CS232439B1 - Process for producing powdered microcrystalline oxycellulose - Google Patents

Abstract

In the method according to the invention, the cellulose material, especially in the form of fibers, for example linters, is firstly freed from the amorphous portion and secondly converted into powder by means of controlled heterogeneous hydrolysis in boiling 0.5N to 4.5N nitric acid, after which the reaction mixture is cooled. Then powdered microcrystalline cellulose is separated from it, which is oxidized in the wet state by activation in nitric acid, then concentrated by centrifugation and placed in a hermetically sealed blender, where an aqueous solution of alkaline nitrite is added to it with stirring and after the reaction, lasting 6 to 12 hours, the reaction mixture is cooled, undergoes an acid washing operation and then is treated according to the purpose of use of the final product, for example it is dewatered, crushed, converted from the acid form to the oxycellulose salt, dried, adjusted and optionally sterilized. The method of producing powdered microcrystalline oxycellulose, or its salts, can be used in healthcare as a hemostatic agent, or for technical purposes, for example for chromatography columns, for filtering wine or fruit juices, or as a selective ion exchanger.

Description

The invention relates to a process for the production of powdered microcrystalline oxycellulose or a salt thereof, for use in particular as a haemosthetic in the medical field or for technical purposes, for example for chromatography columns or for filtering wine or fruit flakes.

The oxycellulose powder is produced by grinding or grinding the oxidized cellulosic fibrous material either wet, for example in a paper mill or Jordan mill, or dry in mills of various designs. Wet grinding must be carried out in an aqueous-alcoholic or aqueous-acetonic solution, since the solubility of oxycellulose or its calcium salt in water increases to 50% by weight as the degree of grinding increases. Dry grinding requires special mills and the actual grinding process is accompanied by an undesirable increase in temperature, which causes a deterioration of the chemical stability of the preparation. In order to achieve a high fineness of pulverulent cellulose, very intensive and long grinding is required, which is energy-intensive, or particle size fractionation must also be carried out.

However, crushing fresh filamentous oxycellulose is a problem, therefore, the process of US Patent No. 3,122,479 uses partially chemically degraded oxycellulose, which is brittle and therefore better crushed, to crush. However, chemical degradation is time-consuming and does not merely embrittle oxycellulose, but also yellow, decarboxylate, and reduce physiological activity. This procedure cannot produce particles below 100 microns in size.

It is also known to produce powdered oxycellulose by powdering or microcrystalline cellulose by mechanical crushing or acid heterogeneous hydrolysis of cellulose with native structure, which is first dried and then oxidized. This oxidation, described by A. M. Seifert and R. B. Hertz in Industrial & Engineer Chemistry, Froduct fiesearch Development, 1966, Vol. 5, No. 1, 41-46, is carried out with nitrogen dioxide gas or a solution thereof in carbon tetrachloride. The disadvantage of oxidizing dry microcrystalline cellulose is its low reactivity due to macromolecules arranged in microcrystals.

This structure hampers the penetration of the reagent and slows the reaction rate. The procedure just described, using microcrystalline cellulose and nitrogen dioxide in a ratio of 1: 1, achieved a degree of substitution of 0.23, i.e. about 6% COOH, after 6 hours, and an oxidation degree of 0.43, i.e. 11% COOH. The powdered oxycellulose thus produced with a low degree of oxidation is not suitable for use in medical practice. Another disadvantage of this process is the relatively high cost of the pulverulent starting cellulose due to its production technology, which requires both a boiling dilute hydrochloric acid resistant material and an increased energy requirement, since drying operations must be included.

A similar result is obtained by the process of U.S. Pat. No. 3,111,513, in which the oxidation is carried out at a ratio of microcrystalline cellulose to nitrogen dioxide of 1: 3 and after 2 1/4 hours a 3.5 ° COOH is achieved, after 17 1/4 hours 7.8% COOH and after 40 hours 12.2% COOH. This implies that the kinetics of microcrystalline cellulose oxidation under these conditions is very slow, and in order to achieve a substitution degree of about 0.5, it is necessary to extend the reaction time to several tens of hours.

According to MS. No. 185,366, powdered oxycellulose or a salt thereof for use as a hemosthetic is prepared by grinding wet or dry oxycellulose prepared by oxidation of a cellulosic material in an oxidation bath containing a mixture of nitric acid and thermally phlegmatized sodium nitrite after radiation irradiation. Wet or dry grinding lasts for hours, is energy efficient, increases the risk of heavy metal contamination of the final product and gives a powder with a particle size of several hundred microns, a relatively coarse powder that limits the use of the product, for example not suitable for aerosol pressure packing. In addition, in dry grinding, there is a risk of explosion at certain concentrations of oxycellulose powder with air, therefore strict safety regulations must be observed.

Finally, a process for the production of powdered oxidized cellulose or salts thereof is known which is based on the process of the aforementioned U.S. Pat. AO No. 185 366, in which a cellulosic material, in particular in the form of fibers such as liners, is treated with an oxidation bath consisting of a mixture of nitric acid and alkaline nitrite phlegmatized by thermal exposure, after which at least partially washed oxycellulose with preserved native structure is converted into oxycellulose in the form of aggregates having a microcrystalline structure by controlled heterogeneous acid hydrolysis in a boiling medium of 7 to 60 minutes and containing N to 3N nitric acid adhered to the oxycellulose from the oxidation bath.

This is followed by treatment according to the intended use of the final product, for example oxycellulose is washed, dewatered, dried, edjusted and optionally sterilized. However, it is also possible, after hydrolysis, to first crush the aggregates, or to carry out the aggregates from the acid form to the oxycellulose salt and, if necessary, to crush the aggregates before proceeding to the aforementioned conventional treatment. Obviously, this method brings a number of advantages over the method of the aforementioned U.S. Pat. No. 185,366, in particular the use of nitric acid for both oxidation and for controlled heterogeneous acid hydrolysis, which is carried out on an undried, i.e., moist oxidized product.

However, this method has several disadvantages. It is a long oxidation time of 24 to 28 hours, a considerable amount of waste water from the washing operation, the formation of excess oxidation baths as a result of reviving the bath by adding concentrated nitric acid, leakage of reaction gases from the open oxidizer into the environment and finally spa.

The aforementioned disadvantages are eliminated by a process for the production of powdered microcrystalline oxycellulose or its salts, in which the cellulosic material is oxidized by nitric acid and alkaline nitrite, after which the oxidized cellulosic material is treated according to the intended use of the final product and in particular in the form of fibers, for example liners, by means of controlled heterogeneous hydrolysis in 0.5N to 4.5N nitric acid both free of amorphous content and converted into powder, after which the reaction mixture is cooled and the powdered microcrystalline cellulose is separated therefrom which is oxidized in the wet state by ecticification in nitric acid, then concentrated by centrifugation and placed in a hermetically sealable mixer, where an aqueous solution of an alkali nitrite, for example sodium, is added under stirring and after a reaction time of 6 and '12 o'clock, sec the reaction was cooled, pass through the acid washing operations and additional stretched forth example is dewatered, crushed, fed from the acid form to a salt oxycellulose, dried, sterilized and possibly adjusted.

After an acidic wash operation in a mixture of water with an alcohol such as ethanol or isopropanol, or water with a ketone such as acetone that is repeated, for example two or three times alternately with centrifugation, the oxidized product can be converted by neutralization, for example with equimolar mixtures of calcium chloride and calcium acetate. , sodium or ammonium salt to a carboxycellulose salt, preferably to a calcium, sodium or ammonium salt.

New and important features of the process according to the invention include:

Activation of microcrystalline cellulose by dispersing it in 60 to 65% nitric acid at room temperature for 15 to 20 minutes.

The material is concentrated by centrifugation to a content of 40 to 60% by weight. This reduces the volume of the product and allows the slurry to be processed.

Oxidation of activated densified microcrystalline cellulose in a sealed blender by the addition of an aqueous solution of 22 to 26% alkali metal nitrite with stirring.

Significantly shorten the reaction time to 6 to 12 hours depending on the desired degree of substitution, which is a quarter to half the time of the processes described above, as the reaction proceeds at a slightly elevated temperature, 35 to 40 ° C, and at a slightly elevated pressure, 0.15 to 0 , 2 MPa.

The essence of the invention is better understood from the description of examples of its implementation.

Example 1

120 L of 1.5 N nitric acid is charged into a 150 L glass reactor equipped with a heating coil, a reflux condenser and a stirrer, which is then boiled.

9.5 kg of air dry cotton liners containing 5 to 7% moisture are gradually added to the boiling acid. The resulting dispersion is initially dense to slurry, but within a few minutes it becomes thin and becomes easily mobile. The dispersion is still stirred to avoid secret boiling. After 15 minutes of boiling, when the linters are already pulverized, the heating and stirring are switched off and the microcrystalline cellulose is separated in a centrifuge or suction, the separator being equipped with a thick filter cloth. The residual moisture in the material is 40-50% depending on the intensity of the separation, and the reaction yield is about 7.1 kg of dry matter, which is 12 to 14 kg of wet microcrystalline cellulose.

This is followed by material activation! In a glass reactor, microcrystalline cellulose is dispersed in 60 to 65% nitric acid at a hydromodule of 1: 4 to 1: 6, here 1: 5, at a temperature of 15 to 20 ° C, for 15 to 20 minutes. The activated microcrystalline cellulose is concentrated by centrifugation to a content of 40 to 60, here 50% by weight of dry matter.

The thus prepared, nitric acid-activated microcrystalline cellulose is placed in a hermetically sealable blender and, with stirring, is added to it an aqueous solution of sodium nitrite having a concentration of 22 to 26, here 24% by weight. The amount of sodium nitrite added is from 1:20 to 1:10 by weight relative to microcrystalline cellulose. parts, here 1:15. The temperature of the slurry is increased to 35-40 ° C due to the exothermic reaction, and at the same time the overpressure is increased to 0.15 to 0.2 MPa. The slurry is occasionally mixed during the reaction.

After 6 to 12, here 10 hours of reaction, the reaction mixture is cooled, the mixer is vented, the nitrous gases are aspirated through alkaline absorption, and the contents of the mixer are transferred to a scrubber equipped with a stirrer for acidic washing of the oxidized material. The wash solution is a mixture of alcohol, here ethanol, with water in a ratio of 1: 1 to 1: 2 wt. parts in the hydromodule 1: 3 to 1: 6, here 1: 5. Instead of ethanol, isopropanol or a ketone, for example acetone with water, can be used in the ratio indicated. Roasting is toasted 2-3 times alternately with blasting.

Finally, the preparation is dewatered with concentrated ethanol or acetone and then dried in a fluidized bed or other suitable oven. The end product is an oxidized powdered microcrystalline cellulose of particle size predominantly above 100 micrometers, which is suitable for medical purposes as a hemostatic or for technical purposes, for example for chromatography columns or for filtering wool or fruit juices.

Example .2

The material prepared according to Example 1 is converted to calcium salt upon completion of the oxidation and after the oxidation mixture has been washed. The reaction proceeds in a scrubber dispersion in which the washed oxidized microcrystalline cellulose is dispersed in a neutralization solution containing an equimolar mixture of calcium chloride and calcium acetate in a ratio 1:10 to 1:15, here 1:12. After dispersing, the pH is determined and lime milk, i.e. a solution of calcium hydroxide in water, is added carefully with vigorous stirring until the pH is stable in the range of 6.2 to 6.4.

Then, the calcium salt of the oxidized microcrystalline cellulose is separated from the neutralizing solution in the centrifuge, which is returned to regeneration. The product is then washed repeatedly by dispersion with water and separation in a centrifuge or suction until the reaction to free calcium ions disappears; it is usually sufficient to repeat these operations two to three times.

The washed calcium salt is thoroughly centrifuged and then dewatered by slurrying in acetone or isopropyl alcohol and centrifuged again. The cycle is repeated one more time to minimize the water content of the product before drying.

The drying is carried out in the usual manner in a hot-air fluid drier. The product obtained having a particle size predominantly above 100 micrometers is then packaged and sterilized, here by geme-radiation. The product is suitable for use as a powder hemostatic.

Example 3

The material prepared according to Example 1 is dispersed in a 1: 1 mixture of water and acetone with a dry matter content of 22 to 25 wt. and the slurry formed is crushed by passing through a gear mill. However, another suitable mill can be used. Then separation, dewatering as in Example 2 is carried out and finally the material is dried in a fluidized bed or other suitable oven.

The microcrystalline oxycellulose fine powder thus produced contains 78 wt. % particles below 40 microns and 22 wt. It is suitable for the same purpose as the product of Example 1.

Example 4

After neutral washing, the material prepared according to Example 2 is dispersed in a 1: 1 mixture of water and isopropyl alcohol with a dry matter content of 16 to 18% by weight. and the formed dispersion is crushed by passing through a corundum disc mill. The crushed oxidized cellulose is then separated and dewatered as in Example 2, and the micronized oxycellulose finely ground powder thus obtained is dried by sucking air at 35 ° C.

Product containing 86 wt. % particles below 35 microns and 14 wt. It is suitable as a hemostatic in the form of an aerosol pressure pack for its fineness.

Example 5

The powdered microcrystalline oxycellulose was prepared according to the procedure of Example 2 except that a concentrated sodium or ammonium acetate solution was used as neutralizing agent. The resulting product is a monocarboxylic cellulose sodium or ammonium salt.

From what has been written so far, it can be seen that the main advantages of the present invention compared to the present state are:

Oxidation of the undried, i.e. wet, hydrolysed cellulosic material, thereby preserving its high reactivity and allowing the oxidation of microcrystalline cellulose with a high carboxyl group content.

Use a minimum amount of nitric acid to effect oxidation. The ratio of nitric acid to microcrystalline cellulose is 1: 1.

Significantly reduce the reaction time to -6-12 hours depending on the degree of substitution desired.

In view of the advantage referred to in point 2, the regeneration of nitric acid is eliminated, thereby simplifying the process.

Minimum amount of waste water and prevent the escape of gaseous fumes of the reaction into the environment.

Reducing the loss of oxidation mixture by about 80% versus drip separation used in the known method, wherein the oxidized gauze retains about 4-5 kg of oxidation mixture per kg of material.

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The use of cellulose with an average polymerization degree having a favorable physiological sorption value of 250 to 400.

Eliminate manual work when handling dispersible material that can be handled as a liquid.

The powdered microcrystalline oxycellulose according to the invention is intended primarily for health care as hernostatics in the form of powders, pastes, petrolatum and suppositories. However, it can also be used for technical purposes, for example for chromatographic columns, for filtering wine or fruit juices, or as a selective ion exchanger.

Claims (2)

SUBJECT OF THE INVENTION Process for the production of powdered microcrystalline oxycellulose or salts thereof, wherein the cellulosic material is oxidized with nitric acid and alkaline nitrite, after which the oxidized cellulosic material is treated according to the intended use of the final product, characterized in that the cellulosic material, especially in the form of fibers, e.g. In the case of boiling 0.5N to 4.5N nitric acid, it is freed from the amorphous fraction and transformed into a powder, the reaction mixture is cooled and then the powdered microcrystalline cellulose is separated, which is wet. oxidized by activation in nitric acid, then concentrated by centrifugation and placed in a hermetically sealable mixer where an aqueous solution of an alkaline nitrite such as sodium is added with stirring and after completion of the reaction for 6 to 12 hours the reaction mixture is cooled, passed through acid wash and by additional treatment, for example, dewatering, crushing, converting from acidic fossils to oxycellulose salt, drying, adjuvating, sterilizing. 2. A method according to claim 1, characterized in that after the acidic washing operation in a mixture of water with an alcohol such as ethanol or isopropanol, or water with a ketone such as acetone which is repeated, for example two or three times alternately with blasting. by neutralization, for example with an equimolar mixture of calcium, sodium or ammonium chloride and acetate to a carboxycellulose salt, preferably to a calcium, sodium or ammonium salt.