CS221227B1 - Method of making the powdered oxidated cellulose - Google Patents

Abstract

The medical and chemical industry of the present invention provides a process for producing oxidized cellulose powder, or salts thereof, with a microcrystalline structure and a hero-static effect. Cululosic material, in particular cotton liners, is oxidized with a mixture of nitric acid and heat-phagged alkaline nitrite. Thereafter, the oxycellulose thus obtained is washed at least in part, whereupon its native structure is converted into microcrystalline by controlled heterogeneous acidic hydroysis, optionally further crushed and / or neutralized from the acid form to the oxycellulose salt. Finally, conventional treatments such as washing, dewatering, drying, adjusting and sterilizing are carried out.

Description

The present invention, in the medical and chemical industries, provides a process for the production of powdered oxidized cellulose or its salts with a microcrystalline structure and a heroostatic effect. The cejulose material, especially cotton liners, is oxidized with a mixture of nitric acid and thermally flogmatized alkaline nitrite. Thereafter, the oxycellulose thus obtained is at least partially washed, whereupon its native structure is converted to microcrystalline by controlled heterogeneous acid hydrolysis, optionally crushed and / or converted by neutralization from the acid form to the oxycellulose salt. Finally, conventional treatments such as washing, dewatering, drying, adjusting and sterilizing are performed.

BACKGROUND OF THE INVENTION The present invention relates to a process for the production of powdered oxidized cellulose or salts thereof with a microcrystalline structure and hemostatic action.

Heretofore, powdered oxidized cellulose or oxycellulose and its salts are made by grinding or grinding oxidized cellulose formed by oxidation of cellulosic fibers, fabrics, knitted fabrics, etc. However, crushing fibrous material is difficult, so the process known from USP 3,112,479 uses oxidized cellulose to crush, which is partially chemically degraded, so it is brittle and therefore better crushed. A disadvantage of this known process is the need for long-term aging of the oxidized cellulose, in which its chemical degradation is associated not only with the embrittlement of the oxidized cellulose but also with its yellowing and reduced physiological activity. This procedure cannot produce particles of colloidal dimensions.

It is also known to produce powdered oxycellulose such that powdered or microcrystalline cellulose is oxidized by mechanical crushing or acid heterogeneous hydrolysis of cellulose with native structure. This oxidation, described by A. M. Belfort and R. B. Wortz in Industrial Chemistry, Product Research Development, 1906, Vol. 5, NO 1, 41-46, is carried out with nitrogen dioxide gas and also with a solution thereof in carbon tetrachloride; the powdered oxycellulose produced by this process exhibits a low degree of oxidation, only 0.23, and is not suitable for medical purposes. Another disadvantage of this process is the relatively high cost of the pulverulent starting cellulose due to its production technology, which requires, on the one hand, a material resistant to boiling dilute hydrochloric acid and, on the other hand, an increased energy requirement, since drying operations must be included.

According to U.S. Pat. No. 185 3:66 to which the present invention is based, powdered oxycellulose and its salts for medical purposes are produced either by wet grinding of fibrous oxidized cellulose in a Hollander or by dry grinding of oxycellulose or its salts after radiation irradiation. Wet grinding or dry grinding takes many hours and is therefore energy intensive, while increasing the risk of heavy metal contamination of the final product and providing a powder of several hundred microns, thus reducing the possibility of use of the product, for example, not suitable for spray packaging.

The above-mentioned disadvantages, among which the complexity of the production process and the time and energy requirements, are intended to eliminate the method for producing pulverized oxidized cellulose or its salts with a hemostatic effect in which the cellulosic material, in particular in the form of fibers, e.g. The treatment of the oxidized cellulosic material, i.e. oxycellulose with a preserved native structure, is adjusted according to the intended use of the end product, for example oxycellulose is washed, dewatered, dried According to the invention, after the treatment of the oxidation bath, i.e. before the treatment, the at least partially washed oxycellulose with the preserved native structure is treated with at least one A member of the group consisting of reshaping oxycellulose with a preserved native structure into oxycellulose in the form of aggregates with a microcrystalline structure with aggregate sizes predominantly over 100 microns by controlled heterogeneous acid hydrolysis, crushing aggregates into particles of predominantly less than 100 microns and the oxycellulose salt form, in each case the oxycellulose being treated by the first operation mentioned in this group and this operation being performed as the first of the selected operations. The controlled heterogeneous acid hydrolysis of the oxidized cellulose is carried out in a boiling medium of 7 to 60 minutes and containing a 1 to 3 N dilute mineral acid, in particular nitric acid adhered to the oxidized cellulose from the oxidation bath. The crushing of the aggregates to particles of a size predominantly below 10 microns, for example 1 to 40 microns, is carried out by mechanical crushing of the hydrolysed oxycellulose aggregates or oxycellulose salt aggregates in the form of an aqueous and / or aqueous-alcoholic and / or aqueous acetonic dispersion containing up to 75 wt. % alcohol with a C 1 to C 3 hydrocarbon chain and / or acetone and 5 wt. % to 35 wt. % dry matter aggregates. Aggregates can be converted from the acid form to an oxycellulose salt, in particular to a calcium, sodium, ferrous, ferrous, aluminum or ammonium salt. The process according to the invention allows five variants of its implementation, the choice of which depends primarily on the intended use of the final product. In the first variant, only a heterogeneous acid hydrolysis is performed from the group of operations. The final product is suitable for technical purposes, for example in chromatography columns or for filtering wine and fruit juices. In the second variant, a heterogeneous acid hydrolysis is carried out from the group of operations and then the aggregate is crushed. The end product is suitable for the same uses as the first process variant, but is substantially finer. In the third variant, from the group of operations, heterogeneous acid hydrolysis is carried out, then crushing the aggregates and finally converting the crushed aggregates by neutralization from the acid form to the oxycellulose salt, the particle size of which is predominantly below 100 microns, especially 1-40 microns. Thus made microcrystalline oxidized cellulose is suitable for spray- _{from the} pack. In the fourth variant, a heterogeneous acid hydrolysis is carried out from the group of operations and then the aggregates are converted from the acid form to the oxycellulose salt by neutralization. This variant enables a safe, dust-free process to produce a powdered oxycellulose substitute produced by the process of art. AO No. 185 366. In the fifth variant, a heterogeneous acid hydrolysis is carried out from the group of operations, and then the aggregates are neutralized from the acid form to the oxycellulose salt, and finally the aggregates are crushed to particles of less than ΙΟΰ microns, for example 1-40 microns. The product differs from the product obtained by the third variant only in its production technology.

In the process according to the invention, the objective of heterogeneous acid hydrolysis of oxycellulose is to cleave the glucosidic linkages of cellulose macromolecules, free up the disordered amorphous regions of the structure, and hydrolyze the cellulose chains to form cellulose aggregates. Mechanical crushing of these aggregates releases so-called microcrystallites, which differ in nature from the original fibers. The type of mineral acid used, its concentration and the temperature of hydrolysis influence the kinetics of the decrease of the polymerization degree of the chains. If a mineral acid other than nitric acid, such as hydrochloric or phosphoric acid or sulfuric acid, is used in the hydrolysis, the nitric acid adhering to the oxycellulose from the oxidation bath must first be thoroughly washed.

An important feature of the process according to the invention is the hydrolysis of the undried oxidation product. Cellulose material, after oxidation according to MS. AO No. 185 '366, in the case of hydrolysis with nitric acid, it is only freed from excess acidity by centrifugation or suction of the oxidation bath and the desired acidity of the hydrolysis bath is achieved by dilution with water.

The process according to the invention has a number of advantages over other known processes for the manufacture of oxidized cellulose powder, such as:

1. Allows the selection of a single acid, nitric acid, both for the preparation of the oxidation bath and for the controlled heterogeneous acid hydrolysis using nitric acid adhering to oxycellulose from the oxidation bath. This simplifies the manufacturing process and reduces the complexity of manufacturing equipment, which may be of commercially available grade 17 stainless steel.

During the acid hydrolysis of oxycellulose, the content of minerals, especially heavy metals, adhered to the original cellulose is significantly reduced, which is important for the physiological application of the final product.

3. The invention makes it possible to process the cellulosic material in the form of fibers, while other known processes for producing powdered oxidized cellulose are treated with a textile product, woven or knitted, which requires spinning and weaving or knitting, while these processes are omitted.

4. The dry crushing of oxidized cellulose, which creates a dust-free, non-explosive atmosphere, is eliminated. All operations, except for some treatment plants, are carried out in aqueous suspension.

5. The invention makes it possible to produce oxycellulose with a precisely defined particle size.

5. The crushing of the hydrolysed oxycellulose requires a minimum amount of energy and a very short time, usually 45 to 60 minutes, while the dry crushing of the oxidized cellulose lasts for hours and degrades and decarboxylates the oxycellulose while avoiding a particle size of 1 to 40 microns ,

7. Microcrystalline oxycellulose, unlike mechanically crushed oxidized®, cellulose, can be applied in the form of a spray because it is substantially finer,

8. The process according to the invention yields a product whose particles are smaller than the particles of powdered oxidized cellulose produced according to U.S. Pat. AO No. 185-316, so that the product exhibits a larger activation surface and thus a higher hemostatic effect and faster hemostasis and resorption in living animal tissue.

Further advantages of the invention will become more apparent from the description of exemplary embodiments thereof.

Example 1

High-temperature, tempered cotton linters weighing 450 g and containing 98.8% by weight % of alpha-cellulose were oxidized according to the procedure of Art. AO No. 185 365; that is, the cotton liners were treated with an oxidation bath containing a mixture of nitric acid and sodium nitrite phlegmatized by heat exposure, after which the oxidized cotton liners were centrifuged to remove the excess oxidation bath. After centrifugation, the oxidized cotton liners contained 51.3 wt. % of the oxidation mixture adhering to the fibers. The following analytical values were determined for a sample of these oxidised cotton liners after washing and drying:

Free uronic carboxylic acid content 13.6%

Solubility in 0.1 N NaOH 100.0%

Ash content 0,21%

Bound nitrogen content 0,38%

Thereafter, the oxidized cotton liners moistened with the fiber-adhering oxidation mixture were dispersed in 10.0 L of distilled water and after mixing the dispersion, the acidity of the liquid sample was determined by titration of the liquid sample and adjusted to 1.5 N HN'0s. The dispersion was transferred to a 2Ό liter glass vessel equipped with a stirrer and a heating or cooling glass coil and brought to boiling for 35 to 40 minutes while maintaining stirring for a period of 35-40 minutes. 12 minutes while maintaining the shape for 7 to 60 minutes. Then the dispersion was cooled by adding 5 liters of cold distilled water and introducing cooling water into a glass coil.

Upon reaching a temperature of 45-50 ° C, stirring was discontinued and the sedimented oxycellulose aggregates were decanted twice after mixing and re-settling with distilled water. The slurry was then first sucked off under suction and then freed of excess acidity by repeated dispersing in clean water or, optionally, in an aqueous alcoholic cell with an acetone solution and suctioning again. Once the acidity of the filtrate reached pH 3-4, as determined by universal pH paper, oxycellulose was aspirated sharply and transferred to a polyethylene container. After determining the dry matter content of a portion of the sample, the resulting oxycellulose weight after hydrolysis was found to be 378 g, corresponding to a 16% weight loss.

The hydrolyzate thus obtained was then dispersed in 1.8 l of a 1: 1 v / v mixture of water and isopropanol containing about 15 wt. %. Instead of an aqueous alcoholic medium, an aqueous or aqueous acetonic medium or a mixture of these mediums may also be used, provided that the dry matter content is in the range of 5 to 35 wt. % and the content of acetone or alcohol or a mixture thereof is 0 to 75 wt. %. The dispersion formed was poured into a 5 liter porcelain ball mill where it was milled for 45 minutes. Instead of a ball mill, another functionally similar device can be used, for example a gear or corundum mill, an atritor, and the like. Crushed oxycellulose aggregates were suction separated on a G3 glass frit and the thus separated oxycellulose powder thus obtained is as described. AO No. 185 366 neutralized to the oxycellulose calcium salt by dispersing in a neutralizing solution containing an equimolar mixture of calcium chloride and acetate in an amount of 6% by weight. % dissolved in an aqueous solution of isopropanol containing 33 vol% isopropanol. The oxycellulose powder could be soaked in a neutralizing solution maintained at a pH between 6.0 and 6.5, and then centrifuged at room temperature and the acidic filtrate returned to the reservoir. Subsequently, a 35 wt.% Dilute acetone solution was soaked and centrifuged. %, thereby displacing the acidity produced by the neutralization. These operations were repeated until the pH of the neutralized solution filtrate reached 6.0 to 6.5. The neutralization solution filtrate was treated by adding a slurry of 10 to 20 wt. % calcium hydroxide to pH 6.0 to 6.5. The product obtained was then first washed with dilute alcohol or acetone at a concentration of 50% by weight. % and then dried on a glass frit 03 by suctioning air at a temperature of 3-8 ° C; the analysis found the following values:

Free uronic carboxyl content 12, β%

Bound calcium content 6.5%

Bound nitrogen content 0,211%

Particle size:

wt. % of product below 40 < % of the product from 40 to 50 'μΐΐϊ

The product thus obtained is particularly suitable for use in medicine as a hemostatic.

Example 2

Air-dry cotton linters weighing 150 g and containing 97.6% by weight % of alpha-cellulose were oxidized according to the procedure of Art. AO No. 185 366 as shown in Example 1. The centrifugation reduced the content of the oxidation mixture in linters to 53% by weight. %. The following analytical values were determined for a sample of these oxidized cotton liners after washing and drying:

Free uronic carboxylic acid content 13,23%

Solubility in 0.1 N NaOH 100 ', 00'%

Ash content 0,07%

Bound nitrogen content 0,12%

Thereafter, the oxidized cotton liners moistened with the fiber-adhering oxidizing bath were dispersed in 4 liters of distilled water, and after mixing the dispersion, the acidity of the liquid sample was determined by titration of the liquid sample and adjusted to 2.5 Ν HNO3.

Thereafter, the dispersion was transferred to a 20-liter glass vessel equipped with a stirrer and a heating coil of glass and brought to boiling for 15 to 40 minutes with stirring. The dispersion was then cooled by adding 3 liters of cold distilled water and introducing cooling water into a glass coil.

Upon reaching 35 ° C, stirring was discontinued and the sedimented oxycellulose aggregates were decanted three times after mixing and resettling with distilled water. The slurry was then aspirated several times on a frit and repeatedly dispersed until the acidity of the filtrate was reduced to a pH of 4-5. After determining the dry matter content of a portion of the sample, a 15.5 percent weight loss was found.

The hydrolyzate thus obtained was then dispersed in 1 liter of neutralization solution consisting of an equimolar mixture of calcium chloride and calcium acetate in an amount of 5% by weight. percent. The neutralization was carried out for 30 minutes with occasional mixing of the dispersion. This was followed by multiple aspiration of the slurry on the frit and dispersion in dilute alcohol or acetone at a concentration of 50% by weight.

percent until the calcium ion reaction disappears in the filtrate.

The neutralized oxycellulose aggregates were then dispersed in 1 liter of a 1: 1 mixture of water and acetone with a dry matter content of 10.0 wt. % and the formed dispersion was poured into a 5 liter porcelain ball mill where it was crushed for 60 minutes. The crushed cellulose aggregates were then separated on a G3 glass frit. The microcrystalline oxycellulose powder thus obtained was then dried by sucking air at a temperature of 35 DEG C. The analysis showed the following values:

Free uranium acid content 12.64%

Solubility in 0.1 N NaOH 68.7.0%

Bound calcium content 5,40%

Ash content 7.83%

Bound nitrogen content 0,34%

Particle size:

wt. % below 40 μπι wt. % from 40 to 45 µm

The microcrystalline oxidized cellulose thus obtained is particularly suitable for spray packaging because of its fineness.

Example 3

The production of oxycellulose in the form of aggregates having a particle size predominantly above 100 microns was carried out according to Example 1 or 2, but with the difference that

A process for the production of powdered oxidized cellulose or salts thereof having a hemostatic effect, wherein a cellulosic material, in particular in the form of fibers, for example liners, is treated with an oxidation bath consisting of a mixture of nitric acid and alkaline nitrite phlegmatized by thermal exposure. the oxidized cellulosic material, i.e. oxycellulose with a preserved native structure, is treated according to the intended use of the end product, for example oxycellulose is washed, dehydrated, dried, adjusted and optionally sterilized, characterized in that after oxidation bath treatment, i.e. before treatment the at least partially washed native cellulose oxycellulose is treated by at least one operation selected from the group consisting of reshaping the native cellulose oxycellulose into oxycellulose in the form of aggregates having a microcrystalline structure of aggregate size While most of the above * 100 microns by controlled heterogeneous acidic hydrolysis of grinding aggregates to a particle size mainly below 100 microns and converting AG10 woman heterogeneous acidic hydrolysis was decided to modify the product by known techniques, i. both the crushing of aggregates and the neutralization of oxycellulose have been deleted.

The product is suitable for technical purposes, for example for chromatography columns or for filtering wine or fruit juices.

Example 4

The preparation of oxycellulose in the form of aggregates having a particle size of predominantly below 100 microns, in particular 1-10 microns, was carried out according to Example 1, but with the exception that the oxycellulose neutralization operation was omitted after the aggregate crushing operation and conventional finishing treatments of the product obtained.

The product thus obtained is suitable for the same purpose of use as the product of the example

Claims (9)

The production of calcium oxycellulose as aggregates having a particle size predominantly above 100 microns was carried out according to Example 2, but with the exception that after the oxycellulose neutralization operation was completed, the crushing operation was omitted and conventional finishing operations of the obtained product were made. The product is a suitable substitute for powdered oxidized cellulose produced according to US. AO No 185 36 * 6. The manufacturing process is safe because the dry crushing operation has been eliminated. In accordance with the present invention, the regatts are neutralized from an acid form to an oxycellulose salt, in which case the oxycellulose is in each case processed by the first operation mentioned in this group and this operation is performed as the first of the selected operations. 2. The process according to claim 1, wherein the controlled heterogeneous acid hydrolysis is carried out in a boiling medium for 7 to 60 minutes and containing 1 to 3 N dilute mineral acid, in particular nitric acid adhered to oxycellulose from the oxidation bath. Method according to claim 1, characterized in that the crushing of the aggregates into particles of a size predominantly below 100 microns, for example 1 to 40 microns, is carried out by mechanical crushing of the hydrolysed oxycellulose aggregates or oxycellulose salt aggregates in the form of aqueous and / or aqueous alcohol or and aqueous acetonic dispersions containing up to 75 wt. % alcohol with a C 1 to C 3 hydrocarbon chain and / or acetone and 5 wt. % to 3.5 wt. % dry matter aggregates. Process according to Claim 1, characterized in that the aggregates are converted from the acid form into an oxycellulose salt, in particular calcium, sodium, iron, iron, aluminum or ammonium salt by neutralization. 5. Process according to claim 1, characterized in that only a heterogeneous acid hydrolysis is carried out from the group of operations. 6. The process of claim 1, wherein the group of operations comprises firstly heterogeneous acid hydrolysis and then crushing the aggregates. 7. The method of claim 1, wherein the group of operations comprises heterogeneous acid hydrolysis, then crushing of the aggregates and finally converting the crushed aggregates by neutralization from the acid form to the oxycellulose salt. 8. The process of claim 1, wherein the group of operations comprises firstly heterogeneous acid hydrolysis and then converting the aggregates by neutralization from the acid form to the oxycellulose salt. 9. The process of claim 1, wherein the group of operations comprises firstly heterogeneous acid hydrolysis, then converting the aggregates by neutralization from the acid form to the oxycellulose salt and finally crushing the aggregates.