KR100469195B1 - Method for Forming Low Substituted Hydroxypropyl Cellulose Particles - Google Patents

Abstract

The present invention relates to a conventional batch process in the preparation of low-substituted hydroxypropyl cellulose, particularly in the formation of low-substituted hydroxypropyl cellulose particles, in the process of dissolving the reaction product with water and neutralizing precipitation by acid. In comparison, it aims to reduce the processing time and the installation place of the apparatus, and furthermore, to form low-substituted hydroxypropyl cellulose particles that tend to reduce ash in subsequent washing steps.

Moreover, this invention performs the process of dissolving the reaction product of alkali cellulose and a hydroxypropylating agent with water, and the process of neutralizing precipitation with an acid continuously.

Description

Method for Forming Low Substituted Hydroxypropyl Cellulose Particles {Method for Forming Low Substituted Hydroxypropyl Cellulose Particles}

The present invention relates to a method for forming particles in a purification process when preparing low-substituted hydroxypropyl cellulose which is added for imparting disintegration or binding property when preparing a preparation in a pharmaceutical or food field.

In solid formulations, such as pharmaceuticals or the food sector, preparations made solely with the main component do not obtain sufficient disintegration even when the drug is administered, and thus the effect is not sufficiently exerted, and the binding properties are poor. There is a problem such as a case where it cannot be maintained. In such a case, low-substituted hydroxypropyl cellulose can be added to the formulation to impart disintegration and binding properties.

As used for this purpose, in addition to low-substituted hydroxypropyl cellulose, there are calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, carboxymethyl starch, and the like. Since it is nonionic, it has the advantage that alteration does not occur by reaction with an ionic chemical etc.

Taking advantage of these advantages, there is a method of dry mixing the powder of low-substituted hydroxypropyl cellulose with a drug and other excipients, and then compressing the granules by kneading with an aqueous solution of water or a water-soluble binder.

Here, in the method for producing low-substituted hydroxypropyl cellulose, alkali cellulose and propylene oxide produced by immersing the pulp in an aqueous solution of caustic soda and then compressed, or reacting the powdered pulp with isopropyl alcohol, 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 to produce alkaline cellulose, adding propylene oxide to react, and the like.

Subsequently, water is added to and dissolved in this crude reaction product, and the remaining alkali is neutralized with an acid. This neutralization results in the formation of low-substituted hydroxypropyl cellulose particles.

In order to remove salt and other impurities generated in this process, the product is washed with water or hot water, the cleaning product is compressed to remove moisture, and then subjected to a process such as drying and pulverization, and finally low-substituted hydroxypropyl cellulose. Can be obtained.

In a conventional method for producing low-substituted hydroxypropyl cellulose, a low-substituted hydroxypropyl by dissolving the crude reaction product in water using a batch kneading device or a vertical mixing device, and then neutralizing by adding an acid. To form cellulose particles. In such a batch kneading apparatus, when the scale is increased, it is necessary to have a large volume of the apparatus itself, which is difficult to industrially treat. In addition, it takes a long time to dissolve this crude reaction product, resulting in low productivity. In addition, in the case of forming particles in a batch manner, coarse particles are likely to be formed during neutralization and it is difficult to reduce ash in subsequent washing since the amount of processing at one time is large and the mixing capacity of the apparatus is not so high. There was.

The present invention has been made in view of the above circumstances, and in the preparation of low-substituted hydroxypropyl cellulose, particularly in the formation of low-substituted hydroxypropyl cellulose particles, a step of dissolving the reaction product with water and a step of neutralizing precipitation by acid. It is aimed to reduce the treatment time and the place of installation of the apparatus compared to the conventional batch method by continuously treating the mixture, and to form low-substituted hydroxypropyl cellulose particles which are likely to reduce ash in a subsequent washing step. .

The present inventors have diligently studied to achieve the above object, and as a result, when forming low-substituted hydroxypropyl cellulose particles, a small space of the apparatus is continuously processed by dissolving the reaction product into water and neutralizing precipitation by acid. The inventors have found that production costs are reduced due to the reduction in size and improvement in processing capacity, and the present invention has been completed.

Accordingly, the present invention provides a method for forming low-substituted hydroxypropyl cellulose particles comprising continuously performing a step of dissolving a reaction product of an alkali cellulose and a hydroxypropylating agent with water and a step of neutralizing precipitation with an acid.

Hereinafter, the present invention will be described in more detail.

As the low-substituted hydroxypropyl cellulose of the present invention, the number of substituted moles of hydroxypropoxyl groups per glucose unit (C ₆ H ₁₀ O ₅ ) is preferably 0.1 to 0.5. If the number of moles of substitution of the hydroxypropoxyl group is less than 0.1, the desired bondability is not shown. If the molar number of the hydroxypropoxyl group is less than 0.1, the desired disintegration property is not exhibited.

In the present invention, the pulp, which is a raw material, is immersed in an aqueous solution of caustic soda at 10 to 50% by weight, followed by reacting the alkali cellulose produced with the propylene oxide at 20 to 90 ° C. for about 2 to 8 hours, or powdered pulp. Known techniques such as addition of caustic soda solution in organic solvents such as isopropyl alcohol, tert-butyl alcohol and hexane to produce alkali cellulose and reaction by addition of hydroxypropylating agents such as propylene oxide and propylene chlorohydrin The crude reaction product can be obtained by.

In the present invention, while supplying the crude reaction product of low-substituted hydroxypropyl cellulose to this continuous kneading apparatus quantitatively using a continuous kneading apparatus, water is quantitatively supplied to the crude reaction product so as to have a predetermined dissolution ratio and continuously dissolved. The neutralization rate of the acid is adjusted to neutralize the amount of caustic soda contained in the solution and its equivalent in the moving solution. If this balance is out of balance, the unneutralized precipitate is discharged, and the product is deteriorated and subsequent cleaning is impossible.

The inlet for water is preferably installed near the inlet of the crude reaction product.

The acid supply port may be one or two or more, and the caustic soda and the equivalent acid may be added separately. Depending on the type of machine used or the variety used, the acid inlet is preferably installed where the crude reaction product has been dissolved. This is because when the acid is added to a place where the dissolution of the crude reaction product is insufficient, the unneutralized substance is discharged, and subsequent washing becomes difficult. Whether or not the dissolution of the crude reaction product is completed is determined on the basis of uniform dispersion or dissolution of the crude reaction product, and specifically depends on methods such as visual confirmation.

This continuous kneading apparatus can shorten the time for dissolving and neutralizing this crude reaction product compared to the batch mixing apparatus and can improve the processing speed. In addition, it can be processed by a small-scale device, which can reduce the installation cost and installation site.

Although the continuous kneading apparatus which can be used for this invention includes a trough (barrel) and a paddle, and consists of a single axis | shaft, a biaxial | shaft, etc., the biaxial type is preferable at the point which is excellent in kneading property.

In such a device, the residence time or kneading state can be adjusted by the combination of paddles embedded therein. In addition, L / D which is the ratio of the trough length and paddle diameter of a continuous kneading apparatus can use about 5-13 grades. If it is less than 5, it is discharged in a state where dissolution neutralization is not completely performed, or it is discharged before neutralization is completely completed. If it is more than 13, over-kneading causes deterioration of the polymerization degree of the product and an increase in the yellowness of the product. do.

The paddle shape can be adjusted in the kneading state by a combination of several paddles, such as flat and spiral.

In addition, one continuous kneading apparatus may be sufficient and it may be divided into two, for melt | dissolution and neutralization.

As a specific example of a continuous kneading apparatus, KRC kneader (made by Kurimoto Co., Ltd., biaxial continuous kneading apparatus) which is a commercial item, an expander (made by Kurimoto Co., Ltd.), etc. are mentioned.

In addition, the kneading apparatus of the present invention is not limited to what is generally called a kneading apparatus, and includes a so-called mixer, kneading extruder, etc. as long as the object, effect and effect of the present invention can be substantially achieved.

When dissolving the low-substituted hydroxypropyl cellulose of the present invention, the weight ratio of the crude reaction product of the low-substituted hydroxypropyl cellulose to water is preferably 0.5 to 5. In addition, this weight ratio is the value when the low substitution degree hydroxypropyl cellulose contained in a crude reaction product is 30-50 weight%, and a crude reaction product contains caustic soda, water, reaction by-products, etc. other.

If the weight ratio is less than 0.5, dissolution is insufficient, and when neutralizing thereafter, it cannot be neutralized uniformly. Moreover, when it exceeds 5, the water content of the neutralization product will become too high, and load will increase in the subsequent washing | cleaning and drying process.

In addition, the temperature at the time of dissolution neutralization of low-substituted hydroxypropyl cellulose is preferably 40 to 80 ° C. In the subsequent washing step, the precipitated particles treated at less than 40 ° C have a poor ash reduction, and when it exceeds 80 ° C, deterioration such as a decrease in the polymerization degree of the product and an increase in the yellowness of the product occur.

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

Thereafter, the slurry obtained by diluting this product (neutralized precipitate) with water or hot water is washed in accordance with a conventional method such as vacuum filtration or pressure filtration, and the obtained washings are compressed and dehydrated by pressure compression in accordance with a conventional method. The resultant is dried by a stationary oven, a fluidized bed dryer, or the like, and then ground using an impact mill, a ball mill, or the like to obtain a final product.

In addition, the average particle diameter of the neutralizing precipitate is about 500 to 2000 µm, depending on the dissolution neutralization conditions. The size of the precipitated particles can be adjusted according to the kneading state or temperature at the time of neutralization, the temperature of the acid for neutralization, and the like. Therefore, the difficulty of the formation of coarse particles at the time of neutralization and the ash reduction by subsequent washing, which is a problem of the conventional batch type, is solved by the present invention.

<Example>

Hereinafter, although an Example and a comparative example are given and this invention is demonstrated concretely, this invention is not limited to the following Example.

<Example 1>

The pulp was immersed in 43 wt% caustic soda solution, and then compressed to give alkali cellulose having a composition of 22.2 wt% NaOH, 44.8 wt% cellulose, and 33.0 wt% water. 350 g of alkaline cellulose was charged in a 5 liter reactor in terms of cellulose, and nitrogen substitution was performed. 79 g (0.226 parts by weight: relative to cellulose) was added thereto, and the reaction was carried out at a jacket temperature of 45 ° C. for 2 hours and at 65 ° C. for 30 minutes to give hydroxypropoxide per glucose unit (C ₆ H ₁₀ O ₅ ). 857 g of a hydroxypropyl cellulose crude reaction product having a number of molar substitutions of 0.25 was obtained. Rotation speed 100rpm, jacket temperature 45 ℃ While quantitatively feeding the crude reaction product at 100 g / min, water was quantitatively supplied at 225 g / min so as to be 2.25 times with respect to the crude reaction product and dissolved continuously. 33% by weight of acetic acid was added to the caustic soda contained in the dissolving solution at a rate of 96 g / min, at a rate of 1/2 of the barrel length as viewed from the crude reaction product inlet, and neutralization precipitation was continuously performed. . The discharged neutralized precipitate was completely neutralized and could be completely processed in 9 minutes. The washing test was performed by the test method mentioned later, and the result is shown in Table 1.

<Example 2>

Rotation speed 100 rpm, jacket temperature 50 ° C, using two-axis continuous kneader (KRC kneader type S2, paddle diameter 50 mmψ, barrel length 400 mm, L / D = 8, inner volume 1.2 liters, Gurimoto Co., Ltd.) While quantitatively supplying 857 g of the crude reaction product reacted in the same manner as described in Example 1 at 100 g / min, the water was quantitatively supplied at 150 g / min so as to be 1.5 times the amount of the crude reaction product. Dissolved. The caustic soda contained in the solution and the equivalent weight of 33% by weight of acetic acid aqueous solution was supplied at a rate of 96 g / min at the side of the crude reaction product inlet, and then quantitatively supplied at half the barrel length to carry out neutralization precipitation continuously. It was. The discharged neutralized precipitate was completely neutralized and could be completely processed in 9 minutes. The washing test was performed by the test method mentioned later, and the result is shown in Table 1.

<Example 3>

Rotation speed 100 rpm, jacket temperature 60 ° C, using a two-axis continuous kneader (KRC kneader type S2, paddle diameter 50 mmψ, barrel length 400 mm, L / D = 8, volume 1.2 liters, manufactured by Kurimoto Co., Ltd.) While 857 g of the crude reaction product reacted in the same manner as described in Example 1 was quantitatively supplied at 50 g / min, water was quantitatively supplied at 40 g / min so as to be 0.8 times the amount of the crude reaction product. Was dissolved. The caustic soda contained in the solution and the equivalent of 33% by weight of acetic acid aqueous solution were supplied at a rate of 48 g / min at a rate of 48 g / min. It was. The discharged neutralized precipitate was completely neutralized and could be fully processed in 18 minutes. The washing test was performed by the test method mentioned later, and the result is shown in Table 1.

<Example 4>

Rotation speed 100 rpm, jacket temperature 70 ° C, using two-axis continuous kneading apparatus (KRC kneader type S2, paddle diameter 50 mmψ, barrel length 400 mm, L / D = 8, volume 1.2 liters, Gurimoto Co., Ltd.) While quantitatively supplying 857 g of the crude reaction product reacted in the same manner as described in Example 1 at 100 g / min, the water was quantitatively supplied at 400 g / min so as to be 4 times the amount of the crude reaction product, and continuously Dissolved. The caustic soda contained in the solution and the equivalent weight of 33% by weight of an aqueous acid solution were supplied at a rate of 96 g / min at a rate of 96 g / min. It was. The discharged neutralized precipitate was completely neutralized and could be completely processed in 9 minutes. The washing test was performed by the test method mentioned later, and the result is shown in Table 1.

Comparative Example 1

A 5 liter batch kneader was filled with 1925 g of water at 50 ° C. to have the same dissolution ratio as in Example 1, and then 857 g of the crude reaction product reacted in the same manner as in Example 1 was dissolved. Needed. Thereafter, 791 g of 33% by weight acetic acid was added at a rate of 20 g / min to neutralize precipitation. The treatment time required a total of 1 hour 40 minutes. The washing test was performed by the test method mentioned later, and the result is shown in Table 1.

Comparative Example 2

A 5 liter batch kneader was filled with 1925 g of water at 50 ° C. so as to have the same dissolution ratio as in Example 1, and the total amount of 857 g of the crude reaction product reacted in the same manner as in Example 1 was added to dissolve. Was needed. Thereafter, 79 l g of 33 wt% acetic acid was added at a rate of 40 g / min to neutralize precipitation, but there were many thin coarse particles. This treatment time required a total of 1 hour 20 minutes. The washing test was done by the test method mentioned later, and the result is shown in Table 1.

<Cleaning test>

The slurry obtained by diluting the neutralized precipitate with hot water at 60 ° C. to 4 mol% in terms of cellulose was depressurized to 49 kPa with a pressure filter, and then subjected to the dehydration operation. Then, 50 g of hot water at 80 ° C. was added to perform the same dehydration operation. . This operation was performed three times, and the washability was evaluated by the average filtration time and the ash content of the third wash. In addition, the measurement of ash was measured based on the Japanese pharmacy room.

Cleaning test result Filtration time (seconds) Ash (% by weight) Example 1 5 0.26 Example 2 3 0.31 Example 3 2 0.40 Example 4 10 0.25 Comparative Example 1 30 1.52 Comparative Example 2 15 6.50

In the preparation of low-substituted hydroxypropyl cellulose, in particular, when forming low-substituted hydroxypropyl cellulose particles, the process of dissolving the reaction product with water and the process of neutralizing precipitation by acid are continuously processed, thereby providing a conventional batch formula. Compared with the method, the manufacturing cost of the product can be reduced by reducing the processing time and the installation place of the apparatus, and further, forming low-substituted hydroxypropyl cellulose particles which tend to reduce ash in a subsequent washing step.

Claims (2)

A method of forming low-substituted hydroxypropyl cellulose particles, comprising continuously performing a step of dissolving a reaction product of an alkali cellulose and a hydroxypropylating agent with water and a step of neutralizing precipitation with an acid. The method for forming low-substituted hydroxypropyl cellulose particles according to claim 1, wherein the continuous treatment of the dissolution step and the neutralization precipitation step is performed using a biaxial continuous kneading apparatus.