JPH0115822B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a method for producing a hydrophilic filler for gel permeation chromatography. More specifically, the present invention relates to a method for producing a hydrophilic packing material for gel permeation chromatography, which is made of a crosslinked polyvinyl alcohol gel containing an isocyanurate ring in its skeleton and has controlled pores and sufficient strength. [Prior art] Gel permeation chromatography (hereinafter referred to as GPC) uses a column packed with gel, and components with a molecular size smaller than the pore size in the packing material (hereinafter referred to as gel) are separated according to their size. It is a type of liquid chromatography that utilizes the principle of penetrating into the gel and allowing larger components to pass through the gel, and sequentially separates and elutes components starting with the larger molecular size. GPC is classified into organic solvent type and aqueous solvent type depending on the solvent used during separation or analysis. Among these, aqueous-based gel permeation chromatography has recently attracted attention because it has high utility in biochemistry-related fields, and there is a strong desire to develop gels that can be processed at high speeds. Gel made by cross-linking dextran with epichlorohydrin (trade name: Cephadex, Pharmacia, Sweden) has been known and often used as a gel for water-based GPC. This gel is obtained by crosslinking dextran dissolved in water with epichlorohydrin in a reversed-phase suspension system, and is
W _R ) determines the properties of gels, and a high W _R is said to be an advantage of gels (see Japanese Patent Publication No. 47-21405). However, as can be seen from the manufacturing method and physical properties, this gel is a soft gel whose pores used for separation are made up of a crosslinked network, and its mechanical strength is low, so it could not be used as a gel for high-speed GPC. Next, it is also known that a water-based gel can be obtained by saponifying particles made of a copolymer of vinyl acetate and 1,4-butanediol divinyl ether (Japanese Patent Publication No. 44-20917). reference). However, as acknowledged by W. Heitz, the inventor of the application, this gel has poor copolymerizability of the monomers used for polymerization (W. Heitz. J. Chromatogr. 53
37 (1970)), the resulting gel did not have sufficient strength and could not be put to practical use in high-speed GPC. Furthermore, it is said that a water-based gel with high mechanical strength can be obtained by, for example, saponifying copolymer particles of diethylene glycol dimethacrylate or glycidyl methacrylate with vinyl acetate and crosslinking with epichlorohydrin (Unexamined Japanese Patent Publication No. (See Publication No. 52-138077). However, the gel obtained by this method has functional groups in its skeleton that can be hydrolyzed by the presence of acids or bases such as ester groups or carboxyl groups, or have functional groups that act as adsorbents depending on the components to be separated. So I don't like it. Furthermore, it is also known that polyvinyl alcohol gel can be obtained by saponifying a copolymer of vinyl acetate and a crosslinking agent having a triazine ring structure (see Japanese Patent Laid-Open No. 58203/1983).
According to this method, it is said that the water content (pore size) of the gel can be changed by appropriately combining the amount of crosslinking agent or the type and amount of diluent added during polymerization. However, as described in Japanese Patent Application Laid-open No. 55-58203, this gel was manufactured for the purpose of desalting an aqueous polymer solution, and therefore the gel actually obtained was inorganic. It has small pores that allow only ions to penetrate into the gel, and can be used to separate salts and proteins that have a high molecular weight and cannot penetrate into the gel, but it may separate components with high molecular weight from each other. There is no mention of this. Moreover, since the purpose is to desalinate aqueous polymer solutions, 42
A gel with a large particle size of about 28 meshes (that is, 350 to 590 μm) is sufficient, and there is no description of a gel with a particle size of 50 μm or less, which particularly requires mechanical strength. However, in order to separate and analyze various components with different molecular weights using high-speed GPC, it is necessary to have pores that are strictly controlled according to the molecular size of the components to be separated and sufficient mechanical strength. Gels of small particle size must be used as fillers. [Object of the Invention] In view of the current state of the prior art, the present inventors conducted intensive research to develop a gel for GPC that satisfies the above-mentioned requirements. We have succeeded in developing a gel that has pores of a size that corresponds to the molecular weight of the components to be separated, which is also capable of separating high-molecular weight components, and has sufficient mechanical strength suitable for high-speed GPC. The present invention has now been accomplished. [Structure of the Invention] That is, according to the present invention, a compound having a carboxylic acid vinyl ester and an isocyanurate ring represented by the following formula (a) (However, R ₁ , R ₂ and R ₃ are each independently −
CH ₂ −CH=CH ₂ , −CH ₂ −C≡CH or

In the crosslinked polyvinyl alcohol gel obtained by hydrolyzing a copolymer with [formula]), the amount of carboxylic acid vinyl ester and the compound (a) is adjusted so that the crosslinking degree X is 0.25≦
_{X ≦ 0.4 ( However , _ _ _ _} : Weight of carboxylic acid vinyl ester used in polymerization (g) W ₂ : Weight of compound (a) used in polymerization (g) n ₁ : Number of vinyl groups possessed by one molecule of carboxylic acid vinyl ester) Furthermore, per 100 parts by weight of the monomer, 20 to 200 parts by weight of an organic solvent that dissolves the monomer but is difficult to dissolve in water, and 10 parts by weight of a linear polymer that dissolves in the monomer. A mixture of the following is added to the monomer to carry out suspension copolymerization, and the gel obtained by hydrolysis has the following physical properties (A) to (D): (A) Hydroxyl group density (q _OH ) 10.2≦q _OH ≦11.2meq/g (B) Water retention capacity (W _R ) 0.5≦W _R ≦2.5g/g (C) Specific surface area (S) 5≦S≦1000m ² /g (D) Exclusion limit molecular weight (Mlim) 10 A method for producing a hydrophilic packing material for gel permeation chromatography having ⁴ ≦Mlim≦10 ⁸ is provided. The hydrophilicity of the gel of the present invention is due to hydroxyl groups. The density of hydroxyl groups (hereinafter referred to as q _OH ) should be set in the range of 10.2 to 11.2 meq/g (when X = 0.25) per gel dry weight. At this time, the rate at which ester groups in the gel skeleton were converted to hydroxyl groups due to hydrolysis, that is, the hydrolysis rate was 81
~100%, and even when X is high, it is preferable that the hydrolysis rate is within this range. If q _OH is larger than this range, the mechanical strength of the gel will decrease, while if it is smaller, the hydrophilicity of the gel will decrease and adsorptivity will appear, so both are unfavorable. Note that q _OH can be determined by reacting the gel with acetic anhydride in a pyridine solvent, measuring the amount of acetic anhydride consumed by reacting with the hydroxyl group, or the change in weight of the gel, and calculating from this. When 1 g of dry gel is reacted with 1 mmol of acetic anhydride, q _OH is 1 meq/g. As mentioned above, the gel of the present invention has a water retention capacity (hereinafter referred to as
(referred to as W _R ) must be in the range of 0.5 to 2.5 g/g. W _R is the amount of water that the gel can contain within the particles when the gel is brought into equilibrium with water, expressed as a value per dry weight of the gel. In other words, W _R is
This is a guideline for the amount of pores in the gel that exerts the GPC effect.
As W _R increases, the weight of the part forming the skeleton per unit volume of gel in water, that is, the weight of the gel itself, decreases relatively. Therefore, if W _R is too large, the mechanical strength of the gel decreases in water, making it impossible to increase the flow rate and increasing pressure loss in the packed column. If W _R is too small
The separation performance of the gel decreases because the amount of internal pores that exert GPC action decreases. Therefore, it is extremely important for the physical properties of a water-based high-speed GPC gel that W _R be within an appropriate range. Conventional soft gels have exclusion limit molecular weight (Mlim)
), that is, if the minimum molecular weight of the component that cannot penetrate into the gel particles increases, W _R inevitably increases and mechanical strength decreases. In other words, in the case of a soft gel, in order to increase Mlim, the degree of crosslinking must be lowered and the network expanded, which inevitably resulted in higher W _R and lower mechanical strength. In contrast, the gel of the present invention
W _R is in the range of 0.5 to 2.5 g/g regardless of Mlim, and even gels with high Mlim can be used for high-speed GPC. This is a breakthrough as an aqueous solvent-based gel for high-speed GPC. W _R involves centrifuging the gel that has been equilibrated with distilled water to remove water adhering to the gel surface, then measuring its weight (W ₁ ), and then drying the gel to obtain the dry weight ( W ₂ ) can be obtained using the following formula. From a practical standpoint, the value of W _R =W ₁ −W ₂ /W ₂ W _R is more preferably in the range of 1.0 to 2.5 g/g. As mentioned above, the gel of the present invention has a specific surface area (hereinafter referred to as S) in the dry state of 5 to 1000 m ² /g.
It is necessary to be within the range of . This specific surface area S
is closely related to the structure of the gel. Generally, organic synthetic polymers with a crosslinked structure swell in a solvent that has an affinity for the polymer, and shrink when dried. In the case of a soft gel in which the solvent-filled pores are maintained only by a network of crosslinks during swelling, when the gel dries, the network can no longer maintain its expanded state and collapses, and most of the pores disappear. In this case, the specific surface area is almost only the value on the outside of the particle, so it generally shows a low value of 1 m ² /g or less. On the other hand, in the case of a hard gel with a firm structure of pores, the pores shrink somewhat even when dried, but maintain most of their swollen state, that is, have permanent pores. Therefore, the specific surface area is much higher than that of a soft gel due to the presence of micropores inside the particles. Even if the gel of the present invention has a high Mlim, it has a structure with tight pores, so the specific surface area when dried exhibits a high value. A gel with a specific surface area value smaller than the above range means that it has a homogeneously crosslinked structure (soft gel) with almost no micropores, and is not preferable as a gel for high-speed GPC. From a practical point of view, the specific surface area of the gel of the present invention is 10~
More preferably, it is in the range of 500 m ² /g. Although there are various methods for measuring the specific surface area, in the present invention, it is determined by the most common BET method using nitrogen gas. In addition, the sample used for specific surface area measurement must be sufficiently dry. Since the gel of the present invention is highly hydrophilic and difficult to dry, it is preferable to equilibrate the water-wet gel with acetone and then dry it under reduced pressure at 60°C or lower. The Mlim of the gels of the invention can vary over a wide range. As mentioned above, Mlim is a value representing the lower limit of the molecular weight of molecules that cannot penetrate into the pores of the gel.
For components with molecular weights smaller than this value,
Separation by GPC is possible, but components with a molecular weight larger than this value do not enter the gel pores and exit through the gaps between gel particles, and have almost the same elution volume regardless of molecular weight, so it is difficult to separate them. I can't. Mlim is determined from the GPC calibration curve. A calibration curve is obtained by plotting the measurement data of a sample with a known molecular weight on a graph of a column packed with gel, with the elution volume on the horizontal axis and the logarithm of the molecular weight on the vertical axis. It consists of a line with a continuous negative slope. In the present invention, Mlim is the vertical axis at the intersection of the extension of a line parallel to the vertical axis and the extension of the inclined line of a calibration curve obtained using polyethylene glycol or dextran as a standard substance with a known molecular weight and distilled water as a solvent. expressed as the value of It should be noted that since the only commercially available water-soluble standard polymers have a molecular weight of less than 2 million, it is not possible to obtain a complete calibration curve for gels with Mlim of 2 million or more. Therefore, the Mlim of such a gel cannot be determined accurately, but the extension of the calibration curve up to a molecular weight of 2 million and the extension of the line parallel to the vertical axis of a gel with a low Mlim measured under similar conditions can be calculated. Estimate the value of Mlim from the intersection. The gel of the present invention has a wide range of values from 10 ⁴ to 10 ⁸ obtained using standard samples of known molecular weights of polyethylene glycol and dextran.
Has Mlim. The average particle size (hereinafter referred to as _W ) of the gel of the present invention is usually in the range of 4 to 200 μm, preferably 4 to 100 μm, and when used as a gel for high-speed GPC, it is in the range of 5 to 50 μm. is even more preferable. _W is measured using a Coulter Counter (Coulter Electronics, Inc., USA) for small particles, or using a microscope or sieve for large particles, and is calculated using the following formula, where ni is the frequency at which the particle size di appears: Desired. _W = Σ(nidi ⁴ )/Σ(nidi ³ ) It is well known that the separation ability of GPC is improved by reducing the particle size of the packing material. However, in order to pass a solvent at a high flow rate through a column filled with a gel of small particle size, the mechanical strength of the gel must be sufficiently large. In the case of conventional soft gels, the liquid passing rate decreased as the particle size decreased, but the gel of the present invention has high mechanical strength and can withstand high flow rates even with the aforementioned small particle size. As described above, the gel of the present invention having the above-mentioned physical properties is produced by combining the vinyl compound (a) having a carboxylic acid vinyl ester and an isocyanurate ring with an organic solvent that dissolves these monomers but is difficult to dissolve in water. , or by carrying out suspension polymerization in the coexistence of a mixture of the organic solvent and a linear polymer dissolved in the monomer, and hydrolyzing the obtained copolymer. The carboxylic acid vinyl ester used in the present invention refers to a compound having one or more polymerizable carboxylic acid vinyl ester groups, such as vinyl acetate, vinyl propionate, vinyl butyrate, vinyl caproate, vinyl pivalate, and adipic acid. It refers to aliphatic carboxylic acid vinyl ester compounds such as divinyl, and aromatic carboxylic acid vinyl ester compounds such as vinyl benzoate and divinyl phthalate.
Among them, vinyl acetate, vinyl propionate, vinyl butyrate,
Vinyl caproate, divinyl adipate, etc. are preferred, and moreover, from the viewpoint of ease of controlling the pore size and pore size distribution,
Particular preference is given to using divinyl adipate alone or in combination with other carboxylic acid vinyl esters. Next, the compound having a triallylisocyanurate ring used in the present invention refers to a compound having the structure (a) below, and is used as a crosslinking agent in the present invention. (However, R ₁ , R ₂ and R ₃ are each independently −
CH ₂ −CH=CH ₂・−CH ₂ −C≡CH or

[Formula] is shown. ) Among them, R ₁ , R ₂ , and R ₃ are all −CH ₂ −CH
Triallylisocyanurate where =CH ₂ is easily available, has good copolymerizability with vinyl esters, and provides excellent physical properties of the resulting gel, so it is preferred. The proportion of the compound having an isocyanurate ring in the monomer should be set so that the degree of crosslinking X is in the range of 0.25≦X≦0.4 (the definition of X is as described above). If the value of crosslinking degree In addition, in the present invention, when carrying out suspension copolymerization of vinyl carboxylate and the compound (a) having an isocyanurate ring, an organic solvent that dissolves the monomer but is difficult to dissolve in water, or the organic solvent and the monomer are used. A mixture of linear polymers that are soluble in the body must be added to the monomer. These organic solvents and linear polymers are used to form permanent pores in the resulting copolymer and to control the pore volume, pore size, or pore size distribution of the pores. Organic solvents that dissolve monomers but are difficult to dissolve in water refer to solvents with a solubility in water of 3 g/100 g of water or less at 20°C, and specifically include toluene, xylene, heptane, octane, and cyclohexane. , n-butyl acetate, iso-butyl acetate, n-hexyl acetate, methyl isobutyl ketone, n-heptanol, etc. The organic solvent is used in an amount of 20 to 200 parts by weight per 100 parts by weight of the monomer.
Used in parts by weight. If the amount is less than this range, the pore volume of the gel becomes too small, resulting in a decrease in separation performance, and if it is too large, the mechanical strength of the gel becomes insufficient, so neither is preferable. Practically speaking, the amount of the organic solvent is preferably in the range of 30 to 150 parts by weight. A linear polymer that dissolves in a monomer is one that dissolves in a monomer.
A linear polymer that dissolves at a concentration of % by weight or more, such as polyvinyl acetate or polystyrene, is 10 parts by weight or less, preferably 0.1 to 10 parts by weight, more preferably 0.1 to 10 parts by weight, based on 100 parts by weight of the monomer. is 0.3~10
Used in parts by weight. By using such a linear polymer in combination with the organic solvent, a gel having a larger pore size, that is, Mlim of 10 ⁴ to 10 ⁸ can be produced. However, if the amount of linear polymer exceeds 10 parts by weight, the mechanical strength of the gel will be insufficient, which is not preferable. The initiator used in the polymerization may be a general radical polymerization initiator used in normal suspension polymerization, such as 2-2'-azobisisobutyronitrile, 2-2'-azobis-(2,4 -dimethylvaleronitrile), and peroxide initiators such as benzoyl peroxide and lauroyl peroxide can be used. When carrying out suspension polymerization, it is best to add a commonly used organic polymer suspension stabilizer such as polyvinyl alcohol or methyl cellulose to the aqueous phase, and if necessary, add a PH buffer such as sodium phosphate. May be used together. By changing the type and amount of the suspension stabilizer or the stirring speed, the particle size of the particulate copolymer obtained by polymerization can be changed. After the granular copolymer obtained by polymerization is extracted to remove the linear polymer, residual monomer, or organic solvent, the resulting copolymer is subjected to a hydrolysis reaction. The hydrolysis reaction refers to a saponification reaction or a transesterification reaction, and is carried out in a known manner using an acid or an alkali in water, alcohol, or a mixture thereof as a solvent. After the hydrolysis reaction, the resulting gel can be classified if necessary and used as a packing material for GPC. The gel of the present invention has the characteristics that even if it has a large Mlim, the W _R is appropriately small and the specific surface area in the dry state is high. From these characteristics, it is clear that the gel of the present invention is a hard gel with so-called permanent pores, with little change in pore structure between wet and dry states. Therefore, compared to soft gels, the mechanical strength of the gel is greater regardless of the size of Mlim, and even when the particle size is reduced, the solvent can be passed through a gel-packed column at a high flow rate. In general, in chromatography, the smaller the packing material, the better the separation performance tends to be. By reducing the particle size of the gel of the present invention, high separation performance can be achieved, and since the gel can be passed through at a high flow rate, the separation time can be significantly shortened. Such excellent properties of the gel of the present invention are due to the fact that the amounts of the vinyl compound having an isocyanurate ring and the organic solvent and linear polymer added to the monomer mixture are within the above-mentioned ranges during the production of the gel. sometimes obtained. Even if any of the ranges is not satisfied, the gel of the present invention cannot be obtained. For example, the gels produced according to the examples of JP-A-55-58203 mentioned above (see Comparative Examples below) do not have permanent pores and therefore have almost no specific surface area. In other words, it has a soft gel-like structure with low mechanical strength, so if a gel with a small average particle size of around 10 μm is used, the rate of solvent passage through the packed column will be slow and it cannot be used as a gel for high-speed GPC. . Furthermore, it is clear that the gel obtained in the comparative example has a low Mlim and is unsuitable for separating high molecular weight components from each other, although it can desalt an aqueous polymer solution. Furthermore, since the gel of the present invention has a hydroxyl group as a hydrophilic group in its skeleton, it does not show adsorption to most components that are solvated in water. Therefore, in the separation and analysis of water-soluble synthetic polymers, polysaccharides, proteins, etc., a calibration curve in which the relationship between elution volume and logarithm of molecular weight is almost a straight line or a smooth curve can be obtained. Furthermore, the pore size of the gel can be controlled depending on the molecular size of the component to be separated. Therefore, it has become possible to use it not only for desalting aqueous polymer solutions, but also for the short-time separation and analysis of water-soluble synthetic polymers, polysaccharides, or proteins having a wide range of molecular weights by high-speed GPC. Examples of the present invention will be described below together with comparative examples, but it goes without saying that the technical scope of the present invention is not limited to these Examples. Example 1 A homogeneous mixture consisting of 100 g of vinyl acetate, 32 g of triallyl isocyanurate (X = 0.25), 99 g of butyl acetate, 6.6 g of polyvinyl acetate (degree of polymerization 500), and 2.6 g of 2,2'-azobisisobutyronitrile. Aqueous solution 1 containing 2% of polyvinyl alcohol (polymerization degree 500, saponification rate 89%) was placed in two flasks and heated at 65°C for 18 hours with stirring, and then at 75°C for 5 hours.
Suspension polymerization was carried out by heating for a period of time to obtain a particulate copolymer. After filtration, washing with water, and extraction with acetone, in a solution consisting of 47 g of caustic soda and 2 methanol.
Hydrolysis reaction of the copolymer was carried out at 40°C for 20 hours. The obtained particles were subjected to sedimentation classification in water to obtain a crosslinked polyvinyl alcohol gel having an average particle size ( _W ) of 14.2 μm. A certain amount of the dried gel was reacted in a pyridine-acetic anhydride solution at 105°C, and the hydroxyl group density (q _OH ) was determined from the change in weight of the gel before and after the reaction, and was found to be 11.2 meq/g. In addition, after putting the gel in equilibrium with water into a glass filter and centrifugally dehydrating it at 3000 rpm, weigh a certain amount of the gel at the top of the glass filter, dry the gel, weigh it again, and determine the water retention amount of the gel from the weight change before and after. (W _R ) was determined to be 1.80 g/g. Further, the specific surface area of the dried gel was determined by BET method using nitrogen gas and was found to be 65 m ² /g. When this gel was packed into a stainless steel column with an inner diameter of 7.5 mm and a length of 50 cm and aqueous solutions of dextran and polyethylene glycol were measured, those with larger molecular weights eluted first. The exclusion limit molecular weight of dextran was 1.5×10 ⁶ . In addition, albumin, ovalbumin, and myoglobin were analyzed using a UV detector (280 nm) using an aqueous solution containing 0.075N sodium sulfate and 0.1M sodium phosphate as a solvent.
As a result, the molecules were eluted in descending order of molecular weight and at a high recovery rate. Sample measurement at flow rate 1
The analysis was carried out at a rate of ml/min and was completed within 20 minutes. Example 2 A homogeneous liquid mixture consisting of 100 g of vinyl acetate, 32 g of triallylisocyanurate (X = 0.25), 99 g of butyl acetate, 4.0 g of polyvinyl acetate (degree of polymerization 500), and 2.6 g of 2,2'-azobisisobutyronitrile. was subjected to suspension polymerization in the same manner as in Example 1, and the resulting particles were subjected to a hydrolysis reaction. The physical properties of the obtained gel are
D _W = 15.1 μm, q _OH = 10.8 meq/g, W _R = 1.92
g/g and specific surface area of 42 m ² /g. This gel was packed into a column in the same manner as in Example 1, and Mlim determined for dextran analysis was 8×10 ⁵ . Comparative Example 1 A homogeneous mixed solution consisting of 90 g of vinyl acetate, 4.5 g of triallyl isocyanurate (X = 0.017), 60 g of doluene, and 0.9 g of benzoyl peroxide was mixed with polyvinyl alcohol (degree of polymerization 500, saponification rate 89%) 2
% in a flask with 210 g of an aqueous solution containing
Suspension polymerization was carried out at 60°C for 16 hours. The obtained particles were mixed with 50g of caustic soda, 100g of methanol, and 100g of
The saponification reaction was carried out at 60°C in a mixed solution of The physical properties of the obtained gel are _W = 14.8 μm, q _OH = 18.2 meq/
g, W _R =3.31 g/g and a specific surface area of 0.1 m ² /g, indicating that there were almost no pores in the gel when dry. Furthermore, this gel was prepared with an inner diameter of 7.5 as in the present invention.
An attempt was made to fill the stainless steel column with a length of 50 cm and allow water to flow through it, but the pressure rose significantly at a flow rate of about 0.1 ml/min or higher, and it could only be used for analysis at extremely low flow rates. Mlim determined by analyzing an aqueous polyethylene glycol solution was approximately 1000, and when albumin, ovalbumin, and myoglobin were analyzed, all were eluted with almost the same elution volume (table below). This indicates that this gel cannot be used to separate these proteins from each other. Furthermore, it took a long time of 2 to 3 hours to measure each sample.

[Table] Comparative Example 2 A gel was obtained in the same manner as in Comparative Example 1, except that 30 g of toluene was used instead of 60 g in Comparative Example 1. The physical properties of the gel are _W = 14.1μm q _OH =
19.5 meq/g and W _R =2.65 g/g, the specific surface area was almost 0, and this gel also had no pores when dried. The Mlim of this gel was determined in the same manner as in Comparative Example 1 and was found to be approximately 800. As a matter of course, proteins such as albumin were eluted with almost the same elution volume, indicating that this method could not be used to separate proteins from each other.

Claims (1)

[Claims] 1. A compound having a carboxylic acid vinyl ester and an isocyanurate ring represented by the following formula (a) (However, R ₁ , R ₂ and R ₃ are each independently −
CH ₂ -CH=CH ₂ , -CH ₂ -C≡CH or [Formula]) In the crosslinked polyvinyl alcohol gel obtained by hydrolyzing a copolymer with carboxylic acid vinyl ester and the above compound (a) The amount of crosslinking degree X is 0.25≦
_{X ≦ 0.4 ( However , _ _ _ _} : Weight of carboxylic acid vinyl ester used in polymerization (g) W ₂ : Weight of compound (a) used in polymerization (g) n ₁ : Number of vinyl groups possessed by one molecule of carboxylic acid vinyl ester) Furthermore, per 100 parts by weight of the monomer, 20 to 200 parts by weight of an organic solvent that dissolves the monomer but is difficult to dissolve in water, and 10 parts by weight of a linear polymer that dissolves in the monomer. Gel permeation chromatography, characterized in that the gel obtained by adding a mixture of the following to monomers, carrying out suspension copolymerization, and hydrolyzing the mixture has the following physical properties (A) to (D): A method for producing a hydrophilic filler for graffiti. (A) Hydroxyl group density (q _OH ) 10.2≦q _OH ≦11.2meq/g (B) Water retention capacity (W _R )0.5≦W _R ≦2.5g/g (C) Specific surface area (S) 5≦S≦1000m ² /g (D) Exclusion limit molecular weight (Mlim) 10 ⁴ ≦Mlim≦10 ⁸