JP2000302802A - Method of forming hydroxypropyl cellulose particle with low degree of substitution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce the treatment time and the space for equipment and to obtain a particle which can easily decrease ash content in a washing step by conducting a step of dissolving a reaction product of an alkali cellulose and a hydroxypropylating agent in water and a step of neutralizing the same with an acid successively. SOLUTION: Water is supplied quantitatively while a crude reaction product is quantitatively supplied into a continuous kneader to successively dissolve and an acid is added to the travelling solution at a regulated addition speed such that the acid is equivalent to the amount of caustic soda present in the solution. Desirably, the water inlet is placed very close to the inlet of the crude reaction product and the acid inlet is provided at the place where the crude reaction product is fully dissolved. Preferably, a twin screw type continuous kneader is used. As the hydroxypropyl cellulose with a low degree of substitution, those with the number of moles of substituting hydroxypropoxyl groups per glucose unit (C6H10O5) of 0.1-0.5 are desired.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a purification step for producing a low-substituted hydroxypropylcellulose to be added for imparting disintegration or binding property when producing a preparation in the field of medicine or food. And a method for forming particles.

[0002]

2. Description of the Related Art In the case of solid preparations such as pharmaceuticals or foods, in the case of preparations containing only the main drug, sufficient disintegration is not obtained even when the drug is administered, and when the medicinal effect is not sufficiently exerted or the binding property is poor. For this reason, there are problems such as cases where the shape cannot be maintained when tablets or granules are formed. In such a case, disintegration and binding properties can be imparted by adding low-substituted hydroxypropylcellulose to the preparation.

[0003] For such purposes,
In addition to low-substituted hydroxypropylcellulose, calcium salt of carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, carboxymethyl starch and the like, but since this low-substituted hydroxypropylcellulose is nonionic, it is ionic. It has the advantage that deterioration due to reaction with a drug or the like hardly occurs.

Utilizing such advantages, a method of dry-mixing a powder of low-substituted hydroxypropylcellulose with a drug or other excipients and tableting, or kneading with water or an aqueous solution of a water-soluble binder, and granulating. To form a granule. Here, the method for producing low-substituted hydroxypropylcellulose is such that pulp is immersed in an aqueous solution of caustic soda and then squeezed to react the alkali cellulose and propylene oxide, or powdered pulp is treated with isopropyl alcohol and tert-butyl alcohol. A crude reaction product can be obtained by adding an aqueous solution of caustic soda in an organic solvent such as hexane or the like to produce alkali cellulose, and adding propylene oxide to react. Next, water is added to the crude reaction product to dissolve it, and then the remaining alkali is neutralized with an acid. This neutralization forms low-substituted hydroxypropylcellulose particles. Washing with water or hot water to remove salts and other impurities generated in this step,
After the washed product is squeezed to remove water, drying and pulverization are performed to finally obtain low-substituted hydroxypropylcellulose.

In a conventional method for producing low-substituted hydroxypropylcellulose, a crude reaction product is dissolved in water using a batch-type kneader or a vertical mixer, and then neutralized by adding an acid. To form low-substituted hydroxypropylcellulose particles. In such a batch-type kneading apparatus, a large volume of the apparatus itself is necessary at the time of scale-up, and it is difficult to industrially process the kneading apparatus. In addition, it takes a long time to dissolve the crude reaction product, resulting in low productivity. Furthermore, when forming particles in a batch system, the amount to be processed at one time is large, and the mixing capacity of the apparatus is not so high, so that coarse particles are easily formed during neutralization, and the ash content is reduced in the subsequent washing. There was a problem that it was difficult.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and is directed to producing a low-substituted hydroxypropylcellulose particle, particularly when forming a low-substituted hydroxypropylcellulose particle, by adding water to the reaction product. By continuously processing the dissolving step and the step of neutralizing and precipitating with an acid, the processing time and the installation place of the apparatus can be reduced as compared with the conventional batch method, and further, the subsequent cleaning step The purpose of the present invention is to form low-substituted hydroxypropylcellulose particles which easily reduce ash content in the above.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, when forming low-substituted hydroxypropylcellulose particles, a step of dissolving the reaction product with water and an acid. The inventors have found that by continuously processing the step of neutralization and precipitation, the production cost can be reduced by reducing the space of the apparatus and improving the processing capacity, and have accomplished the present invention. Accordingly, the present invention provides a method for forming low-substituted hydroxypropylcellulose particles in which a step of dissolving a reaction product of alkali cellulose and a hydroxypropylating agent with water and a step of neutralizing and precipitating with an acid are continuously performed. I do.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. In the low-substituted hydroxypropylcellulose of the present invention, the number of moles of substituted hydroxypropoxyl groups per glucose unit (C ₆ H ₁₀ O ₅ ) is preferably 0.1 to 0.5. When the number of moles of substituted hydroxypropoxyl group is less than 0.1, the desired binding property is not exhibited, and when it exceeds 0.5, the desired disintegration property is not exhibited, and the disintegration time of a formulation such as a molded tablet is prolonged. .

In the present invention, the raw material pulp is
After immersion in an aqueous solution of 0 to 50% by weight of caustic soda, the alkali cellulose produced by squeezing is reacted with propylene oxide at 20 to 90 ° C. for about 2 to 8 hours, or the powdered pulp is treated with isopropyl alcohol, te.
rt-butyl alcohol, a known technique such as adding an aqueous solution of caustic soda in an organic solvent such as hexane to prepare an alkali cellulose, and adding a hydroxypropylating agent such as propylene oxide and propylene chlorohydrin to cause a reaction, and the like, A crude reaction product can be obtained.

In the present invention, the crude reaction product of low-substituted hydroxypropylcellulose is quantitatively supplied to the continuous kneading apparatus using a continuous kneading apparatus, and the crude reaction product is adjusted to have a predetermined dissolution ratio. Water is quantitatively supplied to the product to continuously dissolve it, and neutralization is performed by adjusting the rate of acid addition so that the amount of caustic soda contained in the moving solution becomes equivalent to the amount of caustic soda contained in the solution. If this balance deviates, unneutralized precipitates will be discharged, and the product will be deteriorated and subsequent cleaning will not be possible. It is preferable that the water inlet is provided immediately adjacent to the crude reaction product supply port. One or more acid supply ports may be provided, and caustic soda and an equivalent amount of acid may be divided and added. Although there is a difference depending on the model used or the type of product to be manufactured, it is preferable to set the acid inlet at a place where the dissolution of the crude reaction product is completed. This is because if an acid is introduced into a place where the crude reaction product is not sufficiently dissolved, an unneutralized substance is discharged, and subsequent washing becomes difficult. Whether or not the dissolution of the crude reaction product has been completed is determined based on the fact that the crude reaction product has been uniformly dispersed or dissolved, and specifically determined by visual confirmation or the like. Such a continuous kneading apparatus can shorten the time for dissolving and neutralizing the crude reaction product as compared with a batch type mixing apparatus and can improve the processing speed. In addition, processing can be performed with a small device, and equipment costs and installation locations can be reduced.

The continuous kneading apparatus which can be used in the present invention includes a trough (barrel) and a paddle, and includes a single-shaft, twin-shaft and the like. Is preferred. In such an apparatus, the residence time or kneading state can be adjusted by a combination of built-in paddles. Further, L / D, which is the ratio of the trough length to the paddle diameter of the continuous kneading apparatus, may be about 5 to 13. If it is less than 5, it is discharged before complete dissolution neutralization is performed, or it is discharged before neutralization is completely completed.
If it exceeds 3, excessive kneading causes deterioration such as a decrease in the degree of polymerization of the product and an increase in the yellowness of the product. With respect to the shape of the paddle, the kneading state can be adjusted by a combination of various paddles such as a flat type and a helical type. Further, the continuous kneading device may be one unit, or may be divided into two units for dissolution and neutralization. Specific examples of the continuous kneading device include a commercially available KRC kneader (manufactured by Kurimoto Tekko Co., Ltd., twin-screw continuous kneading device) and an extruder (Kurimoto Tekko Co., Ltd.). In addition, the kneading apparatus of the present invention is not limited to what is generally called a kneading apparatus, as long as the object, action, and effects of the present invention can be substantially achieved,
What is called a kneading extruder etc. is also included.

When the low-substituted hydroxypropylcellulose of the present invention is dissolved, the weight ratio of the crude reaction product of the low-substituted hydroxypropylcellulose to water is preferably 0.5 to 5. In addition, the said weight ratio is 30-50 weight% of low substituted hydroxypropylcellulose contained in a crude reaction product.
The crude reaction product further includes caustic soda, water, reaction by-products, and the like. If the weight ratio is less than 0.5, the dissolution is insufficient, so that it cannot be uniformly neutralized during the subsequent neutralization. On the other hand, if it exceeds 5, the water content of the neutralized product becomes too high, and the load in the subsequent washing and drying steps increases.

The temperature at the time of dissolving and neutralizing the low-substituted hydroxypropylcellulose is preferably 40 to 80 ° C. 4
Precipitated particles treated at a temperature lower than 0 ° C. have a low ash content in the subsequent washing step, and if the temperature exceeds 80 ° C., deterioration such as a decrease in the degree of polymerization of the product and an increase in the yellowness of the product occurs.

The acid used in the neutralization step of the present invention includes:
Examples thereof include organic acids such as acetic acid, formic acid, and propionic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. The concentration thereof can be freely selected, but is preferably 10 to 50% by weight.

Thereafter, the slurry obtained by diluting the crystallized product (neutralized precipitate) with water or hot water is washed according to a conventional method such as vacuum filtration or pressure filtration, and the obtained washed product is washed. According to a conventional method, dewatering is performed by pressing under pressure and decompressing, dried by a stationary oven, a fluidized-bed dryer, or the like, and then pulverized by using an impact pulverizer, a ball mill, or the like to obtain a final product. The average particle size of the neutralized precipitate is about 500 to 2000 μm, depending on the dissolution neutralization conditions. The size of the precipitated particles can be adjusted by the kneading state or temperature during neutralization, the temperature of the acid for neutralization, and the like. Therefore, the present invention solves the problem of the conventional batch method, that is, the difficulty of reducing the ash content due to the formation of coarse particles during neutralization and subsequent washing.

[0016]

The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. Example 1 Pulp was immersed in a 43% by weight caustic soda solution and pressed to obtain alkali cellulose having a composition of 22.2% by weight of NaOH, 44.8% by weight of cellulose, and 33.0% by weight of water. 350 g of alkali cellulose in terms of cellulose was charged into a 5 liter reactor and purged with nitrogen. 79 g of propylene oxide (0.226
Parts by weight of cellulose) and the jacket temperature is 45
The reaction was carried out at a temperature of 65 ° C. for 30 minutes at 65 ° C. to obtain 857 g of a crude reaction product of hydroxypropylcellulose having a hydroxypropoxyl group substitution mole number of 0.25 per glucose unit (C ₆ H ₁₀ O ₅ ). Biaxial continuous kneader (KRC kneader S2 type, paddle diameter 50mmφ, barrel length 400m
m, L / D = 8, internal volume 1.2 liter, manufactured by Kurimoto Teiko Co., Ltd.) at a rotation speed of 100 rpm and a jacket temperature of 45 ° C., while quantitatively supplying the crude reaction product at a rate of 100 g / min. Water is 225 so as to be 2.25 times the product.
Dissolution was continuously performed by supplying a fixed amount at g / min. 33% by weight of acetic acid was supplied at a rate of 96 g / min at a rate of 96 g / min so as to be equivalent to the caustic soda contained in the solution at a rate of 1/2 of the barrel length when viewed from the crude reaction product inlet side. Neutralization precipitation was carried out. The discharged neutralized precipitate was completely neutralized and could be completely treated in 9 minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Example 2 The number of revolutions was measured using a biaxial continuous kneader (KRC kneader S2, paddle diameter 50 mmφ, barrel length 400 mm, L / D = 8, internal volume 1.2 liter, manufactured by Kurimoto Tekko Co., Ltd.). 100r
857 g of a crude reaction product reacted at 100 g / min at a rate of 100 g / min. Water was supplied at a constant rate of 150 g / min to continuously dissolve. A 33% by weight aqueous acetic acid solution was fed at a rate of 96 g / min from the side of the crude reaction product inlet so as to be equivalent to the caustic soda contained in the solution at 1/1 of the barrel length.
The mixture was supplied in a fixed amount to 2 to continuously perform neutralization precipitation. The discharged neutralized precipitate is completely neutralized, and 9
The whole amount could be processed in minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Example 3 The number of revolutions was measured using a biaxial continuous kneading apparatus (KRC kneader S2, paddle diameter 50 mmφ, barrel length 400 mm, L / D = 8, internal volume 1.2 liter, manufactured by Kurimoto Tekko Co., Ltd.). 100
While 857 g of a crude reaction product reacted in the same manner as described in Example 1 at a rpm of 60 ° C. and a jacket temperature of 60 ° C. was supplied quantitatively at 50 g / min, the amount was 0.8 times the amount of the crude reaction product. Water was supplied at a constant rate of 40 g / min to continuously dissolve. A 33% by weight aqueous acetic acid solution was supplied at a rate of 48 g / min to a half of the barrel length when viewed from the crude reaction product inlet so as to be equivalent to the caustic soda contained in the solution, Continuous neutralization precipitation was performed. The discharged neutralized precipitate was completely neutralized and could be completely treated in 18 minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Example 4 The number of revolutions was measured using a biaxial continuous kneader (KRC kneader S2 type, paddle diameter 50 mmφ, barrel length 400 mm, L / D = 8, internal volume 1.2 liter, manufactured by Kurimoto Tekko Co., Ltd.). 100r
857 g of a crude reaction product reacted in the same manner as described in Example 1 at 100 g / min at a jacket temperature of 70 ° C. and water at a rate of 4 times the amount of the crude reaction product. Was continuously supplied at a rate of 400 g / min to perform continuous dissolution. A 33% by weight aqueous acid solution was supplied at a rate of 96 g / min to a volume of 1/3 of the barrel length when viewed from the crude reaction product inlet side so as to be equivalent to the caustic soda contained in the solution, Continuous neutralization precipitation was performed. The discharged neutralized precipitate was completely neutralized and could be completely treated in 9 minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Comparative Example 1 1925 g of water at 50 ° C. was placed in a 5-liter batch kneader so as to have the same dissolution ratio as in Example 1.
A total of 857 g of the crude reaction product reacted in the same manner as described above was charged and dissolved, and it took one hour to completely dissolve. Then, 20 g of 791 g of 33% by weight acetic acid
/ Min to perform neutralization precipitation. The processing time required a total of 1 hour and 40 minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Comparative Example 2 1925 g of water at 50 ° C. was placed in a 5-liter batch kneader so as to have the same dissolution ratio as in Example 1.
A total of 857 g of the crude reaction product reacted in the same manner as described above was charged and dissolved, and it took one hour to completely dissolve. Thereafter, 40 g of 791 g of 33% by weight acetic acid was added.
/ Min, and neutralized precipitation was performed, but the film-like coarse particles were many. This processing time required a total of 1 hour and 20 minutes. A cleaning test was performed by the test method described below, and the results are shown in Table 1.

Washing test The temperature of the crystal was adjusted to 60 ° C. so that the crystal content became 4 mol% in terms of cellulose.
Slurry diluted with hot water of 49 kP with pressure filter
a to perform dewatering operation, followed by hot water 5 at 80 ° C.
0 g was added and the same dewatering operation was performed. This operation 3
The washing was evaluated based on the average filtration time and the ash content of the third washed product. The ash content was measured based on the Japanese Pharmacopoeia.

[0023]

[Table 1]

[0024]

In the production of low-substituted hydroxypropylcellulose, particularly when forming low-substituted hydroxypropylcellulose particles, the step of dissolving the reaction product in water and the step of neutralizing and precipitating with an acid are continuously carried out. By processing, it is possible to reduce the processing time and the installation place of the apparatus as compared with the conventional batch-type method, and further, to form low-substituted hydroxypropylcellulose particles that easily reduce ash in the subsequent washing step. This can reduce the production cost of the product.

 ──────────────────────────────────────────────────の Continued on the front page F term (reference) 4C090 AA03 AA05 BA28 BD24 BD36 CA06 CA18 CA28 CA32 CA36 DA11 DA22 DA27 4F070 AA02 AB02 AC12 AC40 AE30 CA11 DA25 DC16 FA04 FB06 FC04 FC05

Claims (2)

[Claims] 1. A method for forming low-substituted hydroxypropylcellulose particles, comprising continuously dissolving a reaction product of an alkali cellulose and a hydroxypropylating agent with water and neutralizing and precipitating with an acid. 2. The continuous treatment of the dissolving step and the neutralization precipitation step is performed using a biaxial continuous kneading device.
The method for forming low-substituted hydroxypropylcellulose particles according to the above.