JPH0284401A - porous microcellulose particles - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to porous microcellulose particles, and more specifically, they have a large specific surface area and a developed pore structure that are not found in conventional particles, and The present invention relates to porous microcellulose particles characterized by having a type 1 crystal structure. The substance of the present invention is used as an adsorption carrier for foods and medicines, a compression molding aid, a fluidity improver, an additive for cosmetics, and the like.

(Prior Art) Porous cellulose particles have been used in various fields as gel filtration agents, raw materials for cellulosic ion exchangers, carriers for affinity chromatography, polymer carriers, cosmetic additives, and the like.

As a manufacturing method, for example, viscose is dropped in granular form into a coagulation regeneration bath to perform a solid regeneration.
A method for obtaining porous regenerated cellulose particles of ~170 mesh (Japanese Patent Application Laid-Open No. 48-60753), or a method of dissolving cellulose in an ammoniacal copper hydroxide solution and dropping it into benzene containing an emulsifier to disperse the cellulose solution, A method of obtaining cellulose globules by adding it to a regeneration bath (Special Publication No. 52-11)
237) and a method for obtaining porous cellulose spherical particles by saponifying granular particles of cellulose triacetate (Japanese Patent Publication No. 6312099). However, since they are used as chromatographic carriers, the products are usually in a wet state, and when dried they shrink and cannot maintain sufficient pore volume.

In addition, since these processes involve dissolving and regenerating cellulose or cellulose derivatives, their crystal form is the ■ type.

As dry porous cellulose particles, Japanese Patent Publication No. 57-
No. 45254 describes a method for solidifying a viscose suspension in a water-immiscible liquid by heating and then acid decomposition to obtain spherical cellulose particles, in which "up to about 30% Particles with porosity are dimensionally stable;
"It can be dried", but no specific description is given because it is not suitable for the purpose of use. Also, JP-A-63
No. 90501 describes a method for obtaining porous cellulose particles by coagulating and neutralizing a fine particle dispersion of a mixture of cellulose xanthate and an alkaline aqueous solution of a water-soluble polymer compound, and then removing the water-soluble polymer. is shown, but there is no description of the specific surface area. Because these melting and regeneration operations are carried out, the crystal form of the product is still type II.

The crystalline forms of cellulose are known as ■-type, ■-type, ■-type, ■-type, etc. Among them, ■-type is especially known as "natural cellulose", ■
The type is called "regenerated cellulose." Natural cellulose has been used as an edible vegetable fiber since ancient times, and is now widely used as a dispersion stabilizer for liquid foods and as an excipient for pharmaceuticals.Regenerated cellulose is used in clothing materials such as rayon yarn, cupro yarn, It is used as a spherical particle as a carrier for the aforementioned chromatography. The fields of use for the type ■ and type ■ are different, and the difference in crystal form is an issue that should be kept in mind depending on the purpose of use.

It is known that cellulose powder with a large specific surface area can be prepared by using an organic solvent substitution method or a critical point drying method. (Masato Usuda, Paperback Technical Association Journal, Normal (4), 423
-433 (1982)) L or they are approximately 3
It only has pores of 00 Å or less, and does not have larger pores, and its pore volume cannot be said to be sufficient.

(Problems to be Solved by the Present Invention) The present inventor has developed a highly developed pore structure that is different from conventional ones, has a sufficient pore volume, and has a large specific surface area in a dry state. The present invention was achieved as a result of intensive efforts to obtain porous natural cellulose microparticles having the following properties. It is an object of the present invention to provide new porous microcellulose particles.

As mentioned above, conventionally known porous cellulose particles are
Both are for dissolving and dissolving cellulose or cellulose derivatives.
Due to the regeneration process, its crystal form is a ■ type, and it also has a pore structure developed in the dry state (large diameter pores and sufficient pore volume) and a large specific surface area. There was no.

(Means for Solving the Problem) The present invention has a crystal form of ■ type and a specific surface area of 20rrf.
/g or more, has a porous structure with a diameter of 0.01 μm or more, a pore volume of 0.3 cm3/g or more, and an average particle size of at most 100 μm. It is.

The present invention will be explained in detail below.

The crystalline form of the porous cellulose microparticles according to the present invention is a -type, and has the same crystal structure as natural celluloses such as ramie, konton linter, and wood pulp. Furthermore, the porous cellulose microparticles according to the present invention often have a spherical shape in which the ratio of the major axis to the minor axis is relatively close to 1, and the surface thereof may be in a state of having countless minute pores of 1 μm or less.
Alternatively, the porous surface and rod-shaped cellulose particles coexist. Porosity extends not only to the surface but also to the interior, and the volume of pores with a diameter of o, oiμm or more is 0.3c+fl/g or more and the specific surface area is 20rd.
/ g or more.

If any of these three conditions that define the fine pore structure are lacking, the intended effects of the present invention cannot be achieved. Generally, when the pore diameter is large, for example 0.1 μm or more, the pore volume tends to be large, and when the pore diameter is small, the specific surface area tends to be large. However, especially in the case of natural cellulose particles that cannot be dissolved or regenerated,
Although it has been difficult to control these three physical properties, the porous cellulose particles according to the present invention possess these properties, and therefore exhibit extremely excellent properties as adsorption carriers for pharmaceuticals and compression molding aids for powders. It is possible.

Furthermore, the porous cellulose particles according to the present invention have an average particle size of 1
00 μm or less. This generally means that the average particle size is 100
This is because powders larger than μm have poor miscibility with other powders, leading to problems as a powder.For example, the product of the present invention can be used as a fluidity improver for mixed powders in pharmaceutical formulations. When used, if the average particle size is large, it will separate from other powders and will not be able to fully demonstrate its function.

The porous cellulose microparticles of the present invention are produced, for example, by the following method, but are not limited to these methods.

The porous cellulose microparticles of the present invention can be obtained by granulating and drying microparticulate natural cellulose dispersed in an organic solvent using a spray drying method.

The organic solvent slurry of cellulose particles can be prepared in various ways. For example, a natural cellulose raw material is made into fine cellulose particles by chemical treatment (acid hydrolysis, etc.) and/or mechanical treatment (pulverization, grinding, etc.), and at this time, the water serving as a dispersion medium is replaced with an organic solvent. However, by further adjusting the solid content concentration, the slurry to be subjected to spray drying can be adjusted. At this time, the point is that the particulate cellulose needs to be dispersed in the organic solvent, so the objective may be achieved by adding a grinding treatment to the slurry after replacing the organic solvent. Rather, organic solvent replacement operation (organic solvent dispersion, repeated filtration)
The workability is better that way. It is suitable for the intermediate raw material of the present invention that the size of the dispersed fine particles is 10 μm or less, preferably 1uII+ or less. As natural cellulose raw materials, ramie, cotton linters, wood pulp, etc., which have a cellulose type crystal form, are used, and as organic solvents, acetone, methanol, ethanol, isopropyl alcohol, n-hexane, n-pentane, cyclohexane, One or more types of benzene etc. are used. (If two or more types are used, they will be replaced in stages.) Spray drying uses an explosion-proof closed system spray dryer, such as a nitrogen gas circulation type spray dryer, because the slurry dispersion medium is an organic solvent. It is necessary to do so.

(Effects of the Invention) The porous cellulose microparticles obtained by the present invention are natural cellulose particles having a pore structure, pore volume, and specific surface area that have not been previously known. It has excellent self-flowing properties as a body. When mixed with other powders, especially when the product of the present invention has a sharp particle size distribution, the fluidity of the mixed powder is greatly improved.
For example, if it is incorporated into a pharmaceutical formulation and tablets are manufactured by direct powder compression, the weight variation of the tablets is significantly reduced. In addition, because it has a developed pore structure and a sufficient specific surface area, it has excellent compression moldability, which is a necessary property as an additive in direct powder compression, and is especially effective when added to formulations with poor moldability. becomes noticeable. Furthermore, when the present invention is physically mixed with a crude drug that has sublimation properties such as aspirin, the active ingredient is adsorbed into the pores, and the dissolution rate of the active ingredient becomes significantly faster. Therefore, it can be used as a dissolution improving agent for pharmaceutical formulations. is also possible.

Since the product of the present invention is made of natural cellulose, it can be freely consumed as food, and since it is chemically inert, it also contributes to the stabilization of pharmaceutical preparations, enzyme preparations, and other preparations.

In addition, porous cellulose particles are used as column packing materials for liquid chromatography, and it is known that cellulose particles with a ■-type crystal structure can be used for optical resolution of optical isomers of amino acids. Since the porous cellulose fine particles of the present invention have a large specific surface area,
It has excellent performance as such a column packing material.

In addition, the product of the present invention can also be used as a compounding agent for cosmetics. For example, when blended into a solid foundation, it is porous and the particles are not too large, so it spreads well, and due to its cellulose properties (hygroscopicity, etc.), it may contain other cosmetic ingredients, sebum, or sweat. Because the makeup has good properties, makeup (does not easily come off) and has a light feeling of use.

In addition, when incorporated into emulsified cosmetics such as creams and emulsions, the emulsifying properties are stable, the product spreads easily during use, and has a light and moist feel after use.

Prior to Examples, a method for evaluating the physical properties of product particles and a method for measuring the physical properties of tablets will be explained.

<Average particle system (μm)> 50 g of sample is sieved for 30 minutes using a JIS standard sieve (Z8801-1987) using a rotary tube sieve shaker manufactured by Yanagimoto Seisakusho, and the particle size of cumulative 50% by weight is defined as the average particle diameter.

If the particle size was small and the average particle size could not be determined by the sieving method, it was measured using a microscope method.

In the microscopy method, an appropriate amount of sample powder is dispersed in a mixed solution of equal weights of water, ethanol, and glycerin, and this is photographed using an optical microscope.The particle size of each particle in the photograph is measured, and the average diameter is calculated. The mean particle size is taken as the average particle size. The particle diameter was measured as the distance between two parallel lines in one arbitrary direction, and the number of samples was 200.

Pore diameter (μm) and pore volume (cffl/g)
> Pore sizer 9300 manufactured by Shimadzu Corporation was used to determine the pore distribution by mercury porosimetry, and the pore volume was expressed as the volume of particulate mercury penetration.

Specific surface area (bo/g)〉 It was measured by the BET method using nitrogen as an adsorbent.

<Crystal form> X-ray diffraction was performed using an X-ray diffractometer, and determination was made from the diffract plum.

Angle of repose (°)〉 Angle of repose measuring instrument (turntable type) manufactured by Tsutsui Rikagaku Kikai ■
The measurements were made using the cone deposition method.

The number of repetitions is 3 and the average value is taken.

Tablet brightness (kg)> Expressed as the load when the tablet is broken by applying a load in the radial direction using a Schroinger stool tester manufactured by Pro India Sangyo ■. The number of repetitions is lO and the average value is taken.

Tablet weight variation (%)〉 Precisely weigh each of the 10 tablets and determine the coefficient of variation.

(Example) Example 1 A commercially available DP valve was cut off and heated at 105° in a 7% aqueous hydrochloric acid solution.
A wet cake (moisture content: 50
%) 3.0 kg was kneaded and ground in a 1042 kneader for about 1 hour. The water content of this ground wet cake was replaced with isobrobyl alcohol (hereinafter abbreviated as IPA), and the final solid content (cellulose content) concentration was 5.5% by weight, water content was 0.4% by weight, and IPA The slurry was adjusted so that the amount was 94.1% by weight. At this time, most of the particulate cellulose was ground to 1 μm or less.

When this slurry was spray-dried using a nitrogen circulation type spray dryer, a powder consisting of extremely spherical particles could be obtained. The coarse particles of 45 μm or more of this powder should be cut according to JIS 2880145μ Tsuru)
The sieved fraction was designated as sample A. The basic physical properties of sample A are
Shown in the table.

Example 2 A wet cake obtained in the same manner as in Example 1 was mixed with IPA.
The mixture was dispersed in water, filtered, dehydrated, and redispersed twice, and then redispersed three times at a processing pressure of 400 kg/cI11 using a Gorlin homogenizer 15M manufactured by Nippon Seiki Seisakusho. Spray dried. The slurry before drying has a solid content concentration of 9.8% by weight and a water content of 2.5% by weight.
The composition was 87.7% by weight of IPA. The obtained sample was passed through a standard sieve (JIS Z 8801250μm
) to cut coarse particles of 250 pm or more,
The spherical sample with a diameter of 250 μm or less was designated as sample B. Sample B
The basic physical properties of are shown in Table 1.

Comparative Example I 1 kg of wet cake obtained in the same manner as in Example 1
was dispersed in acetone 21, filtered and dehydrated.

This acetone-substituted wet cake was placed in a high-speed mixing granulator model NSK 250 manufactured by Itsuhashi Seisakusho, and was crushed and granulated for 1 minute at a stirring blade rotation speed of 500 rpm. This 710
Fraction below um (JIS Z 8801710μm
) was dried at 50°C for 18 hours to obtain a spherical sample C. The basic physical properties of Sample C are shown in Table 1.

Comparative Example 2 A commercially available microcrystalline cellulose "Avicel PH-101J" manufactured by Asahi Kasei Industries Ltd. was used as a sample. The basic physical properties of the sample are shown in Table 1.

Table 1 As can be seen from Table 1, fine granular cellulosic IPA
Sample A and Sample B, which are spray-dried slurry products, have sufficiently large pore volumes and specific surface areas, and have an average particle size of 1100.
It was below a.

Incidentally, although the pore volume of sample B is larger than that of sample A, the specific surface area is smaller because the pore sizes are different. (The pores of sample A are smaller than those of sample B.) Sample C, which is a cellulose particle prepared without milling or spray drying, had a sufficient pore volume but a low specific surface area. However, existing cellulose powder samples are unsatisfactory in both pore volume and specific surface area.

As described above, by performing the operations shown in the examples, it was found that the crystal form was type I, the specific surface area was 20 rrf/g or more, and the diameter was 0.01 mm.
It was possible to obtain novel porous cellulose microparticles in which the volume of pores of μm or more is 0.3 cm 3 /g or more and the average diameter of particles is 100 μm or less.

Hereinafter, the present invention will be explained in detail with reference to usage examples.

Usage example 1 90g each of samples A and B and a pantam mill manufactured by Line Ironworks, AP-B type (screen diameter used: 0.5φ)
Pharmacopoeia zenacetin (manufactured by Yamamoto Chemical Industry ■) 6
0g, Pharmacopoeia cornstarch (manufactured by Hikaku Kagaku@) 30g, milk TL! (After mixing 20 g of 100 mesh H (manufactured by DMv) in a plastic bag for 3 minutes, 1.5 g of pharmacopoeia magnesium stearate (manufactured by Taihei Kagaku Sangyo ■) was added, and the mixture was further mixed for 30 seconds. The tablets were compressed using an RT-S-9 type rotary tableting machine using a 8 mmφ, 121 cm punch at a rotation speed of 25 rp11 and a molding pressure of 1000 kgf/cn! to obtain tablets weighing 200 cm. The physical properties of are shown in Table 2.

Comparative Example 1 Samples C and D were compressed into tablets in the same manner as Example 1. The results are shown in Table 2.

Comparative Use Example 2 A commercially available microcrystalline cellulose "Avicel Ptl-301J (manufactured by Asahi Kasei Kogyo ■)" was used as Sample E and tablet-molded in the same manner as in Use Example 1. The results are shown in Table 2.

Table 2 Looking at Table 2, it can be seen that the angles of repose of samples A and B are lower than the others. (Here, the angle of repose is a value measured for the mixed powder subjected to tableting.) If the angle of repose is low, it is expected that the weight variation of the tablets made by tableting will be low, but Sample A , B also have lower weight variations than the others. The value of weight variation indicates the quality of filling the tablet into the die of the tablet machine rather than the fluidity of the powder, and the adaptability of the powder to the direct powder compression method is determined based on this value. This is because even if the angle of repose is low, there is a large variation in weight, which is a common phenomenon, such as the relationship between sample size and E.Also, the hardness, which is one of the important properties for tablets, is also important for this invention. Sample A, which is a product
, B has a higher value than sample E, which is a commercially available excipient for direct injection. Sample C has moderate values for each value, but its large particle size makes it poorly compatible with other powders, causing problems of separation and segregation.

As described above, the porous cellulose microparticles of the present invention have excellent properties as a compression molding aid and fluidity improver for direct tabletting of pharmaceutical preparations.

Patent applicant: Asahi Kasei Industries, Ltd.

Claims (1)

[Claims] The crystal form is type I, the specific surface area is 20 m^2/g or more, and the volume of pores with a diameter of 0.01 μm or more is 0.3 cm^.
Porous microcellulose particles having a porous structure of 3/g or more and an average particle size of at most 100 μm