JP2009143997A - Method for producing hydroxy propyl cellulose - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing hydroxy propyl cellulose which is industrially simple and efficient. <P>SOLUTION: A low crystalline powder cellulose is reacted with propylene oxide in the presence of a catalyst to obtain hydroxy propyl cellulose. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing hydroxypropylcellulose.

Hydroxypropyl cellulose is used in additives for pharmaceutical preparations, coating agent compositions and the like, and its uses are diverse. A general method for producing hydroxypropyl cellulose is so-called arcelization or mercerization in which cellulose and a large amount of water and a large excess of alkali metal hydroxide such as sodium hydroxide are mixed in a slurry state to form alkali cellulose. It is manufactured by carrying out an extremely complicated activation process called “alkaline”, and allowing propylene oxide to act on the cellulose. In the arserification step, operations such as filtration or squeezing are required to remove excess alkali and water from the prepared alkali cellulose.
However, even if this filtration or squeezing operation is performed, water of the same weight or more remains in the alkali cellulose. Alkali cellulose obtained by the arserification treatment is considered to have an alcoholate in most of the hydroxyl groups in the cellulose molecule, and is usually about 3 mol amount, at least 1 mol amount per glucose unit in the cellulose molecule. The above alkali is contained. Hydroxypropyl cellulose can be obtained by adding propylene oxide to cellulose activated by this arseration, but water of the same weight or more remaining at the time of arserization also reacts with propylene oxide (hydration). A large amount of by-products such as glycol is generated. Therefore, in order to increase the reaction rate to cellulose, it is usually necessary to use an excessive amount of propylene oxide.

As a reaction method for propylene oxide to alkali cellulose, a slurry method using a large amount of solvent is generally used (see, for example, Patent Documents 1 to 4).
For example, Patent Document 1 discloses a method using a mixed solvent of a hydrocarbon solvent selected from benzene, toluene, xylene, hexane, heptane and the like and a polar solvent such as isopropanol and tert-butanol as a solvent. Patent Document 2 discloses a method using a hydrophilic polar solvent such as isopropanol, tert-butanol, acetone, tetrahydrofuran, or dioxane as a solvent. Patent Document 3 discloses a method using aliphatic ketones such as methyl isobutyl ketone, methyl-n-amyl ketone, methyl-n-hexyl ketone, ethyl-n-butyl ketone, di-n-propyl ketone, and diisobutyl ketone as a solvent. It is disclosed. Patent Document 4 discloses a method in which (poly) ethylene glycol dialkyl ethers such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether are used as a solvent in addition to aliphatic ketones. However, in any of these methods, since it is necessary to use alkali cellulose, it is difficult to suppress by-products such as propylene glycol as described above, and a large amount derived from excess alkali used for arserization after the reaction. It is also necessary to remove the neutralized salt. Therefore, development of a simple and efficient method for producing hydroxypropyl cellulose, particularly development of an efficient method for producing hydroxypropyl cellulose by catalytic reaction, has been an extremely useful problem from an industrial viewpoint.

Japanese Examined Patent Publication No. 45-4754 Japanese Patent Publication No. 60-9521 Japanese Patent Laid-Open No. 11-21301 JP 2000-186101 A

  An object of this invention is to provide the manufacturing method of a hydroxypropyl cellulose which is industrially simple and efficient.

The present inventors have found that the catalytic reaction with propylene oxide proceeds efficiently by using powdered cellulose having a reduced crystallinity.
That is, the present invention is a method for producing hydroxypropyl cellulose, in which low crystalline powdery cellulose is reacted with propylene oxide in the presence of a catalyst.

  According to the present invention, it is possible to provide an industrially simple and efficient method for producing hydroxypropylcellulose.

[Preparation of low crystalline powdered cellulose]
In general, cellulose has several known crystal structures, and is defined as the crystallinity from the ratio of the amorphous part and the crystal part present in a part. The “crystallinity” in the present invention is natural. The degree of crystallinity of type I derived from the crystal structure of cellulose is shown, and is defined by the degree of crystallinity represented by the following formula (1) obtained from the powder X-ray crystal diffraction spectrum.
Crystallinity (%) = [(I _22.6 −I _18.5 ) / I _22.6 ] × 100 Formula (1)
[I _22.6 is the diffraction intensity of the lattice plane (002 plane) (diffraction angle 2θ = 22.6 °) in X-ray diffraction, and I _18.5 is the diffraction intensity of the amorphous portion (diffraction angle 2θ = 18.5 °). Show
Further, the “low crystallinity” of the low crystalline powdery cellulose in the present invention indicates a state in which the ratio of the amorphous part is large in the crystal structure of the above cellulose, and preferably the crystallization obtained from the above formula (1). The degree is desirably 50% or less.
Since generally known powdered cellulose also has a very small amount of amorphous part, the crystallinity thereof is generally in the range of 60 to 80% according to the above formula (1) used in the present invention. It is so-called crystalline cellulose contained, and its reactivity in cellulose ether synthesis is extremely low.

  The low crystalline powdery cellulose used in the present invention can be prepared from a sheet-like or roll-like pulp having a high cellulose purity obtained as a general-purpose raw material. The method for preparing the low-crystalline powdery cellulose is not particularly limited. For example, JP-A-62-236801, JP-A-2003-64184, JP-A-2004-331918, etc. Mention may be made of the preparation methods described.

Moreover, for example, the method of preparing by processing the chip-like pulp obtained by roughly pulverizing the sheet-like pulp with an extruder and further with a ball mill can also be mentioned.
As the extruder used in this method, a single-screw or twin-screw extruder can be used, and from the viewpoint of applying a strong compressive shear force, a so-called kneading disk portion is provided in any part of the screw. There may be. Although there is no restriction | limiting in particular as a processing method using an extruder, The method of throwing chip-like pulp into an extruder and processing continuously is preferable.
As the ball mill, a known vibration ball mill, medium stirring mill, rolling ball mill, planetary ball mill, or the like can be used. There is no restriction | limiting in particular in the material of the ball | bowl used as a medium, For example, iron, stainless steel, an alumina, a zirconia etc. are mentioned. The outer diameter of the ball is preferably 0.1 to 100 mm from the viewpoint of efficiently amorphizing the cellulose. In addition to the ball, a medium such as a rod or tube can be used as the medium.
The treatment time of the ball mill is preferably 5 minutes to 72 hours from the viewpoint of reducing the crystallinity. In this treatment, in order to minimize denaturation and deterioration due to generated heat, the treatment is preferably performed at 250 ° C. or less, preferably in the range of 5 to 200 ° C., and further if necessary. , Under an inert gas atmosphere such as nitrogen.
By using the method as described above, it is possible to control the molecular weight, and it is possible to easily prepare powdered cellulose having a high degree of polymerization and low crystallinity, which is generally difficult to obtain. As, it is 100-2000, More preferably, it is 100-1000.

The crystallinity of the low-crystalline powdery cellulose used in the present invention is preferably 50% or less as determined from the above formula (1). If this crystallinity is 50% or less, the reaction with propylene oxide proceeds very well. In this respect, 40% or less is more preferable, and 30% or less is still more preferable. In particular, in the present invention, it is most preferable to use amorphous cellulose that has been completely amorphized, that is, the degree of crystallinity obtained from the above formula is approximately 0%.
The average particle size of the low crystalline powder cellulose is not particularly limited as long as the powder can maintain a good fluidity, but is preferably 300 μm or less, more preferably 150 μm or less, and particularly preferably 50 μm or less. In addition, although it is 20 micrometers or more from a viewpoint of industrial implementation, 25 micrometers or more are preferable. However, in order to avoid the incorporation of a minute amount of coarse particles due to aggregation or the like, it is preferable to use an under-sieved product using a sieve of about 25 to 100 μm as necessary for the reaction.

[Production of hydroxypropyl cellulose]
In the present invention, hydroxypropylcellulose can be obtained by reacting the low crystalline powdered cellulose obtained above with propylene oxide.

  The degree of substitution per glucose unit of the hydroxypropyl group in the hydroxypropyl cellulose obtained in the present invention can be set to a desired degree of substitution, but is preferably 0.01 to 3, more preferably 0.00. 1-2.

  The amount of propylene oxide used in the present invention is preferably in the range of 0.01 to 3 mol times per glucose unit in the cellulose molecule, and more preferably in the range of 0.1 to 2 mol times. When the amount of propylene oxide used is in this range, the reaction efficiency of propylene oxide with respect to cellulose is extremely high, so that hydroxypropyl cellulose having a desired substitution degree can be obtained.

  Although there is no restriction | limiting in particular as a catalyst used by this invention, A base catalyst or an acid catalyst can be used. Examples of the base catalyst include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, trimethylamine, triethylamine, and triethylenediamine. Secondary amines. Examples of the acid catalyst include Lewis acid catalysts such as lanthanide triflate. Of these, basic catalysts are preferred, alkali metal hydroxides are particularly preferred, and sodium hydroxide and potassium hydroxide are most preferred. These catalysts can also be used 1 type or in combination of 2 or more types.

The catalyst can be added by adding a high-concentration aqueous solution or by adding a dilute solution to remove the excess water content, and the reaction can be carried out in a slurry state or a high viscosity state. However, it is preferable to maintain a fluid powder state, and therefore, the water content when added in a dilute aqueous solution is preferably 100% by weight or less based on cellulose.
The amount of catalyst used is sufficient for both cellulose and propylene oxide. Specifically, an amount corresponding to 0.1 to 50 mol% per glucose unit in the cellulose molecule is preferable. Is more preferably an amount corresponding to 1 to 30 mol%, and most preferably an amount corresponding to 5 to 25 mol%.

The reaction of cellulose and propylene oxide in the present invention is preferably performed while maintaining the powder state as described above, but can also be performed in a dispersed state using a solvent other than water. Among these, as the non-aqueous polar solvent, a low-reactivity secondary or tertiary lower alcohol solvent such as isopropanol or tert-butanol generally used in the arserization treatment; tetrahydrofuran, 1,4-dioxane And ether solvents such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether; and hydrophilic polar solvents such as acetone and dimethyl sulfoxide.
On the other hand, it is also possible to carry out the reaction in a dispersed state using a non-aqueous low polarity or non-polar solvent such as toluene, benzene, hexane or other hydrocarbon oil.
Any of these solvents can be easily mixed with propylene oxide, but it is not necessary to dissolve the powdered cellulose, and it is preferable to use it in a state in which the cellulose can be well dispersed without causing aggregation. However, when these solvents are used in a large amount, the base catalyst such as alkali may be diluted and the reaction rate may be lowered. Therefore, when using a non-aqueous solvent, the amount used is a low crystalline powder. It is preferable to make it 10 weight times or less with respect to cellulose.

The method for adding propylene oxide in the present invention is not particularly limited. For example, (a) a method in which propylene oxide is dropped after adding a catalyst to cellulose, (b) propylene oxide is added to cellulose in a lump, and thereafter A method in which a catalyst is gradually added and allowed to react is mentioned. Among these, from the viewpoint of avoiding the polymerization of propylene oxide itself, the method (a) is more preferable. Moreover, when making it react at the temperature more than the boiling point of a propylene oxide, it is preferable to carry out, using a reaction apparatus provided with the reflux pipe | tube, dropping propylene oxide gradually.
In any method, the water content with respect to cellulose in the reaction system is preferably 100% by weight or less. If the moisture content with respect to cellulose is within this range, the cellulose can be reacted in a fluid powder state without excessive aggregation. In this respect, 80% by weight or less is more preferable, and 5 to 50% by weight is most preferable.

In the present invention, since the reaction selectivity of propylene oxide to cellulose is extremely high, it is not necessary to use an excessive amount of propylene oxide, and there is very little by-product such as propylene glycol obtained as a by-product derived from propylene oxide. Moreover, since it is a catalytic reaction, the amount of neutralized salt derived from the catalyst can also be reduced. Since these by-products and waste are extremely small, purification after completion of the reaction (such as washing) is easy, and industrial utility is extremely high.
In the present invention, it is preferable to react low-crystalline powdery cellulose, catalyst and propylene oxide in a fluid powder state, but the cellulose powder and catalyst are mixed in advance with a mixer or shaker, or mixed with a mixer or the like. It is also possible to carry out the reaction by adding propylene oxide after uniformly mixing and dispersing as necessary with a mill or the like.
As a reaction apparatus that can be used in the present invention, a reactor that can mix low crystalline cellulose, a catalyst, and propylene oxide as uniformly as possible is preferable. In addition to a mixer such as the mixer described above, JP-A-2002-114801 A mixer such as a so-called kneader used for kneading resin or the like as disclosed in paragraph [0016] is most preferable.

The reaction temperature in the present invention is preferably in the range of 0 to 150 ° C, but from the viewpoint of avoiding polymerization of propylene oxides and avoiding rapid reaction, the range of 10 to 100 ° C is more preferable. A range of ˜80 ° C. is particularly preferred.
In addition, the reaction in the present invention is preferably performed under normal pressure, but it is preferably performed in an inert gas atmosphere such as nitrogen as necessary from the viewpoint of avoiding coloring during the reaction.
After completion of the reaction, a small amount of unreacted propylene oxide is distilled off, and then the catalyst is neutralized with an acid or alkali, washed with water-containing isopropanol, water-containing acetone solvent, etc., if necessary, and then dried. By doing so, hydroxypropyl cellulose can be obtained. Furthermore, further derivatization is possible, for example, by synthesizing cationized hydroxypropylcellulose by reacting glycidyltrimethylammonium chloride without removing the catalyst after completion of the reaction.

  In the present invention, the hydroxypropyl group may be bonded to a hydroxyl group at any position in the glucose unit in the cellulose molecule, but can be adjusted to a desired degree of substitution per glucose unit. From this, the hydroxypropyl cellulose obtained by this invention can be utilized very extensively as a component mix | blended with a pharmaceutical formulation and a coating agent composition.

(1) Moisture content with respect to cellulose The moisture content with respect to cellulose was measured at 150 ° C. using “FD-610” manufactured by Kett Scientific Laboratory as an infrared moisture meter.
In order to confirm the optimal moisture content of cellulose in the present invention, after adding a predetermined amount of water to the non-crystallized cellulose obtained in Production Example 1 described later, it is vigorously stirred and shaken, and its agglomerated state is visually observed. Were observed repeatedly.
As a result, the produced non-crystallized powdered cellulose contains at least 5% by weight of water. However, in order to react low crystalline powdered cellulose in a fluid powder state, the water content is set to 100%. It was determined that the content was preferably not more than wt%, more preferably not more than 80 wt%, most preferably not more than 50 wt%, and even more preferably not more than 30 wt%.

(2) Calculation of crystallinity The crystallinity of cellulose is calculated according to the above formula from the peak intensity of the diffraction spectrum measured under the following conditions using “Rigaku RINT 2500VC X-RAY diffractometer” manufactured by Rigaku Corporation. It was.
X-ray source: Cu / Kα-radiation, tube voltage: 40 kv, tube current: 120 mA, measurement range: 2θ = 5-45 °, measurement sample: produced by compressing pellets of area 320 mm ² × thickness 1 mm, X-ray Scan speed: 10 ° / min
(3) Measurement of degree of polymerization of powdered cellulose The degree of polymerization of powdered cellulose was measured by the copper ammonia method described in ISO-4312 method.
(4) Calculation of the degree of substitution The degree of substitution indicates the average amount of hydroxypropyl groups introduced per unit of glucose in cellulose, and is generated using the method described in Macromol. Biosci., 5,58 (2005). The product was acetylated by a conventional method and calculated from various NMR spectrum analysis of the acetylated product.
(5) Measurement of average particle diameter of powdered cellulose The average particle diameter of powdered cellulose was measured using a laser diffraction / scattering particle size distribution measuring apparatus “LA-920” manufactured by Horiba, Ltd.

Production Example 1 (Production of Amorphized Powdered Cellulose)
A wood pulp sheet (Bolleguard's pulp sheet, crystallinity 74%) was shredded (manufactured by Meiko Shokai Co., Ltd., “MSX2000-IVP440F”) into a chip shape.
Next, the obtained chip-like pulp was charged into a twin screw extruder (“EA-20” manufactured by Suehiro EPM Co., Ltd.) at 2 kg / hr, a shear rate of 660 sec ⁻¹ , a screw rotation speed of 300 rpm, and cooling water from the outside. The powder was processed by one pass while flowing.
Next, the obtained powdered cellulose was put into a batch-type medium stirring mill (“Sand grinder” manufactured by Igarashi Machine Co., Ltd .: container volume 800 mL, filled with 720 g of 5 mmφ zirconia beads, filling rate 25%, stirring blade diameter 70 mm). While passing cooling water through the container jacket, the mixture is pulverized for 2.5 hours at a stirring speed of 2000 rpm and a temperature of 30 to 70 ° C., and powdered cellulose (crystallinity 0%, polymerization degree 600, average particle size 40 μm) Got. For the reaction of the powdered cellulose, an unsieved product (90% of the input amount) with a sieve having an opening of 32 μm was used.
In addition, the powder cellulose from which each crystallinity differs was prepared by changing the processing time in a ball mill process.

Example 1
A 1 L kneader (manufactured by Irie Shokai Co., Ltd., PNV-1 type) was charged with 100 g of the amorphous cellulose (crystallinity 0%, polymerization degree 600) obtained in Production Example 1, and then 24% hydroxylated. 16 g of sodium aqueous solution (NaOH amount: 0.10 mol) was added while spraying, and the mixture was stirred for 4 hours under a nitrogen atmosphere. Thereafter, 35 g of propylene oxide (0.62 mol, manufactured by Kanto Chemical Co., Ltd., special grade reagent) was added dropwise over 3 hours, and then stirred at room temperature for 22 hours. During the reaction, the cellulose maintained a fluid powder state. After distilling off unreacted propylene oxide (residual amount of 6 mol% of raw material), neutralize with acetic acid, remove the product from the kneader, wash with hydrous isopropanol (water content 15%) and acetone, and dry under reduced pressure. Hydroxypropyl cellulose was obtained as 117 g of a white solid. From the NMR analysis after acetylation by an ordinary method using acetic anhydride in pyridine, the substitution degree as a hydroxypropyl group was 0.71 per glucose unit, and the reaction proceeded well.

Example 2
Into a 1 L kneader (manufactured by Irie Shokai Co., Ltd., PNV-1 type) connected with a cooling pipe, 90.0 g of non-crystalline cellulose (crystallinity 0%, polymerization degree 600) obtained in Production Example 1 was charged. As a solvent, 700 ml of dimethyl sulfoxide (8 times by weight with respect to non-crystallized cellulose) was added, and 16.0 g (NaOH amount 0.10 mol) of a 24% aqueous sodium hydroxide solution was added with stirring. For 3 hours. Thereafter, the temperature was raised to 50 ° C., 30 g of propylene oxide (0.52 mol, manufactured by Kanto Chemical Co., Ltd., special grade reagent) was added dropwise over 3 hours, and then stirred as it was for 5 hours. Thereafter, unreacted propylene oxide was distilled off, neutralized with acetic acid, and the product was taken out of the kneader. After washing with water-containing isopropanol (water content 15%) and acetone, it was dried under reduced pressure to obtain hydroxypropylcellulose as 108 g of a white solid. The degree of substitution as a hydroxypropyl group was 0.65 per glucose unit, and the reaction proceeded well.

Example 3
100 g of amorphous cellulose (crystallinity 0%, polymerization degree 600) obtained in Production Example 1 and 4.0 g of sodium hydroxide (NaOH amount 0.10 mol) were stirred by a ball mill (Atryr manufactured by Mitsui Mining Co., Ltd.). In addition, in a nitrogen atmosphere, mixing was performed using steel balls (filling rate: 30%). This was transferred to a 1 L kneader equipped with a cooling tube, heated to 70 ° C., and 35 g of propylene oxide (0.62 mol, manufactured by Kanto Chemical Co., Ltd., special grade reagent) was added dropwise over 5 hours under nitrogen flow. When the mixture was further stirred for 5 hours, no residual raw material propylene oxide was observed. During the reaction, the cellulose maintained a fluid powder state. After neutralizing with acetic acid, the product was taken out from the ball mill, washed with water-containing isopropanol (water content 15%) and acetone, and then dried under reduced pressure to obtain hydroxypropylcellulose as 115 g of a white solid. The degree of substitution as a hydroxypropyl group was 0.69 per glucose unit, and the reaction proceeded well.

Example 4
In a 1 L flask connected to a cooling tube, 60.0 g of the non-crystalline cellulose obtained in Production Example 1 (crystallinity 0%, polymerization degree 600), 360 g of triethylene glycol dimethyl ether (based on non-crystalline cellulose) 6 weight times) was added, 10.0 g of 48% sodium hydroxide aqueous solution (NaOH amount 0.120 mol) was added, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then heated to 50 ° C. with stirring. Next, 30 g of propylene oxide (0.52 mol, manufactured by Kanto Chemical Co., Ltd., special grade reagent) was added dropwise over 3 hours, and the mixture was stirred at 50 ° C. for 5 hours. Unreacted propylene oxide was distilled off, neutralized with acetic acid, and the product was washed with water-containing isopropanol (water content 15%) and acetone, and then dried under reduced pressure to obtain hydroxypropylcellulose as 70 g of a white solid. . The degree of substitution as a hydroxypropyl group was 0.63 per glucose unit, and the reaction proceeded well.

Comparative Example 1
In a 3 L four-necked flask, 100 g of highly crystalline powdered cellulose (manufactured by Nippon Paper Chemical Co., Ltd., cellulose powder KC Flock W-50 (S); crystallinity 74%, polymerization degree 500) is added, and dimethyl sulfoxide 2 L In addition, it was dispersed. Next, 32 g of a 48 wt% sodium hydroxide aqueous solution (NaOH amount 0.38 mol) was added with stirring under a nitrogen atmosphere. After stirring at room temperature for 1 hour, 40 g (0.69 mol) of propylene oxide was added dropwise over 1 hour, and the mixture was stirred at room temperature for 22 hours. After neutralizing with acetic acid and distilling off the unreacted propylene oxide and the solvent, the product was taken out from the flask, washed with water-containing isopropanol (water content 15%) and acetone, and then dried under reduced pressure to give 102 g of hydroxypropylcellulose. As a pale brown white solid. The degree of substitution as a hydroxypropyl group was only 0.06 per glucose unit in the cellulose molecule.

  From the above results, it can be seen that Examples 1 to 3 can efficiently obtain hydroxypropylcellulose having a desired degree of substitution compared to Comparative Example 1.

  According to the present invention, hydroxypropylcellulose can be produced by an industrially simple and efficient method, and the obtained hydroxypropylcellulose is suitable for uses such as pharmaceutical preparations and coating agent compositions. Can be used.

Claims (6)

  A process for producing hydroxypropyl cellulose, comprising reacting low-crystalline powdery cellulose with propylene oxide in the presence of a catalyst.   The method for producing hydroxypropylcellulose according to claim 1, wherein the reaction is carried out in the presence of a catalytic amount of a catalyst.   The method for producing hydroxypropyl cellulose according to claim 1 or 2, wherein the crystallinity of the low-crystalline powdery cellulose is 50% or less.   The manufacturing method of the hydroxypropyl cellulose in any one of Claims 1-3 whose water content with respect to low crystalline powdery cellulose is 100 weight% or less.   The manufacturing method of the hydroxypropyl cellulose in any one of Claims 1-4 made to react using a non-aqueous solvent 10 weight times or less with respect to low crystalline powdered cellulose.   The manufacturing method of the hydroxypropyl cellulose in any one of Claims 1-5 which uses an alkali metal hydroxide as a catalyst.