阅读说明：本技术 利用高加速度振动实现动态超快速无团聚冷冻干燥的方法 (Method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration ) 是由 谯志强 屈延阳 于 2021-08-12 设计创作，主要内容包括：本发明公开了一种利用高加速度振动实现动态超快速无团聚冷冻干燥的方法,包括以下步骤：将湿物料置于密封容器内,在高加速度振动状态下,将湿物料冷却到冰晶点温度附近；维持高加速度振动,对湿物料施加高真空状态,使密封容器内的湿物料形成“冰沙”；维持高加速度振动、高真空状态,对“冰沙”施加加热状态,密封容器内的“冰沙”将会因吸热而升华变为气体；继续保持高加速度振动、高真空、加热状态,直至密封容器内的气体全部被真空抽走,从而实现湿物料干燥。解决了传统的预冷冻-真空升华冷冻干燥方法和已有的改进型冷冻干燥方法所具有的干燥时间长、能耗高、产物难以避免团聚需要二次分散等缺点。(The invention discloses a method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration, which comprises the following steps of: placing the wet material in a sealed container, and cooling the wet material to be near the temperature of an ice crystal point under the high-acceleration vibration state; maintaining high acceleration vibration, and applying a high vacuum state to wet materials to enable the wet materials in the sealed container to form 'ice sand'; maintaining high acceleration vibration and high vacuum state, applying heating state to the ice sand, and sublimating the ice sand in the sealed container into gas due to heat absorption; and continuously keeping the high-acceleration vibration, high vacuum and heating states until all the gas in the sealed container is pumped away by vacuum, thereby realizing the drying of the wet material. Solves the defects of long drying time, high energy consumption, difficult product agglomeration avoidance, secondary dispersion and the like of the traditional pre-freezing-vacuum sublimation freeze-drying method and the existing improved freeze-drying method.)

1. The method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration is characterized by comprising the following steps of:

placing the wet material in a sealed container, and cooling the wet material to be near the temperature of an ice crystal point under the high-acceleration vibration state;

maintaining high acceleration vibration, and applying a high vacuum state to wet materials to enable the wet materials in the sealed container to form 'ice sand';

maintaining high acceleration vibration and high vacuum state, applying heating state to the ice sand, and sublimating the ice sand in the sealed container into gas due to heat absorption;

and continuously keeping the high-acceleration vibration, high vacuum and heating states until all the gas in the sealed container is pumped away by vacuum, thereby realizing the drying of the wet material.

2. The method of claim 1, wherein the vibration frequency of the high acceleration vibration state is in the range of 1 Hz-2000 Hz and the acceleration is in the range of 10 g-100 g.

3. The method of claim 2 wherein the high acceleration vibration is applied at a vibration frequency in the range of 10Hz to 100 Hz.

4. The method of claim 1, wherein the high vacuum state is 1-400 Pa.

5. The method of claim 4, wherein the high vacuum state is 10 Pa-40 Pa.

6. The method of claim 1, wherein the temperature of the ice crystal is 0 ℃ to 0.3 ℃ around.

7. The method for achieving dynamic ultrafast agglomeration-free freeze-drying by using high acceleration vibration as claimed in claim 1, wherein the applying of high vacuum state to the wet material to form "smoothie" in the wet material in the sealed container comprises: starting the vacuum extractor, quickly reducing the gas pressure in the sealed container to below 200Pa, and keeping for 8-10 minutes until all water is completely converted into solid 'ice sand'.

8. The method of claim 1 wherein the heating step is a gradual temperature ramp from about 0 ℃ to about 30 ℃ at a ramp rate of 2 ℃/min.

Technical Field

The invention relates to the technical field of chemical production of superfine materials, nano materials, pharmacy and the like, in particular to a method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration.

Background

The freeze drying method is a drying method which utilizes the principle of ice crystal sublimation to directly sublimate water or liquid phase in the wet material which is frozen into solid phase into vapor without melting in the high vacuum environment. The drying method can be carried out at normal temperature and low temperature, and meets the requirements of drying heat-sensitive materials; meanwhile, the osmotic pressure which is generated by changing liquid state into gas state and enables the material to agglomerate and reunite is eliminated, the hard agglomeration of the material can be avoided to a certain extent, and the porous structure of the material is kept. Therefore, the method is widely applied to the fields of pharmacy, food processing, powder or nano material preparation and the like.

However, in the conventional tray type freeze-drying device and method (for example, JP1988173852, JP1995197775, etc.), a prefreezing process is required to freeze the wet material containing the liquid phase into a solid phase, and the wet material contained in the tray is subjected to local extrusion during the prefreezing process because the freezing process is advanced layer by layer from outside to inside, and the material dispersed in the liquid phase is easily agglomerated into a blocky porous structure. Therefore, materials (especially powder materials, nano materials and the like) obtained by the traditional pre-freezing-sublimation freeze drying method are always in a porous soft agglomerated block structure on the microscopic scale, and are not beneficial to subsequent direct use; particularly in the pharmaceutical industry, the freeze-dried bulk drug powder often needs to be further dispersed into highly dispersible powder, which increases the risks of contamination and operation safety during the dispersion process.

Another disadvantage of conventional tray freeze-drying devices is that the larger volume of ice formed by the pre-freezing process tends to be left standing in the vacuum system as it sublimes under high vacuum. The essence of sublimation under high vacuum lies in that heat is transferred from the surface of the ice to the inside layer by layer, the heat transfer speed is limited by the small surface area and the standing state of the ice, so that the heat transfer efficiency is low, the sublimation speed is slow, the process time for executing the freeze drying process is usually dozens of hours, the rapid production is not facilitated, and meanwhile, the energy consumption and the CO2 emission of the whole freeze drying process are greatly increased.

Some improved freeze-drying methods, such as KR1020180028233A, which propose a freeze-drying method using liquid nitrogen as coolant, although the material can be prevented from being extruded and agglomerated during the pre-freezing process to some extent by the rapid freezing of liquid nitrogen, the sublimation drying process is still slow, and more energy is consumed because the pre-freezing uses a large amount of liquid nitrogen.

Although patent EP 1601919B 1, patent WO2004/073845A3 and patent WO2004/073845a2 propose a rapid vacuum freeze-drying device and method under stirring conditions, which can reduce the volume of ice crystals and achieve rapid sublimation drying, the ice crystals are gradually reduced by stirring, the volume is still large, and the introduction of stirring brings about the problem of sealing under high vacuum, which makes the equipment expensive.

USP7188993, EP2018783465, EP2018867320, RU2016117488, and chinese patent ZL201610320677.2, etc. although various forms of vibration devices and methods for solid-liquid, solid-solid material mixing are proposed, there is no provision of how to design a method for freeze-sublimation drying using rapid vibration.

Disclosure of Invention

The invention aims to provide a method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration, so as to solve the problems in the background technology.

In order to realize the purpose of the invention, the invention provides the following technical scheme:

a method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration comprises the following steps:

placing the wet material in a sealed container, and cooling the wet material to be near the temperature of an ice crystal point under the high-acceleration vibration state;

maintaining high acceleration vibration, and applying a high vacuum state to wet materials to enable the wet materials in the sealed container to form 'ice sand';

maintaining high acceleration vibration and high vacuum state, applying heating state to the ice sand, and sublimating the ice sand in the sealed container into gas due to heat absorption;

and continuously keeping the high-acceleration vibration, high vacuum and heating states until all the gas in the sealed container is pumped away by vacuum, thereby realizing the drying of the wet material.

In some embodiments, the vibration frequency range of the high acceleration vibration state is 1Hz to 2000Hz, and the acceleration is 10g to 100 g.

In some embodiments, the vibration frequency range of the high acceleration vibration state is 10Hz to 100 Hz.

In some embodiments, the high vacuum state is between 1Pa and 400 Pa.

In some embodiments, the high vacuum state is between 10Pa and 40 Pa.

In some embodiments, the ice crystal point temperature is from 0 ℃ to 0.3 ℃.

In some embodiments, the applying a high vacuum to the wet material to form "smoothie" in the wet material in the sealed container comprises: starting the vacuum extractor, quickly reducing the gas pressure in the sealed container to below 200Pa, and keeping for 8-10 minutes until all water is completely converted into solid 'ice sand'.

In some embodiments, the heating state is a gradual temperature increase from about 0 ℃ to 30 ℃, with the temperature increase rate being maintained at 2 ℃/min.

In some embodiments, the time for continuing to maintain the high acceleration vibration, high vacuum, heating state is 25min to 35 min.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a method for realizing dynamic ultra-fast agglomeration-free freeze drying by utilizing high-acceleration vibration. The main principle is that liquid boiling near the ice crystal point temperature under high vacuum absorbs heat to promote the super-fast freezing of wet material under high acceleration vibration to form single ice block with small volume and no extrusion to the inner material; because the surface area of the 'ice sand' is huge, the obtained fine 'ice sand' is easy to perform quick and efficient heat exchange with a container under high-acceleration vibration, and therefore the quick and efficient drying process and the energy conservation are realized. The material after drying is promoted not to form porous soft aggregates any more without an extrusion pre-freezing process and a sublimation process under high-acceleration vibration, and highly dispersed medicine or material powder can be directly obtained.

Drawings

For a clearer explanation of the embodiments or technical solutions in the prior art of the present application, the drawings used in the description of the embodiments or prior art will be briefly described below, it is obvious that the drawings in the following description are only references to some embodiments in the present application, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1a is a photograph showing the appearance of a freeze-dried product obtained by the drying method of the example of the present invention.

FIG. 1b is a photograph showing the appearance of a freeze-dried product obtained by a conventional method.

Detailed Description

The present invention will be further described with reference to the following examples, which are intended to illustrate only some, but not all, of the embodiments of the present invention. Based on the embodiments of the present invention, other embodiments used by those skilled in the art without any creative effort belong to the protection scope of the present invention.

The technical scheme adopted by the invention is as follows:

the method is a novel freeze drying method for pre-freezing wet materials near the temperature of ice crystal points into ice sand under high acceleration vibration and high vacuum, and then heating the ice sand under the high acceleration vibration and high vacuum to sublimate the ice crystals so as to obtain dry materials.

The wet material pre-freezing step under high acceleration vibration and high vacuum in the invention content is that under high acceleration vibration, the wet material is firstly cooled to the temperature near the ice crystal point, then a high vacuum state is applied, because the saturated true air pressure of the liquid phase under high vacuum is rapidly reduced, a small part of the liquid phase medium in the wet material is rapidly boiled and absorbs heat, thereby leading the rest of the liquid phase to be rapidly frozen to form the ice crystal; the presence of high acceleration vibration causes the resulting ice crystals to have a very small volume, which results in "smoothie".

In the sublimation drying step of the 'smoothie' material under high-acceleration vibration and high vacuum in the invention, the formed 'smoothie' with a large surface area can be subjected to rapid heat exchange along with the temperature rise of a container or the environment under the high-acceleration vibration and high vacuum, and as a result of the heat exchange, solid-phase ice in the 'smoothie' is removed in a mode of sublimating into gas under the high vacuum, so that the material is dried.

The high acceleration vibration in the invention can be realized by placing a high vacuum container containing wet materials on a vibration table driven by electromagnetic vibration, wherein the vibration frequency range can be 1 Hz-2000 Hz, and the optimized vibration frequency range is 10 Hz-100 Hz.

The acceleration of the high-acceleration vibration can reach 10 g-100 g.

In the high vacuum state, the high vacuum state is in the range of 1-400 Pa, wherein the optimized range is in the range of 10-40 Pa.

The invention is further illustrated by the following examples

Example 1:

taking nano triaminotrinitrobenzene with the water content of about 40 percent as an example, the method provided by the invention is implemented by the following steps.

Step 1, placing about 1kg of a nano triamino trinitrobenzene wet material with the water content of about 40 percent into a sealed container which can vibrate at high acceleration, pump high vacuum and be heated and cooled, starting a cooling cycle under the condition that the container is in a high acceleration vibration state of 100Hz, cooling the wet material in the container by cooling liquid, reducing the temperature of the wet material to 0 ℃, and approaching the ice crystal temperature of water under normal pressure;

and 2, after the wet material in the container in a high-acceleration vibration state reaches 0 ℃, starting a vacuumizing device and a switch, quickly reducing the gas pressure in the container to be below 200Pa, quickly boiling part of water in the container at the moment, and simultaneously absorbing a large amount of heat to freeze the wet material to form fine ice sand containing the nano triamino trinitrobenzene. The low temperature cycle is maintained for about 10 minutes until all water is completely converted to solid "smoothie".

Step 3, after all the moisture of the material is completely frozen, continuously vacuumizing the material under a high-acceleration vibration state, and keeping the steam pressure within the range of 10 Pa; and simultaneously, switching the cooling circulation mode into the heating circulation mode, gradually raising the temperature of the heating liquid from the vicinity of 0 ℃ to 30 ℃, and keeping the temperature raising rate at 2 ℃/min, wherein the solid ice sand in the container is quickly sublimated into gas due to heat absorption.

And 4, continuously keeping the high acceleration vibration, the high vacuum state and the temperature of 30 ℃ for about 30min, sublimating the ice sand in the container into gas, vacuumizing the gas to remove the gas, stopping the vibration and the heating, slowly exhausting the gas and removing the vacuum to finally obtain about 600g of dry and highly dispersed nano triamino trinitrobenzene powder.

The nano triamino trinitrobenzene which is subjected to ultra-fast freeze drying by adopting the method provided by the invention is compared with wet nano triamino trinitrobenzene with the water content of about 40 percent which is put into a tray and pre-frozen by adopting a common refrigerator, and then is subjected to sublimation drying in a common vacuum freeze dryer. The specific surface area of the obtained product was measured by a nitrogen adsorption and desorption method, and a picture of the appearance of the product was taken by a camera. The results of the comparative tests are shown in Table 1, and the photographs of the appearance of the products are compared as shown in FIG. 1a and FIG. 1b below. The device for realizing ultra-fast agglomeration-free vacuum freeze drying by high-acceleration vibration can greatly reduce energy consumed by freeze drying, reduce process time, improve production efficiency and improve specific surface area and dispersity of products.

TABLE 1 comparison of the present invention with conventional freeze-drying for the treatment of wet nano triaminotrinitrobenzene material

Example 2:

taking nano hexanitrostilbene with the water content of about 35 percent as an example, the method provided by the invention is implemented by the following steps.

Step 1, placing about 2kg of nano hexanitrostilbene wet material with the water content of about 35 percent in a sealed container which can vibrate at high acceleration, pump high vacuum and can be heated and cooled, starting cooling circulation when the container is firstly in a vibration state that the container is at the frequency of 1500Hz and the acceleration of 100G, cooling the wet material in the container by cooling liquid, reducing the temperature of the wet material to 0.3 ℃, and approaching the ice crystal temperature of water under normal pressure;

and 2, starting a vacuumizing device and a switch after the wet material in the container in a high-acceleration vibration state reaches 0.3 ℃, quickly reducing the gas pressure in the container to about 230Pa, quickly boiling part of water in the container at the moment, and simultaneously absorbing a large amount of heat to freeze the wet material to form fine 'ice sand' containing the nano hexanitrostilbene. The low temperature cycle is maintained for about 8 minutes until all water is completely converted to solid "smoothie".

Step 3, after all the moisture of the material is completely frozen, continuously vacuumizing the material under a high-acceleration vibration state, and keeping the steam pressure within the range of 200 Pa; and simultaneously, switching the cooling circulation mode into the heating circulation mode, gradually raising the temperature of the heating liquid from the vicinity of 0 ℃ to 20 ℃, and keeping the temperature raising rate at 1 ℃/min, wherein the solid ice sand in the container is quickly sublimated into gas due to heat absorption.

And 4, continuously keeping the high acceleration vibration, the high vacuum state and the temperature of 20 ℃ for about 30min, sublimating the ice sand in the container into gas, vacuumizing the gas to remove the gas, stopping the vibration and the heating, slowly exhausting the gas and removing the vacuum to finally obtain 650g of dry and highly dispersed nano hexanitrostilbene powder.

The nanometer hexanitrostilbene powder which is subjected to ultra-fast freeze drying by adopting the method provided by the invention is compared with wet nanometer hexanitrostilbene powder with the water content of about 35 percent which is put in a tray and is pre-frozen by adopting a common refrigerator, and then is subjected to sublimation drying in a common vacuum freeze dryer. The specific surface area of the obtained product was measured by a nitrogen adsorption and desorption method, and the appearance was observed visually, and the results of the comparative test are shown in table 2. The device for realizing ultra-fast agglomeration-free vacuum freeze drying by high-acceleration vibration can greatly reduce energy consumed by nano hexanitrostilbene freeze drying, reduce process time, improve production efficiency and improve specific surface area and dispersity of products.

TABLE 2 comparison of the present invention with conventional freeze-drying for processing wet nano-hexanitrostilbene powder

Example 3:

the method provided by the invention is implemented by the following steps by taking azithromycin raw material slurry with the water content of about 30 percent as an example.

Step 1, placing about 2kg of azithromycin raw material slurry with the water content of about 30 percent into a sealed container which can vibrate at high acceleration, pump high vacuum and be cooled by heating, firstly, starting cooling circulation when the container is in a vibration state that the container is at the frequency of 10Hz and the acceleration of 10G, cooling wet materials in the container by cooling liquid, reducing the temperature of the wet materials to 0.2 ℃, and approaching the temperature of ice crystals under the normal pressure of water;

and 2, starting a vacuumizing device and a switch after the wet material in the container in a high-acceleration vibration state reaches 0.2 ℃, quickly reducing the gas pressure in the container to about 100Pa, quickly boiling part of water in the container at the moment, and simultaneously absorbing a large amount of heat to freeze the wet material to form fine 'smoothie' containing the azithromycin bulk drug. The low temperature cycle is maintained for about 8 minutes until all water is completely converted to solid "smoothie".

Step 3, after all the moisture of the material is completely frozen, continuously vacuumizing the material under a high-acceleration vibration state, and keeping the steam pressure within the range of 150 Pa; and simultaneously, switching the cooling circulation mode into the heating circulation mode, gradually raising the temperature of the heating liquid from the vicinity of 0 ℃ to 20 ℃, and keeping the temperature raising rate at 1 ℃/min, wherein the solid ice sand in the container is quickly sublimated into gas due to heat absorption.

And 4, continuously keeping the high-acceleration vibration state, the high-vacuum state and the temperature of 20 ℃ for about 30min, sublimating the ice sand in the container into gas, vacuumizing the gas to remove the gas, stopping vibrating and heating the container, slowly exhausting the gas and removing the vacuum to finally obtain about 700g of dry and high-dispersion azithromycin bulk drug powder.

The azithromycin bulk drug powder which is subjected to ultra-fast freeze drying by adopting the method provided by the invention is loaded in a tray with azithromycin bulk drug slurry with the water content of about 30 percent, pre-frozen by adopting a common refrigerator, and then sublimation dried in a common vacuum freeze dryer for comparison. The appearance of the resulting product was visually observed, and the results of the comparative test are shown in Table 3. The device for realizing ultra-fast agglomeration-free vacuum freeze drying by high-acceleration vibration can greatly reduce the energy consumed by the freeze drying of azithromycin bulk drugs, reduce the process time, improve the production efficiency, improve the product dispersibility and avoid the secondary crushing and the secondary pollution risk caused by the secondary crushing.

TABLE 3 comparison of the present invention with conventional freeze-drying for processing azithromycin syrup

Although the present invention has been described herein with reference to the illustrated embodiments thereof, which are intended to be preferred embodiments of the present invention, it is to be understood that the invention is not limited thereto, and that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure.