JP2024002633A - Concentrating method for raw material liquid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a concentrating method for raw material liquid, in a method for concentrating raw material liquid using a freeze-drying method, for shortening freeze-drying time in a freeze-drying process and obtaining an active ingredient at a high recovery rate by preliminarily concentrating the raw material liquid at a high concentration ratio while controlling a solvent composition of the raw material liquid to be suitable for freeze-drying.

SOLUTION: A concentrating method for raw material liquid comprises the steps of: removing a solvent from raw material liquid containing a solute and the solvent to obtain a concentrate of the raw material liquid, wherein the solvent contains water and an organic solvent, and wherein the concentrating method comprises a first step of obtaining pre-concentrated liquid of the raw material liquid by performing a first treatment and a second treatment in combination, the first treatment removing the solvent in the raw material liquid by a forward osmosis method, and a second treatment removing a solvent in the raw material liquid by a membrane distillation method, and a second step of further removing the solvent from the pre-concentrated liquid by freeze-drying to obtain a product.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention relates to a raw material liquid concentration system. Specifically, after performing the first step of concentrating the raw material liquid by separating a portion of the solvent while controlling the composition of the raw material liquid using forward osmosis and membrane distillation methods, the raw liquid is further concentrated using the freeze-drying method. The present invention relates to a method for concentrating a raw material liquid, in which a second step is performed.
In the first step, the active ingredients in the raw material liquid are concentrated by suppressing deterioration, reduction, etc. of the components in the raw material liquid and controlling the solvent composition to be suitable for freeze-drying, and then performing the second step. The present invention relates to a method for concentrating a raw material liquid, which allows a solute to be obtained at a high recovery rate and further shortens the freeze-drying time in the second step.

In various applications, it is often necessary to concentrate specific components (solutes) present in the raw material liquid.
Typical concentration methods include vacuum distillation, reverse osmosis (RO), forward osmosis (FO), membrane distillation (MD), and freeze-drying. There is.

In the vacuum distillation method, the solvent is removed by reducing the pressure of the raw material liquid. However, according to the vacuum distillation method, it is necessary to heat the raw material liquid to about 50° C., so there are concerns about problems such as changes in the quality of the active ingredients in the raw material liquid.
The RO method is a method using a membrane that allows solvent to permeate at the molecular level. In the RO method, the raw material liquid is pressurized to a predetermined high pressure, then supplied to a reverse osmosis (RO) membrane module, and the solvent (typically water) in the raw material liquid is removed by passing through the RO membrane. This is a method of concentrating the raw material liquid. However, since this RO method requires pressurizing the raw material liquid, if it is applied to a raw material liquid containing a large amount of high molecular weight substances, clogging of the RO membrane is likely to occur. Therefore, the RO method may be inappropriate for application to raw material liquids for pharmaceuticals, foods, drinks, etc., for example. Furthermore, in the RO method, the osmotic pressure of the solvent (filtered solvent) in the concentrated raw material liquid does not exceed the pressure of the high-pressure pump used for pressurization. Therefore, the concentration rate of the raw material liquid by the RO method has a limit depending on the capacity of the pump.

The FO method is a technology that uses an osmotic pressure difference as a driving force to separate and concentrate a solvent from a raw material liquid. In the FO method, the raw material liquid and the inducing solution, which has a higher osmotic pressure than the raw material liquid, are brought into contact through a forward osmosis (FO) membrane, thereby diffusing the solvent from the raw material liquid into the inducing solution. This is a method of concentrating. Since the FO method does not require heating or pressurization, it is expected that the desired concentration effect can be maintained for a long time even with a raw material liquid containing a large amount of high molecular weight substances and the like.

The MD method is a technology that uses a vapor pressure difference as a driving force to separate and concentrate a solvent from a raw material liquid. In the MD method, the vapor of the solvent in the raw material liquid that evaporates on the surface of a hydrophobic membrane diffuses and permeates through the membrane and condenses on the other membrane surface, thereby separating and concentrating the solvent from the raw material liquid. It is a technology that In the MD method, for example, the raw material liquid is brought into contact with cooling water whose temperature is lower than that of the raw material liquid through a membrane, and the solvent vapor in the raw material liquid is transferred from the raw material liquid to the cooling water, so that the raw material liquid is The concentrated DCMD method (Direct Contact MD) is well known.
Like the FO method, the MD method does not require heating or pressurization, so it is expected that the desired concentration effect can be maintained for a long time even with a raw material liquid containing a large amount of high molecular weight substances.

The freeze-drying method is a technique of freezing a raw material liquid and then sublimating the solvent in the raw material liquid to separate and concentrate the solvent from the raw material liquid. The freeze-drying method is also used in the manufacturing process of pharmaceuticals because it can remove water without damaging cells, tissues, proteins, etc. On the other hand, the freeze-drying method has drawbacks such as high implementation cost, long drying time, and low energy efficiency.
The freeze-drying method requires a vacuum pump to create a high vacuum, a heat source for sublimation, a cooling unit to recover the solvent vapor generated from the raw material liquid as a liquid or solid, and the energy cost is high. . In addition, if the raw material liquid must be completely frozen in advance and there is an unfrozen portion, collapse (a foaming contraction phenomenon caused by evaporation drying caused by insufficient freezing) may occur and the product may become unusable. There is.

When the raw material liquid is dried by freeze-drying, the freeze-drying time increases significantly as the volume, thickness, etc. of the frozen body increases. Furthermore, the higher the proportion of organic solvent remaining in the raw material liquid, the lower the freezing temperature and the longer the freezing time. On the other hand, if all the organic solvent in the raw material liquid is removed, the solute may precipitate and concentration may not be possible.
Considering these circumstances, in order to apply the freeze-drying method to concentrate the raw material liquid, it is necessary to concentrate the raw material liquid as much as possible with a composition suitable for freeze-drying before subjecting it to freeze-drying. It is being

In the manufacturing process of pharmaceuticals, intermediate products containing a large amount of water are passed through the manufacturing process, so it is necessary to concentrate and dry the raw material liquid in order to obtain the final product.
In this regard, Non-Patent Document 1 states that since most biopharmaceuticals pass through intermediate products containing a large amount of water, the pharmaceutical production process is It is disclosed that the freeze-drying method is mainly used for drying. On the other hand, disadvantages of the freeze-drying method include high implementation costs, long drying times, and low energy efficiency.

In order to shorten the drying time of such a freeze-drying process, Patent Document 1 proposes performing preliminary concentration using an RO method prior to freeze-drying. Furthermore, Patent Document 2 proposes performing preliminary concentration using the FO method prior to freeze-drying.

International Publication No. 2020/158456 International Publication No. 2020/241795

Japan Journal of Food Engineering, Vol. 19, No1, pp15-24, March, 2018

The RO method described in Patent Document 1 does not require heating of the raw material liquid, so it has the advantage of less deterioration of the active ingredients due to heat. However, since the RO method requires pressurization of the raw material liquid, if pressure-sensitive substances are included in the raw material liquid, they may deteriorate. Furthermore, since the concentration rate of the RO method has a limit due to the pressurizing capacity of the pump, it may not be possible to concentrate the raw material liquid to a great extent before freeze-drying.
Therefore, the RO method may not be suitable as a preconcentration method performed prior to the freeze-drying method.

The FO method described in Patent Document 2 cannot control the solvent composition when concentrating the raw material liquid. Therefore, if the proportion of organic solvent in the pre-concentrated liquid obtained by the FO method is high, freeze-drying will take a long time, or the pre-concentrated liquid will not freeze sufficiently, resulting in collapse and becoming unusable as a product. There are cases.
Further, in the FO method, back diffusion in which the inducer substance in the inducer solution moves toward the raw material liquid side may occur, so the solute in the inducer solution may mix into the raw material concentrate. In this case, the freeze-drying time of the pre-dried product may become longer, or components that cannot be removed by freeze-drying may remain in the product, resulting in a lower recovery rate of the active ingredient.
Therefore, the FO method may not be suitable as a preconcentration method performed prior to the freeze-drying method.

As described above, the preconcentration method of the raw material liquid prior to freeze-drying controls the solvent composition to be suitable for freeze-drying while suppressing alteration, deformation, and outflow of the active ingredients in the raw liquid as much as possible. However, there is a need for a concentration method that can obtain a concentrate at a high concentration ratio. An effective method for concentrating a raw material liquid by combining a pre-drying method performed prior to freeze-drying having such characteristics and a freeze-drying method has not yet been established.
Therefore, an object of the present invention is to preconcentrate the raw material liquid at a high concentration ratio while controlling the solvent composition to be suitable for freeze-drying in a method for concentrating a raw material liquid using the freeze-drying method. It is an object of the present invention to provide a method for concentrating a raw material liquid, which shortens the process and obtains an active ingredient with a high recovery rate.

The present invention is as follows.
<<Aspect 1>> A method for concentrating a raw material liquid, in which the solvent is removed from a raw material liquid containing a solute and a solvent to obtain a concentrate of the raw material liquid, the method comprising:
the solvent contains water and an organic solvent,
The concentration method includes a first treatment in which the solvent in the raw material liquid is removed by forward osmosis, and a second treatment in which the solvent in the raw material liquid is removed in a membrane distillation method. a first step of obtaining a preconcentration of the liquid;
A method for concentrating a raw material liquid, comprising a second step of further removing the solvent from the pre-concentrated liquid by freeze-drying to obtain a product.
<Aspect 2> In the second treatment, the raw material liquid and the cooling water are brought into contact with each other through a hydrophobic porous membrane, and the solvent in the raw material liquid is passed through the hydrophobic porous membrane. The method for concentrating a raw material liquid according to aspect 1, wherein the solvent in the raw material liquid is removed by moving the raw material liquid into cooling water.
<Aspect 3> The hydrophobic porous membrane used in the second treatment is a hollow fiber hydrophobic porous membrane,
The hollow fiber hydrophobic porous membrane is used in the form of a membrane module having a hollow fiber bundle constituted by a plurality of the hollow fiber hydrophobic porous membranes.
The raw material liquid concentration method according to aspect 2.
<<Aspect 4>> The raw material liquid concentration method according to Aspect 3, wherein a hydrophobic polymer is attached to at least a portion of the hollow fiber hydrophobic porous membrane.
<Aspect 5> The hydrophobic polymer is a polymer having at least one side chain selected from the group consisting of (per)fluoroalkyl group, (per)fluoropolyether group, alkylsilyl group, and fluorosilyl group. , the raw material liquid concentration method according to aspect 4.
<Aspect 6> The material constituting the hydrophobic porous membrane is polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene/tetrafluoroethylene copolymer, and polychlorotrifluoroethylene. The raw material liquid concentration method according to any one of aspects 2 to 5, comprising at least one resin selected from the group consisting of ethylene.
<<Aspect 7>> Any one of Aspects 1 to 5, wherein in the first step, the first treatment and the second treatment are performed in parallel, and the raw material liquids after each treatment are mixed. The raw material liquid concentration method described in .
<<Aspect 8>> The raw material liquid concentration method according to any one of Aspects 1 to 5, comprising performing the second treatment after the first treatment in the first step.
<<Aspect 9>> The raw material liquid concentration method according to any one of Aspects 1 to 5, comprising performing the first treatment after performing the second treatment in the first step.
<Aspect 10> The solvent according to any one of aspects 1 to 5, wherein the solvent of the raw material liquid is a mixed solvent containing water and one or two selected from the group consisting of acetonitrile and isopropanol. Raw material liquid concentration method.
<Aspect 11> The method for concentrating a raw material liquid according to any one of aspects 1 to 5, wherein the solute of the raw material liquid is a pharmaceutical raw material.

In the raw material liquid concentration system of the present invention, by the first step that combines forward osmosis and membrane distillation, it is possible to concentrate the raw material liquid at a high concentration ratio while controlling the solvent composition of the raw material liquid to a composition suitable for freeze-drying. can. Therefore, a high-quality product can be obtained while shortening the freeze-drying time in the second step of freeze-drying.
The present invention is applicable to, for example, the concentration of pharmaceutical raw materials, the treatment of precursor solutions for chemical species synthesis, the concentration of oral liquids (liquid foods, drinks, etc.), and the associated water discharged from gas fields (including shale gas fields) and oil fields. It can be suitably applied to applications such as processing.

FIG. 1 is a conceptual diagram for explaining an example of an embodiment of the raw material liquid concentration method of the present invention. FIG. 2 is a conceptual diagram for explaining another example of the embodiment of the raw material liquid concentration method of the present invention. FIG. 3 is a conceptual diagram for explaining the outline of the configuration of the first step in the raw material liquid concentration method carried out in Examples 1 to 4. FIG. 4 is a conceptual diagram for explaining the outline of the configuration of the first step in the raw material liquid concentration method implemented in Comparative Examples 1 and 2.

Preferred embodiments of the invention will now be described in specific detail by way of non-limiting example.

<Raw material liquid concentration method>
The raw material liquid concentration method of the present invention includes:
A method for concentrating a raw material liquid, the method comprising: removing the solvent from a raw material liquid containing a solvent and a solute to obtain a concentrate of the raw material liquid;
the solvent contains water and an organic solvent,
The concentration method includes:
A first treatment of the solvent in the raw material liquid by a forward osmosis method and a second treatment of removing the solvent in the raw material liquid by a membrane distillation method are performed in combination to obtain a pre-concentrated solution of the raw material liquid. , the first step;
a second step of further removing the solvent from the preconcentrate by lyophilization to obtain a product;
This is a raw material liquid concentration method.

In the first step, the order of performing the first treatment and the second treatment is arbitrary. for example,
After performing the first processing, the second processing may be performed;
The first process may be performed after the second process;
The first process and the second process may be performed simultaneously.
Performing the first treatment and the second treatment simultaneously means, for example, performing the first treatment and the second treatment in parallel and mixing the raw material liquids after each treatment.

The first treatment and the second treatment are preferably performed cyclically. for example,
The raw material liquid is stored in a raw material liquid tank, and a part of the raw material liquid in the raw material liquid tank is taken out and subjected to a first treatment and a second treatment in this order, and after the first treatment and the second treatment. repeating the operation of returning the raw material liquid to the raw material liquid tank;
The raw material liquid is stored in a raw material liquid tank, and a part of the raw material liquid in the raw material liquid tank is taken out and subjected to a second treatment and a first treatment in this order, and after the second treatment and the first treatment. repeating the operation of returning the raw material liquid to the raw material liquid tank;
The raw material liquid is stored in the raw material liquid tank,
Repeating the operation of taking out a part of the raw material liquid in the raw material liquid tank, subjecting it to a first treatment, and returning the raw material liquid after the first treatment to the raw material liquid tank; repeating the operations of taking out a portion, subjecting it to a second treatment, and returning the raw material liquid after the second treatment to the raw material liquid tank in parallel (simultaneously);
The following methods are preferred.

An overview of the raw material liquid concentration method of the present invention will be described below, with reference to FIG. 1 as necessary.

FIG. 1 shows a conceptual diagram for explaining an example of an embodiment of the raw material liquid concentration method of the present invention.
The first step of the raw material liquid concentration method of the present invention is performed in combination of a first treatment using a forward osmosis method and a second treatment using a membrane distillation method.
In the first treatment, the raw material liquid (a) and the inducing solution (d) are brought into contact with each other through a forward osmosis membrane (o), and the solvent in the raw material liquid is transferred to the inducing solution. While concentrating, the inducing solution (d) is diluted to obtain a pre-concentrated solution and a diluted inducing solution.
In the first treatment in the first step of the raw material liquid concentration system of FIG. 1, a forward osmosis membrane unit (200) that performs a forward osmosis process is used. The internal space of this forward osmosis membrane unit (200) is divided by the forward osmosis membrane (o) into two parts: a raw material liquid side space (R) and an induction solution side space (D). The raw material liquid (a) stored in the raw material liquid tank (100) is introduced into the raw material liquid side space (R) of the forward osmosis membrane unit (200). On the other hand, the inducing solution (d) stored in the inducing solution tank (400) is introduced into the inducing solution side space (D) of the forward osmosis membrane unit (200).

The raw material liquid (a) contains a solute and a solvent. The inducing solution (d) contains an inducing substance and a solvent. The osmotic pressure of the inducing solution (d) is set to be higher than that of the raw material solution (a).
When the raw material liquid (a) and the inducing solution (d) come into contact with each other through the forward osmosis membrane (o), the solvent in the raw material liquid (a) is It passes through the forward osmosis membrane (o) and moves to the inducing solution (d) side.
In the present invention, the solvent of the raw material liquid (a) contains water and an organic solvent. In this case, among the solvents in the raw material liquid (a), both water and the organic solvent pass through the forward osmosis membrane (o) and move to the inducing solution (d) side. At this time, the ratio of water and organic solvent passing through the forward osmosis membrane (o) to the inducing solution (d) is determined by the ratio of organic solvent contained in the raw material solution (a) and the inducing solution (d). Dependent.
As a result of the above, water and a certain proportion of the organic solvent in the solvent are removed from the raw material liquid (a), resulting in a pre-concentrated liquid (c) which is a concentrated raw material liquid, and a diluted derived solution. A dilute inducing solution (e) is obtained.
In the method of FIG. 1, the pre-concentrate liquid (c) is returned to the raw material liquid tank (100), and the diluted draw solution (e) is returned to the draw solution tank (400), and each is recycled.

In the first treatment, the direction in which the raw material liquid (a) and the inducing solution (d) flow is not particularly limited, and may be countercurrent or cocurrent.
The forward osmosis treatment in the first treatment may be performed by a total filtration method or a cross-flow filtration method. The forward osmosis treatment in the first treatment is preferably carried out by a cross-flow filtration method from the viewpoint of the filtration flow rate and suppression of membrane contamination.

In the second concentration process, the raw material liquid (a) and the cooling water (f) are brought into contact through the hydrophobic porous membrane (p), and the solvent in the raw material liquid is transferred to the cooling water (f) side. By doing so, the raw material liquid is concentrated, and the solvent that has moved to the cooling water (f) side through the hydrophobic porous membrane (p) is diluted by the cooling water (f), resulting in a pre-concentrated liquid and a diluted solvent liquid. get.

In the first step of the raw material liquid concentration method shown in FIG. 1, the second treatment uses a membrane unit for membrane distillation (300) that performs a membrane distillation process. The internal space of this membrane unit for membrane distillation (300) is divided into two, a raw material liquid side space (R) and a cooling water side space (F), by a hydrophobic porous membrane (p). The raw material liquid (a) stored in the raw material liquid tank (100) is introduced into the raw material liquid side space (R) of the membrane unit for membrane distillation (300). On the other hand, the cooling water (f) stored in the cooling water tank (500) is introduced into the cooling water side space (F) of the membrane unit for membrane distillation (300).
The raw material liquid (a) contains a solute and a solvent (b). Cooling water (f) contains cooling water and solvent (b). The proportion of the solvent (b) is 0 to 50 wt% relative to the cooling water (f).

When the raw material liquid (a) and the cooling water (f) come into contact with each other through the hydrophobic porous membrane (p), the vapor pressure difference between the two liquids is used as a driving force to drive the solvent in the raw material liquid (a). passes through the hydrophobic porous membrane (p) and moves to the cooling water (f) side.
In the present invention, the solvent of the raw material liquid (a) contains water and an organic solvent. In this case, among the solvents in the raw material liquid (a), mainly the organic solvent passes through the hydrophobic porous membrane (p) and moves to the cooling water (f) side. On the other hand, the rate at which water, which has a lower vapor pressure than the organic solvent, moves to the cooling water (f) side is smaller than that of the organic solvent. At this time, the ratio of water and organic solvent that passes through the hydrophobic porous membrane (p) and moves to the cooling water (f) side is determined by the ratio of water and organic solvent between the raw material liquid (a) and the cooling water, respectively. Determined by the vapor pressure difference.
As a result of the above, the organic solvent and a small amount of water among the solvents are removed from the raw material liquid (a), and the pre-concentrated liquid (c) is a concentrated raw material liquid and contains a diluted solvent. An aqueous solution (g) is obtained. In addition, by appropriately setting the proportion of the solvent (b) in the cooling water (f) and adjusting the vapor pressure difference between the raw material liquid (a) and the cooling water (f), the raw material liquid (a) after concentration can be adjusted. ) makes it possible to control the solvent concentration.
In the method of FIG. 1, the pre-concentrate liquid (c) is returned to the raw material liquid tank (100), and the aqueous solution (g) is returned to the cooling water tank (500), so that they are recycled.
In the second treatment, the direction in which the raw material liquid (a) and the cooling water (f) flow is not particularly limited, and may be countercurrent or cocurrent.

In the example of FIG. 1, in the first step, the above-mentioned first treatment and second treatment are performed in parallel to concentrate the raw material liquid (a) and obtain a pre-concentrated liquid (c). .
In the second step, in the freeze-drying unit (600), the pre-concentrated liquid (c) obtained in the first step is further concentrated by a freeze-drying method, and the water content is preferably reduced to 3% by mass or less. A product (h) is obtained.
Freeze-drying typically involves three stages within the chamber of the freeze-drying unit (600):
(A) Freezing stage;
(B) a primary drying stage; and (C) a secondary drying stage.
Step (A) is a step of freezing the solvent in the pre-concentrate obtained in the first step. In step (B), the chamber pressure is lowered (for example, lowered to 13.3 Pa or less) and heat is applied to the frozen material to sublimate the solvent. In step (C), the temperature is increased to remove water, including binding solvents such as water of crystallization, and drying until the residual solvent content in the preconcentrate drops to the desired level.
In the manner described above, a product (h) obtained by further concentrating the preconcentrated liquid (c) is obtained. Here, as a method of accelerating the solvent removal, a method of flowing dry gas into the chamber may be used as a method other than reducing the chamber pressure.

Between the first step and the second step, there may be a step of performing a pre-stage of the freeze-drying method.
Preliminary steps in the freeze-drying method include, for example, a preliminary freezing step, a sterilization step, and the like.
The first step and the second step may be performed continuously without any time interval, or may be performed at a predetermined time interval. For example, the pre-concentrate obtained in the first step may be temporarily stored and the second step may be performed after a predetermined period of time has elapsed. However, it is more preferable in terms of time efficiency to connect the first step and the second step and perform the concentration continuously without any time interval.

Even if a solvent composition analysis step is included between the first step and the second step to confirm that the pre-concentrated liquid obtained in the first step is concentrated with a predetermined solvent composition. good. The measurement in the solvent composition analysis step may be performed within the apparatus that performs the first step, or may be performed by extracting a portion of the pre-concentrated liquid after the first step.

FIG. 2 shows a schematic diagram for explaining another example of the embodiment of the raw material liquid concentration method of the present invention.
The raw material liquid concentration method of FIG. 2 includes, in the first step, performing a first treatment using a forward osmosis membrane unit (200), performing a second treatment using a membrane distillation membrane unit (300), In the second step, freeze-drying is performed using the freeze-drying unit (600), which is the same as the raw material liquid concentration method shown in FIG. Note that in FIG. 2, illustrations of the raw material liquid tank, the induction solution tank, and the cooling water tank are omitted.
In the raw material liquid concentration method of FIG. 1, in the first step, the pre-concentrated liquid (c) obtained from the forward osmosis membrane unit (200) of the first treatment and the membrane distillation membrane unit (200) of the second treatment are used. The pre-concentrated liquid (c) obtained from step 300) is returned to the raw material liquid tank, used for circulation, and then provided to the freeze-drying unit (600) of the second step.
However, in the raw material liquid concentration method of FIG. The difference is that the pre-concentrated liquids (c) are passed through each unit in one pass, preferably mixed together, and then provided to the freeze-drying unit (600) of the second step.

《Each element of the raw material liquid concentration system》
The outline of the concentration of the raw material liquid by the raw material liquid concentration method of the present invention has been described above. Subsequently, each element constituting the raw material liquid concentration method of the present invention will be explained in detail below.

<Raw material liquid (a)>
The raw material liquid (a) is a fluid containing a solute and a solvent, which is intended to be concentrated by the system of the present invention. This raw material liquid (a) may be an emulsion as long as it is a fluid.

Examples of the raw material liquid (a) applicable to the present invention include pharmaceutical raw materials, foods, seawater, and produced water discharged from gas fields and oil fields. In the raw material liquid concentration system of the present invention, a concentrate from which the solvent has been removed can be obtained while arbitrarily controlling the solvent composition in the raw material liquid (a). However, considering the advantage of being able to concentrate without the need for heating, it is possible to maintain the efficacy of pharmaceutical ingredients when the raw material liquid concentration system of the present invention is applied to concentrate pharmaceuticals or their raw materials that are concerned about decomposition due to heating. It is possible to concentrate in a state where the solute is concentrated, and furthermore, it is possible to concentrate while suppressing the precipitation of solute. As a result, it becomes possible to concentrate valuable materials with almost no loss.

The raw material liquid (a) applied to the present invention is preferably a pharmaceutical raw material.
Pharmaceutical raw materials to be concentrated include, for example, useful substances selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody-drug conjugates (ADCs), and vitamins, and this solute. is preferably dissolved or dispersed in a solvent.

Amino acids include essential amino acids, non-essential amino acids, and unnatural amino acids. Examples of essential amino acids include tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, and the like. Examples of non-essential amino acids include arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, and glutamic acid.

An unnatural amino acid refers to any artificial compound that does not exist in nature and has an amino acid skeleton within the same molecule, and can be synthesized by bonding various labeling compounds to the amino acid skeleton. The "amino acid skeleton" contains carboxyl groups, amino groups in amino acids, and parts that connect these groups. "Label compound" refers to dye compounds, fluorescent materials, chemiluminescent materials, enzyme substrates, coenzymes, antigenic materials, and protein binding materials known to those skilled in the art.
An example of an unnatural amino acid is a "labeled amino acid" which is an amino acid bound to a labeling compound. Examples of labeled amino acids include amino acids in which a labeling compound is bonded to an amino acid having an amino acid skeleton containing an aromatic ring such as a benzene ring in its side chain. Further, examples of unnatural amino acids imparted with specific functions include, for example, photoresponsive amino acids, photoswitch amino acids, fluorescent probe amino acids, fluorescently labeled amino acids, and the like.

A peptide refers to a compound in which 2 or more amino acid residues and less than 70 amino acid residues are bonded, and may be chain-like or cyclic. Examples of the peptides to be concentrated include L-alanyl-L-glutamine, β-alanyl-L-histidine cyclosporine, and glutathione.

A protein generally refers to a compound in which amino acid residues are bonded that has a longer chain than a peptide. As the protein, for example, those applicable as protein preparations are preferable. Examples of protein preparations include interferon α, interferon β, interleukins 1 to 12, growth hormone, erythropoietin, insulin, granular colony stimulating factor (G-CSF), tissue plasminogen activator (TPA), and natriuresis. Examples include peptides, blood coagulation factor VIII, somatomedin, glucagon, growth hormone releasing factor, serum albumin, calcitonin, and the like.

Examples of sugars include monosaccharides (e.g., glucose, fructose, galactose, mannose, ribose, deoxyribose, etc.), disaccharides (e.g., maltose, sucrose, lactose, etc.), and sugar chains (e.g., glucose, galactose, mannose, etc.). In addition to fucose, xylose, glucuronic acid, iduronic acid, etc.; saccharide derivatives such as N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, etc.).

Examples of vaccines include hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, new coronavirus vaccine, etc.;
Examples of nucleic acids include oligonucleotides, RNA, aptamers, decoys, etc.;
Examples of antibiotics include streptomycin, vancomycin, etc.;
Each can be mentioned.

Examples of vitamins include vitamin A, vitamin B, and vitamin C, and the concept also includes derivatives and salts of these. The B vitamins include, for example, vitamin B6, vitamin B12, and the like.

The number average molecular weight of the solute contained in the raw material liquid may be about 100 to 50,000, preferably about 100 to 30,000, more preferably about 100 to 10,000, and about 100 to 6,000. It is particularly preferable that there be.
If the molecular weight of the solute is too small, it may pass through forward osmosis membranes and semipermeable membranes during membrane distillation, and if the molecular weight is too large, the solute may adhere to the membrane surface, which is undesirable. .
When the molecular weight is relatively small (for example, when the molecular weight is 500 or less), the number average molecular weight of the solute can be determined by calculation from the chemical formula of the solute. On the other hand, when the molecular weight of the solute is relatively large (for example, when the molecular weight exceeds 500), the number average molecular weight can be determined as the number average molecular weight in terms of polyethylene glycol measured by GPC.

<Inducing solution (d)>
The inducing solution (d) is a fluid that contains an inducing substance and a solvent, has a higher osmotic pressure than the raw material solution (a), and does not significantly denature the forward osmosis membrane (o).

<Inducer>
Examples of the inducer that can be used in the present invention include alcohols, inorganic salts, sugars, and polymers. Therefore, the inducing solution in the present invention may be a solution containing one or more selected from alcohols, inorganic salts, sugars, polymers, and the like.
Examples of the alcohol include monoalcohols such as methanol, ethanol, 1-propanol, 2-propanol, and isopropanol; and glycols such as ethylene glycol and propylene glycol.
Examples of inorganic salts include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium sulfate, magnesium sulfate, sodium thiosulfate, sodium sulfite, ammonium chloride, ammonium sulfate, ammonium carbonate, etc.;
Examples of sugars include common sugars such as sucrose, fructose, and glucose, and special sugars such as oligosaccharides and rare sugars;
Examples of the polymer include polymers such as polyethylene oxide and propylene oxide, and copolymers thereof.

The concentration of the inducer in the inducing solution (d) is set so that the osmotic pressure of the inducing solution (d) is higher than the osmotic pressure of the raw material solution (a). The osmotic pressure of the inducing solution (d) may vary within this range as long as it is higher than the osmotic pressure of the raw material solution (a).
To determine the osmotic pressure difference between two liquids, for example, one of the following methods can be used.
(1) In the case of two-phase separation after mixing two liquids: After two-phase separation, it is determined that the osmotic pressure of the liquid whose volume has increased is higher, or
(2) When two phases do not separate after mixing two liquids: Two liquids are brought into contact through a forward osmosis membrane (o), and the liquid whose volume increases after a certain period of time is judged to have a high osmotic pressure. do. The certain period of time at this time depends on the osmotic pressure difference, but is generally in the range of several minutes to several hours.

The inducing substance in the inducing solution (d) is preferably the same type as the organic solvent contained in the solvent of the raw material solution (a).

<Cooling water (f)>
The cooling water (f) may be water or a mixed solution of water and an organic solvent. The cooling water (f) is a fluid that has a lower vapor pressure than the raw material liquid (a) and does not wet the hydrophobic membrane (p). Since the lower the temperature, the lower the vapor pressure, the temperature of the cooling water (f) is preferably lower than that of the raw material liquid (a).

<Solvent of raw material liquid (a)>
The solvent of the raw material liquid (a) contains water and an organic solvent.
The solvent of the raw material liquid (a) is a liquid containing water and an organic solvent, and is not limited as long as it can dissolve or disperse the solute in the raw material liquid (a). Examples of organic solvents contained in the solvent include low molecular alcohols such as methanol, ethanol, and isopropanol; compounds called VOCs (Volatile organic compounds) such as acetonitrile, toluene, xylene, and ethyl acetate; Examples include acids called VA (Volatile acids) such as acetic acid, folic acid, propionic acid, and butyric acid.
In the present invention, in particular, from the viewpoint of solute stability, a mixed liquid containing water and one or two selected from the group consisting of acetonitrile and isopropanol is used as a solvent for the raw material liquid (a). It is preferable.

<Pre-concentrated liquid (c)>
The pre-concentrated liquid (c) obtained by concentrating the raw material liquid (a) through the first step is obtained by maintaining the components in the raw material liquid (a) and separating the solvent. In the raw material liquid concentration system of the present invention, the amount of solvent separated from the raw material liquid (a) can be arbitrarily controlled. Furthermore, by controlling the operating methods of the first treatment and the second treatment, the composition of the solvent can also be controlled as desired.

According to the first step of the present invention, water in the solvent is preferentially separated in the first treatment, and organic solvent in the solvent is preferentially separated in the second treatment. Therefore, by operating the first treatment and the second treatment in combination and adjusting the degree of contribution of each, the solvent composition of the pre-concentrated liquid can be arbitrarily controlled.

According to the first treatment in the present invention, the osmotic pressure of the raw material solution (a) is lowered by the inducing solution (
As long as the osmotic pressure of d) is not exceeded, it is possible to concentrate the raw material solution (a) to around its saturation concentration. In addition, according to the second treatment, as long as the membrane for membrane distillation is not wetted by the solvent of the raw material liquid (a) and the vapor pressure does not become lower than the vapor pressure of the cooling water (f), the raw material liquid (a) It is possible to remove the solvent from.
In the present invention, in the first step, the raw material liquid (a) can be concentrated by controlling the solvent composition to be suitable for freeze-drying, so the freeze-drying time in the second step described later can be shortened, and the time is reduced. In addition, it is possible to make the freeze-drying process, which requires a large amount of energy, more efficient.

A solvent composition suitable for freeze-drying is a composition in which the proportion of organic solvent in the raw material liquid (a) is appropriately controlled. The appropriate composition varies depending on the type of solvent and solute in the raw material solution (a) and the freeze-drying conditions.
Generally, if the concentration of the organic solvent in the raw material liquid (a) is too high, the freezing step during freeze-drying will take a long time, and in some cases, freezing may not be possible. On the other hand, if the organic solvent concentration is too low, the solute in the raw material liquid (a) may precipitate, making it impossible to achieve sufficient concentration. Therefore, it is desirable to concentrate the raw material liquid (a) while keeping the concentration of the organic solvent within an appropriate range.
Specifically, the ratio of the mass of the organic solvent in the preconcentrate (c) obtained in the first step to the total mass of the solvent in the preconcentrate (c) is 30% by mass or less. The content is preferably 20% by mass or less, particularly preferably 20% by mass or less. On the other hand, in order to avoid precipitation of the solute and obtain a product (h) of desired quality, the mass proportion of the organic solvent in the solvent of the pre-concentrate (c) is preferably 1% by mass or more.
Further, it is preferable that the pre-concentrated liquid (c) is in a state in which the solvent has been removed as much as possible. Specifically, the ratio of the mass of the solvent in the preconcentrate (c) obtained in the first step to the total mass of the preconcentrate (c) is preferably 11.0% by mass or less, It is more preferably 10.5% by mass or less, and even more preferably 10.0% by mass or less. On the other hand, in order to effectively carry out the freeze-drying process and obtain a product (h) of the desired quality, the mass proportion of the solvent in the preconcentrate (c) should be 1% by mass or more. is preferred.

In the first step of the invention, concentration is performed using a combination of forward osmosis and membrane distillation. Therefore, through this first step, it is possible to obtain a high concentration ratio while controlling the solvent composition of the raw material liquid (a) to a composition suitable for freeze-drying in the second step. There are various types of raw material liquids (a) to which this method can be applied, and virtually any liquid can be concentrated. Therefore, according to the present invention, a high quality concentrate can be obtained with high efficiency even in cases where it is impossible or difficult to apply conventional techniques.

<First step>
In the first step in the raw material liquid concentration method of the present invention, concentration is performed by forward osmosis.
Concentration by the forward osmosis method in the present invention uses, for example, a forward osmosis membrane unit whose internal space is divided into two parts, a raw material liquid side space (R) and a draw solution side space (D), by a forward osmosis membrane (o). It may be implemented by

<Forward osmosis membrane (o) of forward osmosis membrane unit>
The forward osmosis membrane (o) of the forward osmosis membrane unit is a membrane that has the function of allowing the solvent in the raw material liquid (a) to pass therethrough, but not allowing or making it difficult for the solute to pass therethrough.
The forward osmosis membrane (o) used in the first treatment in the first step of the raw material liquid concentration method of the present invention may be a membrane having the function of a reverse osmosis membrane. However, the reverse osmosis process, which removes the solvent by pressure, and the forward osmosis process, which uses the difference in osmotic pressure between the raw material solution and the draw solution, are not suitable due to the difference in the driving force utilized for solvent removal. The membrane structure is different.
Therefore, in the raw material liquid concentration method of the present invention, it is preferable to use a membrane having a high function as a forward osmosis membrane as the forward osmosis membrane (o).

Examples of the shape of the forward osmosis membrane (o) include a hollow fiber shape and a flat membrane shape.
As the forward osmosis membrane (o), a composite membrane having a separation active layer on a support layer (support membrane) is preferable. The support membrane may have an appropriate shape depending on the shape of the desired forward osmosis membrane, and may be, for example, a flat membrane or a hollow fiber membrane.
When a flat membrane is used as a support membrane, a separation active layer may be provided on one or both sides of the support membrane.
When a hollow fiber membrane is used as a support membrane, a separation active layer may be provided on the outer surface, inner surface, or both surfaces of the hollow fiber membrane.

The support membrane in this embodiment is a membrane for supporting the separation active layer, and it is preferable that the support membrane itself does not substantially exhibit separation performance for the object to be separated. As this support membrane, any material including known microporous support membranes, nonwoven fabrics, etc. can be used.
A preferred support membrane in this embodiment is a porous hollow fiber support membrane. This porous hollow fiber support membrane has pores on its inner surface with a pore diameter of preferably 0.001 μm or more and 0.1 μm or less, more preferably 0.005 μm or more and 0.05 μm or less. On the other hand, the structure from the inner surface of the porous hollow fiber supported membrane to the outer surface in the depth direction of the membrane is as sparse as possible while maintaining strength, in order to reduce the permeation resistance of the permeating fluid. It is preferable. Preferably, the sparse structure of this portion is, for example, a net-like structure, a finger-like void structure, or a mixed structure thereof.

As the separation active layer in the flat membrane or hollow fiber forward osmosis membrane (o), for example, polysulfone, polyethersulfone, polyvinylidene fluoride, polyacrylonitrile, polyethylene, polypropylene, polyamide can be used, since they have a high rejection rate of the inducing substance. It is preferable that the thin film layer is mainly composed of at least one selected from cellulose acetate, cellulose acetate, and the like. More preferably, the main component is at least one selected from polysulfone, polyethersulfone, polyvinylidene fluoride, polyacrylonitrile, and polyamide, and particularly preferably a polyamide layer.

In this embodiment, it is preferable to use a hollow fiber forward osmosis membrane (o), particularly a composite hollow fiber having a separation active layer made of a polymer thin film on the inner surface of a hollow fiber porous support membrane. is preferred.
The forward osmosis membrane unit is preferably in the form of a forward osmosis membrane module, in which a plurality of forward osmosis membrane thread bundles are preferably accommodated in a suitable housing.

When using a hollow fiber forward osmosis membrane, the outer diameter of the hollow fiber membrane is preferably 300 μm or more and 5,000 μm or less, more preferably 350 μm or more and 4,000 μm or less, and the inner diameter of the hollow fiber membrane is preferably 200 μm or more. It is 4,000 μm or less, more preferably 250 μm or more and 1,500 μm or less. If the inner diameter of the hollow fiber is less than 200 μm, the pressure loss when fluid flows inside the hollow fiber membrane becomes large, and the pressure in the hollow fiber becomes large. Furthermore, the contact area between the raw material liquid and the membrane surface per unit volume increases, and as a result, solutes contained in the raw material liquid tend to stick to the membrane surface. When the inner diameter of the hollow fiber exceeds 4,000 μm, the contact area between the raw material liquid and the membrane surface becomes excessively small, and the separation efficiency between the solvent and the solute may be impaired.

<Second processing>
In the second process in the first step of the raw material liquid concentration system of the present invention, concentration is performed by membrane distillation.
Concentration by the membrane distillation method in the present invention is, for example, a direct contact type in which the internal space is divided into two parts, a raw material liquid side space (R) and a cooling water side space (F), by a hydrophobic porous membrane (p). It may be carried out using a membrane distillation unit (DCMD unit).

<Hydrophobic porous membrane (p) of DCMD unit>
The hydrophobic porous membrane (p), which is a membrane for membrane distillation, must pass only the organic solvent vapor and water vapor in the solvent contained in the raw material liquid, but not the raw material liquid itself.
When the ratio of the organic solvent in the solvent of the raw material liquid (a) is high, the surface tension of the raw material liquid (a) is low. Therefore, in this case, the raw material liquid (a) enters the pores of the compositional porous membrane in a liquid state, passes through the hydrophobic porous membrane (p), and flows to the cooling water (f) side. So-called "wetting" may occur. When wetting occurs, the solute in the raw material liquid (a) flows out into the cooling water (f), resulting in a decrease in the recovery rate of the concentrated liquid. In order to avoid this, a highly hydrophobic membrane is preferred as the hydrophobic porous membrane (p).

Water contact angle is used as an index representing the hydrophobicity of the hydrophobic porous membrane (p). In this method, the hydrophobicity of a membrane is evaluated by the contact angle between a water droplet placed on the surface of the membrane and the membrane. From the viewpoint of avoiding wetting of the membrane, the hydrophobic porous membrane (p) used in the second treatment in the first step of the raw material liquid concentration method of the present invention has a surface water contact angle of 90° or more. The angle is preferably 100°, and even more preferably 110° or more.
In the second treatment of the present invention, when using a hydrophobic porous membrane (p) in the form of a hollow fiber membrane, it is preferable that the raw material liquid (a) is allowed to flow within the inner space of the hollow fiber membrane. Therefore, it is preferable that at least the inner surface of the hollow fiber membrane-like hydrophobic porous membrane (p) exhibits the water contact angle described above.
Moreover, in this case, it is preferable that the outer surface of the hollow fiber membrane in contact with the cooling water (f) also exhibits the above-mentioned water contact angle.

Preferably, the hydrophobic porous membrane in this embodiment has pores with an average pore diameter of 0.02 μm or more and 0.5 μm or less, and a porosity of 60% or more and 90% or less.
From the viewpoint of obtaining high vapor permeability, the porosity of the hydrophobic porous membrane (p) is preferably 60% or more, more preferably 70% or more. On the other hand, the porosity of the hydrophobic porous membrane (p) is preferably 90% or less, in order to maintain the strength of the membrane itself well and prevent problems such as breakage during long-term use. More preferably, it is 85% or less.

The materials constituting the hydrophobic porous membrane (p) include polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene/tetrafluoroethylene copolymer, polychlorotrifluoroethylene, etc. At least one resin selected from the group consisting of: When such a material is used, a membrane having desired porosity can be easily obtained.
Furthermore, in order to increase the hydrophobicity of the membrane, the hydrophobic porous membrane (p) may be coated with a hydrophobic polymer. The hydrophobic polymer may be attached to a portion of the membrane surface or may be attached to the entire membrane.

The hydrophobic polymer is preferably a polymer having a fluorine atom-containing group in its side chain. Such a polymer is preferably a polymer having at least one type of side chain selected from a (per)fluoroalkyl group, a (per)fluoropolyether group, an alkylsilyl group, and a fluorosilyl group. By attaching the above hydrophobic polymer to the hydrophobic porous membrane (p), the hydrophobicity of the hydrophobic porous membrane (p) can be further improved. As a result, even when a raw material liquid with a high organic solvent concentration is used, the hydrophobic porous membrane (p) can be stably operated for a long time without wetting.

In this embodiment, any of a hollow fiber membrane, a tubular membrane, and a flat membrane can be applied as the hydrophobic porous membrane (p).

When using a hollow fiber-like hydrophobic porous membrane (p), the thickness of the hydrophobic porous membrane (p) should be 10 μm or more from the viewpoint of achieving both vapor permeability and mechanical strength of the membrane. ,000 μm or less, and more preferably 20 μm or more and 500 μm or less. If the film thickness is 1,000 μm or less, high vapor permeability can be obtained, and if the film thickness is 10 μm or more, the film can be used for a long period of time without deforming.
The outer diameter of the hollow fiber hydrophobic porous membrane (p) is preferably 300 μm or more and 5,000 μm or less, more preferably 350 μm or more and 4,000 μm or less, and the inner diameter is preferably 200 μm or more and 4,000 μm or less. , more preferably 250 μm or more and 1,500 μm or less.
When the hydrophobic porous membrane (p) is a hollow fiber membrane having a size within this range, a good balance between membrane strength and effective area of the membrane is achieved.

The membrane distillation membrane unit used in the second treatment is preferably in the form of a membrane distillation membrane module configured by housing a plurality of hydrophobic porous membrane (p) yarn bundles in a suitable housing. It is preferable to use one.

<Temperature of raw material liquid (a), induction solution (d), and cooling water (f)>
In the first treatment of the first step, the temperature of the raw material liquid (a) introduced into the raw material liquid side space (R) of the forward osmosis membrane unit is not particularly limited, but is preferably 3°C or more and 60°C or less. The temperature is more preferably 5°C or higher and 50°C or lower. If the temperature of the raw material liquid (a) is less than 3°C, the vapor pressure of the organic solvent or water contained in the solvent of the raw material liquid may become too low, and the permeation flow rate may become slow; Some of the solutes in (a) may be denatured.
The temperature of the induction solution (d) introduced into the induction solution side space (D) of the forward osmosis membrane unit is not particularly limited, but is preferably 5°C or more and 60°C or less, more preferably 10°C or more and 50°C or less. It is. If the temperature of the inducing solution (d) is less than 5°C, the solubility of the solute in the raw material liquid may decrease and the solute may easily precipitate during the concentration operation. ) may be partially denatured.
The temperature of the cooling water (f) is not particularly limited. However, from the viewpoint of creating an appropriate vapor pressure difference between the raw material liquid (a) and the cooling water (f), the temperature of the cooling water (f) is preferably lower than the temperature of the raw material liquid (a). Therefore, the temperature of the cooling water (f) is preferably 3°C or more and 60°C or less, more preferably 3°C or more and 50°C or less. When the temperature of the cooling water (f) is less than 3° C., there is an increased risk that the cooling water, which is mostly composed of water, will freeze, making stable operation difficult. On the other hand, if the temperature of the cooling water (f) exceeds 60°C, water vapor may move from the cooling water (f) to the raw material liquid (a).

The solute recovery rate was calculated using the following formula.
Recovery rate (%) = (mass of solute contained in pre-concentrated liquid (c)) / (mass of solute contained in raw material liquid (a)) x 100

<Second process>
In the second step in the raw material liquid concentration method of the present invention, the pre-concentrated liquid (c) obtained in the first step is freeze-dried to obtain a further concentrated product (h).
Any known freeze-drying technique may be used for freeze-drying in this system, and typical processes are as described above.

<Solute retention of the raw material liquid concentration method of the present invention>
According to the raw material liquid concentration method of the present invention as described above, a highly concentrated concentrate in which the solvent composition in the raw material liquid (a) is arbitrarily controlled can be efficiently obtained.
The analysis of the components in the obtained concentrate may be appropriately selected depending on the types of components contained in the raw material liquid and its concentrate. For example, various known analysis methods such as ICP-OES (inductively coupled radio frequency plasma optical emission spectrometer), ion chromatography (IC) method, gas chromatography (GC) method, etc. can be used.

《Raw material liquid concentration system》
According to another aspect of the invention, a feed liquid concentration system is provided.
The raw material liquid concentration system of the present invention includes:
A raw material liquid concentration system for removing the solvent from a raw material liquid containing a solute and a solvent to obtain a concentrate of the raw material liquid, comprising:
the solvent contains water and an organic solvent,
The concentration system performs a combination of a first treatment in which the solvent in the raw material liquid is removed by forward osmosis, and a second treatment in which the solvent in the raw material liquid is removed by a membrane distillation method, to a first step of obtaining a preconcentration of the liquid;
and a second step of further removing the solvent from the pre-concentrated liquid by freeze-drying to obtain a product.

For details of each element of the raw material liquid concentration system of the present invention, the above explanation regarding the raw material liquid concentration method of the present invention can be referred to.

EXAMPLES Hereinafter, the present invention will be specifically explained based on Examples, but the present invention is not limited to the Examples below.

《Fabrication of raw material liquid concentration system》
<Preparation of forward osmosis membrane unit>
A polysulfone hollow fiber ultrafiltration membrane having an inner diameter of 0.7 mm and an outer diameter of 1.0 mm was used as the base layer. The above polysulfone membrane was cut into 15 cm long pieces, 130 of them were filled into a cylindrical plastic housing with a diameter of 2 cm and a length of 10 cm, and both ends were fixed with adhesive, so that the effective inner surface area of the membrane was approximately 0.02 m ² hollow fibers. A supported membrane support layer module was produced.
10 g of m-phenylenediamine and 0.8 g of sodium lauryl sulfate were placed in a 0.5 L container, and 489.2 g of pure water was added and dissolved to prepare 0.5 kg of a first solution used for interfacial polymerization.
In another 0.5 L container, 0.8 g of trimesic acid chloride was placed, and 399.2 g of n-hexane was added and dissolved to prepare 0.4 kg of a second solution used for interfacial polymerization.
These solutions are passed through the hollow fiber support layer module in the order of the first solution and the second solution so as to pass through the inside of the hollow fiber membrane, and interfacial polymerization is performed on the inner surface of the hollow fiber. , a separation active layer was formed on the hollow fiber support layer. Thereafter, the inside of the hollow fiber was washed with pure water to produce a forward osmosis membrane module, which was used as a forward osmosis membrane unit.

The amount of water permeated through this forward osmosis membrane unit was measured using pure water as the raw material liquid and 3.5% by mass saline as the induction solution, and found to be 10.12 kg/(m ² ×hr).

<Preparation of membrane unit for membrane distillation>
A PVDF membrane with an inner diameter of 0.7 mm, an outer diameter of 1.3 mm, and an average pore diameter, maximum pore diameter, and porosity of 0.21 μm, 0.29 μm, and 72%, respectively, determined according to ASTM-F316-86. The porous hollow fiber membrane was cut into a length of 15 cm. The 130 fibers were filled into a cylindrical plastic housing with a diameter of 2 cm and a length of 10 cm, and both ends were fixed with adhesive to produce a hollow fiber membrane module.
In Examples 3 and 4, this hollow fiber membrane module was used as it was as a membrane unit for membrane distillation.
In Examples 1 and 2, this hollow fiber membrane module coated with a water repellent as described below was used as a membrane unit for membrane distillation.
The water repellent "FS-1610TH-1.0" manufactured by Fluoro Technology Co., Ltd. is passed through the hollow fiber membrane module described above so as to pass through the inside of the hollow fiber membrane. It was applied to the surface and the membrane wall near the membrane surface. After removing the water repellent from the hollow fiber membrane module, it was dried to create a membrane module for membrane distillation containing the hollow fiber membrane coated with the water repellent. It was used as a membrane unit for distillation.
The effective internal surface area of the hollow fiber membrane in the obtained membrane module was 0.02 m ² both with and without coating of water repellent.

A 3.5% by mass saline solution heated to 65°C was flowed inside the hollow fiber membrane of the membrane distillation unit as a raw material liquid at a flow rate of 300 mL/min, and pure water cooled to 20°C was poured outside the hollow fiber membrane as cooling water. was flowed at a flow rate of 300 mL/min, and the water permeation rate of this membrane unit for membrane distillation was calculated from the increase in the weight of cooling water per certain period of time, and was found to be 20.02 kg/(m ² ×hr).

<freeze drying>
In the second step of freeze-drying, the sample was frozen using a freeze-dryer freezer manufactured by SP Industries (product name: "SP VirTis Freezemobile Shell Bath Freezer"), and then Freeze-drying was performed using

《GC measurement conditions》
Gas chromatography (GC) measurements for calculating the organic solvent concentrations in the pre-concentrated solutions of the following Examples and Comparative Examples were performed under the following conditions.
GC device: Manufactured by Agilent Technologies, model number “7890A”
Column: manufactured by Agilent, product name "J&W DB-5", 30 m x 0.25 mm I. D. ×Liquid phase thickness 0.25μm)
Column heating conditions: Hold at 40°C for 2 minutes, then raise the temperature to 190°C at 10°C/min, then raise the temperature to 250°C at 30°C/min, hold at 250°C for 6 minutes, and finish Carrier Gas: Helium Carrier gas flow rate: 1mL/min
Inlet temperature: 250℃
Interface temperature: 280℃
Split ratio: Splitless Ion source temperature: 230℃
Ionization method: Electron ionization method Ionization voltage: 70eV
Measurement mass range: 10-500

《ICP-OES measurement conditions》
ICP analysis measurements for calculating the solute recovery rates of the following Examples and Comparative Examples were performed under the following conditions.
ICP-OES device: Manufactured by Hitachi High-Tech Science Co., Ltd., model number "SPS6100"
Carrier gas: Argon Repeat measurement time: 30 seconds Stabilization delay time: 20 seconds Pump speed: 8 rpm

<Concentrator 1>
In Examples 1 to 6, concentration was performed using the concentrator 1 having the configuration shown in FIG.
2,000 g of raw material liquid (a) was placed in a stainless steel raw material liquid tank (100). The raw material liquid (a) can be supplied from the bottom of the raw material liquid tank (100) to the forward osmosis membrane unit (200) and the membrane unit for membrane distillation (300), respectively, and the raw material liquid is concentrated by each unit. Piping was installed so that (a) was returned to the bottom of the raw material liquid tank (100). Although the raw material liquid tank (100) is in a closed state, it has a structure in which the pressure inside the tank is maintained at normal pressure even if the raw material liquid (a) decreases. In addition, a pump (P), a flow meter (not shown), and a valve (not shown) for adjusting the flow rate are arranged in the piping from the raw material liquid tank (100) to the forward osmosis membrane unit (200). can be controlled appropriately.
An inlet pipe and an outlet pipe were connected to the side pipe of the forward osmosis membrane unit (200) so that the inducing solution (d) could flow therethrough. The induction solution (d) is stored in an induction solution tank (400), and is passed through a pump (P), a flow meter (not shown), and a valve (not shown) that adjusts the flow rate to a forward osmosis membrane unit ( 200).
In the forward osmosis membrane unit (200), the solvent (b) (water and organic solvent) moves from the raw material liquid (a) to the induction solution (d). Therefore, as the concentration operation continues, the volume of the inducing solution (d) increases. Therefore, the inducing solution tank (400) is provided with an overflow port, and a structure is adopted in which a part of the increased inducing solution (d) is discharged to the outside of the inducing solution tank (400).

A pump (P), a flow meter (not shown), and a valve (not shown) for adjusting the flow rate were arranged in the piping from the raw material liquid tank (100) to the membrane unit for membrane distillation (300). The raw material liquid (a) is supplied to a membrane unit for membrane distillation (300) via a constant temperature device (not shown) and a heat exchanger (not shown) for adjusting the raw material liquid (a) to a constant temperature. The concentrated raw material liquid (a) returns to the raw material liquid tank (100) from the outlet side of the membrane unit for membrane distillation (300).
An inlet pipe and an outlet pipe were connected to the side pipe of the membrane unit for membrane distillation (300) so that cooling water (f) could flow therethrough. Cooling water (f) is stored in a cooling water tank (500), and is passed through a pump (P), a flow meter (not shown), and a valve (not shown) that adjusts the flow rate to a membrane for membrane distillation. unit (300). The cooling water (f) is supplied to the membrane unit for membrane distillation (300) via a constant temperature device (not shown) and a heat exchanger (not shown) for adjusting the cooling water (f) to a constant temperature. be done.
Since the solvent (b) (water and organic solvent) moves from the raw material liquid (a) to the cooling water (f) in the membrane unit for membrane distillation (300), the volume increases as the concentration operation continues. Therefore, the cooling water tank (500) is provided with an overflow port to discharge a portion of the increased cooling water (f) to the outside of the system.

<Concentrator 2>
In Comparative Examples 1, 2, and 6, concentration was performed using the concentrator 2 having the configuration shown in FIG.
2,000 g of raw material liquid (a) was placed in a stainless steel raw material liquid tank (100). The raw material liquid (a) can be supplied from the bottom of the raw material liquid tank (100) to the forward osmosis membrane unit (200), and the raw material liquid (a) concentrated by the forward osmosis membrane unit (200) is transferred to the raw material liquid tank. Piping was assembled so that it returned to the bottom of (100). In the forward osmosis membrane unit (200), the solvent (b) (water and organic solvent) in the raw material liquid (a) is transferred to the inducing solution (d), and the raw material liquid (a) is concentrated.
Moreover, although the raw material liquid tank (100) is in a closed state, it has a structure in which the pressure inside the tank is maintained at normal pressure even if the raw material liquid (a) decreases.

The piping system from the raw material liquid tank (100) to the forward osmosis membrane unit (200) is equipped with a pump (P), a flow meter (not shown), and a valve (not shown) for adjusting the flow rate. can be controlled appropriately.
An inlet pipe and an outlet pipe were connected to the side pipe of the forward osmosis membrane unit (200) so that the inducing solution (d) could flow therethrough. The induction solution (d) is stored in an induction solution tank (400), and is passed through a pump (P), a flow meter (not shown), and a valve (not shown) that adjusts the flow rate to a forward osmosis membrane unit. (200).

[Example 1]
<First step>
In Example 1, the concentrator 1 is used to perform forward osmosis treatment using a forward osmosis membrane module as a forward osmosis membrane unit, and membrane distillation treatment using a hollow fiber membrane module coated with a water repellent as a membrane unit for membrane distillation. The first step was carried out using a combination of the following.
A solution obtained by adding 6.0 g (0.3% by mass) of oxidized glutathione (hereinafter referred to as GSSG) as a solute to a mixed solvent consisting of 1,760 g of water and 240 g of acetonitrile (MeCN) was added to a simulated solution of raw material solution (a). It was filled into the raw material liquid tank (100).
The induction solution tank (400) was filled with 2,000 g of a 50% by mass aqueous isopropyl alcohol solution.
The cooling water tank (500) was filled with 2,000 g of water.
This raw material solution (a) and the induction solution (d) were flowed through the forward osmosis membrane unit (200). The direction of the raw material liquid (a) and the direction of the inducing solution (d) were made to flow in parallel.
On the other hand, the raw material liquid (a) and the cooling water (f) were passed through the membrane unit for membrane distillation (300). The direction of the raw material liquid (a) and the direction of the cooling water (f) were made to flow in parallel.
In the first step, with the above configuration, concentration was performed by a combination of forward osmosis membrane method and membrane distillation method to obtain a pre-concentrated liquid.
As a result of the 8-hour concentration operation, a pre-concentrated liquid (c) with a concentration ratio of 10.3 times was obtained. The mass proportion of the organic solvent in the solvent of this pre-concentrated solution (c) was measured and found to be 7% by mass.
During the first concentration step, the temperature of the raw material liquid was 20 to 25°C, and the temperature of the cooling water was 15°C.
Furthermore, analysis of the pre-concentrated solution (c) confirmed that the recovery rate of GSSG was 99.9% and that GSSG was not denatured.

<Second process>
In the second step, the pre-concentrate liquid (c) obtained in the first step is pre-frozen using the above-mentioned freeze dryer freezer, and then the internal pressure is reduced to 10 Pa or less in the above-mentioned freeze dryer. Freeze-drying was performed under reduced pressure.
After the completion of the first step, the pre-concentrate liquid (c) is transferred to the manifold and the freezing step of the second step is started, and the moisture content of the product (h) after freeze-drying is 3% by mass or less. The end point was the time at which the freeze-drying time was reached. The moisture content was measured using a Karl Fischer moisture measurement system (automatic titrator "MATi10" manufactured by Metrohm AG).
The freeze-drying time of the pre-concentrate solution (c) of Example 1 was 28 hours.
Furthermore, analysis of the product (h) after freeze-drying confirmed that GSSG was not denatured.

[Examples 2 to 4]
In Example 2, the concentration operation consisting of the first step and the second step was carried out in the same manner as in Example 1, except that the solvent composition of the raw material liquid (a) was changed as shown in Table 1. went.
In Examples 3 and 4, the solvent composition of the raw material liquid (a) was changed as shown in Table 1, and a hollow fiber membrane module not coated with a water repellent was used as the membrane unit for membrane distillation. A concentration operation consisting of a first step and a second step was performed in the same manner as in Example 1.
The results are shown in Table 2.

[Example 5 and 6]
In Examples 5 and 6, the solvent composition of the raw material solution (a) was changed as shown in Table 1, and in the first step, only the forward osmosis treatment using the concentrator 1 was performed for 4 hours. After stopping the treatment, only membrane distillation treatment was further performed for 4 hours. In the second step, the pre-concentrate solution (c) was freeze-dried in the same manner as in Example 1.
The results are shown in Table 2.

[Comparative Examples 1 and 2]
In Comparative Examples 1 and 2, the solvent composition of the raw material liquid (a) was changed as shown in Table 1, and the first step was performed only by forward osmosis treatment using the concentrator 2. A concentration operation consisting of a first step and a second step was carried out in the same manner as in Example 1.
The results are shown in Table 2.

<Comparative example 3>
In Comparative Example 3, a concentration operation consisting of a first step and a second step was carried out in the same manner as in Example 1, except that the first step was performed using a reverse osmosis membrane method.
As the reverse osmosis membrane, a low-pressure type reverse osmosis membrane manufactured by Nitto Denko Co., Ltd. (product number "NTR-759HR") was used to concentrate the raw material liquid (a) at an operating pressure of 3.0 MPa.
The results are shown in Table 2.
In the first step of Comparative Example 3, clogging of the reverse osmosis membrane was frequently observed, and the amount of water permeation decreased significantly over time. The water permeation amount at the initial stage of concentration was 3.2 kg/(m ² ×hr), but it decreased to 0.1 kg/(m ² ×hr) after 8 hours.

<Comparative example 4>
In Comparative Example 4, the first step was carried out in the same manner as in Example 1, except that in the first step, a reverse osmosis method was adopted instead of a forward osmosis method, and the reverse osmosis membrane method and membrane distillation method were performed in parallel. A concentration operation consisting of the step 1 and the second step was carried out.
The results are shown in Table 2.

<Comparative example 5>
In Comparative Example 5, a concentration operation consisting of a first step and a second step was carried out in the same manner as in Example 1, except that the first step was performed by vacuum distillation.
The vacuum distillation was performed at 50° C. and 10.0 to 15.0 kPa using a distillation column equipped with a vacuum system.
The results are shown in Table 2.

<Comparative example 6>
In Comparative Example 6, the first step and the second step were carried out in the same manner as in Example 1, except that in the first step, the vacuum distillation method was performed for 4 hours, and then the forward osmosis membrane method was performed for another 4 hours. A concentration operation consisting of the following steps was performed.
The results are shown in Table 2.

<Comparative example 7>
In Comparative Example 7, the pre-concentrated liquid (c) obtained in the first step performed in the same manner as in Example 1 was vacuum-dried. Vacuum drying was performed using a vacuum dryer under the conditions that the temperature inside the chamber was set to 40° C. and the pressure inside the chamber was reduced to 10 Pa or less.
The results are shown in Table 2.

<Comparative example 8>
In Comparative Example 8, a concentration operation consisting of the first step and the second step was performed in the same manner as in Example 7, except that the solvent composition of the raw material liquid (a) was changed as shown in Table 1. .
The results are shown in Table 2.

In Tables 1 and 2, "FO" indicates forward osmosis, "MD" indicates membrane distillation, and "RO" indicates reverse osmosis.

From the above results, in Examples 1 to 6 in which the first and second steps prescribed in the present invention were adopted, high concentration concentration was possible in the first step, and the solute recovery rate was 99.0% or more. In addition, concentration can be controlled to a solvent composition suitable for freeze-drying in the second step.
Therefore, in these Examples, it was verified that the time required for freeze-drying in the second step could be shortened compared to the Comparative Example.
Furthermore, it was verified that denaturation of the final product after the second step could be suppressed by employing freeze-drying in the second step.

100 Raw material liquid tank 200 Forward osmosis membrane unit 300 Membrane distillation membrane unit 400 Deriving solution tank 500 Cooling water tank 600 Freeze-drying unit a Raw material liquid c Preconcentration liquid d Deriving solution e Diluted deriving solution f Cooling water g Aqueous solution h Product o Forward osmosis membrane p Hydrophobic porous membrane D Inducing solution side space R Raw material liquid side space F Cooling water side space

Claims (11)

A method for concentrating a raw material liquid, the method comprising: removing the solvent from a raw material liquid containing a solute and a solvent to obtain a concentrate of the raw material liquid;
the solvent contains water and an organic solvent,
The concentration method includes a first treatment in which the solvent in the raw material liquid is removed by forward osmosis, and a second treatment in which the solvent in the raw material liquid is removed in a membrane distillation method. a first step of obtaining a preconcentration of the liquid;
A method for concentrating a raw material liquid, comprising a second step of further removing the solvent from the pre-concentrated liquid by freeze-drying to obtain a product. In the second treatment, the raw material liquid and cooling water are brought into contact with each other through a hydrophobic porous membrane, and the solvent in the raw material liquid is passed through the hydrophobic porous membrane and transferred into the cooling water. The method for concentrating a raw material liquid according to claim 1, wherein the solvent in the raw material liquid is removed by removing the solvent from the raw material liquid. The hydrophobic porous membrane used in the second treatment is a hollow fiber hydrophobic porous membrane,
The hollow fiber hydrophobic porous membrane is used in the form of a membrane module having a hollow fiber bundle constituted by a plurality of the hollow fiber hydrophobic porous membranes.
The raw material liquid concentration method according to claim 2. 4. The raw material liquid concentration method according to claim 3, wherein a hydrophobic polymer is attached to at least a portion of the hollow fiber hydrophobic porous membrane. 4. The hydrophobic polymer is a polymer having at least one side chain selected from the group consisting of (per)fluoroalkyl group, (per)fluoropolyether group, alkylsilyl group, and fluorosilyl group. The raw material liquid concentration method described in . The material constituting the hydrophobic porous membrane is a group consisting of polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene/tetrafluoroethylene copolymer, and polychlorotrifluoroethylene. The raw material liquid concentration method according to any one of claims 2 to 5, comprising at least one resin selected from the following. 6. The method according to claim 1, wherein the first step includes performing the first treatment and the second treatment in parallel, and mixing the raw material liquids after each treatment. Raw material liquid concentration method. The raw material liquid concentration method according to any one of claims 1 to 5, wherein the first step includes performing the second treatment after performing the first treatment. The raw material liquid concentration method according to any one of claims 1 to 5, wherein the first step includes performing the first treatment after performing the second treatment. The raw material liquid concentration according to any one of claims 1 to 5, wherein the solvent of the raw material liquid is a mixed solvent containing water and one or two selected from the group consisting of acetonitrile and isopropanol. Method. The raw material liquid concentration method according to any one of claims 1 to 5, wherein the solute of the raw material liquid is a pharmaceutical raw material.

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