WO2015102265A1

WO2015102265A1 - Method for preparing hydroxypropyl methylcellulose acetate succinate (hpmcas) grains having controlled grain size distribution, and hpmcas powder

Info

Publication number: WO2015102265A1
Application number: PCT/KR2014/012307
Authority: WO
Inventors: 방성환; 신주희; 손진열; 박경열; 전정희; 정지선; 이상엽
Original assignee: 삼성정밀화학(주)
Priority date: 2013-12-31
Filing date: 2014-12-15
Publication date: 2015-07-09

Abstract

Disclosed are a method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) grains and HPMCAS grains. The disclosed method for preparing HPMCAS grains comprises: a step (esterification step) of esterifying hydroxypropyl methylcellulose (HPMC), acetic anhydride, and succinic anhydride in a reaction medium in the presence of a catalyst so as to obtain a reaction solution containing HPMCAS; and a step (granulating step) of putting the reaction solution into water continuously or intermittently so as to form grains.

Description

Preparation method of hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles with particle size distribution and HPMCAS powder

A method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles with controlled particle size distribution and HPMCAS powder are disclosed. More specifically, the fraction of particles having a suitable particle size range is high and the dissolution rate in a solvent is high. Methods of making hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles and HPMCAS powders are disclosed.

Conventional processes for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) include three reaction raw materials (ie, hydroxypropyl methylcellulose, acetic anhydride and the like) in a reaction medium such as acetic acid in the presence of a catalyst such as sodium acetate. After succinic anhydride) was esterified to prepare a reaction solution, a predetermined ratio of purified water was added to the reaction solution to generate HPMCAS particles.

However, the HPMCAS powder produced by the above method has a problem that the fraction of particles having a suitable particle size range is low and the dissolution rate in the solvent is slow.

One embodiment of the present invention provides a method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles comprising the step of adding a solution containing hydroxypropyl methylcellulose acetate succinate (HPMCAS) to water.

Another embodiment of the present invention provides an HPMCAS powder prepared by the method for preparing HPMCAS particles.

One aspect of the invention,

Esterification of hydroxypropyl methylcellulose (HPMC), acetic anhydride and succinic anhydride in the reaction medium in the presence of a catalyst to obtain a reaction solution comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS) (ester reaction step) ); And

It provides a method for producing hydroxypropyl methyl cellulose acetate succinate (HPMCAS) particles comprising the step of adding the reaction solution to water continuously or intermittently to produce particles (particleing step).

The catalyst may include an alkali metal salt of acetic acid, and the alkali metal salt of acetic acid may include at least one of sodium acetate and potassium acetate.

The reaction medium may include at least one compound selected from the group consisting of acetic acid, propionic acid and butyric acid.

The hydroxypropyl methyl cellulose (HPMC) may include a degree of substitution of methoxyl group of 1.6-2.0 and degree of substitution of hydroxypropoxy group of 0.2-0.3.

The amount of the acetic anhydride and the amount of the succinic anhydride used in the esterification step may be 140 to 240 parts by weight and 20 to 60 parts by weight based on 100 parts by weight of the hydroxypropyl methylcellulose (HPMC).

The esterification step may be performed for 3 to 24 hours at 60 ~ 100 ℃.

The method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles further includes adjusting the temperature of the reaction solution (temperature control step of the reaction solution) between the esterification step and the granulation step. can do.

The temperature of the reaction solution and the temperature of the water used in the granulation step may be 45 ~ 60 ℃ and 20 ~ 30 ℃, respectively.

The total content of the water used in the granulation step may be 12 to 20 times the total content of the reaction medium used in the esterification step.

The granulation step may be performed by adding the reactant to the water.

Another aspect of the invention,

As hydroxypropyl methylcellulose acetate succinate (HPMCAS) prepared according to the above method, a hydroxypropyl methylcellulose acetate succinate (HPMCAS) powder having a fraction of 25% by weight or more is provided. .

The hydroxypropyl methylcellulose acetate succinate powder (HPMCAS) powder has an acetyl group substitution degree of 0.3 to 0.75, a methoxyl group substitution degree of 1.6 to 2.0, a hydroxypropoxy group substitution degree of 0.2 to 0.3, and a saturation of 0.1 to 0.45. And hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles having a degree of cynoyl group substitution.

According to the method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles according to an embodiment of the present invention, the fraction of particles having a suitable particle size range is high and the dissolution rate in the solvent is fast HPMCAS powder can be obtained.

1 is an IR spectrum of the reaction product prepared in Example 1, Example 3 and Comparative Example 1.

2 is XRD spectra of reaction products prepared in Example 1, Example 3, and Comparative Example 1. FIG.

In the present specification, the degree of substitution of methoxyl group, the degree of substitution of hydroxypropoxyl group and the degree of substitution of other substituents means the average number of hydroxyl groups substituted with each of the above substituents per glucose unit in the cellulose derivative, as shown in the following formula (1). .

Formula 1

N is an integer of 1 or more.

Hereinafter, a method for preparing hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles according to an embodiment of the present invention (hereinafter, simply referred to as "method for preparing HPMCAS particles") will be described in detail.

In the method for preparing HPMCAS particles according to one embodiment of the present invention, hydroxypropyl methylcellulose acetate succinate is produced by esterifying hydroxypropyl methylcellulose (HPMC), acetic anhydride and succinic anhydride in a reaction medium in the presence of a catalyst. Obtaining a reaction solution containing (HPMCAS) (ester reaction step), and introducing the reaction solution into water continuously or intermittently to produce particles (particleing step).

The catalyst plays a role of promoting the esterification reaction.

The content of the catalyst may be 40 to 200 parts by weight based on 100 parts by weight of the HPMC.

The reaction medium serves to disperse the catalyst, the HPMC, the acetic anhydride and the succinic anhydride to increase the contact area therebetween.

The amount of the reaction medium used in the esterification step may be 200 to 2,000 parts by weight based on 100 parts by weight of the HPMC.

The HPMC may include a degree of substitution of methoxyl group of 1.6 to 2.0 and degree of substitution of hydroxypropoxy group of 0.2 to 0.3.

The amount of acetic anhydride and the amount of the succinic anhydride used in the esterification step may be 140 to 240 parts by weight and 20 to 60 parts by weight based on 100 parts by weight of the HPMC.

The esterification step may be performed for 3 to 24 hours at 60 ~ 100 ℃. When the esterification step is performed during the time range in the temperature range, sufficient esterification reaction may proceed at an appropriate energy cost.

The manufacturing method of the HPMCAS particles may further include adjusting the temperature of the reaction solution (temperature control step of the reaction solution) between the esterification step and the granulation step.

In the temperature control step of the reaction solution, the reaction solution obtained in the esterification step may be heated or cooled.

The water used in the granulation step may be purified water.

The temperature of the reaction solution used in the granulation step may be 45 ~ 60 ℃. When the temperature of the reaction solution is within the above range, the viscosity of the reaction solution is appropriate, so that the time for introducing the reaction solution into the water is short, the process efficiency may be increased, and particles having an appropriate size may be generated.

The temperature of the water used in the granulation step may be 20 ~ 30 ℃. When the temperature of the water is within the above range, after the HPMCAS particles are generated, residues such as the reaction medium may be dissolved in the water to be efficiently separated from the HPMCAS particles, and the generated HPMCAS particles may not aggregate with each other. Can be.

The total content of the water used in the granulation step may be 12 to 20 times the total content of the reaction medium used in the esterification step. When the total amount of water used is within the above range, the produced HPMCAS particles may be prevented from agglomerating with each other to form a large lump, and process efficiency may be improved due to the use of an appropriate amount of water.

The granulation step may be performed by adding the reactant to the water.

The HPMCAS powder may be a fraction of the particles having a size of 841 ~ 1,190㎛ 25% by weight or more, for example, 60% by weight or more. Accordingly, when the HPMCAS powder is dissolved in a solvent, the dissolving velocity may be improved and the dissolution time may be shortened. The solvent may be an aqueous alcohol solution. For example, the solvent may be an aqueous ethanol solution.

Assuming that the same weight of HPMCAS powder is dissolved in a solvent, as the mean particle size of the HPMCAS powder increases, the total surface area of the HPMCAS particles contained in the HPMCAS powder decreases, so that the total dissolution time increases. There is a possibility.

On the other hand, when the mean particle size of the HPMCAS powder is reduced to 150㎛ or less, the surface of the fine particles are rapidly dissolved to give a sticky property in a moment, the surface of this property is the surrounding particles It is possible to cause agglomeration of the fruit and generate huge mass.

The HPMCAS powder has hydroxypropyl methyl having an acetyl group substitution degree of 0.3 to 0.75, a methoxyl group substitution degree of 1.6 to 2.0, a hydroxypropoxy group substitution degree of 0.2 to 0.3, and a succinoyl group substitution degree of 0.1 to 0.45. Cellulose acetate succinate (HPMCAS) particles.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example

Examples 1-4 and Comparative Examples 1-3

(Esterification step)

In a 1 Liter reactor equipped with a stirrer, 50 g of hydroxypropyl methylcellulose (HPMC) (with a degree of methoxyl group substitution of 1.85 and a degree of hydroxypropoxy group substitution of 0.27) per glucose unit, 250 g of acetic acid, 50 g of sodium acetate, 20 g of succinic anhydride and 120 g of acetic anhydride were added thereto. As a result, a first mixture was obtained. Thereafter, the first mixture was heated at 85 ° C. for 3 hours with stirring to proceed with the esterification reaction. As a result, a second mixture containing HPMCAS (also referred to as "reaction liquid") was obtained.

(Particulation step)

After controlling the temperature of the reaction solution, the temperature controlled reaction solution was added to purified water at a predetermined temperature and granulated. As a result, a slurry containing HPMCAS particles was obtained.

(Post-processing step)

The slurry was filtered, washed thoroughly with water and then dried at 85 ° C. for 5 hours to give a solid.

Examples 5-6

In the esterification step, 50 g of hydroxypropyl methylcellulose (HPMC) (having a degree of substitution of methoxyl group of 1.85 and a degree of substitution of hydroxypropoxyl group of 0.27) per glucose unit, 250 g of acetic acid, 50 g of sodium acetate, and 25 g of succinic anhydride And a solid was prepared in the same manner as in Examples 1 to 4 and Comparative Examples 1 to 3 except for changing the content of the reaction raw material using 75 g of acetic anhydride.

Comparative Example 4

Solids were prepared in the same manner as in Example 1 of US Pat. No. 4,226,981. That is, in the granulation step, the same method as in Examples 1 to 4 and Comparative Examples 1 to 3, except that the purified water was added to the reaction solution at a time instead of adding the reaction solution to the purified water. A solid was obtained.

In each of the above Examples and Comparative Examples, the temperature of the reaction solution, the temperature of purified water, and the amount of purified water are shown in Table 1, respectively.

Table 1

	Temperature of reaction solution (℃)	Purified water temperature (℃)	Amount (purified) of purified water (relative to acetic acid usage)
Example 1	50	20	x 15
Example 2	60	20	x 15
Example 3	60	30	x 15
Example 4	60	20	x 12
Example 5	60	20	x 15
Example 6	60	20	x 15
Comparative Example 1	70	20	x 15
Comparative Example 2	60	40	x 15
Comparative Example 3	60	20	x 8
Comparative Example 4	60	20	x 15

Evaluation example

Evaluation example 1

Chemical structures of the solids prepared in Examples 1, 3 and Comparative Example 1 were analyzed by the following method, and the results are shown in FIGS. 1 and 2.

(IR analysis: Infrared spectroscopy analysis)

Each solid was mixed at a ratio of KBr and 100: 1 (KBr: solid) by weight to obtain a mixture. The mixture was then compressed to give a transparent disc. The disc was then analyzed with an IR analyzer (JASCO, FT-IR 4100) to obtain an IR spectrum. The IR spectrum is shown in FIG. 1.

(XRD analysis: X-ray diffraction analysis)

Each solid was analyzed by XRD (Bruker AXS GmbH, D8 ADVANCE) to obtain XRD spectra. The XRD spectrum is shown in FIG. 2.

1 and 2, it can be seen that the solids prepared in Examples 1 and 2 are the same materials as the solids prepared in Comparative Example 1. Since the material prepared in Comparative Example 1 was prepared in the same manner as in Example 1 of US Pat. No. 4,226,981, it can be seen that it is HPMCAS. Accordingly, it can be confirmed indirectly that the solids prepared in Examples 1 and 2 are also HPMCAS.

Evaluation example 2

Substitution degree and viscosity of each solid prepared in Examples 1 to 6, Comparative Example 1 and Comparative Example 4 were measured by the following method, and the results are shown in Table 2 below. The solids prepared in Comparative Examples 2 and 3 showed that particles were completely aggregated with each other as a result of visual observation, and thus were excluded from Evaluation Example 2 because there was no commercial meaning.

(Degree of substitution)

The degree of substitution of each solid was analyzed by HPLC (Agilent 1100 series, Hewlett-Packard-Strasse 8) to obtain the type and content data of the components of the solid, and then measured using the data.

(Viscosity measurement)

First, 4.3 g of sodium hydroxide was dissolved in purified water containing no carbon to prepare 1,000 mL of sodium hydroxide solution. Thereafter, 2 g of each solid and the sodium hydroxide solution were mixed to prepare 100 g of a solid solution. Then, the solid solution was shaken for 30 minutes to completely dissolve each of the solids, and then the temperature of the solid solution was adjusted to 20 ± 0.1 ° C. Then, the viscosity of the solid solution was measured with a Ubbelohde viscometer (Cannon instrument company, Glass capillary viscometer).

TABLE 2

	Viscosity (cps)	Degree of substitution per glucose unit
	Viscosity (cps)	Acetyl group	Succino Diary	Methoxyl group	Hydroxypropoxyl group
Example 1	2.92	0.37	0.23	1.79	0.23
Example 2	2.90	0.39	0.23	1.79	0.23
Example 3	2.89	0.40	0.23	1.81	0.23
Example 4	2.93	0.38	0.23	1.80	0.23
Example 5	2.92	0.36	0.36	1.64	0.21
Example 6	2.87	0.34	0.37	1.77	0.22
Comparative Example 1	2.89	0.38	0.23	1.81	0.23
Comparative Example 4	2.94	0.39	0.23	1.80	0.23

Evaluation example 3

The particle size distribution and dissolution time in the solvent of the solids prepared in Examples 1 to 6, Comparative Example 1 and Comparative Example 4 were measured, and the results are shown in Tables 3 to 5, respectively. The solids prepared in Comparative Examples 2 and 3 showed that particles were completely aggregated with each other as a result of visual observation, and thus were excluded from Evaluation Example 3 because there was no commercial meaning.

(Measurement of particle size distribution of all solids)

Each of the solids was dried in an oven to obtain 500 g of dried solids (water content: less than 1% by weight). Then, the dried solids are stacked on top of each other and stacked on top of the five Sieves (Retsch, Test Sieve No. 16 to 20) mounted on a Sieve shaker (Retsch, AS 200), and then the Sieves are completely It was sealed. Subsequently, the Sieve shaker was operated for 15 minutes, and then the Sieves were separated from each other, and the fraction of solids filtered through each of the Sieves was measured. The results are shown in Table 3 below. In Table 3 below, Test Sieve No. More than 16 is for Test Sieve No. The fraction of solids filtered out of 16 Sieve, Test Sieve No. 16-20 is the Test Sieve No. Test Sieve No. 16 through Sieve. The fraction of solids filtered out of any one of 17 to 20 Sieves, Test Sieve No. Less than 20 is Test Sieve No. The fraction of solids that passed through 20 Sieve. In Table 3 below, Test Sieve No. If 16-20 is expressed as actual particle size, it is 841-1,190㎛. That is, Test Sieve No. 16 has a mesh size of 1,190 µm and Test Sieve No. 16; The mesh size of 20 is 841 μm.

TABLE 3

	Particle size distribution (wt%)
	Test Sieve No.
	More than 16	16-20	Less than 20
Example 1	27.8	62.1	10.1
Example 2	12.3	72.4	15.3
Example 3	28.3	60.8	10.9
Example 4	23.6	67.0	9.4
Example 5	9.2	58.6	32.2
Example 6	10.5	64.8	24.7
Comparative Example 1	71.4	24.5	4.1
Comparative Example 2	Agglomerated	-	-
Comparative Example 3	Agglomerated	-	-
Comparative Example 4	82.3	15.8	1.9

Referring to Table 3, each of the solids prepared in Examples 1 to 6 compared to the solids prepared in Comparative Examples 1 and 4 Test Sieve No. The fraction of solids having a particle size of 16-20 (ie, 841-1,190 μm) was found to be high.

(Measurement of particle size distribution of solids with particle size less than Test Sieve No. 20)

Test Sieve No. The particle size distribution of only the solid that passed 20 was analyzed by a particle size analyzer (HORIBA, LA-950 Laser Particle Size Analyzer), and the results are shown in Table 4 below. In Table 4, D10, D50 (average particle size) and D90 mean particle diameters corresponding to 10%, 50%, and 90% of the total volume when the volume is accumulated from the small particles by measuring the particle diameter of the solid particles, respectively. . In addition, in Table 4 below, the 80% span value was calculated by Equation 1 below.

[Equation 1]

80% Span Value = (D90-D10) / D50

In addition, in Table 4, the median size means the size of the particle corresponding to a cumulative particle size distribution value of 50% in the particle size distribution of the solid.

Table 4

	D50 (μm)	Medium size (㎛)	80% span value	D10 (㎛)	D90 (㎛)
Example 1	357.67	318.13	1.49	138.44	612.45
Example 2	342.15	317.06	1.38	136.91	574.45
Example 3	357.13	320.60	1.47	137.52	608.80
Example 4	345.23	322.90	1.48	135.89	613.97
Example 5	330.09	259.50	1.64	120.21	545.57
Example 6	343.00	277.86	1.55	130.72	560.18
Comparative Example 1	380.14	349.85	1.40	153.68	642.56
Comparative Example 4	437.18	411.52	1.21	191.79	691.32

Referring to Table 4, the solids (ie, HPMCAS) prepared in Examples 1 to 6, Comparative Example 1 and Comparative Example 4 was found to have a D50 greater than 150㎛. Based on the experience of the present inventors, when the solid D50 is 150 μm or less, the surface of the microparticles in the solid rapidly dissolves and becomes sticky while the solid is dissolved in a solvent, and then aggregates with the surrounding particles to form a large mass. There is a problem to form.

(Measuring Dissolution Time in Solvent)

All of the solids and Test Sieve No. When a solid having a particle size of less than 20 is dissolved in a solvent, the time (ie, dissolution time) for dissolving each solid completely is measured, and the results are shown in Table 5 below. Specifically, each of the solids was dried in an oven to obtain 30 g of dried solids (water content: less than 1% by weight). Thereafter, a mixed solvent (80 wt% ethanol and 20 wt% water) was prepared. Subsequently, each of the dried solids was slowly added to the mixed solvent while stirring the mixed solvent at a stirring speed of 200 rpm. In this process, the process of dissolving each of the solids in the mixed solvent was closely observed, and the dissolution time was measured.

Table 5

	Dissolution time (min)
	Solids	Test Sieve No. Solids with a particle size of less than 20
Example 1	27.3	15.4
Example 2	25.3	14.6
Example 3	33.5	15.4
Example 4	27.5	15.3
Example 5	23.7	14.2
Example 6	24.3	14.4
Comparative Example 1	89.9	15.5
Comparative Example 4	107.5	15.6

Referring to Table 5, the solids prepared in Examples 1 to 6 (ie, HPMCAS) have a shorter dissolution time of the total solids compared to the solids prepared in Comparative Examples 1 and 4 (ie, HPMCAS). Test Sieve No. Dissolution times of solids with a particle size of less than 20 were found to be similar or short.

Although preferred embodiments of the present invention have been described above with reference to the drawings and embodiments, these are merely exemplary, and various modifications and equivalent other embodiments are possible to those skilled in the art. You will understand. Therefore, the protection scope of the present invention should be defined by the appended claims.

Claims

Esterification of hydroxypropyl methylcellulose (HPMC), acetic anhydride and succinic anhydride in the reaction medium in the presence of a catalyst to obtain a reaction solution comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS) (ester reaction step) ); And

Method for producing hydroxypropyl methyl cellulose acetate succinate (HPMCAS) particles comprising the step of adding the reaction solution to water continuously or intermittently to produce particles (particleing step).
The method of claim 1,

The temperature of the reaction solution and the temperature of the water used in the granulation step is 45 ~ 60 ℃ and 20 ~ 30 ℃ hydroxypropyl methylcellulose acetate succinate (HPMCAS) particle production method.
The method of claim 1,

The total content of the water used in the granulation step is 12 to 20 times the total content of the reaction medium used in the esterification step of producing a hydroxypropyl methylcellulose acetate succinate (HPMCAS) particles.
Hydroxypropyl methylcellulose acetate succinate (HPMCAS) prepared according to any one of claims 1 to 3, wherein the fraction of particles having a size of 841 ~ 1,190㎛ hydroxypropyl methylcellulose Acetate Succinate (HPMCAS) Powder.
The method of claim 4, wherein

Hydroxypropyl methylcellulose having an acetyl group substitution degree of 0.3-0.75, a methoxyl group substitution degree of 1.6-2.0, a hydroxypropoxy group substitution degree of 0.2-0.3, and a succinoyl group substitution degree of 0.1-0.45 per glucose unit. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) powder comprising acetate succinate (HPMCAS) particles.