bag in water of a 2L glass flask, introducing a proper amount of hydrogen for 2h, continuously stirring for 12h, and monitoring pH change in the water of the beaker by a precise pH monitor at different times. Stirring for 24h until the PH is stable, taking out the dialysis bag, replacing the flask, filling with water again by 2L, putting into the dialysis bag, continuing stirring, adding a small amount of ethanol (10-20 ml of 50% ethanol) into the dialysis bag, stopping ultrasonic waves intermittently at 10% of micro amplitude for 30s for 1min, stopping ultrasonic waves for 30s, stopping 1min, stopping ultrasonic waves after reciprocating for 30min, continuing stirring for 12h, replacing the flask water again, continuing stirring overnight, until the PH in the soaking solution (flask water) of the dialysis bag is stable, simultaneously, taking out the dialysis bag, filtering to obtain an initial precipitate, putting the initial precipitate on a heating plate, evaporating to a nearly dry state (namely evaporating the solvent), putting the initial precipitate into a flat chassis to keep the height of 2cm, putting the primary precipitate in a freeze drying device at 50 ℃ below zero after the refrigerator is refrigerated for 12h, keeping the pressure of a drying box for 12Pa, reducing the pressure of the drying box to 1Pa after the pre-drying for 3h, drying the drying under vacuum for 2h, slowly heating to 35 ℃ and continuing drying for 9h. Gadolinium butoxide as a white powder was obtained (see fig. 1 for detection). The detection purity is 99.8 percent (HPLC), the single impurity content is less than 0.025 percent, and the free gadolinium content is less than 0.01 percent.
Example 4:
taking 80g of crude gadobutrol, adding 800ml of pure water for dissolution, adding 500g of active carbon for decolorization, then dropwise adding 100ml of 0.2% NH4OH solution, adding pure water for redissolution after rotary evaporation of the obtained filtrate to remove solvent, placing the filtrate into a dialysis bag (spectrolabs) with a molecular weight cut-off (MWCO) of 500Da, immersing the dialysis bag into water of a 2L glass flask, introducing a proper amount of hydrogen for 2h, continuously stirring for 12h, and monitoring pH change in the water of the beaker at different times by a precise pH monitor. Stirring for 24h until pH is stable, taking out a dialysis bag, replacing water in the flask, filling 2L again, adding a small amount of ethanol (10-20 ml of 50% ethanol) into the dialysis bag, stopping ultrasonic waves by Branson digital ultrasonic waves intermittently at a trace amplitude of 10% for 30s, stopping ultrasonic waves for 1min, stopping ultrasonic waves after reciprocating for 30min, continuing stirring for 12h, replacing water in the flask, continuing stirring overnight until the water conductivity in the flask is less than 20 mu s, and filtering to obtain an initial precipitate. The solvent was removed by rotary evaporation of the primary precipitate to give gadobutrol as a white solid. The purity is 99.8 percent (HPLC), the content of single impurity is less than 0.03 percent, and the content of free gadolinium is less than 0.01 percent.
Example 5:
taking 80g of crude gadobutrol, adding 800ml of pure water for dissolution, adding 500g of active carbon for decoloration, then dropwise adding 100ml of 0.2% NH4OH solution, rotationally evaporating the obtained filtrate to remove the solvent, then adding pure water for dissolution again, adjusting the PH to be between 6 and 6.8, stopping the intermittent ultrasonic treatment of the Branson digital ultrasonic treatment for 30 minutes after 30 seconds by using 10% micro-amplitude, simultaneously introducing a proper amount of hydrogen, continuing stirring for 12 hours, monitoring the PH change in beaker water at different times until PH is stable by using a precise PH monitor, enabling the water conductivity to be less than 20 mu s, purifying by using Amberchrome CG161M resin column (eluting by using water/ethanol), continuously stirring and filtering the obtained filtrate to obtain primary precipitate, placing the primary precipitate on a heating plate, evaporating to be close to a dry state, then placing the primary precipitate in a flat chassis for keeping the height of 2cm, placing the flat chassis in a freezing and drying device at the temperature of minus 50 ℃ after refrigerating for 12 hours, keeping the pressure of a drying box for 3 hours, reducing the pressure of the drying box to 1Pa, drying in vacuum for 2 hours, slowly heating to 35 ℃ and continuing drying for 9 hours. The white powder gadobutrol was obtained with a purity of 99.9% (HPLC), a single impurity content of < 0.02% and a free gadolinium content of < 0.01% (see FIG. 2).
Example 6:
taking 80g of crude gadobutrol, adding 800ml of pure water for dissolution, adding 500g of active carbon for decolorization, then dropwise adding 100ml of 0.2% NH4OH solution, rotationally evaporating the obtained filtrate to remove the solvent, then adding pure water for redissolution, purifying (eluting with water/ethanol) by using an Amberchrome CG161M resin column, placing the obtained filtrate into a dialysis bag (Spectrum labs) with a molecular weight cut-off (MWCO) of 500Da, adding a small amount of ethanol (50% ethanol of 10-20 ml), immersing the dialysis bag into water of a 2L glass flask, stopping ultrasonic waves by Branson digital waves for 30 minutes after intermittent ultrasonic waves with a 10% trace amplitude for 1 minute, stopping ultrasonic waves for 30 minutes, stopping ultrasonic waves after reciprocating for 30 minutes, simultaneously introducing a proper amount of hydrogen for 2 hours, continuing stirring for 12 hours, replacing flask water for 2L, stirring overnight, monitoring the pH change in the beaker water to be stable by a precise pH monitor at different times, and filtering to obtain a primary precipitate. Placing the primary precipitate on a heating plate, evaporating to a nearly dry state, namely evaporating the solvent, placing the solvent in a flat chassis to keep the height of 2cm, refrigerating the solvent in a refrigerator for 12 hours, placing the refrigerator in freeze drying equipment at-50 ℃, keeping the pressure of a drying box at 12Pa, pre-drying for 3 hours, reducing the pressure of the drying box to 1Pa, drying in vacuum for 2 hours, slowly heating to 35 ℃, and continuing drying for 9 hours. The white powder gadobutrol is obtained, the purity is 99.9% (HPLC) through detection, the single impurity content is less than 0.02%, and the free gadolinium content is less than 0.01%.
Comparative example 1 commercial gadobutrol injection (15ml:9.0708g,Bayer Pharma AG)
Comparative example 2: gd-DTPA (gadofoshan injection) (15ml:7.5g,BAYER PHARMA)
Test 1: nephrotoxicity detection
In the detection of kidney function injury, KIM-1 is an index of early change of phenotype, is taken as a type I transmembrane glycoprotein, is hardly expressed in normal kidney tissues, and obviously increases in kidney tissues with kidney toxicity of a rat contrast agent. The experiment adopts ELISA method to divide 120 healthy mice into 6 groupsBy Gd respectively 3+ Tail intravenous injection with concentration of 0.1mmol/kg, samples of comparative examples 1 and 2 and examples 1-6, 12h before injection and 24h after injection, average value of urine detection KIM-1 value obtained for each group of mice, and kit of U.S. R&D company urine original detection kit; and detecting by adopting a full-automatic biochemical analyzer. Analysis was performed using SPSS20.0 statistical software, and group differences were compared using t-test, with P<A difference of 0.05 is statistically significant. As shown in Table 1, the comparative differences between the three groups of examples other than example 5 were statistically significant (P<0.05)。
TABLE 1 changes in renal injury index before and after contrast media injection in mice
As can be seen from the results in table 1, the Gd-DTPA gadolinium contrast agent of comparative example 2 has higher nephrotoxicity, and does not show a metabolic decrease trend with time, and may take longer to be excreted, with a greater probability of damage to the kidneys. In other examples 1-6, where gadobutrol was purified, products with lower free gadolinium content had better safety than commercial products. Of these, the product of example 5 had the lowest KIM-1 value, and the three groups were almost identical and decreased to normal levels over time, and it was considered that the kidneys of the group were virtually intact. Example 3 while the KIM-1 value is also lower, the rate of decrease over time is not as good as the other example products. The differences in the products of examples 3-6 may be related to the various steps in their preparation and the sequential operation of the process, particularly the freeze drying process.
The test results show that the product with higher purity is obtained by optimizing the preparation process, and simultaneously, due to the combination effect of the steps of ultrasonic chemical reaction, freeze-drying and the like, the reaction time is shortened, the yield is improved, the crystallization step is simplified, and the product is possibly related to cavitation and a molecular internal linking structure.
The above embodiments do not limit the scope of the present invention, and those skilled in the art can make various changes and applications of the present invention according to the above description.
Claims (2)
1. A refining method of gadobutrol comprises the following steps:
dissolving gadobutrol crude product in pure water, decolorizing with active carbon, and dripping NH 4 And (3) carrying out rotary evaporation on a solvent in the obtained filtrate, adding purified water to dissolve again, regulating the pH to be between 6 and 6.8, carrying out digital ultrasonic treatment, carrying out intermittent ultrasonic treatment by standing for 1 minute after ultrasonic treatment with 10% trace amplitude for 30 seconds, carrying out ultrasonic treatment for 30 minutes, introducing a proper amount of hydrogen gas, continuously stirring for 12 hours, monitoring the pH change in beaker water to be stable by a precise pH monitor at different time, carrying out gradient elution on the obtained filtrate by using water and ethanol, continuously stirring and filtering the obtained filtrate to obtain an initial precipitate, evaporating the initial precipitate to be nearly dried by using a heating plate, placing the initial precipitate in a flat chassis for about 2cm, refrigerating for 12 hours in a refrigerator, placing the frozen drying equipment at minus 40-50 ℃, keeping the pressure of a drying box at 10-13Pa, pre-drying for 2-5 hours, reducing the pressure of the drying box to 1Pa, carrying out vacuum drying for 2 hours, slowly heating to 35 ℃, and continuously drying for 8-10 hours to obtain white powder.
2. The method of claim 1, wherein: the freeze drying method is that the primary sediment is placed in a flat chassis to be kept at the height of 2cm, the primary sediment is placed in freeze drying equipment at the temperature of minus 50 ℃ after being refrigerated for 12 hours in a refrigerator, the pressure of a drying box is kept at 12Pa, after the primary sediment is pre-dried for 3 hours, the drying box is depressurized to 1Pa, the primary sediment is dried for 2 hours in vacuum, the primary sediment is slowly heated to the temperature of 35 ℃ and is dried for 9 hours.
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