CN106853295A - One kind is based on the scattered method for crystallising of film - Google Patents

Abstract

The scattered method for crystallising of film is based on the invention provides one kind, dispersant is evenly dispersed into the solution containing material to be crystallized by the scattered method of film, make material to be crystallized solubility reduction in the solution, so as to crystallize out.The membrane material can be reverse osmosis membrane, NF membrane, milipore filter, ceramic membrane, porous metal film etc..The method for crystallising can obtain crystal formation more preferably, and segregative crystal improves crystal product quality；The product larger to molecular weight may also function as improving the effect of crystallization operation speed.

Description

A Crystallization Method Based on Film Dispersion

technical field

The invention relates to a crystallization technology, which can be used in fields such as chemical industry and pharmacy that require a crystallization method to obtain products. Specifically, it relates to a crystallization method based on film dispersion.

Background technique

Crystallization technology is a commonly used method to obtain solid products in chemical, pharmaceutical and other fields. Usually, the crystallization process can remove impurities and improve product quality.

There are many crystallization methods and new crystallization processes and technologies are constantly emerging. The following two methods are frequently used in crystallization techniques:

One is that the material that needs to be crystallized is dissolved in a kind of solvent (hereinafter referred to as solvent one), and then another solvent is added (hereinafter referred to as solvent two, also referred to as dispersant in the present invention), so that the material that needs to be crystallized is dissolved in During the mixing process of the two solvents, the solubility gradually decreased and crystals were precipitated. Both solvent 1 and solvent 2 can be water or organic solvents. Some products use a mixture of water and organic solvents or a mixture of organic solvents as solvent 1. Through the principle that different solvents have different solubility for different impurities, different types of impurities can be removed at the same time. Purpose.

The second is to dissolve the substance to be crystallized in water or a mixed solution of water and an organic solvent, add an aqueous solution of acid, alkali, or salt, and adjust the pH value or salt concentration of the crystallization system to achieve the purpose of reducing the solubility of the substance to be crystallized, thereby obtaining crystals.

The same thing about these two crystallization methods is that it is necessary to add dispersant solvent two to the crystal system dissolved in solvent one to reduce the solubility of the whole system to the substance to be crystallized. In most cases, good crystals can be obtained. However, in some cases, it is difficult to obtain good crystals by using this method, resulting in difficulties in subsequent solid-liquid separation, a decrease in product quality, and sometimes even failure to obtain crystals, resulting in crystallization failure. The reason for the difficulty or failure of crystallization is that when the dispersant is added, since the dispersant has a very low solubility for the substance that needs to be crystallized, the solubility of the substance that needs to be crystallized drops sharply in the local area where the dispersant contacts the crystallization solution, and it precipitates quickly instead of crystallizing out. Which contains a lot of impurities. On the other hand, the solubility of some impurities has a small gap with the solubility of the substance that needs to be crystallized, and they also precipitate in the local area where the dispersant contacts the crystallization solution and pollute the finished product.

In order to solve this problem, a method that is often used is to reduce the speed of adding the dispersant, slowly dissolve the precipitated crystalline substances or impurities, and then slowly grow the crystalline substances on the previously produced crystal surface, but this method leads to The crystallization time is greatly extended, and it takes several days or even longer for some products with slow crystal growth to obtain products that are easy to separate and of acceptable quality. Another method is to use a method similar to a shower head, and disperse the dispersant into small droplets as much as possible when adding the dispersant, so as to reduce the area where the local solubility rapidly decreases, but the effect of this method is limited.

Contents of the invention

In order to solve the above-mentioned problems in the prior art, the present invention proposes a method for dispersing crystallization using membrane technology.

Technical scheme of the present invention is as follows:

A crystallization method is to add a dispersant to a solution containing a substance to be crystallized, so that the solubility of the substance to be crystallized in the solution is reduced, thereby crystallizing out, it is characterized in that the dispersant is uniformly dispersed to in a solution containing the substance to be crystallized.

The method of film dispersion is to use the permeability of the film material to uniformly permeate the dispersant. The dispersant is able to permeate the membrane material, but the molecules of the substance to be crystallized are not or only slightly permeable. According to the characteristics of the substance to be crystallized and the dispersant, a specific membrane material is selected, and the optional membrane material includes but not limited to reverse osmosis membrane, nanofiltration membrane, ultrafiltration membrane, ceramic membrane, porous metal membrane, etc.

The substance to be crystallized is dissolved in water, an organic solvent, a mixed solution of water and an organic solvent or a mixed solution of multiple organic solvents, that is, a solution containing the substance to be crystallized.

The dispersant is usually a poor solvent for the substance to be crystallized, which can be an organic solvent, or water or water acid, alkali, or salt solution. Due to the obvious principle of this method, organic solvent mixtures, organic solvent aqueous solutions, and The mixture of organic solution, water, acid, alkali and salt is suitable for the crystallization method described in the present invention.

When realizing above-mentioned crystallization method specifically, the present invention has designed the device that crystallization container, dispersant container and film material are combined, and crystallization container and dispersant container are separated with film material, and the solution containing the substance to be crystallized is placed in crystallization container In the process, the dispersant is stored or added dropwise in the dispersant container, and the dispersant evenly penetrates the membrane material and enters the crystallization container.

The present invention also provides a crystallization device, comprising a crystallization container, a dispersant container and a film material, the crystallization container and the dispersant container are separated by the film material, and the edge of the film material and the connection between the two containers are sealed with a sealing material.

The membrane material in the above crystallization device may be reverse osmosis membrane, nanofiltration membrane, ultrafiltration membrane, ceramic membrane or porous metal membrane, etc.

Preferably, both the crystallization container and the dispersant container are equipped with stirrers.

Membrane technology is a new technology that has been widely used in the fields of chemical industry, medicine, and environmental protection. Its core material is a membrane material that can pass molecules of different sizes. Currently, commonly used materials include reverse osmosis membranes, nanofiltration membranes, ultrafiltration membranes, and ceramics. membrane, porous metal membrane, etc. The present invention applies the membrane method to the crystallization technology, and has achieved very great achievements. The pore diameter of the membrane material is below microns, even below nanometers, and tens of thousands, hundreds of thousands or even more transparent pores are distributed per square millimeter. Compared with the existing showerhead dispersion method, the method of the present invention can obtain Greater dispersion, and smaller localized regions of low solubility. The invention adopts a film method to add a dispersant to carry out crystallization, which can obtain better crystal forms and easily separate crystals, improves the quality of crystallized products, and can also increase the crystallization operation speed for products with large molecular weights.

Description of drawings

Fig. 1 is a schematic structural diagram of the crystallization device used in the embodiment of the present invention, wherein: 1 - crystallization container, 2 - dispersant container, 3 - membrane material.

detailed description

The present invention will be further described below through the description of specific embodiment, but this is not limitation to the present invention, those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as not departing from the basic principle of the present invention Thoughts are all within the scope of the present invention.

The present invention has made an attempt to change the crystallization process. In the crystallization experiment of adding a dispersant, a membrane material was introduced. Through multiple experimental verifications, it was found that adding a dispersant through a membrane dispersion method can obtain crystals with better crystal forms and easy separation. , the effect of improving the quality of crystallized products, and the crystallization of macromolecular products can also increase the crystallization speed. Among them, the membrane materials have tried reverse osmosis membrane, nanofiltration membrane, ultrafiltration membrane, ceramic membrane, porous metal membrane, the solvent one tried in the crystallization process has a mixed solution of water, ethanol, acetone and water, and the solvent two tried in the crystallization process ( That is, dispersants) include water, ethanol, acetic acid solution, ammonia solution, and sodium chloride solution.

The crystallization method of the present invention requires that the membrane material used cannot or seldom pass through the substance molecules to be crystallized, but can pass through the dispersant molecules.

Dispersant dispersing methods can include: directly store the dispersant in the dispersant container, and gradually disperse it into the crystallization container; first add a small amount of solvent in the dispersant container, and slowly add the dispersant in it. In our experiment, the first The crystal form and quality of the product obtained by the two methods are better than the first method.

In the present invention, all the experiments carried out by the membrane materials can obtain better crystal forms and better product quality than conventional dispersant addition methods, but the membrane materials with less molecular weight are not helpful to improve the operating speed or even The operating speed is reduced, and the membrane with larger permeable molecules can increase the operating speed.

The content of the present invention is further explained or illustrated by examples below, but these examples should not be construed as limiting the protection scope of the present invention.

In order to carry out this experiment, we made the crystallization equipment shown in Figure 1: it includes two parts: a dispersion vessel with stirring and a crystallization vessel with stirring, which are separated by a membrane material, and the edge of the membrane material is separated from the two parts by a sealing material. The container is tightly connected.

Example 1

Get certain liposoluble antibiotic production crystallization solution, its solvent is the mixed solution of ethanol, acetone and water. The dispersant that needs to be added is water, which is crystallized by conventional dripping method as experiment No. 1; water is added to the dispersion container and diffused into the crystallization container through the reverse osmosis membrane for crystallization as experiment No. 2. In the course of many experiments, we found that the conventional crystallization method can obtain separable crystals within about 5 hours at the fastest, and because the antibiotic molecule can only be blocked by the reverse osmosis membrane, and the speed of water passing through the reverse osmosis membrane is too low, Experiment #2 took about 11.5 hours to complete. Therefore, we divided the No. 1 experiment into two groups, numbered 1-1 and 1-2 respectively, and uniformly controlled the dripping time of water to be 5 and 11.5 hours, and the obtained finished products were separated and dried to test their purity. In order to judge the difficulty of separation, we use the time to filter and wash the crystals until there is no liquid dripping for 1 minute as the standard for judging the difficulty of separation. The overall results of the experiment are shown in Table 1:

Table 1

experiment number Crystallization time Crystal Separation Finished product testing purity 1-1 5 hours Suction filtration for 10 hours and 57 minutes 93.87% 1-2 11.5 hours Suction filtration for 3 hours and 21 minutes 95.79% number 2 11.5 hours Suction filtration for 13 minutes 97.22%

It can be seen from the above experiments that the use of reverse osmosis membrane dispersion crystallization method reduces the difficulty of crystal separation and improves product quality, but there is no advantage in crystallization operation time.

Example 2

Get a certain water-soluble antibiotic to produce crystallization liquid, and its solvent is water. The dispersant that needs to be added is 95% ethanol, which is crystallized by conventional dropwise method as experiment No. 1; 95% ethanol is directly added to the dispersion container and diffused into the crystallization container through nanofiltration membrane as experiment No. 2; first in the dispersion container A small amount of water was added, and 95% ethanol was added dropwise thereto as Experiment No. 3. The membrane material used is a nominal 350-450D nanofiltration membrane. Experiments No. 2 and No. 3 were carried out for about 4.5 hours and 6.5 hours respectively, and the fastest time for obtaining separable crystals in No. 1 experiment was about 4.5 hours. Therefore, we divided No. 1 experiment into two groups, numbered 1-1, 1-2, uniformly control the time of adding 95% ethanol at 4.5 and 6.5 hours, and check the purity of the obtained finished product after separation and drying. The overall results of the experiment are shown in Table 2:

Table 2

experiment number Crystallization time Crystal Separation Finished product testing purity 1-1 4.5 hours Suction filtration for 5 hours and 46 minutes 97.87% 1-2 6.5 hours Suction filtration for 2 hours and 37 minutes 97.99% number 2 4.5 hours Suction filtration for 11 minutes 98.43% number 3 6.5 hours Suction filtration for 9 minutes 98.72%

It can be seen from the above experiments that the use of nanofiltration membrane dispersed crystallization reduces the difficulty of crystal separation, improves product quality, and has no obvious advantage in crystallization operation time.

Example 3

Get a macromolecular water-soluble antibiotic to produce crystallization liquid, its solvent is water, pH5.5. The dispersant that needs to be added is 2% ammonia solution, and the final pH needs to be controlled at 7.5. Experiment No. 1 was crystallized by conventional dropping method; Experiment No. 2 was directly added 2% ammonia water to the dispersion container; Experiment No. 3 was first added a small amount of water to the dispersion container, and then 2% ammonia water was added dropwise therein. The membrane material used is a nominal 1000D ultrafiltration membrane. Experiments No. 2 and No. 3 were carried out for about 2 hours and 45 minutes and 4 hours and 15 minutes respectively, and the fastest time for obtaining separable crystals in No. 1 experiment was about 5 hours. The obtained finished product is separated, dried and tested for purity. The overall results of the experiment are shown in Table 3:

table 3

experiment number Crystallization time Crystal Separation Finished product testing purity number 1 5 hours Suction filtration for 7 hours and 35 minutes 93.25% number 2 2 hours and 45 minutes Suction filtration for 19 minutes 95.88% number 3 4 hours and 15 minutes Suction filtration for 14 minutes 96.24%

It can be seen from the above experiments that the use of ultrafiltration membrane dispersed crystallization reduces the difficulty of crystal separation, improves product quality, and shortens the crystallization operation time.

Example 4

When separating the protein impurities produced by the fermentation of certain antibiotics, the protein crystallization solution is obtained, the solvent is water, and the pH is 6.0. The dispersant that needs to be added is 30% ammonium sulfate solution. Crystallization by conventional dropping method is experiment No. 1; adding 30% ammonium sulfate solution directly into the dispersion container is experiment No. 2; first adding a small amount of water into the dispersion container, and then adding 30% ammonium sulfate solution dropwise to it as experiment No. 3 . The membrane material used is a nominal 20nm flake ceramic membrane. Experiments No. 2 and No. 3 were carried out for about 1 hour and 25 minutes and 2 hours and 10 minutes respectively, and the fastest time for obtaining separable crystals in No. 1 experiment was about 6.5 hours. The obtained finished product is separated and dried to detect the protein content. The overall results of the experiment are shown in Table 4:

Table 4

experiment number Crystallization time Crystal Separation Detection of protein content number 1 6.5 hours Suction filtration for 11 hours 25.73% number 2 1 hour 25 minutes Suction filtration for 35 minutes 40.77% number 3 2 hours and 10 minutes Suction filtration for 27 minutes 50.92%

It can be seen from the above experiments that the use of ceramic membrane dispersed crystallization reduces the difficulty of crystal separation, improves product quality, and greatly shortens the crystallization operation time.

Example 5

Same as in Example 4, when protein impurities are separated, a protein crystallization liquid is obtained, the solvent of which is water, and the pH is 9.0. The dispersant that needs to be added is 5% acetic acid solution to make the final pH reach 6.0. The crystallization by conventional drop method was used as experiment No. 1; directly adding 5% acetic acid solution in the dispersion container was used as experiment No. 2; a small amount of water was first added to the dispersion container, and then 5% acetic acid solution was added dropwise to it as experiment No. 3. The membrane material used is a nominally 20nm porous titanium metal membrane. Experiments No. 2 and No. 3 were carried out for about 1 hour and 20 minutes and 2 hours and 15 minutes respectively, and the fastest time for obtaining separable crystals in No. 1 experiment was about 7 hours. The obtained finished product is separated and dried to detect the protein content. The overall results of the experiment are shown in Table 5:

table 5

experiment number Crystallization time Crystal Separation Detection of protein content number 1 7 hours Suction filtration for 10 hours and 35 minutes 26.28% number 2 1 hour 20 minutes Suction filtration for 32 minutes 41.53% number 3 2 hours and 15 minutes Suction filtration for 24 minutes 51.90%

From the above experiments, it can be seen that the adoption of porous metal film dispersion crystallization method reduces the difficulty of crystal separation, improves product quality, and greatly shortens the crystallization operation time.

Claims (10)

1. a kind of method for crystallising, dispersant is added in the solution containing material to be crystallized, makes material to be crystallized molten Solubility reduction in liquid, so as to crystallize out, it is characterised in that the dispersant is uniform by the scattered method of film Be distributed in the solution containing material to be crystallized.

2. method for crystallising as claimed in claim 1, it is characterised in that the scattered method of film is to utilize membrane material The permeability of material equably passes through dispersant.

3. method for crystallising as claimed in claim 2, it is characterised in that the membrane material is reverse osmosis membrane, nanofiltration Film, milipore filter, ceramic membrane or porous metal film.

4. method for crystallising as claimed in claim 2, it is characterised in that the molecule of material to be crystallized can not or pole It is micro to pass through the membrane material.

5. method for crystallising as claimed in claim 1, it is characterised in that the solution containing material to be crystallized is Refer to that need the material of crystallization to be dissolved in water, organic solvent, water mixes with organic solvent mixed solution or various organic solvents The solution that solution is formed.

6. method for crystallising as claimed in claim 1, it is characterised in that the dispersant be material to be crystallized not Good solvent.

7. the method for crystallising as described in claim 1~6 is any, it is characterised in that using membrane material by crystallisation vessel It is separated with dispersion agent container, the solution containing material to be crystallized is placed in crystallisation vessel, then in dispersion Dispersant is stored or is added dropwise in agent container, and dispersant uniformly enters in crystallisation vessel through membrane material, makes material to be crystallized Crystallize out.

8. a kind of crystallization apparatus, including crystallisation vessel, dispersion agent container and membrane material, the crystallisation vessel and dispersion Agent container is separated by membrane material, and the edge of membrane material is sealed with two container junctions with encapsulant.

9. crystallization apparatus as claimed in claim 8, it is characterised in that the membrane material is reverse osmosis membrane, nanofiltration Film, milipore filter, ceramic membrane or porous metal film.

10. crystallization apparatus as claimed in claim 8, it is characterised in that the crystallisation vessel and dispersion agent container are equal With agitator.