JP5745230B2 - Vinylpyrrolidone polymer and method for producing the same - Google Patents

Description

  The present invention relates to a vinylpyrrolidone polymer and a method for producing the same.

  Vinylpyrrolidone polymers (for example, polyvinylpyrrolidone) are safe functional polymers in the form of powder or aqueous solution, pharmaceutical additives, cosmetics, medical materials, pharmaceutical and agrochemical intermediates, food additives, photosensitive electronics Widely used in applications such as materials and tackifiers, or in various special industrial applications. Among these, water-soluble vinyl pyrrolidone polymer powder (water-soluble polyvinyl pyrrolidone powder) is used as a binding agent and excipient for pharmaceutical tablets, and as a raw material solution for producing hollow fiber membranes for artificial dialysis. It is widely used as a viscosity adjusting agent for a hollow fiber membrane for artificial dialysis. For example, in Patent Documents 1 to 4, a raw material liquid containing polysulfone or polyethersulfone as a film-forming polymer and polyvinylpyrrolidone as a hydrophilic polymer is extruded from a spinneret, and water is the main component. A method for producing a hollow fiber membrane by immersing and coagulating in a coagulation bath and then winding is disclosed.

  By the way, when the vinylpyrrolidone-based polymer is used as a pharmaceutical additive or a raw material for a hollow fiber membrane for artificial dialysis, a high degree of safety is required, for example, low endotoxin activity. This is because endotoxin exhibits biological activities such as fever, decrease in white blood cells and platelets, bone marrow hemorrhage necrosis, and blood sugar reduction in vivo.

  However, some conventional vinylpyrrolidone polymers have a relatively high endotoxin activity, and therefore, it was necessary to deactivate the endotoxin of the vinylpyrrolidone polymer. At that time, since endotoxin is stable to heat and endotoxin cannot be inactivated by ordinary sterilization treatment, a dry heat method or the like is adopted as a method for inactivating endotoxin.

  The dry heat method is a sterilization method in which microorganisms and proteins are heat-denatured by heating at 160 to 200 ° C. for 30 minutes to 2 hours. According to the regulations of the Japanese Pharmacopoeia, 120 to 160 ° C. If it is 170-180 degreeC for 60 minutes, the process for 30 minutes is considered a normal method if it is 180-190 degreeC. Further, it is said that a dry heat treatment at 250 ° C. for at least 1 hour is necessary for inactivation of endotoxin (Non-patent Document 1). However, when the vinyl pyrrolidone polymer is treated at a high temperature of 250 ° C., there is a problem that the vinyl pyrrolidone polymer is denatured or decomposes to cause significant yellowing.

JP-A-10-121324 JP 2002-239348 A JP 2003-245524 A JP 2006-239576 A

Natsuko Yamada, 9 others, “Disinfectant Text 3rd Edition”, [online], October 2008, Yoshida Pharmaceutical Co., Ltd. [searched December 2, 2009], Internet <URL: http: // www. yoshida-pharm.com/text/index.html>

  The present invention has been made in order to solve the above-described problems, and an object of the present invention is to provide a vinylpyrrolidone polymer having low endotoxin activity and low degree of yellowing.

  As a result of intensive studies, the present inventors have determined that if a monomer containing N-vinyl-2-pyrrolidone is polymerized using a solvent containing water with low endotoxin activity as a reaction solvent, the endotoxin activity is low and yellowing occurs. The present inventors have found that a vinylpyrrolidone-based polymer having a low degree of can be obtained.

  That is, the vinylpyrrolidone-based polymer of the present invention is characterized by having a hue of 30 or less and an endotoxin activity of 1 EU / g or less.

  The present invention provides a method for producing the above vinylpyrrolidone-based polymer, comprising a step of reducing the endotoxin activity of water, and a solvent containing water having a reduced endotoxin activity obtained through the step. And a process for polymerizing a monomer containing -2-pyrrolidone.

  The present invention includes a step of removing insoluble matter from water and a step of sterilizing water from which the insoluble matter obtained through the step has been removed, and the step of reducing the endotoxin activity after the sterilizing step It is a preferred embodiment to do. It is preferable to obtain water having an endotoxin activity of 1 EU / g or less by the step of reducing the endotoxin activity.

  According to the present invention, a vinylpyrrolidone polymer having low endotoxin activity and low yellowing can be provided.

(Vinyl pyrrolidone polymer)
The vinylpyrrolidone polymer of the present invention has low endotoxin activity and low degree of yellowing. Specifically, the vinylpyrrolidone polymer of the present invention has an endotoxin activity of 1 EU / g or less and a hue of 30 or less.

  Further, the vinyl pyrrolidone polymer of the present invention has not only a K value of 25 to 35 (more preferably 27 to 32) but also a 75 to 95 (more preferably 80 to 90). The endotoxin activity and hue are shown.

  Below, the suitable manufacturing method of the vinylpyrrolidone type polymer which shows the said endotoxin activity and hue according to this invention is demonstrated.

(Method for producing vinyl pyrrolidone polymer)
The method for producing a vinylpyrrolidone-based polymer of the present invention comprises a step of reducing the endotoxin activity of water (hereinafter referred to as an endotoxin deactivation step), and a water having a reduced endotoxin activity obtained through the step (hereinafter referred to as deactivation). And a step of polymerizing a monomer containing N-vinyl-2-pyrrolidone in the solvent (hereinafter referred to as a polymerization step). To do.

  According to the production method of the present invention, even if the vinyl pyrrolidone polymer has a large K value (specifically, 75 to 95), the polymer exhibiting the above endotoxin activity and hue maintains high productivity. However, it can be manufactured. The reason is as follows. That is, as a method for obtaining a vinylpyrrolidone polymer having low endotoxin activity, a solution of the vinylpyrrolidone polymer is filtered with a filter having an endotoxin removal ability described later to remove endotoxin in the vinylpyrrolidone polymer. Although a method is also conceived, this solution is not practical because it is highly viscous and may take a long time for filtration or clogging. Further, as described above, when the vinylpyrrolidone polymer is subjected to a dry heat treatment, the vinylpyrrolidone polymer may be altered or decomposed and colored.

  On the other hand, when N-vinyl-2-pyrrolidone is polymerized using deactivated water as a reaction solvent as in the present invention, a solution of the polymer is used to remove endotoxin in the vinylpyrrolidone polymer. Therefore, even when the K value of the vinylpyrrolidone polymer increases and the viscosity of the polymer solution increases, it does not take a long time to filter the solution. In addition, since the endotoxin activity of the vinylpyrrolidone polymer is low, it is not necessary to subject the polymer to a dry heat treatment, so that the vinylpyrrolidone polymer can be prevented from yellowing due to the treatment.

  The detail of each process of the manufacturing method of the vinylpyrrolidone-type polymer of this invention is as follows. In addition, the water used for the manufacturing method of this invention is not specifically limited, For example, purified water, pure water, ultrapure water, distilled water, ion-exchange water etc. are mentioned.

<Endotoxin deactivation process>
The method for reducing the endotoxin activity of water is not particularly limited. For example, a method for removing endotoxin from water by filtering water with a filter having an ability to remove endotoxin (hereinafter referred to as an endotoxin removal filter) Examples thereof include a method of inactivating endotoxin in water by irradiating water such as electron beam or gamma ray to water, or subjecting water to dry heat treatment. These methods may be performed alone or in combination. When a large amount of inactivated water is required, it is preferable to adopt a method of filtering water with a filter for removing endotoxin.

  When an endotoxin removal filter is used in this step, the material of the filter is not particularly limited as long as it does not cause corrosion, dissolution, or alteration due to water. For example, in addition to polytetrafluoroethylene (PTFE) and metal, cellulose acetate, cellulose nitrate, polyethersulfone, polypropylene, and polyamide filters can be used.

  The pore diameter of the endotoxin removal filter is not particularly limited as long as endotoxin can be removed (adsorption removal), and the upper limit thereof may be 2 μm (more preferably 1 μm, and even more preferably 0.5 μm). Further, the lower limit of the pore diameter is not particularly limited, but a polyamide filter having a pore diameter of 0.2 μm and a cellulose acetate filter having a pore diameter of 0.45 μm are commercially available, and these pore diameters are easy to obtain. Is preferably the lower limit.

  When an endotoxin removal filter is used in this step, two or more filters having different materials and pore sizes may be used in combination.

  The deactivated water obtained in this step preferably has an endotoxin activity of 1 EU / g or less (more preferably 0.5 EU / g or less, and even more preferably 0.2 EU / g or less). Thereby, it becomes easy to suppress the endotoxin activity of the vinylpyrrolidone polymer obtained by polymerizing N-vinyl-2-pyrrolidone or the like in a solvent containing water to 1 EU / g or less.

<Water storage process>
In the present invention, the endotoxin deactivation step may be performed every time the polymerization step is performed to prepare deactivated water. However, this may require time and effort to produce the vinylpyrrolidone polymer. Therefore, the present invention may include a step of temporarily storing the deactivated water obtained through the endotoxin deactivation step in a storage tank or the like, and the polymerization step may be performed using the stored deactivation water. By storing the deactivated water, the reaction solvent (deactivated water) can be quickly supplied during the polymerization step, so that the production efficiency of the vinylpyrrolidone polymer is improved.

  In addition, in this invention, when performing a superposition | polymerization process using the stored deactivation water, it is preferable that the said endotoxin deactivation process is again performed to the said deactivation water. This is because when the deactivated water is supplied to the polymerization process by using the air such as outside air, the fungi and endotoxin in the air may be mixed into the deactivated water. .

<Insoluble matter removal process>
In the present invention, it is preferable to remove insoluble matters from water before the endotoxin deactivation step. Distilled water, ion-exchanged water, and the like contain various insoluble materials such as scales and fungi. When water containing such insoluble materials is used as a reaction solvent, a vinylpyrrolidone polymer is obtained. An insoluble matter will also be contained in the polymer obtained. In addition, when endotoxin deactivation treatment using an endotoxin removal filter is performed on water containing insoluble matter, the endotoxin removal filter is easily clogged. On the other hand, the occurrence of the above problem can be avoided by performing the insoluble matter removing step.

  The method for removing the insoluble matter from the water is not particularly limited, and examples thereof include a porous filter having a pore size smaller than that of the insoluble matter and a method of filtering water using a filter having an adsorption ability for the insoluble matter. It is done. These insoluble matter removing filters may be used alone or in combination.

  The material for the insoluble matter removing filter may be the same as the endotoxin removing filter. In the case of using a porous filter, the pore size of the filter is preferably 50 μm or less (more preferably 30 μm or less, and further preferably 20 μm or less). If the pore diameter exceeds 50 μm, insoluble matter in water may not be removed. The lower limit of the pore diameter is not particularly limited, but is preferably 1 μm (more preferably 1.5 μm, still more preferably 2 μm). If the pore size is smaller than 1 μm, the water filtration rate may be slow. Also in this step, two or more types of filters having different materials and pore diameters may be used in combination.

  As a preferable embodiment of this step, there is a method in which water is first filtered using a porous filter having a pore size smaller than that of the insoluble material, and then filtered using a filter having an adsorption ability for the insoluble material.

<Sterilization process>
In the present invention, it is preferable to sterilize the water after the insoluble matter removing step. Even if the insoluble matter removal step does not completely remove fungi in water, a polymer obtained by producing a vinylpyrrolidone polymer using water as a reaction solvent in which such fungi are insufficiently removed May contain fungi.

  The method for sterilizing water is not particularly limited, and may be performed by a conventionally known method. Examples thereof include deoxygenation treatment, radiation irradiation, and boiling treatment. These sterilization methods may be performed alone or in combination of two or more.

  Endotoxin is also referred to as endotoxin, and is released when a bacterium dies and lyses, is mechanically destroyed, or divides. For this reason, endotoxin may be liberated in water by the sterilization process, and the endotoxin activity of the resulting polymer may be increased. However, this endotoxin is inactivated by the endotoxin deactivation process.

<Solvent>
The present invention is characterized in that a monomer containing N-vinyl-2-pyrrolidone is polymerized in a solvent containing deactivated water obtained through the above steps. With this configuration, it is possible to prevent the endotoxin derived from the solvent from being mixed into the vinyl pyrrolidone polymer, so that a vinyl pyrrolidone polymer having low endotoxin activity can be produced.

  Such a solvent is not particularly limited as long as it can be used as a polymerization reaction solvent such as N-vinyl-2-pyrrolidone and can prevent mixing of endotoxin. A mixed solvent of this deactivated water and a lower alcohol can be mentioned. Examples of the lower alcohol include methyl alcohol, ethyl alcohol, isopropyl alcohol, diethylene glycol and the like. It is preferable that the content of the lower alcohol in the mixed solvent does not exceed 50% by mass.

<Polymerization process>
A method for polymerizing a monomer containing N-vinyl-2-pyrrolidone is not particularly limited. For example, an azo compound and / or a monomer solution obtained by adding a monomer to a solvent may be used. Or the method of superposing | polymerizing by adding an organic peroxide, the method of superposing | polymerizing by adding hydrogen peroxide as a polymerization initiator, etc. are mentioned. Moreover, you may add arbitrary chain transfer agents, a pH adjuster, a buffering agent, etc. other than a polymerization initiator as needed.

  The concentration of the polymerization initiator in the polymerization reaction may be appropriately adjusted according to the amount of the monomer component used, and is not particularly limited. For example, the concentration is 0.001 with respect to 100 parts by mass of the monomer. It is preferably no less than part by mass (more preferably no less than 0.005 part by mass, and even more preferably no less than 0.01 part by mass). It is preferable.

<Amount of monomer in monomer solution>
The amount of the monomer added to the solvent is preferably 5 parts by mass or more (more preferably 10 parts by mass or more, more preferably 15 parts by mass or more), and 150 parts by mass or less (more preferably) with respect to 100 parts by mass of the solvent. 120 parts by mass or less, more preferably 110 parts by mass or less.

<Other monomers>
In the present invention, the polymerization step may be performed using only N-vinyl-2-pyrrolidone as the monomer component, but the polymerization step may be performed using other monomer components in combination. Examples of such other monomers include (meth) acrylic acid, maleic acid, acrylamide-2-methylpropane sulfonic acid, vinyl sulfonic acid, allyl sulfonic acid, and salts thereof, divinylbenzene, and polyethylene glycol di (meth) ) Multifunctional monomers such as acrylate, (meth) acrylic acid ester, maleic acid ester, (meth) acrylamide, N-vinylacetamide, N-vinylformamide, N-vinylimidazole, vinylpyridine, alkyl vinyl ether, acrylonitrile, Examples thereof include one or more monomers selected from the group of styrene, vinyl acetate, allyl alcohol, olefins and the like. Note that (meth) acrylic acid esters include alkyl esters having 1 to 20 carbon atoms, dimethylaminomethylalkyl esters, quaternary salts thereof, hydroxyalkyl esters, and the like. The content of these other monomers is preferably from 0 to 50 mol%, more preferably from 0 to 20 mol%, more preferably from 0 to 10 mol, based on the entire structural unit constituting the polymer. % Is more preferable.

<PH adjustment step before polymerization>
In the present invention, when performing the polymerization reaction, a pH adjuster may be added to the monomer solution before polymerization to adjust the pH of the monomer solution. This is to prevent the monomer (N-vinyl-2-pyrrolidone) from being hydrolyzed.

As the pH adjuster used in this step, a known compound can be used. For example, amine compounds such as primary amines, secondary amines, tertiary amines; NaOH, KOH, Ca (OH) ₂ And alkali (earth) metal hydroxides such as Na ₂ CO ₃ and carbonates such as guanidine carbonate. These pH adjusters may be used alone or in combination of two or more. Of these pH adjusters, secondary amines are preferred.

  The pH adjuster may be added as it is or as an aqueous solution. In the case of an aqueous solution, it is preferable to use deactivated water.

  In this step, the pH of the monomer solution before polymerization is preferably 7 or more, and preferably 10 or less (more preferably 9 or less).

  Secondary amines that can be used to adjust the pH include, for example, aliphatic secondary amines such as dimethylamine and diethylamine; aliphatic diamines and triamines such as N-ethylethylenediamine and diethylenetriamine; N-methylbenzylamine Aromatic diamines such as N-methylethanolamine, N-ethylethanolamine and the like; dialkanolamines such as diethanolamine and dipropanolamine; cyclic amines such as pyrrolidine, piperidine, piperazine, N-methylpiperazine and morpholine And so on. These secondary amines may be used alone or in combination of two or more. Of these secondary amines, dialkanolamines and dialkylamines are preferred, dialkanolamines are more preferred, and diethanolamines are particularly preferred.

<Polymerization initiator: azo compound and / or organic peroxide>
When adding an azo compound and / or organic peroxide as a polymerization initiator to a monomer solution (including a pH-adjusted monomer solution; the same applies hereinafter), nitrogen gas is blown into the monomer solution in advance, The oxygen concentration in the monomer solution may be adjusted to preferably 1 ppm (volume basis) or less, more preferably 0.5 ppm (more preferably 0.2 ppm) or less. In addition, the monomer solution is preferably 40 ° C. or higher (more preferably 50 ° C. or higher, more preferably 60 ° C. or higher), preferably 100 ° C. or lower (more preferably 90 ° C. or lower, more preferably 80 ° C. or lower). It may be heated. Thereby, a polymerization reaction can be advanced rapidly.

  Examples of the azo compound that can be used as a polymerization initiator include 2,2′-azobis (isobutyronitrile), 2,2′-azobis (2-methylbutyronitrile), 2,2′-azobis (2 , 4-dimethylvaleronitrile). These azo compounds may be used alone or in combination of two or more. The azo compound used as a polymerization initiator may be added as it is, or may be added as an aqueous solution. In the case of an aqueous solution, it is preferable to use deactivated water.

  Examples of the organic peroxide that can be used as the polymerization initiator include benzoyl peroxide, cumene hydroperoxide, dicumyl peroxide, and t-butyl hydroperoxide. These organic peroxides may be used alone or in combination of two or more. The organic peroxide used as a polymerization initiator may be added as it is, or may be added as an alcohol solution.

  Moreover, you may start superposition | polymerization with the redox type | system | group polymerization initiator which uses said organic peroxide and a reducing agent together.

  Examples of the reducing agent include low valences such as iron (II), tin (II), titanium (III), chromium (II), V (II), Cu (II), and the like represented by mole salts. Salts of metals in the state; amine compounds such as monoethanolamine, diethanolamine, triethanolamine, hydroxylamine, hydroxylamine hydrochloride, hydrazine and their salts; alkali metal sulfites such as sodium sulfite and sodium bisulfite; Lower oxides such as phosphoric acid and sodium hypophosphite and salts thereof; Invert sugars such as D-fructose and D-glucose; L-ascorbic acid (salt), L-ascorbic acid ester, erythorbic acid (salt), erythorbine Acid ester; and the like.

  The mixing ratio (mass ratio) of the organic peroxide and the reducing agent is not particularly limited and may be appropriately selected depending on the molecular weight of the polymer, but is preferably 10: 1 to 100: 1.

  Specific examples of the combination of the organic peroxide and the reducing agent include, for example, a combination of benzoyl peroxide and an amine, and a combination of cumene hydroperoxide and a metal compound such as iron (II) or Cu (II).

<Polymerization initiator: hydrogen peroxide>
When hydrogen peroxide is used as a polymerization initiator in the monomer solution, a metal catalyst may be added to the monomer solution in advance, and ammonia or a secondary amine may be added as a promoter.

  Hydrogen peroxide used as a polymerization initiator may be added as it is or as an aqueous solution. In the case of an aqueous solution, it is preferable to use deactivated water.

  The metal catalyst is not particularly limited as long as it is a conventionally known metal catalyst used for polymerization of N-vinyl-2-pyrrolidone. Specific examples include heavy metal salts such as copper sulfate (II), copper chloride (II), and copper acetate (II). The addition amount of the metal catalyst may be appropriately adjusted according to the charged amount of N-vinyl-2-pyrrolidone, and is not particularly limited, but with respect to N-vinyl-2-pyrrolidone, by mass ratio, The lower limit is preferably 50 ppb (mass basis), and the upper limit is preferably 600 ppb.

  Ammonia used as a cocatalyst may be added as it is or as an aqueous solution. In the case of an aqueous solution, it is preferable to use deactivated water. The addition amount of ammonia is preferably adjusted as appropriate so that the final vinyl pyrrolidone-based polymer has an ammonia content of 50 to 4000 ppm (mass basis).

  When a secondary amine is used as a cocatalyst in addition to ammonia, the secondary amine may be added as it is or may be added as an aqueous solution. In the case of an aqueous solution, it is preferable to use deactivated water. As the secondary amine used as the cocatalyst, those listed when the pH adjusting agent is described can be used. The amount of secondary amine added is such that the final amine content of the vinylpyrrolidone polymer finally obtained is 500 ppm (mass basis) or more (more preferably 1000 ppm or more), 5000 ppm or less (more preferably 4000 ppm or less). It is preferable to adjust as appropriate.

<Polymerization temperature>
What is necessary is just to set suitably the reaction temperature in a polymerization reaction according to kinds, such as a reaction raw material, Preferably it is 40 to 100 degreeC, More preferably, it is 50 to 95 degreeC, More preferably, it is 60 to 90 degreeC.

<PH adjustment step during polymerization>
In the present invention, a secondary amine or an aqueous solution thereof may be added to the reaction solution to adjust the pH to a predetermined value at an appropriate stage from the start to the end of the polymerization reaction. This is to prevent the monomer (N-vinyl-2-pyrrolidone) from being hydrolyzed. Further, by using a secondary amine, it is possible to suppress insolubilization of a part of the polymer when the obtained polymer solution is dried.

  As the secondary amine that can be used for adjusting the pH of the reaction solution during the polymerization, the secondary amines listed as those that can be used as a pH adjusting agent in the pH adjusting step before the polymerization can be used. The secondary amine added to adjust the pH of the reaction solution during the polymerization may be the same as or different from the secondary amine added to adjust the pH of the aqueous monomer solution. .

  The use amount of the pH adjuster may be appropriately adjusted according to the use amount of the monomer, and is not particularly limited. For example, the pH of the reaction solution is preferably 7 or more, preferably 10 or less (more Preferably, it should be 9 or less.

<Monomer reduction process by addition of acid>
In the present invention, it is preferable to add an acid or an aqueous solution thereof to the polymer solution after the polymerization reaction. At this time, it is preferable to carry out the reaction while maintaining the reaction temperature during the polymerization reaction. As a result, the monomer (N-vinyl-2-pyrrolidone) is hydrolyzed with an acid to reduce the amount of the unreacted monomer (that is, the residual amount of the monomer in the polymer solution). it can.

  Examples of acids that can be used to reduce the amount of unreacted monomers include inorganic acids such as hydrochloric acid; low-boiling organic acids such as formic acid and acetic acid; oxalic acid, malonic acid, succinic acid, aspartic acid, citric acid, and the like. Examples thereof include high boiling point organic acids such as acid, glutamic acid, fumaric acid, malic acid, maleic acid, phthalic acid, trimellitic acid and pyromellitic acid, and these may be used alone or in combination of two or more. Preferred is a high boiling polyvalent carboxylic acid having a boiling point (for example, 100 ° C. or higher) higher than the polymer solution temperature at the time of addition, and malonic acid is particularly preferred. In addition, in this invention, when adding the aqueous solution of an acid to a polymer solution, it is preferable to use a deactivation water.

  The amount of acid used may be appropriately adjusted according to the amount of monomer used during the polymerization reaction, and is not particularly limited. For example, the pH of the reaction solution after polymerization is 5 or less (more preferably 4 or less), preferably 3 or more.

<PH adjustment step after polymerization>
In the present invention, after the unreacted N-vinyl-2-pyrrolidone is hydrolyzed with an acid, a secondary amine or an aqueous solution thereof is added to the polymer solution after polymerization to adjust the pH of the polymer solution to a predetermined value. It is preferable to adjust the value. Thereby, the temporal stability of the polymer in the polymer solution can be enhanced. In addition, when a secondary amine is used, the polymer solution is dried when the obtained polymer solution is dried while preventing a part of the polymer from being insolubilized during neutralization (when the secondary amine is added). It can suppress that a part of becomes insoluble. At this time, it is preferable to carry out the reaction while maintaining the reaction temperature during the polymerization reaction (or during the acid addition).

  As the secondary amine that can be used for adjusting the pH of the polymer solution after the polymerization, secondary amines listed as those that can be used as a pH adjusting agent in the pH adjusting step before the polymerization can be used. The secondary amine added to adjust the pH of the polymer solution after polymerization is a secondary amine added to adjust the pH of the monomer aqueous solution, and the pH of the reaction solution is adjusted during the polymerization. It may be the same as or different from the secondary amine to be added.

  The amount of secondary amine used in this step may be appropriately adjusted according to the amount of acid used, and is not particularly limited. For example, the pH of the polymer solution is preferably 4 or more (more preferably 5 or more) and 7 or less.

<Insoluble matter removal step in vinylpyrrolidone polymer solution>
In the present invention, it is preferable to remove insolubles from the solution of the vinylpyrrolidone polymer obtained through the above-described steps. Later, when the vinylpyrrolidone polymer of the present invention is used for hollow fiber membranes or membrane filter applications, the amount of insoluble matter filtered off by the filter is reduced when the raw material solution in which the polymer is dissolved is filtered and purified. Therefore, the frequency of filter replacement can be suppressed. As a result, productivity of the hollow fiber membrane and the like can be improved.

  Examples of the method for removing insoluble substances include a method of passing a solution of a vinylpyrrolidone polymer through a filter having a pore size of 20 to 100 μm.

  The material of the filter used in this step is not particularly limited as long as it does not cause corrosion, dissolution, or alteration due to the polymer, and examples thereof include polytetrafluoroethylene (PTFE) and metal filters.

  In this step, two or more types of filters having different materials and pore diameters may be used in combination.

<Drying process>
In the present invention, the vinylpyrrolidone polymer solution obtained by the above production method may be dried and then pulverized to obtain a vinylpyrrolidone polymer powder.

  The method for drying the vinylpyrrolidone polymer solution may be a conventionally known method, and is not particularly limited. Examples thereof include a spray dryer drying method and a drum dryer drying method. Conditions such as drying temperature and time may be appropriately adjusted according to the amount of the vinylpyrrolidone polymer solution to be dried, and are not particularly limited. For example, the temperature is preferably 100 ° C. or more (more preferably 120 ° C. or higher), preferably 160 ° C. or lower (more preferably 150 ° C. or lower), preferably within 1 hour, more preferably within 30 minutes, and even more preferably within 10 minutes.

  The method for pulverizing the dried vinylpyrrolidone polymer may be a conventionally known method, and is not particularly limited. For example, a dry coarse pulverization method using a pin mill, a hammer mill or the like; a jet mill, a roller mill And dry fine pulverization using a ball mill, micron mill, etc. The pulverization conditions are not particularly limited, and may be set as appropriate so as to obtain a desired particle size according to the use of the powder.

  In addition, when employ | adopting the spray dryer drying method as a drying method, even if a grinding | pulverization process is abbreviate | omitted, it can be set as vinylpyrrolidone type polymer powder.

  Here, the vinylpyrrolidone-based polymer powder may be in the form of, for example, granules, granules, spheres, lumps, scales, and amorphous. In addition, the size of the vinylpyrrolidone polymer powder may be appropriately adjusted according to the use of the powder, and is not particularly limited. However, the average particle size is not limited in terms of workability and solubility. Is preferably 10 μm or more and 3,000 μm or less, more preferably 50 μm or more and 1,000 μm or less, and further preferably 80 μm or more and 800 μm or less. Here, the “average particle size” is a numerical value measured by a method described later.

<Outside air fungus removal process>
In the present invention, it is preferable that at least the drying step (preferably the step after the polymerization step) is performed in an environment that does not come into contact with untreated outside air (that is, outside air that has not been subjected to fungal removal treatment). Thereby, it can prevent that fungi mix in a vinylpyrrolidone polymer from outside air during a manufacturing process. Moreover, since endotoxin is encapsulated in fungi, by preventing the contamination of fungi, the endotoxin derived from the fungi can also be prevented as a result.

  As a method for carrying out the present invention in an environment that does not come into contact with untreated outside air, for example, in the outside air from which fungi have been removed (hereinafter referred to as fungus-removed outside air), the above-described steps according to the present invention are performed, A method in which the fungus-removed outside air is filled also between the above steps is mentioned.

  The method for removing fungi from the outside air is not particularly limited, and the outside air can be converted into a MEPA (Medium Efficiency Particulate Air) filter, a HEPA (High Efficiency Particulate Air) filter, and an ULPA (Ultra Low Penetration Filter). The method of passing is mentioned.

  In the present invention, when the drying step is carried out in an environment that does not come into contact with untreated outside air, the generated exhaust gas (water vapor) has a reduced endotoxin activity. It may be reused in the manufacturing process. This makes it possible to keep the manufacturing cost of the vinylpyrrolidone polymer low.

(Use)
The vinylpyrrolidone-based polymer of the present invention is used for, for example, cosmetics, medical and agrochemical intermediates, food additives, photosensitive electronic materials, tackifiers, and various special industrial applications (for example, hollow fiber membranes and It can be used for production of membrane filters. In particular, since endotoxin activity is low, it is suitable for the production of hollow fiber membranes and membrane filters.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention. In the following examples and comparative examples, “parts” and “%” mean parts by mass and mass%, respectively.

  First, endotoxin activity, hue, K value, solid content, average particle diameter, residual N-vinyl-2-pyrrolidone amount of vinylpyrrolidone polymer powder; concentration of vinylpyrrolidone polymer solution, K value, hue; And each measuring method of the endotoxin activity of the ion exchange water and the deactivation water used by this invention is demonstrated.

(1) Endotoxin activity of polymer powder The endotoxin activity of vinylpyrrolidone polymer powder was measured according to the method described in the Japanese Pharmacopoeia. Details are as follows.

(Create a calibration curve)
A 1000 EU / mL control endotoxin standard was prepared by adding distilled water for injection to the Japanese Pharmacopoeia endotoxin 1000 standard. This standard is then serially diluted with water for injection to give endotoxin activity of 0 EU / mL, 0.002 EU / mL, 0.003 EU / mL, 0.005 EU / mL, 0.01 EU / mL. Standard samples of 0.1 EU / mL and 1.0 EU / mL were prepared.

  200 μl of each standard sample is added to a lysate reagent (Limulus ES-II single test, manufactured by Wako Pure Chemical Industries, Ltd.), stirred well, and then set on an endotoxin measuring device (ET-2000, manufactured by Wako Pure Chemical Industries, Ltd.). The time until gelation was measured. A double logarithmic calibration curve was prepared with gelation time on the X axis and endotoxin activity on the Y axis.

  The standard sample was set in the endotoxin measuring apparatus within 30 seconds after adding the lysate reagent.

(Measurement of endotoxin activity)
0.1 g of each powder of vinylpyrrolidone polymer obtained in Examples or Comparative Examples was added to 9.9 g of distilled water for injection and dissolved to prepare a vinylpyrrolidone polymer solution.

  After adding 200 μl of the obtained polymer solution to a lysate reagent (Limulus ES-II single test, Wako Pure Chemical Industries, Ltd.) and stirring well, it is set in the endotoxin measuring apparatus and the time until gelation is measured. did. This operation was performed twice, and the average value was defined as the time until gelation of each vinylpyrrolidone polymer.

  In addition, it was set to the endotoxin measuring apparatus within 30 seconds after adding a polymer solution to a lysate reagent.

  The endotoxin activity in the polymer solution is obtained from the calibration curve and the time until the vinyl pyrrolidone polymer is gelled. From the polymer concentration in the polymer solution, the endotoxin activity in the vinyl pyrrolidone polymer powder ( Unit: EU / g) was determined.

(2) Hue of polymer powder The hue of vinylpyrrolidone polymer powder was determined based on the method described in JIS K3331. Details are as follows.

(Preparation of APHA standard solution)
Reagent-grade potassium chloroplatinate (second, K ₂ PtCl ₆ ) 1.245 g (containing 0.5 g as Pt), and reagent-grade cobalt chloride (CoCl ₂ · 6H ₂ O) 1.000 g (0.25 g as Co) And 100 ml of pure water (containing 36%) was added and dissolved by heating. After cooling, pure water was added to make 1000 ml. This stock solution is APHA. No. This corresponds to 500.

The APHA stock solution was diluted with pure water to prepare the following standard solutions.
APHA. No. 5 10 15 20 25 30 35 40 45 50
Stock solution volume (ml) 1 2 3 4 5 6 7 8 9 10

(Measurement of hue)
Using each of the vinylpyrrolidone polymer powders obtained in the examples or comparative examples, solutions having a solid content concentration of 5% were prepared, and then placed on white paper so that they could be visually observed under natural light. Then, the corresponding APHA standard solution was selected by comparing with each APHA standard solution from above and used as the hue of the vinylpyrrolidone polymer powder.

(3) K value of polymer powder The K value was determined by measuring the relative viscosity of a 1% aqueous solution of each powder of vinylpyrrolidone polymer at 25 ° C. with a capillary viscometer, and the viscosity formula of the following Fikencher:

[ _Wherein η _rel is the relative viscosity, c is the concentration of the aqueous solution (g / 100 mL), that is, the number of grams of vinylpyrrolidone polymer contained in 100 mL of the aqueous solution, and k ₀ represents a variable related to the K value]
To by substituting a value obtained by 1,000 times the value of the obtained k ₀ (hereinafter, thus the method for obtaining the K value may be referred to as "Fikentscher method".). The larger the K value, the higher the molecular weight.

(4) Solid content of polymer powder 2 g of polymer powder was quickly put into an aluminum cup whose mass was measured in advance, and precisely weighed to a unit of 0.1 mg. Next, the aluminum cup was housed in a hot air dryer adjusted to 150 ± 5 ° C. and dried for 1 hour, and then the aluminum cup was taken out of the dryer, immediately covered and cooled in a desiccator for 60 minutes. After cooling, it was precisely weighed to the nearest 0.1 mg. The solid content was calculated according to the following formula. The solid content was measured at three points and the average value was taken.
Solid content (%) = (W × 100) / S
[Wherein, W is the mass of polymer powder after drying (g), S is the amount of polymer powder collected (g)]

(5) Average particle diameter of polymer powder Vinylpyrrolidone polymer powder was dispersed in ethyl acetate. Subsequently, the particle size distribution of the obtained dispersion was measured using a laser diffraction particle size distribution analyzer SALD-3000 (manufactured by Shimadzu Corporation). The median diameter of the obtained particle size distribution data was defined as the average particle diameter.

(6) Method for measuring the amount of residual N-vinyl-2-pyrrolidone in polymer powder The amount of N-vinyl-2-pyrrolidone remaining was determined by preparing a 5% aqueous solution of vinylpyrrolidone polymer powder and performing liquid chromatography. The amount of N-vinyl-2-pyrrolidone remaining in the aqueous solution was measured using a graph at an absorption wavelength of 235 nm, and the relative amount of N-vinyl-2-pyrrolidone relative to the content of the vinylpyrrolidone polymer powder was measured. The remaining amount was calculated.

(7) Concentration of aqueous polymer solution 2 g of each aqueous solution of the vinylpyrrolidone polymer obtained in Examples or Comparative Examples was quickly put into an aluminum cup whose mass was measured in advance, and precisely weighed to a unit of 0.1 mg. Next, the aluminum cup was housed in a hot air dryer adjusted to 150 ± 5 ° C. and dried for 1 hour, and then the aluminum cup was taken out of the dryer, immediately covered and cooled in a desiccator for 60 minutes. After cooling, it was precisely weighed to the nearest 0.1 mg. The concentration was calculated according to the following formula. In addition, the density | concentration measured 3 points | pieces and took the average value.
Concentration of polymer aqueous solution (%) = (W × 100) / S
[Wherein, W is the mass of the polymer after drying (g), and S is the amount of polymer aqueous solution collected (g)].

(8) K value of aqueous polymer solution Using each aqueous solution of the vinylpyrrolidone polymer obtained in Examples or Comparative Examples, aqueous solutions having a vinylpyrrolidone polymer concentration of 1% were prepared.

K value, the obtained vinylpyrrolidone polymer concentration of 1% aqueous solution, the relative viscosity measured with a capillary viscometer at 25 ° C., by substituting the viscosity formula of the Fikentscher, resulting in k ₀ It is a numerical value obtained by multiplying the value by 1,000.

(9) Hue of aqueous polymer solution The hue of the aqueous vinylpyrrolidone polymer solution was determined based on the method described in JIS K3331. Details are as follows.

(Measurement of hue)
Using each aqueous solution of the vinylpyrrolidone polymer obtained in Examples or Comparative Examples, aqueous solutions having a vinylpyrrolidone polymer concentration of 5% were prepared, and then placed on white paper under natural light. The corresponding APHA standard solution was color-selected from above with the naked eye, and the corresponding APHA standard solution was selected as the hue of the vinylpyrrolidone-based polymer aqueous solution.

(10) Endotoxin activity of ion-exchanged water and deactivated water 1.0 g of ion-exchanged water or deactivated water was added to 9.0 g of distilled water for injection to prepare a diluted solution of ion-exchanged water or deactivated water.

  After adding 200 μl of the diluted solution of ion-exchanged water or inactivated water to the lysate reagent (Limulus ES-II single test, manufactured by Wako Pure Chemical Industries, Ltd.) and stirring well, set it in the endotoxin measuring device, The time until gelation was measured. This operation was performed twice, and the average value was defined as the time until gelation of the diluted solution of ion-exchanged water or inactivated water.

  In addition, it was made to set to the endotoxin measuring apparatus within 30 second after adding the diluted solution of ion-exchange water or a deactivation water to a lysate reagent.

  From the calibration curve obtained by the method for measuring endotoxin activity of the polymer powder (preparation of calibration curve) and the time to gelation of the diluted solution of ion-exchanged water or inactivated water, Endotoxin activity was determined, and endotoxin activity (unit: EU / g) of ion-exchanged or deactivated water was determined from the concentration of ion-exchanged or deactivated water in the diluted solution.

Example 1
<Insoluble matter removal process>
Pass through 1000 parts of ion-exchanged water (average value 30 EU / g) as a filter for removing insoluble matter through a filter with a pore size of 3 μm (manufactured by Cuno Co., Ltd., Polynet (registered trademark) NT09T030S0BA) to remove insoluble matter (coarse foreign matter). Removed. Subsequently, as a filter for removing insoluble matter, it was passed through a filter for adsorbing foreign matters (Zeta Plus (registered trademark) JB12D50SP, manufactured by Cuno Co., Ltd.) to remove insoluble matters (fine foreign matter) and endotoxin.

<Sterilization process>
1000 parts of ion-exchanged water obtained through the insoluble matter removing step was boiled under normal pressure for 30 minutes and sterilized.

<Endotoxin deactivation process>
The endotoxin was removed by passing 1000 parts of ion-exchanged water after the sterilization process as a filter for removing endotoxin through a polyamide filter having a pore diameter of 0.2 μm (manufactured by Cuno Co., Ltd., Sterasure (registered trademark) PSA020F02BA).

  It was 0.2 EU / g when the endotoxin activity of the water (deactivated water) which reduced the obtained endotoxin activity was measured.

<Polymerization process>
A reactor equipped with a stirrer, a thermometer, and a reflux tube was charged with 640 parts of ion-exchanged water (deactivated water) obtained through the above steps and 160 parts of N-vinyl-2-pyrrolidone, and diethanolamine as a pH adjuster. 0.02 part was added to prepare a monomer aqueous solution having a pH of 8.3. While stirring the aqueous monomer solution, nitrogen gas was introduced to remove dissolved oxygen (oxygen concentration 0.2 ppm; volume basis), and then the reactor was heated so that the internal temperature of the reactor became 75 ° C. To this reactor, as a polymerization initiator, a solution prepared by dissolving 0.44 parts of 2,2′-azobis (2-methylbutyronitrile) in 4.5 parts of isopropanol was added to initiate polymerization. After the polymerization initiator was added, the temperature of the jacket warm water was increased according to the internal temperature from the time when the internal temperature was increased due to the polymerization reaction, and the polymerization reaction was carried out.

<Monomer reduction process by addition of acid>
After the reaction was continued for about 3 hours after the addition of the polymerization initiator, an aqueous solution in which 0.14 part of malonic acid was dissolved in 1.8 parts of ion-exchanged water (deactivation water) as an acid was added. The pH was adjusted to 3.7, and the internal temperature was maintained at 90 ° C. for 90 minutes.

<PH adjustment step after polymerization>
Next, an aqueous solution in which 0.24 parts of diethanolamine is dissolved in 2.7 parts of ion-exchanged water (deactivated water) as a pH adjuster is added to adjust the pH of the reaction solution to 6.6, and at 90 ° C. for 30 minutes. While maintaining the internal temperature, an aqueous solution containing 20% vinylpyrrolidone polymer was obtained.

<Drying and grinding process>
The obtained aqueous solution was put into a drum dryer, and after drying for 20 seconds under the operating conditions of a drum surface temperature of 140 ° C. and a drum rotation number of 1.5 rpm, the resulting dried product was put into a crusher and then coarsely crushed, Then, the mixture was pulverized using a pulverizer (Victor Mill / VP-1 manufactured by Hosokawa Micron Corporation) to obtain a vinylpyrrolidone polymer powder. Table 1 shows the characteristics of the powder.

  The drum dryer and the crusher are installed in a drying chamber in which air passed through a HEPA filter (high air volume type HEPA filter 23CW79J, manufactured by Shinwa Tech Co., Ltd.) is circulated. The polymer was prevented from coming into contact with fungi in the outside air.

(Comparative Example 1)
In Example 1, in place of the ion-exchanged water (deactivated water) obtained through the insoluble matter removing step, the sterilizing step, and the endotoxin deactivating step, these steps (ie, untreated) ion-exchanged water are not used. A vinylpyrrolidone polymer powder was obtained in the same manner as in Example 1 except that was used.

<Dry heat treatment process>
The obtained vinylpyrrolidone polymer powder was treated with a hot air dryer at 170 ° C. for 2 hours to inactivate endotoxin. Table 1 shows the characteristics of the powder after the dry heat treatment.

(Comparative Example 2)
In Example 1, in place of the ion-exchanged water (deactivated water) obtained through the insoluble matter removing step, the sterilizing step, and the endotoxin deactivating step, these steps (ie, untreated) ion-exchanged water are not used. A vinylpyrrolidone polymer powder was obtained in the same manner as in Example 1 except that was used. Table 1 shows the characteristics of the powder.

(Example 2)
<Polymerization process>
430.8 parts of ion-exchanged water (deactivated water) obtained through the insoluble matter removing step, the sterilizing step, and the endotoxin deactivating step, and 0.00023 part of copper (II) sulfate as a metal catalyst are used in the reactor. The temperature was raised to 80 ° C. Next, while maintaining 80 ° C., 450 parts of N-vinyl-2-pyrrolidone, 0.9 part of 25% aqueous ammonia and 1.25 parts of diethanolamine as a co-catalyst, and 9 parts of 30% hydrogen peroxide water as a polymerization initiator Each was added dropwise over 180 minutes. After completion of the dropwise addition, 2.7 parts of 30% hydrogen peroxide solution was added in three portions at 1.5 hour intervals. After the third addition, the solution was further maintained at 80 ° C. for 1 hour, and an aqueous vinylpyrrolidone polymer solution Got.

<Drying and grinding process>
The obtained aqueous solution was dried and pulverized in the same manner as in Example 1 to obtain a vinylpyrrolidone polymer powder. Table 2 shows the characteristics of the powder.

(Comparative Example 3)
In Example 2, in place of the ion-exchanged water (deactivated water) obtained through the insoluble matter removing step, the sterilizing step, and the endotoxin deactivation step, these steps (ie, untreated) ion-exchanged water are not used. A vinylpyrrolidone polymer powder was obtained in the same manner as in Example 1 except that was used.

<Dry heat treatment process>
The obtained vinylpyrrolidone polymer powder was treated with a hot air dryer at 170 ° C. for 2 hours to inactivate endotoxin. Table 2 shows the characteristics of the powder after the dry heat treatment.

(Comparative Example 4)
In Example 2, in place of the ion-exchanged water (deactivated water) obtained through the insoluble matter removing step, the sterilizing step, and the endotoxin deactivation step, these steps (ie, untreated) ion-exchanged water are not used. A vinylpyrrolidone polymer powder was obtained in the same manner as in Example 1 except that was used. Table 2 shows the characteristics of the powder.

  From the comparison between Example 1 and Comparative Examples 1 and 2 (Table 1) and the comparison between Example 2 and Comparative Examples 3 and 4 (Table 2), according to the production method of the present invention, endotoxin activity is It can be seen that a vinylpyrrolidone-based polymer that is low and has a low degree of yellowing can be obtained efficiently regardless of the K value.

  The vinylpyrrolidone-based polymer of the present invention itself is used as a raw material or additive, for example, in applications such as cosmetics, medical and agrochemical intermediates, food additives, photosensitive electronic materials, tackifiers, or various special products. It can be used in a wide range of fields for industrial applications (for example, production of hollow fiber membranes and membrane filters).

Claims (6)

Reducing the endotoxin activity of water;
A step of polymerizing a monomer containing N-vinyl-2-pyrrolidone in a solvent containing water with reduced endotoxin activity obtained through the step to obtain a vinylpyrrolidone polymer solution;
Produced by a production method comprising a step of drying a vinylpyrrolidone-based polymer solution in the air removed from fungi,
A vinylpyrrolidone-based polymer having a Hazen color number (APHA) of 30 or less and an endotoxin activity of 1 EU / g or less in a 5% aqueous solution. A method for producing the vinylpyrrolidone polymer according to claim 1,
Reducing the endotoxin activity of water;
A step of polymerizing a monomer containing N-vinyl-2-pyrrolidone in a solvent containing water with reduced endotoxin activity obtained through the step to obtain a vinylpyrrolidone polymer solution;
And a step of drying the vinylpyrrolidone-based polymer solution in the air from which fungi are removed.   The manufacturing method of Claim 2 including the process of adding the high boiling polyhydric carboxylic acid whose boiling point is 100 degreeC or more, or its deactivation aqueous solution after a polymerization reaction. Removing insoluble matter from water;
The method according to claim 2, wherein the step of reducing the endotoxin activity is carried out after the step of sterilization, including a step of sterilizing water from which insoluble substances obtained through the step have been removed. The production method according to claim 2 or 4 , wherein water having an endotoxin activity of 1 EU / g or less is obtained by the step of reducing the endotoxin activity.   The manufacturing method in any one of Claims 2-5 including the process made into a powder by grind | pulverizing the vinylpyrrolidone-type polymer after drying in fungi removal external air.