JPH039926A - Preparation of fine particle of chitosan - Google Patents

Abstract

PURPOSE:To obtain a fine particle of chitosan with a particle diameter of 300mum or smaller and uniform particle size distribution by mixing an acidic soln. of chitosan with a water-soluble cationic polymer compd. to form a fine particle dispersion of chitosan, coagulating the fine particle of chitosan and neutralizing it with an alkali. CONSTITUTION:An acidic soln. of chitosan and a water-soluble cationic polymer compd. are mixed to form a fine particle dispersion of chitosan, which is coagulated by mixing it with a coagulating agent. Then, the fine particle of chitosan is neutralized with an alkali. As the water-soluble cationic polymer compd., e.g. an ammonium salt of the formula is cited. In the formula, R<1> and R<2> are the same or different from each other and each is a hydrogen atom, a 1-5C lower alkyl group or a benzyl group; X(-) is a monovalent anion; n is a number expressing the degree of polymn. As the cationic polymer compd., it is pref. that the number-average mol.wt. is 1,000-100,000 and it is used as an aq. soln. with 10-20wt.%.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing minute chitosan particles.

More specifically, the present invention relates to a method for producing microspherical chitosan particles suitable for chromatography fillers, carriers for immobilized enzymes, and the like.

(Prior art) In chitin, N-acetyl-D-gelcosaelectron is β-(1→
4) It is a bonded polysaccharide, and is present in large quantities in the carapace of crabs, shrimps, etc. Chitosan is an N-deacetylated product of chitin, and is a C-2
The acetamido group at the position becomes a free amino group, and the degree of deacetylation is usually about 10 to 90%. Chitin and chitosan are collectively called chitin. Chitin is insoluble in general organic solvents due to its crystalline structure due to the extremely strong intermolecular forces of aquinoacetyl groups, but chitosan is soluble in dilute acetic acid, dilute formic acid, etc. Therefore, it is easy to mold a chitinous article from a chitosan solution, and six methods have been proposed for making chitin particles into fine particles by making a chitosan solution into fine particles.

As a method for producing chitosan particles, JP-A-56-1
No. 8148 and Japanese Unexamined Patent Publication No. 58-57401,
A manufacturing method is disclosed in which a hydrophobic solvent containing an emulsifier is added to an acidic aqueous solution of chitosan to form an emulgene, and this is embedded in an aqueous alkaline solution to coagulate and precipitate chitosan into granules. In these methods, chitosan is made into fine particles in a hydrophobic solvent, so it is necessary to lower the chitosan concentration in the chitosan acidic aqueous solution, and the resulting granules have weak strength and uniform particle morphology. The drawback was that it was difficult to obtain.

Special MI Sho 61-403871 published &, Unexamined Patent Publication Sho 111-
Publication No. 78504 discloses a method for producing particulate chitosan with extremely uniform particle size by dropping an acidic chitosan solution into a basic solution and coagulating it. In these methods, an acidic chitosan solution is allowed to fall from a nozzle into a coagulation bath in the form of droplets for 2 () to 42 J! / x (84G - 36011 m) is clearly obtained.

JP-A-62-210101 discloses that porous ultrafine particles of 20 μm or less can be obtained by spraying an acidic chitosan aqueous solution into a high-temperature atmosphere, drying it, and then neutralizing it in a basic solution. is clearly indicated.

(Problems to be Solved by the Invention) The purpose of the present invention is to obtain minute chitosan particles with a particle diameter of 500 μm or less and uniform particle size, and to obtain fine chitosan particles having a uniform particle size and a chitosan acidic solution and a water-soluble cationic polymer compound. mix,
The present invention provides a novel manufacturing method for producing chitosan microparticles.

(Means for Solving the Problems) The present invention involves mixing an acidic chitosan solution and a water-soluble cationic polymer compound to produce a chitosan fine particle dispersion, and then coagulating the chitosan fine particles by mixing with a coagulant. This is achieved by a method for producing minute chitosan particles, which is characterized by the steps of:

The constituent elements of the present invention will be explained in detail.

The chitosan used in the present invention is obtained by washing crab and shrimp shells with water, removing calcium carbonate with dilute hydrochloric acid, heating in an aqueous sodium hydroxide solution, and treating chitin with an alkali to remove proteins. Examples include those having a degree of polymerization necessary for the shape and a degree of deacetylation of 70% or more.

The chitosan acidic solution in the present invention refers to a homogeneous solution in which the above-mentioned chitosan is dissolved in an acidic aqueous solution. Examples of the acidic aqueous solution include aqueous solutions consisting of acetic acid, dichloroacetic acid, hydrochloric acid, formic acid, and sulfamic acid alone or in combination. Chitosan can be dissolved in these acidic aqueous solutions by a known method, and the chitosan concentration depends on the degree of polymerization of the chitosan used, but is usually 0.01 to 10 wt.
%.

The water-soluble cationic polymer compound to be used is, for example, the following formula (1), where 11 and 1 are the same or different and are a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a benzyl group, and xl is - ammonium salt represented by the following formula (summer), where n is a number representing the degree of polymerization;
I is a hydrogen atom or a methyl group, R4,11 and R
6 are the same or different and are a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a benzyl group, and X! is one equivalent of an anion, and m is a number representing the degree of polymerization; and an ammonium salt represented by the following formula (■) 1
, furnace 8 where BF B, a and R are the same or different and are a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, or a benzyl group, XI is an anion equivalent to -, and I is Examples include ammonium salts represented by:

In the above formula (I), R1 and R1 are the same or different and are a hydrogen atom, a lower alkyl group having 1 to S carbon atoms, or a benzyl group. Lower alkyl groups may be straight or branched, for example methyl, ethyl, n-
Propyl, 180-propyl, n-propyl, n-butyl, 5ec-butyl, 1SO-butyl, t-butyl, n-pentyl, and the like can be mentioned. As the lower alkyl group, methyl and ethyl are preferred.

xl is a -equivalent anion, such as a chloride ion, a bromide ion, or a 1/2 sulfate ion. Further, n is a number representing the degree of polymerization, and is, for example, 5 to 1,500, preferably 8 to 1,200.

A lower alkyl group having 1 to 6 carbon atoms represented by R4, Bl or RS in the above formula (1) and X! Specific examples of the one-equivalent anion represented by are the same as the above-mentioned specific examples of the lower alkyl group having 1 to 6 carbon atoms and the one-equivalent anion in the above formula (1). In the above formula (1), m is a number representing the degree of polymerization, and is, for example, S to 1000, preferably 6 to 80G.

Specific examples of the lower alkyl group having 1 to S carbon atoms represented by BT R1 or R in the above formula (1) and the sous equivalent anion represented by XI are as follows:
It is the same as the above specific example of the lower alkyl group of ~lS and one equivalent of an anion. In the above formula (1), l is a number representing the degree of polymerization, for example, S to 1000, preferably 6 to 800.

Cationic polymer compound (formula (1) above, (1)
and ammonium salts of (1)), for example, poly(N,N-dimethyl-3,6-methylene-piperidium chloride), poly(N,N-diethyl-5,6
-methylenepiperidium chloride), privinylbenzyltrimethylammonium chloride, polyvinylbenzyltriethylammonium chloride, polymethacrylooxyethyltrimethylammonium chloride, polymethacrylooxyethyltriethylammonium chloride, and the like.

The cationic polymer compound is, for example, sOO to 150,000, preferably too much to 100,000, more preferably 500,000
It has a number average molecular weight of 0 to 10,000.

According to the method of the present invention, the chitosan acidic solution and the water-soluble cationic polymer compound are first mixed. For mixing, any means can be used as long as a chitosan fine particle dispersion is produced.

For example, mechanical stirring using stirring blades, baffles, etc., ultrasonic stirring, or mixing using a static mixer can be carried out alone or in combination.

The water-soluble cationic polymer compound is preferably used as an aqueous solution, more preferably the concentration of the cationic polymer compound is 6 to 50% by weight, preferably 7 to 25% by weight,
In particular, it is used as a 10-20% by weight aqueous solution.

The chitosan acidic solution and the cationic polymer compound are 1 to 50 parts by weight, more preferably 6 to 16 parts by weight, particularly preferably 6 parts by weight of the cationic polymer compound per 1 part by weight of chitosan.
~10 parts by weight is used and mixed. The temperature during mixing is sG°C or higher, preferably 60-80°C.
Performed in the range of °C. At temperatures lower than 60° C., it is not possible to obtain a base chitosan microparticle dispersion capable of providing the desired microchitosan particles.

According to the method of the present invention, the produced chitosan fine particle dispersion is coagulated and neutralized to produce chitosan fine particles. Coagulation and neutralization may be performed simultaneously or sequentially.

If coagulation and neutralization are carried out over time, coagulation can be carried out by cooling the dispersion or mixing it with a coagulant, and then neutralization is carried out by contacting with an alkali. .

The above-mentioned coagulation reaction is carried out while adding a mixing operation to the generated dispersion, but the mixing operation can be stopped and a coagulant added, or the dispersion can be coagulated by adding the dispersion to a solution containing a coagulant. You can also do it.

Furthermore, the coagulation reaction is carried out at a temperature lower than the temperature at which the dispersion is produced.

As the coagulant, alcohols such as methanol and ethanol, alkaline substances such as sodium hydroxide and potassium hydroxide, or mixtures thereof are used.

The acidic dispersion containing coagulated chitosan particles is then neutralized. Neutralization is performed with an alkaline substance such as sodium hydroxide to completely neutralize and regenerate the coagulated chitosan particles.

It is also possible to separate the coagulated chitosan particles from the acidic dispersion and neutralize the coagulated chitosan particles.

The micro chitosan particles thus obtained are filtered, washed with water and dried. Drying methods include vacuum drying,
Examples include a method of freeze-drying.

(Example) Example 1 Chitosan (Niaron Flock manufactured by Kyowa Yushi ■) 70f was added to 6
It was dissolved in 950 g of 6 wt% aqueous hydrochloric acid solution at 0°C.

A portion of this solution 601 was mixed with 14ON of a 20 wt % aqueous solution of methacryloxyethylammonium chloride (molecules J128,000) at a temperature of 60° C. and a stirring rotation speed of 20 rpm for 10 minutes to obtain a fine particle dispersion of chitosan.

Stop stirring and leave for 2 hours! Cool to 6℃, then stir again at 5Q! Methanol was added while stirring at 60°C, and the solidified fine particles were separated using a G4 glass filter and neutralized by washing with a 5 wt% NaOH aqueous solution. It was dried in a vacuum dryer at ℃.The obtained chitosan fine particles had an average particle size of 20 μm.

Example 2 Chitosan (Niaronfloc manufactured by Kyowa Yushi ■) 70F was added to 6
It was dissolved in 5 wt% aqueous hydrochloric acid solution 950f at 0°C.

This solution 601 and poly(N,N-dimethyl-5,5-methylene-piperidium chloride) with a molecular weight of 50,000!
A fine particle dispersion of chitosan was obtained by stirring and mixing 140 g of Owt% aqueous solution at a temperature of 60° C. and a stirring rotation speed of 20 rpm for 10 minutes.

Stirring was stopped and the mixture was cooled to 25°C over 2 hours, and then methanol was added while stirring at a stirring speed of 6 rpm, solidified, and the solidified fine particles were filtered from door to door using a G4 glass filter. It was washed and neutralized. Furthermore, it was thoroughly washed with 60°C warm water and dried in a 60°C vacuum dryer.

The obtained chitosan fine particles have an average particle size! It was 0 μm.

(Effect of the invention) The fine chitosan particles obtained according to the production method of the present invention have a particle size of ! It has a narrow and uniform particle size distribution of 00 μm or less, and is suitable for use as a chromatography packing material, a carrier for immobilized enzymes, and the like.

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Claims (1)

[Claims] A microscopic method characterized by mixing an acidic chitosan solution and a water-soluble cationic polymer compound to produce a chitosan fine particle dispersion, coagulating the chitosan fine particles by mixing with a coagulant, and then neutralizing with an alkali. Method for producing chitosan particles.