JPH0724824B2 - Removal method of endotoxin in pure water production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention activates endotoxin derived from a bacterium that grows or proliferates in a pure water production system by carbonizing a porous spherical crosslinked synthetic polymer or by carbonizing it. And a strongly acidic anion exchange resin and / or a strongly acidic cation exchange resin mixed with the treated carbonaceous adsorbent.

[Conventional technology]

Endotoxin (bacterial endotoxin) is a complex phospholipid polysaccharide (lipopolysaccharide) that exists as a cell membrane component of Gram-negative bacteria, and is a typical pyrogenic substance.

Each country's pharmacopoeia stipulates that water for injection must not contain pyrogens as well as bacteria.

In addition, as the degree of integration of semiconductor devices has increased, the purity of pure water used for this has been improved to the utmost limit, in so-called ultrapure water, the viable cell count that is the source of pyrogens is 0.02 cells / ml or less. Strict standards are required.

To obtain pure water containing no pyrogen, the purified water is usually purified by a distillation operation. However, pure water obtained by one-time distillation can be used for the Limulus test [blood cell extract of horseshoe crab, Limulus amoebosite. -Tests based on gelation reaction between lysate (Limulus Amerbocyte Lysate) and endotoxin] are often positive.

Therefore, recently, Japanese Patent Nos. 989058 and 738632
Membrane separation methods have come into use, as seen in No. Membrane separation methods are usually more
Rather, it is incorporated and used as a component of an extremely expensive ultrapure water production system. Specifically, not only pyrogen but also city water containing a large amount of various ions, organic substances, etc. is passed through the activated carbon and ion exchange resin, and then stored, and further, an ultraviolet sterilizer for sterilization and a regenerative mixed bed. This is a method of treating with a type ion exchange resin tower and then with a permeable membrane such as an ultrafiltration membrane or a reverse osmosis membrane.

Even though bacteria are naturally proliferative and sterilized, endotoxin concentration is increased as the number of killed bacteria trapped in the system, especially on the surface of the permeable membrane increases. It is presumed that this is one of the causes of the unexpected deterioration of the performance of the permeable membrane, such as rapid increase in the permeable membrane.

It is known that the water obtained in this way, which does not contain pyrogen, is easily exposed to bacterial contamination and then endotoxin is produced within a short period of time when it is once exposed to the outside under aseptic control.

In response to this, there is a strong demand for a drug, a special adsorbent, and the like, which can easily and effectively obtain endotoxin-free water.

Various attempts have been made on the pyrogen treatment by the adsorption method.

Taking ion exchange resins, synthetic adsorbents, and various activated carbons as examples, the ion exchange resins include, for example, the porous ion exchange resin Amberlite 200 or the same IRA-938 (Amberlite is a registered trademark of Rohm and Haas). That there is a slight effect on the results, and the effect on synthetic adsorbents such as Amberlite XAD resin and activated carbon is questionable. No. 8 1547 to 1 of the Chemical Society of Japan (1973)
Reported on page 553.

[Problems to be solved by the invention]

It is an object of the present invention to provide a method for removing endotoxin to an ultratrace concentration in pure water production.

Another object of the present invention is to provide ultrapure water for various uses or an improved method for removing endotoxin which enables the production of ultrapure water.

[Means for solving problems]

The above object of the present invention is achieved by the following endotoxin removal method.

A deionized water from a treatment step with an ion exchange resin in a pure water production system is carbonized or activated by carbonizing or activating a porous spherical crosslinked polymer, and an ion exchange resin, particularly a strong basic anion. A method for removing endotoxin in pure water production, which comprises treating with a mixed system of an exchange resin and / or a strongly acidic cation exchange resin. Here, as a carbonaceous adsorbent obtained by carbonizing the above porous spherical cross-linked polymer by thermal decomposition, JP-A-51-1
26390, JP-A-49-53594, JP-A-53-50088, JP-A-52-30799, JP-A-51-63619 and the like carbonaceous adsorbent produced by the method Is what you want.

As the porous spherical crosslinked polymer, generally, a copolymer composed of a monovinyl monomer and a polyvinyl monomer is most preferable.

The above monomers are copolymerized by a known suspension polymerization method or the like to obtain a spherical copolymer.

Specifically, those composed of styrene and divinylbenzene are the best known.

Naturally, the present invention can be completed even with a copolymer composed of a monovinyl monomer other than these and another polyvinyl monomer.

Thus, in order to obtain porosity, it is important to add a known additive in an amount sufficient to impart porosity during polymerization such as suspension polymerization.

Typical additives for this are called precipitants,
A solvent that dissolves in the monomer and does not swell the resulting copolymer,
Further, it is called a swelling agent and is a solvent that dissolves in a monomer and swells the resulting copolymer, or a mixed solvent in which the above-mentioned swelling agent and a precipitant coexist, and further these swelling agent and this swelling agent and a uniform liquid phase. An organic liquid consisting of a monovinyl linear polymer capable of forming, and soluble in the monomer mixture,
Examples thereof include insoluble polymer substances such as polyalkylene glycol which are inactive to the produced copolymer, but are not limited to these, and other known pore-forming agents can naturally be used. Is.

The porous cross-linked copolymer produced by such a method may be subjected to sulfonation, chlormethylation, or the like by a known method in some cases, and then, even if it is an ion-exchange resin obtained by ammonoization, It is preferable as well as the porous copolymer.

These porous spherical crosslinked copolymers may be commercial products. For example, a commercially available amberlite ion exchange resin series or a synthetic adsorbent series may be used. Further, many commercially available products such as Diaion (registered trademark of Mitsubishi Kasei Co., Ltd.) and Dowex (registered trademark of Dow Chemical Co.) It can be used.

A desired adsorbent is produced by carbonizing the porous spherical crosslinked copolymer thus obtained by a known method.

This porous spherical cross-linked polymer, after infusibilizing treatment with sulfuric acid, nitrogen dioxide, chlorine, etc., at 300 ~ 900 ℃,
Pyrolysis yields the desired carbonaceous adsorbent.

The adsorbent thus obtained can be used as it is, but if desired, it is also suitable to further activate it sufficiently by using steam, an aqueous solution of zinc chloride or the like.

A specific example of such a commercially available adsorbent is ROHM
The Ambersorb series manufactured by And Haas is known.

This adsorbent is spherical, has a small amount of ash, and is characterized by high wear resistance and high physical strength.

These secondary characteristics have special significance in the treatment of endotoxin in pure water.

In addition to the effective adsorbability of endotoxin by this adsorbent, these characteristics make it possible to treat endotoxin in pure water without deteriorating water quality.

That is, ordinary activated carbon for water treatment not only serves as a hotbed for the growth of bacteria due to its amorphous shape, but also is crushed due to its small physical strength or abrasion resistance and remains in the treatment system as fine particles. However, it causes problems such as deterioration of water quality.

The biggest difference between this adsorbent and commercially available powdered or granular activated carbon is that its physical structure is fundamentally different from activated carbon, and the skeletal structure of the porous spherical polymer is carbonized, and after activation, It is to be held as it is.

It is presumed that this difference contributes to the large difference in the adsorption amount for endotoxin.

Regarding the adsorption and removal of endotoxin by ion exchange resin alone, there have been few attempts, but according to the above-mentioned "Removal of heat-generating substances by ion exchange, adsorption and membrane permeation" of the Chemical Society of Japan, among the tested resins, Then, MR type strong acid cation exchange resin is preferable as the cation exchange resin, and gel type strong basic (II type dimethyl ethanol ammonium type) anion exchange resin or super MR type is used as the anion exchange resin. Strongly basic (type I trimethylammonium type) anion exchange resin gives good treatment results,
That is, lipopolysaccharide 0 as a bacterial pyrogen.
It is said that the rabbits passed the heat release test on the treated water of 33 ppm (330 ng / ml) or 3.3 ppm (3,300 ng / ml) of raw water by column treatment using an ion exchange resin.

However, it is described that a stable treatment effect could not be expected when the cycle was repeated with mixed beds of these ion exchange resins.

The inventors have conducted extensive studies on the removal of pyrogens from water, and applied for a patent for a carbonaceous adsorbent itself for removing pyrogens and a method for removing endotoxin in pure water production using the same (Japanese Patent Application No. 62-76094). No.) has already been done.

The results of the research conducted by the inventors show that an extremely small amount (50 ng / ml) was added to pure water.
(Below) In batch adsorption removal of dissolved endotoxin with a strongly basic anion exchange resin, the strongly basic anion exchange resin is extremely effective in removing endotoxin in pure water. It has been found that porous type or MR type, which is rich and has a large surface area, or type I resin is more effective than type II resin.

At present, treatment with a membrane plays a major role in the production of pyrogen-free water for medicines and pharmaceuticals.

Regarding the removal of bacteria, which is a major problem in the production of ultrapure water for the semiconductor industry, sterilization with an ultraviolet sterilizer and physical removal with a membrane are the mainstream. Gram-negative bacteria, which are endotoxin-producing bacteria, are the priority strains, and when they die, endotoxins are released, and there is a movement to regulate them.

Regarding this endotoxin removal, there was no doubt that the ion exchange resin incorporated in the pure water or ultrapure water production equipment also played its role, but as described above, as the cycle was repeated, It had a drawback that the effect of the treatment became unstable.

However, the removal method of the present invention enables highly stable, reliable, and effective removal of endotoxin over a long period of time.

As a simple and practical method, a strong acid cation exchange resin and / or a strong base in an ion exchange resin tower in a pyrogen-free water production apparatus for medicines, pharmaceuticals, or an ultrapure water production apparatus for semiconductor production is used. The synthetic spherical carbonaceous adsorbent of the present invention is mixed and used in a mixed bed or a single bed of a cationic anion exchange resin, or a column in which these are preliminarily mixed and charged is used in the apparatus or at the point of use ( The desired purpose can be achieved only by incorporating immediately before the used point.

Instead of mixing, a mixed bed of ion-exchange resins or a single bed having a synthetic carbonaceous adsorbent on the upper part of the bed may be used.

The ion exchange resin used in the present invention is a commercially available gel type, MR type, or porous type strong acidic and / or strong base that is currently usable for the production of pyrogen-free water or ultrapure water. It is a cationic ion exchange resin. However, it is inconvenient if the Chatillon value (crush strength value by a crush strength tester) is substantially 0 kg / cm ² .

Since the synthetic carbonaceous adsorbent has extremely high physical strength, the ion exchange resin, which has extremely low physical strength when mixed with it, is crushed during use and becomes a fine particle substance with pyrogen-free water and This is because the inside of the pure water production system is contaminated.

It is also possible to use ordinary activated carbon instead of this spherical synthetic carbonaceous adsorbent, but since this is an irregular shape, it will rather be a hotbed of microorganisms and can not be used. Absent.

〔The invention's effect〕

According to the present invention, the carbonaceous adsorbent is only mixed or installed in an existing single-bed type or mixed-bed type ion-exchange resin column, and it is not necessary to separately install a new column, which is economical. Moreover, contrary to the sole use of the ion exchange resin, a synergistic effect is produced, and pure water or ultrapure water containing no endotoxin can be stably provided.

Further, when the present invention is incorporated into an existing pyrogen-free water or ultrapure water producing apparatus, the effect of reducing the load on the membrane and extending the life can be expected.

〔Example〕

 Hereinafter, the present invention will be specifically described with reference to examples.

Synthesis Example 1 of carbonaceous adsorbent Dissolve 5.0 g of polyvinyl alcohol, 2 g of carboxymethyl cellulose and 56 g of NaCl in 1.5 l of distilled water to prepare styrene 200
g, divinylbenzene (purity 59%) 132g, butanol 240
A mixture of g and 1.5 g of benzoyl peroxide was added, and the mixture was reacted at 85 ° C. for 6 hours with stirring. 40 g of the obtained porous spherical crosslinked polymer was subjected to a sulfonation reaction in 500 g of 15% fuming sulfuric acid at 110 ° C for 6 hours, followed by washing with H ₂ SO ₄ , followed by washing with water and drying. Let

Then, the temperature was raised to 950 ° C. in N ₂ at a rate of 300 ° C./Hr, and firing was performed.

The apparent specific gravity of the fired product was 0.5, and the pore volume was 0.6 cc / g.

The porous spherical carbon of this fired product was heated to 800 in a steam atmosphere.
Activated for 2 hours at ℃, surface area 1100m ² / g
Of carbonaceous adsorbent was obtained.

Synthesis example of carbonaceous adsorbent 2 Polyvinyl alcohol 5g, carboxymethyl cellulose
2.5g, NaCl56g dissolved in distilled water 1.5l, styrene 200
g, divinylbenzene (commercial product 59%) 132g, toluene 240
g, and a mixture of 1.5 g of benzoyl peroxide, and under stirring 85
The reaction was carried out at 6 ° C for 6 hours.

40 g of the obtained porous spherical polymer was added to 1% in 500 g of 15% fuming sulfuric acid.
The sulfonation reaction was carried out at 10 ° C. for 6 hours, followed by washing with sulfuric acid, washing with water and drying.

Then, the temperature was raised to 950 ° C. in N ₂ at a rate of 300 ° C./Hr, and firing was performed.

The porous spherical carbon of this fired product had an apparent specific gravity of 0.55 and a pore volume of 0.6 cc / g.

This was activated in a steam atmosphere at 800 ° C. for 2 hours to obtain a carbonaceous adsorbent having a surface area of 1020 m ² / g.

Example 1 Using tap water as raw water, a granular activated carbon tower, a gel-type cation exchange resin tower, a gel-type anion exchange resin tower, and then an ion exchange resin tower group composed of a mixed-bed type porous spherical crosslinked polymer. Deionized water production equipment at room temperature of about 20 ℃
When operated intermittently with a water intake of about 100 l for about 4 hours each time, after about 2 weeks, endotoxin had flowed out into deionized water at an average level of 1.5 ng / ml.

The water purity of about 1 minute at the start of intermittent operation reached 18.2 MΩcm and TOC of 100 ppb or less in-line, and there was no problem as a performance as a deionized water production apparatus. Therefore, the treated water pipe was branched into six pipes, and the first pipe system had a diameter of 1.1 cm and a height of 75 cm and was filled with 60 ml of the carbonaceous adsorbent of Synthesis Example 1 and the second pipe. System diameter 2.0c
m height 75 cm glass column 60 m carbonaceous adsorbent of Synthesis Example 1
1, strongly acidic cation exchange resin Amberlite IR-124 H type 4
0 ml, and strongly basic anion exchange resin Amberlite I
RA-402BL OH type 80ml well mixed and packed, and the third piping system diameter 2.0cm height 75cm glass column 60ml carbonaceous adsorbent of Synthesis Example 2, Amberlite IR-124 H type 40m
l, and amber light IRA-402BL OH type 80ml well mixed and filled, the diameter of the 4th piping system 2.0cm height 75c
Amberlite IRA-402BL OH type 1 for m glass column
Filled with a sufficient mixture of 20 ml and 60 ml of Ambersorb XE-340, the fifth pipe system has a diameter of 1.6 cm and a height of 75 cm. The 6th piping system is 1.6 cm in diameter and 75 cm in height and is 75 cm in glass column. Weakly acidic cation exchange resin Amberlite IRC-50 H type 40 ml and weak basic anion exchange resin Amberlite. 80 ml of IRA-93 free base type was thoroughly mixed and packed so that the packing layers in each column had almost the same height, and the same flow rate SV = 8 (8 times the amount of adsorbent per hour) Water flow was started by passing the amount of treated water).

The amount of endotoxin at the detection limit of 0.01 ng / ml was as shown on the next page.

Example 2 Using tap water containing 40 ng / ml of Pyrogen as raw water, deionized water treated with a granular activated carbon tower, a gel type cation exchange resin tower, a gel type anion exchange resin tower, and a mixed bed type porous ion exchange resin tower was used. It was placed in a water tank having a capacity of 200 liters. In this water tank, the deionized water production system on the raw water supply side automatically operates so that the water storage capacity is always 200 l.

Ultraviolet sterilizer, 2 liter regenerative mixed bed type ion exchange resin tower, ultrafiltration membrane, and then to the tap at the point of use, unused water is returned to the water tank. In the water production system, about 100 liters per time and a purity of 18.2 MΩcm were collected, and one week after the start of water collection, water was sampled from the sampling point between the regenerative mixed bed ion exchange resin tower and the ultrafiltration membrane, and analyzed. , Endotoxin was present at 0.15 ng / ml.

Therefore, this regenerative mixed bed type ion exchange resin tower was removed, and MR type ion exchange resin Amberlite 200C H type and IRA-900 OH type 1: 1 mixture 1.5l and Ambersorb X
When a column with a diameter of 8 cm and a height of 50 cm filled with a mixture of 500 ml of E-347 was placed after the UV sterilizer, the endotoxin level in the system was 0.01 ng / ml even when water was passed for 3 months.
It was below.

In the comparative example using 2 l of the MR type ion exchange resin mixture alone, the outflow of endotoxin exceeded the detection limit after 1 month.

The endotoxin concentration was measured by using a horseshoe crab blood cell extract manufactured by Wako Pure Chemical Industries, Ltd. and a toxinometer manufactured by the same company.

The ion exchange resin used is regenerated by using 4% HCl for the cation exchange resin, 10 equivalents per resin, SV =
4. Regenerate at room temperature. Anion exchange resin was regenerated with 4% NaOH at 20 equivalents per resin, SV = 4, 50 ° C, and then washed until traces of HCl and NaOH were not observed. It was

When the ion exchange resin was regenerated, endotoxin-free pure water was used as water.

Claims (1)

[Claims] 1. A carbonaceous adsorbent obtained by carbonizing or activating carbonized porous spherical crosslinked polymer with deionized water obtained from a treatment step with an ion exchange resin in a pure water production system and a strong basic anion exchange. A method for removing endotoxin in pure water production, which comprises treating with a mixed system of a resin and / or a strongly acidic cation exchange resin.