DD249274A1 - PROCESS FOR PREPARING ADSORBER POLYMERS FOR THE HAEMOPERFUSION - Google Patents

Abstract

The invention relates to a process for the preparation of highly porous adsorber polymers which can be used in haemoperfusion. The adsorber polymers are prepared by postcrosslinking of chloromethyl group-containing crosslinked polystyrenes in the presence of swelling inert agents and Friedel-Crafts catalysts and removal of the inert agent and a post-treatment for cleaning, coating and sterilization of the material.

Description

The methods of synthesizing the starting polymers and the methods of introducing the chloromethyl groups are known. The aromatic polymers which serve as the basis for the adsorbers are products obtained by bead polymerization of a mixture of one or more monovinyl compounds, one or more polyvinyl compounds with or without the addition of one or more copolymerizable polar vinyl compounds and with or without the addition of Inert materials are produced. Examples of suitable monovinyl compounds which may be mentioned are: styrene, substituted styrenes and vinylnaphthalene. Preferred polyvinyl compounds are divinylbenzenes and trivinylbenzene. Mainly cross-linked styrene Technische was of technical importance. B. based on styrene and divinylbenzene optionally with the addition of other polar monomers, such as acrylic acid esters and acrylonitrile and / or falling or swelling Inertmitteln such. As aliphatic or aromatic hydrocarbons. To obtain optimum Adsorberpolymerer is based on a copolymer which according to the invention has a divinylbenzene content of 2 to 8 wt .-%. The introduction of the chloromethyl groups in such polymers is mitChlormethylierungsmittein in a known manner as monochlorodimethyl, dichlorodimethyl ether, mixtures of formaldehyde or formaldehyde-donating substances and hydrogen chloride or with further addition of methanol and a chlorine donor such as SOCI _2, CISO ₃ H and SO ₂ Cl ₂ possible , Mixtures of methylal and a chlorine donor are also usable.

A polymer which is substituted by such a chloromethylation process is aminated after removal of excess chloromethylating agent by washing with a suitable solvent, preferably methanol, also industrially for the preparation of anion exchangers suitable for industrial use with a suitable amine. If such a methanol-moist chloromethylate is used for the post-crosslinking in the presence of a Friedel-Crafts catalyst and in the presence of an inert agent, for. For example, dichloroethane, at elevated temperature, so obtained although postcrosslinked polymers, but which do not meet the requirements of a polymer adsorber for use in hemoperfusion in terms of their porosity and surface. The resulting postcrosslinked polymers have surfaces between 50-600 m ² / g. However, a technical chloromethylate can surprisingly according to the invention then be converted in a highly effective adsorber by post-crosslinking, if before the addition of the Friedel-Crafts catalyst and before the necessary increase in temperature removal of the solvent used as a detergent of the technical chloromethylate, eg. Methanol to values <5% by weight by removing the solvent either by drying or by displacement with a chlorohydrocarbon, preferably dichloroethane or tetrachloroethane.

The, as described above, largely solvent-free chloromethyl-containing starting polymers, if necessary, in a further amount of a halogen-containing hydrocarbon, such as. For example, dichloroethane or tetrachloroethane, a Friedel-Crafts catalyst such as Eisenendreichlorid, tin tetrachloride or aluminum trichloride was added and the post-crosslinking with simultaneous formation of porosity at temperatures greater than 75 ° C brought about.

The swelling of the chloromethyl-containing polymer in inert chlorohydrocarbon is generally sufficient after 1 to 4 hours at room temperature, the type of inert and the ratio of the polymer to the inert agent of decisive influence on the porosity and thus on the final product properties. By the process according to the invention, dichloroethane and tetrachloroethane have proved particularly suitable as inert agents. However, other inert agents are not excluded. The ratio of polymer to inert can be varied from the Unterschußquellung, just stirred, up to the excess swelling with very good stirrability. The recoverability is dependent on the degree of chloromethylation and the starting crosslinking.

The catalyst concentration can be varied within wide limits and also affects the final product properties. Thus, incomplete postcrosslinking has a negative influence on the formation of porosity. According to the invention, the proportion of catalyst should be at least 20% by weight, based on the polymer, and the degree of chloromethylation should be at least 0.4, but preferably 0.7. The reaction temperature and reaction times are also influential and the final product properties, with temperatures between 75 to 12O ⁰ C and reaction times of 2 to 20h favorable reaction parameters. A gradual heating of 30 to 60 minutes, about 40, 50, 60, 70 and 8O ⁰ C has proved to be advantageous for the pattern formation. After completion of the reaction, the product must be freed from the chlorinated hydrocarbon and hydrophilized. For this purpose, a washing with methanol has proven particularly useful.

The synthesis of the adsorbent polymers by the process according to the invention offers the following advantages: contrary to the prior art, in which industrially difficult-to-access starting materials, e.g. bifunktionel Ie compounds for post-crosslinking and low-crosslinked starting polymers are used, which result in the post-crosslinking to adsorbents with non-optimal adsorption capacity per unit volume, now technically readily available chloromethylated polymers are used, the improved adsorption capacities, based on the volume unit deliver. As a result, only about one third of the Friedel-Crafts catalyst compared to the stand needed. Due to the lower swelling of the starting polymers, further savings of up to about 50% are possible.

The adsorber polymers produced according to the invention have significantly higher surface areas and thus adsorption capacities than the comparable commercial products. The drug adsorption could be increased by about 60% compared to conventional adsorber polymers used for hemoperfusion. The products are characterized by a good hydrophilicity and are after drying or washing processes well and directly wetted with water again.

To improve the blood compatibility, it is possible to alkalinize still existing chloromethyl groups or to etherify with polyols or polyethylene glycols.

Before being used for hemoperfusion, the adsorber polymers are conditioned. To this end, a further purification step, characterized by washing processes with organic solvents such as tetra, acetone, methanol, toluene and water, as well as a coating step with e.g. Poly (2-hydroxyethylene methacrylate), cellulose acetate, collodion or albumin for better blood compatibility and a sterilization step necessary.

Example 1:

In a sulfonating flask equipped with a thermometer, reflux condenser and stirrer, 100 g of a chloromethylated 3.5% crosslinked styrene-divinylbenzene copolymer having a chlorine value of 19.3% are admixed with 275 g of dichloroethane, swollen at room temperature for 2 h and then admixed with 65 g of aluminum trichloride. Thereafter, for one hour at 40, 50, 60 and 70 ⁰ C and 20 h at 83-85 ° C stirred. The mixture is hydrolyzed with water, washed with methanol and again with water.

The product has the following characteristics:

Surface: Water content:

1 080 mVg 48.5%

Surface per volume unit wet adsorber: 312m ² / ml

Example 2:

As in Example 1, 100 g of the same chloromethylated 3.5% crosslinked styrene-divinylbenzene copolymer are mixed with 320 g of tetrachloroethane, swollen at room temperature for 4 h and then mixed with 15 ml of tin tetrachloride and one hour at 60.70, 80.90 ⁰ C and another 10 Stirred at 105 ° C h. The cooled product is separated and washed with methanol, methanol-water 50:50 and water

 The product has the following characteristics:

Surface: Water content:

1155m ² / g 41.2%

Surface per volume unit wet adsorber: 460m ² / ml.

Example 3:

In a sulphonation flask of the same equipment as in Example 1, 550 g 3.5% cross-linked chloromethylated styrene-divinylbenzene copolymer are added with a chlorine value of 18.3% and treated with 1 650g dichloroethane and stirred for 2 h at room temperature. Thereafter, 200 ml of tin tetrachloride are metered and stirred for one hour at 40, 50, 60.7O ⁰ C and 15h at 83-85 ⁰ C. The reaction product is separated and washed with methanol, methanol-water 50:50 and water. The product was analyzed as follows:

Surface: . Water content:

1 361 m ² / g 41.9%

Surface per unit volume of wet adsorber: 573m ² / ml.

An adsorbent polymer prepared according to this example was washed with acetone and 60 ° C hot water and subjected to a drug adsorption test. A comparison with other adsorbents used in hemoperfusion shows the following composition:

Table 1: Pharmakaadsorption after 2 h contact time

Adsorber type Imipramine (mg / ml) Talinolol (mg / ml) Atropine sulfate (mg / ml) Gluthalimide din (mg / ml) Dihydropyri- (mg / ml) Hemoresin Wofatit UH91 Example 3 (Invention According to) 10.3 9.3 12.9 9.4 3.8 9.05 7.1 4.1 11.0 8.4 11.9 12.7 7.8 6.6 12.2

Claims (1)

Claim: Process for the preparation of highly porous adsorber polymers based on crosslinked aromatic polymers which can be used for hemoperfusion, characterized in that technical-grade chlorosilated solvent-free divinylbenzene crosslinked polystyrenes are postcrosslinked in the presence of swelling inerting agents, preferably chlorohydrocarbons and Friedel-Crafts catalysts, and subsequently freed from the inert medium , wherein the crosslinker content, based on divinylbenzene, 2 to 8 wt .-% and the degree of substitution of chloromethyl groups is greater than 0.4 and products are obtained, the surfaces have greater than 800m ² / g and greater than 300m ² / ml of water-moist adsorbent polymers, their possible Any residual chloromethyl groups still present are optionally saponified in alkaline form or etherified with polyols or polyethylene glycols, and are purified, coated and sterilized before use in hemoperfusion. Field of application of the invention In the treatment of patients with functional or renal dysfunction, acute intoxication, liver failure, including hepatorenol syndrome, it is possible to rid the blood of harmful substances such as toxins and urine-containing substances. This task can be solved by using adsorbent polymers by hemoperfusion. Characteristic of the known technical solutions Adsorber polymers are generally prepared by suspension polymerization of monomers with a crosslinking agent in the presence of inert substances. The inert materials are removed from the polymer again after the polymerization and, together with the crosslinker, are responsible for the degree of porosity. Suitable inerting agents include, for example, aliphatic and aromatic hydrocarbons, alcohols, esters, ketones and soluble polymers. According to this principle, the porosity is controllable, but surface values and adsorption capacities of certain adsorption charcoals can not be achieved (J. Seidl, Chem. Prumysl 25 [50], 416-419). Further synthetic principles therefore describe other ways to obtain even more porous adsorbents with improved adsorption properties. The principle of the post-crosslinking of polymers is disclosed here as a solution. US Pat. No. 4,191,813 describes the post-crosslinking of low-crosslink vinylbenzyl chloride copolymers in the presence of swelling inducers by Friedel-Crafts catalysts. U.S. Pat. No. 4,263,407 discloses the route via slightly crosslinked macroreticular aromatic polymers by postcrosslinking. For this purpose, the polymer is swollen in an inert swelling agent which contains the crosslinker in the form of polyfunctional alkylating, acylating or sulfur halides and in the presence post-crosslinked by Friedel-Crafts catalysts. Davankov (Angew. Macromolecular Chemistry 91 [1980], 127-142, DD-PS 85644) and DD-PS 125.824 describe the same principle on polystyrene and styrene-divinylbenzene copolymers, respectively, to 1 mol% of crosslinking. Besides polyfunctional alkylating and acylating agents, monochloride methyl ethers are used. The cited methods have disadvantages which consist in the fact that in the synthesis of Adsorberpolymeren by post-crosslinking partially technically difficult to access starting materials, such as the vinylbenzyl chloride used, the polyfunctional crosslinkers or polymers containing up to 1 mol% Divinylbenzenvernetzung must be used. For hemoperfusion adsorber polymers have been used, which are prepared by the method of copolymerization of crosslinking agents in high concentrations in the presence of inert agents. As will be shown, these products are clearly inferior to those of the process according to the invention in the adsorption capacities. Object of the invention The aim of the invention is the simplest possible method for the production of adsorbents with high surface area and improved adsorptive properties in hemoperfusion. » Explanation of the essence of the invention The object of the invention was to develop on the basis of technical preliminary and intermediate products, a method which corresponds to the objective of the invention. It has now been found that it is possible to produce adsorbents with a correspondingly large surface area (> 800 m ² / g) and improved adsorptive properties for pharmaceuticals, blood poisons and urinary substances, if technical chloromethyl-containing polymers, preferably styrene-divinylbenzene copolymers in the presence of swelling Intenuated na.chvernetzt, wherein the degree of crosslinking is 2 to 8 wt .-% of divinylbenzene and the degree of substitution of chloromethyl groups is greater than 0.4 (11.5% Cl), preferably 0.7 (17.8% Cl).