Hydroxypropyl methylcellulose acetate succinate powder, and method of producing the same

Abstract

To provide a method of producing hydroxypropyl methylcellulose acetate succinate powder that is capable of inhibiting aggregation among particles of the precipitated esterified cellulose ether and reducing the amount of formed fine powder, thereby producing the esterified cellulose ether in high yield.SOLUTION: A method of producing hydroxypropyl methylcellulose acetate succinate powder comprises an esterification reaction step, a precipitation step, a washing / recovering step, and a drying step, wherein the precipitation step is a step of introducing the reaction solution, obtained in the esterification reaction step, and water into a mixer provided with a rotatable rotor having blades and a perforated plate arranged to surround the rotor in a direction perpendicular to a radial direction of the rotor to allow a suspension containing precipitated hydroxypropyl methylcellulose acetate succinate particles to pass through the perforated plate to be discharged therethrough.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a hydroxypropyl methylcellulose acetate succinate powder and a method for producing the same. [Background technology]

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as "HPMCAS") is an esterified cellulose ether in which some of the hydrogen atoms of the hydroxyl groups of cellulose are replaced with four types of substituents: methyl group (-CH3), hydroxypropyl group (-CH2CH(OH)CH3), acetyl group (-COCH3), and succinyl group (-COC2H4COOH). It is widely used in applications such as solid dispersions for improving the dissolution of poorly water-soluble drugs and enteric coating for tablets.

[0003] Esterified cellulose ethers, such as HPMCAS, can be produced by known methods. In known production methods, a reaction solution containing an esterified cellulose ether is brought into contact with water to precipitate the esterified cellulose ether and to wash and remove impurities. Methods for bringing a reaction solution containing an esterified cellulose ether into contact with water include, for example, a method of adding a large amount of water, specifically, 10 times the volume of water, to a reaction solution containing an esterified cellulose ether (Patent Document 1), a method of combining a reaction solution containing an esterified cellulose ether with water for at least 800 s, and a method of removing impurities by washing the reaction solution containing an esterified cellulose ether with water. -1 (Patent Document 2), and a method in which a reaction solution containing an esterified cellulose ether is continuously or intermittently added to water (Patent Document 3). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 4,226,981 [Patent Document 2] Special Publication No. 2015-512456 [Patent Document 3] Special Publication No. 2017-501239 Summary of the Invention [Problem to be solved by the invention]

[0005] However, in the method described in Patent Document 1, the precipitated esterified cellulose ether causes aggregation between particles, so that the esterified cellulose ether cannot be obtained in a granular form. In addition, in the method described in Patent Document 1, the aggregation between the particles of the obtained particles prevents water from penetrating between the particles, so that impurities cannot be sufficiently removed, and there is room for improvement. In the method described in Patent Document 2, the precipitated esterified cellulose ether contains a lot of fine powder, which leads to a decrease in yield due to the outflow of fine powder when filtering and washing the impurities. In addition, there is a problem that the final product obtained by the method described in Patent Document 2 has poor fluidity and is poor in handleability as a powder. In addition, in the method described in Patent Document 3, although the amount of fine powder produced is small, the shape of the produced esterified cellulose ether particles is distorted, and the fluidity as a powder is poor. In addition, the method described in Patent Document 3 has a problem that a large amount of water is required to produce esterified cellulose ether particles, and the amount of wastewater treatment increases. The present invention has been made in consideration of the above circumstances, and aims to provide a production method for obtaining an esterified cellulose ether in a high yield while preventing aggregation between particles of precipitated esterified cellulose ether and suppressing the amount of fine powder generated, and to provide an esterified cellulose ether powder having improved powder fluidity. [Means for solving the problem]

[0006] As a result of extensive investigations to solve the above problems, the inventors have discovered that by using a mixer equipped with a rotatable rotor equipped with blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor in the precipitation step of a production method for HPMCAS, it is possible to prevent agglomeration between precipitated HPMCAS particles while suppressing the amount of fine powder generated, thereby producing HPMCAS in a high yield and to obtain an HPMCAS powder with good flowability, which has led to the completion of the present invention. According to the present invention, there are provided the following method for producing hydroxypropyl methylcellulose acetate succinate powder and hydroxypropyl methylcellulose acetate succinate powder. [1] an esterification reaction step of carrying out an esterification reaction between hydroxypropyl methylcellulose, an acetylating agent and a succinoylating agent in the presence of an aliphatic carboxylic acid to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate; a precipitation step of introducing the reaction solution and water into a mixer having a rotatable rotor with blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and passing a suspension containing precipitated hydroxypropyl methylcellulose acetate succinate particles through the perforated plate and discharging the suspension; a washing and recovering step of washing the hydroxypropyl methylcellulose acetate succinate particles in the suspension and recovering the washed hydroxypropyl methylcellulose acetate succinate particles; a drying step of drying the washed hydroxypropyl methylcellulose acetate succinate particles; A method for producing a hydroxypropyl methylcellulose acetate succinate powder comprising at least [2] The perforated plate has an opening of 0.1 to 10.0 mm 2 The method for producing the hydroxypropyl methylcellulose acetate succinate powder according to [1], wherein the powder has an opening area of ​​100 nm or less. [3] The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to [1] or [2], wherein the peripheral speed of the outermost periphery of the blade is 5.0 to 20.0 m / s. [4] The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to any one of [1] to [3], wherein an amount of water added to the reaction solution is 200 to 600 parts by mass per 100 parts by mass of the reaction solution. [5] The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to any one of [1] to [4], wherein, when the particle size distribution of the hydroxypropyl methylcellulose acetate succinate particles in the suspension is evaluated by a wet sieving test according to JIS Z8815, the average particle size is 500 to 2000 μm, and the proportion of particles having a particle size of 250 μm or less to the total mass is 15.0% or less. [6] Hydroxypropyl methylcellulose acetate succinate powder having an average particle size of more than 300 μm and not more than 1000 μm according to the dry sieving test described in JIS Z8815, a loose bulk density of 0.30 g / mL or less, and a compressibility (the ratio of the difference between the loose bulk density and the packed bulk density to the packed bulk density) of 10% or less. Effect of the Invention

[0007] According to the present invention, HPMCAS can be produced in a high yield while suppressing the amount of fine powder generated, and HPMCAS powder having good flowability can be obtained. Therefore, the HPMCAS produced by the production method of the present invention is useful for applications such as solid dispersions for improving the dissolution of poorly water-soluble drugs and enteric coating of tablets. [Brief description of the drawings]

[0008] [Figure 1] 1 is a schematic diagram showing a structure of a rotatable rotor having blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor. [Figure 2A]FIG. 1 is a conceptual diagram showing an example of a perforated plate having square openings. [Figure 2B] FIG. 2 is a conceptual diagram showing an example of a perforated plate having rectangular openings. [Figure 2C] FIG. 2 is a conceptual diagram showing an example of a perforated plate having circular openings. [Diagram 3] 1 is a flowchart showing the classification of all particles of hydroxypropyl methylcellulose acetate succinate into four particles: fine particles, long fibrous particles (LF1 and LF2), short fibrous particles (SF1 and SF2), and spherical particles (S1 and S2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] [Method of producing hydroxypropyl methylcellulose acetate succinate powder] The method for producing hydroxypropyl methylcellulose acetate succinate powder of the present invention includes at least an esterification reaction step, a precipitation step, a washing and recovery step, and a drying step.

[0010] <Esterification reaction process> In the esterification reaction step, an esterification reaction is carried out between hydroxypropyl methylcellulose, an acetylating agent, and a succinoylating agent in the presence of an aliphatic carboxylic acid to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate.

[0011] Hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") is a non-ionic water-soluble cellulose ether. HPMC may be synthesized by a known method or may be commercially available. HPMC can be obtained, for example, by contacting a solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide with pulp in a sheet, chip or powder form to form alkali cellulose, and then adding an etherifying agent such as methyl chloride and propylene oxide to carry out an etherification reaction.

[0012] From the viewpoint of obtaining HPMC having a small number of non-dissolved fibers, the DS of the methoxy group in HPMC is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and even more preferably 1.60 to 2.00. From the viewpoint of obtaining HPMC having a small number of non-dissolved fibers, the MS of the hydroxypropoxy group in HPMC is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.2 to 0.65. The term "insoluble fiber" refers to the portion of HPMC that is insoluble in water. HPMC is water-soluble by partially etherifying the hydroxyl groups of cellulose and weakening the hydrogen bonds within and between the molecules of cellulose. Since it is difficult to perform etherification completely uniformly industrially, HPMC may contain a portion that is insoluble in water, i.e., insoluble fiber, due to an insufficient degree of substitution of ether groups or an uneven degree of substitution of ether groups. If the final HPMCAS contains a large amount of insoluble fiber, the enteric coating becomes uneven, reducing the yield of the enteric coating formulation, or the filter frequently becomes clogged during the filtration process of the coating solution, reducing productivity. Therefore, it is preferable that the HPMC, which is the raw material for HPMCAS, has a small number of insoluble fibers. The number of insoluble fibers can be determined by analyzing an aqueous solution of HPMC with a device such as a Coulter counter. The DS of the methoxy group in HPMC represents the degree of substitution, which is the average number of methoxy groups per unit of anhydrous glucose, and the MS of the hydroxypropoxy group in HPMC represents the molar substitution, which is the average number of moles of hydroxypropoxy groups per mole of anhydrous glucose. The DS of the methoxy group in HPMC and the MS of the hydroxypropoxy group can be calculated by converting values ​​obtained by measurement based on the 18th Edition of the Japanese Pharmacopoeia.

[0013] From the viewpoint of kneading properties in the esterification reaction step, the viscosity of a 2% by mass aqueous solution of HPMC at 20° C. is preferably 1.0 to 50.0 mPa·s, more preferably 2.0 to 20.0 mPa·s, and even more preferably 2.0 to 5.0 mPa·s. The viscosity of a 2% by mass aqueous solution of HPMC at 20° C. can be measured in accordance with the capillary viscometer method in the “Viscosity Measurement Method” described in the “General Test Methods” of the 18th Edition of the Japanese Pharmacopoeia.

[0014] Examples of the aliphatic carboxylic acid include aliphatic carboxylic acids having 2 to 4 carbon atoms, such as acetic acid, propionic acid, and butyric acid, with acetic acid being preferred from an economical viewpoint. The amount of the aliphatic carboxylic acid used is preferably 3.00 to 10.00 mol, and more preferably 4.00 to 8.00 mol, per 1 mol of HPMC, from the viewpoint of dissolving HPMC and increasing the reaction rate.

[0015] The acetylating agent includes acetic anhydride, acetyl chloride, etc., with acetic anhydride being preferred from the economical viewpoint. The amount of the acetylating agent used is not particularly limited as long as the desired degree of substitution of HPMCAS can be obtained, but from the viewpoint of reaction efficiency, it is preferably 0.20 to 1.50 mol, more preferably 0.40 to 1.30 mol, per mol of HPMC.

[0016] Examples of the succinoylating agent include succinic anhydride and succinyl chloride, with succinic anhydride being preferred from the economical viewpoint. The amount of succinoylating agent used is not particularly limited as long as the desired degree of substitution of HPMCAS is obtained, but from the viewpoint of reaction efficiency, it is preferably 0.10 to 1.50 mol, more preferably 0.20 to 1.20 mol, per mol of HPMC.

[0017] The esterification reaction may be carried out in the presence of a catalyst. From an economical viewpoint, the catalyst is preferably an alkali metal carboxylate such as sodium acetate or potassium acetate. The catalyst may be used alone or in combination of two or more kinds, as necessary. In addition, a commercially available catalyst may be used. The amount of the catalyst used may be selected arbitrarily taking into consideration the degree of substitution of HPMCAS, but from the viewpoint of reaction efficiency, it is preferably 0.10 to 2.00 mol, more preferably 0.30 to 1.90 mol, per mol of HPMC.

[0018] The reaction temperature in the esterification reaction step is preferably 60 to 120°C, more preferably 60 to 100°C, from the viewpoint of the reaction rate. The reaction time in the esterification reaction step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of obtaining HPMCAS with a desired degree of substitution.

[0019] From the viewpoint of reaction efficiency, the esterification reaction is preferably carried out using a stirring device capable of uniformly dispersing and mixing the highly viscous reaction raw materials. The stirring device used in the reaction is not particularly limited, but for example, a kneader type mixer having a biaxial stirring blade, a vertical stirring tank having two or more stirring shafts and stirring blades, etc. can be used.

[0020] After the esterification reaction, if necessary, unreacted acetylating agent and succinoylating agent may be treated, and in order to control the viscosity of the reaction solution containing HPMCAS, water may be added to the reaction solution containing HPMCAS to an extent that does not cause precipitation of HPMCAS particles (the treatment of mixing with water after the reaction is also referred to as "post-treatment") to obtain a reaction solution of post-treated HPMCAS. The amount of water added to the reaction solution in the post-treatment of the esterification step is preferably 10 to 450 parts by mass, and more preferably 50 to 300 parts by mass, per 100 parts by mass of HPMC, from the viewpoints of improving transportability of the HPMCAS reaction solution and preventing precipitation of HPMCAS particles.

[0021] <Precipitation process> Next, a precipitation step in which a reaction solution containing HPMCAS is mixed with water to obtain a suspension in which HPMCAS particles are precipitated will be described. In the precipitation step, the reaction solution and water are introduced into a mixer having a rotatable rotor equipped with blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and a suspension containing the precipitated HPMCAS particles is passed through the perforated plate and discharged. If a mixer without a perforated plate surrounding the rotor is used in the precipitation process, the precipitated HPMCAS particles may be discharged without being uniformly mixed in the mixer, and insufficient mixing may result in aggregation of the HPMCAS particles, whereas excessive mixing may result in the precipitated HPMCAS particles becoming finer, leading to an increase in fine powder. In the present invention, by passing the suspension containing the HPMCAS particles precipitated in the precipitation step through the perforated plate and discharging it, the precipitated HPMCAS particles are subjected to a uniform mixing action, which makes it possible to suppress aggregation between the precipitated HPMCAS particles, miniaturization of the precipitated HPMCAS particles, and an increase in fine powder.

[0022] An example (front view) of a mixer including a rotatable rotor with blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor is shown in Fig. 1. The mixer shown in Fig. 1 includes a rotor 2 and blades 1 on a central axis 3. The mixer shown in Fig. 1 also includes a perforated plate 5 having openings 4 in a direction perpendicular to the radial direction of the rotor 2 so as to surround the rotor 2.

[0023] The number, arrangement, and shape of the blades in the rotatable rotor are not particularly limited. For example, the blades may have a shape extending from the center to the outer periphery of the rotor. The blades extending from the center to the outer periphery of the rotor may be linear, streamlined, or discontinuous.

[0024] In a rotatable rotor having the blades, the shortest distance between the outermost surface of the blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor is preferably greater than 0 mm and not greater than 3.0 mm, more preferably greater than 0 mm and not greater than 1.0 mm, from the viewpoint of preventing aggregation between the resulting HPMCAS particles.

[0025] The speed (circumferential speed) of the outermost blades of the rotating rotor is preferably 5.0 to 20.0 m / s, more preferably 5.0 to 18.0 m / s, and even more preferably 5.0 to 15.0 m / s, from the viewpoints of preventing the HPMCAS particles precipitated in the mixer from being pulverized due to excessive mixing action and of precipitating the HPMCAS particles through sufficient mixing action to produce HPMCAS in a high yield.

[0026] The shear rate generated by the rotational motion of the rotating rotor is preferably 800 s from the viewpoint of suppressing adhesion and coagulation of the HPMCAS particles in the suspension containing the HPMCAS particles. -1 More than 10,000s, preferably -1 More than 15,000s, more preferably -1 The upper limit of the shear rate generated by the rotational motion of the rotor is not particularly limited, but may be, for example, 100,000 s -1 The shear rate (s -1 ) is calculated by dividing the peripheral speed (m / s) of the blade tips of the rotating rotor by the shortest distance (m) between the outermost surface of the blades of the rotating rotor and the porous plate surrounding the rotor on the outside in a direction perpendicular to the radial direction of the rotor.

[0027] The perforated plate has one or more openings. The opening area per opening is preferably 0.1 to 10.0 mm from the viewpoints of preventing adhesion of HPMCAS particles in the suspension containing the HPMCAS particles to each other, suppressing the amount of fine powder generated due to the reduction in the particle size of the HPMCAS particles, and increasing the recovery rate of HPMCAS. 2 , more preferably 0.3 to 8.0 mm 2, and more preferably 0.5 to 5.0 mm 2 It is. From the viewpoint of ensuring a high processing speed of the reaction liquid containing HPMCAS, the ratio of the opening area to the total area of ​​the perforated plate (opening ratio) is preferably 1 to 90%, more preferably 10 to 90%, and even more preferably 20 to 90%.

[0028] The shape of the openings in the perforated plate is not particularly limited. For example, as shown in Fig. 2, the openings may be square (Fig. 2A), rectangular (Fig. 2B), round (Fig. 2C), or other polygonal shapes. From the viewpoint of suppressing the generation of fine powder and obtaining HPMCAS in a high yield, round holes are preferred.

[0029] The temperature of the reaction solution containing HPMCAS used in the precipitation step is preferably 10 to 60°C, more preferably 20 to 50°C, from the viewpoint of suppressing adhesion and aggregation of HPMCAS particles in a suspension containing HPMCAS particles.

[0030] The viscosity of the HPMCAS-containing reaction solution used in the precipitation step at 40°C is preferably 10,000 to 100,000 mPa·s, more preferably 20,000 to 80,000 mPa·s, and even more preferably 30,000 to 50,000 mPa·s, from the viewpoint of suppressing the generation of fine powder and obtaining HPMCAS in a high yield. The viscosity of the HPMCAS-containing reaction solution is measured at a shear rate of 10 sec in accordance with the viscosity measurement method using a cone-plate type rotational viscometer described in JIS Z8803. -1 It can be measured at.

[0031] The amount of water to be mixed with the reaction solution containing HPMCAS is preferably 100 to 1,000 parts by mass, more preferably 150 to 800 parts by mass, and even more preferably 200 to 600 parts by mass, per 100 parts by mass of the reaction solution containing HPMCAS, from the viewpoint of suppressing adhesion and aggregation between HPMCAS particles in the suspension containing precipitated HPMCAS particles. The temperature of the water to be mixed with the reaction solution containing HPMCAS is preferably 5 to 30°C, more preferably 5 to 20°C, from the viewpoint of suppressing adhesion and aggregation between HPMCAS particles in the suspension containing precipitated HPMCAS particles.

[0032] The average particle size of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles is preferably 500 to 2000 μm, more preferably 600 to 1800 μm, and even more preferably 700 to 1700 μm, from the viewpoint of suppressing the amount of fine powder generated and producing HPMCAS in a high yield. The average particle size of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles can be measured by a wet sieving test described in JIS Z8815. That is, the horizontal axis is the sieve opening (μm) and the vertical axis is the cumulative sieve mass (%), and the sieve opening and the cumulative sieve mass (%) of each sieve opening are plotted. The value of the sieve opening at the intersection of the straight line connecting two points that sandwich 50% of the cumulative sieve mass and 50% of the cumulative sieve mass is the average particle size of the HPMCAS particles. The cumulative sieve mass (%) can be calculated from the mass of the HPMCAS particles remaining on the sieve after pouring the suspension containing the precipitated HPMCAS particles into a sieve, pouring pure water over the HPMCAS particles until the liquid passing through the sieve becomes transparent, and transferring the suspension to a container for mass measurement. The proportion of fine powder having a particle size of 250 μm or less in the total mass of HPMCAS particles in the suspension containing precipitated HPMCAS particles is preferably 15.0% or less, more preferably 14.0% or less, and even more preferably 13.0% or less, from the viewpoint of producing HPMCAS in a high yield. There is no particular lower limit, but it is, for example, more than 0%. The proportion of fine powder having a particle size of 250 μm or less to the total mass of HPMCAS particles in a suspension containing precipitated HPMCAS particles can be calculated from the total mass of HPMCAS particles remaining on each sieve with a mesh size of 250 μm or less relative to the total mass of HPMCAS particles remaining on each sieve after the wet sieving test.

[0033] <Cleaning and recovery process> Next, a washing and recovery step of washing the HPMCAS particles in the suspension and recovering the washed HPMCAS particles will be described. In the washing and recovery step, acetic acid, succinic acid, and the like which are by-produced in the esterification reaction step are removed. The washing method is not particularly limited, but examples include a method in which a portion of the water in a suspension containing HPMCAS particles is removed by centrifugation, filtration, squeezing, decantation, or the like, and then the particles are repeatedly suspended in a clear solvent. The type of solvent used for washing is not particularly limited, but water is preferable from an economical viewpoint. The temperature of the solvent used for washing is preferably 5 to 50°C, more preferably 10 to 40°C, from the viewpoint of suppressing adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles.

[0034] After the washing and collecting step, before moving to the drying step, the suspension containing the HPMCAS particles may be deliquified to obtain a hydrous HPMCAS cake in order to reduce the drying load. The deliquification method is not particularly limited, but a part of the water in the suspension containing the HPMCAS particles is removed by centrifugation, pressure filtration, vacuum filtration, squeezing, or the like. The water content of the hydrous HPMCAS cake is preferably 90% or less, more preferably 80% or less, from the viewpoint of reducing the drying load. The lower limit is not particularly limited, but is, for example, 20% or more. The moisture content of the HPMCAS hydrous cake can be measured according to the method described in the Japanese Pharmacopoeia, 18th Edition, "General Test Methods, 2. Physical Test Methods, Loss on Drying Test Method." Specifically, the moisture content of the HPMCAS hydrous cake is defined as {(mass of HPMCAS hydrous cake - bone dry mass of HPMCAS) / (mass of HPMCAS hydrous cake)} x 100%. Here, "mass of HPMCAS hydrous cake" refers to the mass of HPMCAS precisely weighed according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method." Additionally, "bone dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method."

[0035] From the viewpoint of producing HPMCAS in a high yield, the yield after the washing step (hereinafter also referred to as "washing yield") is preferably 80% or more, more preferably 85% or more. The upper limit of the yield after the washing step is not particularly limited, but is, for example, less than 100%. The yield after the washing step is specifically defined as (the bone dry mass of HPMCAS particles in the suspension containing the washed HPMCAS particles, or the bone dry mass of HPMCAS in the HPMCAS wet cake) / (theoretical yield of HPMCAS)×100%. Here, the "theoretical yield of HPMCAS" refers to the theoretical yield calculated from the reaction efficiency of the esterification agent in the esterification reaction step.

[0036] <Drying process> Next, the drying step for drying the washed HPMCAS particles will be described. The drying temperature (product temperature) in the drying step is preferably 20 to 100°C, more preferably 25 to 80°C, from the viewpoint of preventing aggregation of the HPMCAS particles. The drying time in the drying step is preferably 5 hours or less, more preferably 3 hours or less, from the viewpoint of preventing aggregation of the HPMCAS particles. The lower limit of the drying time in the drying step is not particularly limited as long as the moisture content of the HPMCAS powder can be sufficiently reduced, but is, for example, 10 minutes or more. The drying apparatus used is not particularly limited, but for example, a fluidized bed dryer, a grooved agitator dryer, a vacuum dryer, or the like can be used.

[0037] [Hydroxypropyl methylcellulose acetate succinate powder] The moisture content of the dried HPMCAS powder is preferably more than 0% and not more than 5.0%, more preferably 0.5% or more and not more than 3.0%, from the viewpoint of obtaining an HPMCAS powder with good fluidity. The moisture content of the HPMCAS powder can be measured according to the method described in the Japanese Pharmacopoeia, 18th Edition, "General Test Methods, 2. Physical Test Methods, Loss on Drying Test Method." Specifically, the moisture content of the HPMCAS powder is defined as {(mass of HPMCAS powder - bone dry mass of HPMCAS powder) / (mass of HPMCAS powder)} x 100%. Here, "mass of HPMCAS powder" refers to the mass of the HPMCAS powder when it is precisely weighed according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method." Additionally, "bone dry mass of HPMCAS" refers to the mass of HPMCAS after it has been dried according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method."

[0038] The DS of the methoxy group in HPMCAS is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and even more preferably 1.60 to 2.00. The MS of the hydroxypropoxy group in HPMCAS is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and even more preferably 0.20 to 0.65. The DS of the acetyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and further preferably 0.20 to 0.80. The DS of the succinyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and further preferably 0.10 to 0.60. From the viewpoint of solubility, the ratio of the DS of the acetyl group to the DS of the succinyl group in HPMCAS (acetyl group / succinyl group) is preferably 0.50 to 4.00, and more preferably 0.80 to 3.70. The DS of the methoxy, acetyl, and succinyl groups in HPMCAS represents the degree of substitution and is the average number of methoxy, acetyl, and succinyl groups per unit of anhydroglucose, and the MS of the hydroxypropoxy groups in HPMCAS represents the molar substitution and is the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The DS of the methoxy group, acetyl group, and succinyl group and the MS of the hydroxypropoxy group in HPMCAS can be calculated from the values ​​obtained by the method described in the individual drug articles "Hypromellose acetate succinate" in the 18th Edition of the Japanese Pharmacopoeia.

[0039] The average particle size of the HPMCAS powder as determined by a dry sieving test is preferably more than 300 μm and not more than 1000 μm, more preferably more than 350 μm and not more than 950 μm, and even more preferably more than 350 μm and not more than 900 μm. The average particle size as determined by a dry sieving test can be measured by the dry sieving test described in JIS Z8815. That is, the horizontal axis represents the sieve opening (μm) and the vertical axis represents the cumulative sieve mass (%). When each sieve opening and the cumulative sieve mass (%) of each sieve opening are plotted, the value of the sieve opening at the intersection of the straight line connecting two points that sandwich 50% of the cumulative sieve mass and 50% of the cumulative sieve mass is taken as the average particle size of the HPMCAS powder.

[0040] The loose bulk density of the HPMCAS powder is preferably 0.5 g / mL or less, more preferably 0.45 g / mL or less, even more preferably 0.35 g / mL or less, and most preferably 0.30 g / mL or less. The lower limit of the loose bulk density is not particularly limited, but is, for example, 0.10 g / mL or more. The loose bulk density refers to the bulk density in a loosely packed state, and can be measured by using a powder property evaluation device to pass a sample through a sieve with a mesh size of 1 mm into a cylindrical container (material: stainless steel) with a diameter of 5.05 cm and a height of 5.05 cm (volume 100 ml) uniformly from above (23 cm), and then leveling the top surface and weighing it. A specific example of the powder property evaluation device is the powder property evaluation device POWDER TESTER PT-S manufactured by Hosokawa Micron Corporation.

[0041] The packed bulk density of the HPMCAS powder is preferably 0.5 g / mL or less, more preferably 0.45 g / mL or less, even more preferably 0.40 g / mL or less, and most preferably 0.35 g / mL or less. The lower limit of the packed bulk density is not particularly limited, but is, for example, 0.15 g / mL or more. The packed bulk density is the bulk density when the cylindrical container is tapped to make it densely packed. Tapping is an operation in which a cylindrical container filled with a sample is repeatedly dropped from a certain height to give a light impact to the bottom, making the sample densely packed. In practice, the sample is filled into the cylindrical container in the same manner as in the measurement of the loose bulk density, and the top surface is leveled and weighed, and then a cap is placed on the cylindrical container, and the sample is added up to the top edge, and tapping is performed 180 times with a tapping height of 1.8 cm. After the tapping is completed, the cap is removed, and the sample is leveled and weighed on the top surface of the cylindrical container, and the bulk density in this state is taken as the packed bulk density.

[0042] From the viewpoint of obtaining good flowability, the degree of compression of the HPMCAS powder is preferably 10% or less, more preferably 8% or less, even more preferably 6% or less, and most preferably 5% or less. The lower limit is not particularly limited, but is more than 0%. The degree of compression is a value calculated from the loose bulk density and the packed bulk density by the following formula. Compressibility (%) = {(packed bulk density - loose bulk density) / packed bulk density} x 100

[0043] In this specification, HPMCAS powder is classified into four types of particles: "long fiber particles", "short fiber particles", "spherical particles", and "fine particles". Figure 3 is a flowchart summarizing the method of classifying "total particles A" of HPMCAS powder into four types of particles: "fine particles B", "long fiber particles (LF1 and LF2)", "short fiber particles (SF1 and SF2)", and "spherical particles (S1 and S2)". The volume fraction of each particle in the HPMCAS powder can be calculated by measuring the following shape parameters such as fiber length (LEFI), fiber diameter (DIFI), elongation ratio, aspect ratio, and circularity using dynamic image analysis. Dynamic image analysis is a method of continuously taking images of particles dispersed in a fluid such as a gas or a solvent, and performing binarization and analysis to determine particle size and particle shape. For example, it can be measured using a dynamic image analysis type particle size distribution measuring device QICPIC / R16 (manufactured by Sympatec Co., Ltd.).

[0044] The total particles (A) are divided into particles (C) with a fiber length (Length of Fiber: LEFI) of 40 μm or more and fine particles (B) with a fiber length of less than 40 μm. LEFI is defined as the length between both ends of a particle, which is the longest path from one end of the particle outline to the other end. Note that the detection limit of the QICPIC / R16 equipped with the M7 lens is 4.7 μm, so particles less than 4.7 μm are not detected. However, the volume of particles with a LEFI less than 4.7 μm accounts for a very small proportion of the total volume of the HPMCAS powder, so it can be ignored for the purposes of this invention.

[0045] Particles (C) with a LEFI of 40 μm or more are divided into primary spherical particles (S1) with an elongation ratio (DIFI / LEFI), which is the ratio of the diameter of fiber (DIFI) to the LEFI, of 0.5 or more, and particles (D) with an elongation ratio of less than 0.5. DIFI is defined as the minor axis of a particle and is calculated by dividing the projected area of ​​the particle by the sum of the lengths of all the fiber branches.

[0046] Particles (D) with a LEFI of 40 μm or more and an elongation ratio of less than 0.5 are divided into particles (E) with an aspect ratio, which is the ratio (Fmin / Fmax) of the minimum Feret diameter (Fmin) to the maximum Feret diameter (Fmax), of less than 0.5, and particles (F) with an aspect ratio of 0.5 or more. The aspect ratio of both particles is greater than 0 and less than 1. The Feret diameter is the distance between two parallel tangents that sandwich a particle, and the maximum Feret diameter (Fmax) is the maximum diameter when the direction is changed from 0° to 180° between the two tangents that sandwich a particle, and the minimum Feret diameter (Fmin) is the minimum diameter when the direction is changed from 0° to 180° between the two tangents that sandwich a particle.

[0047] Fibrous particles (E) having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of less than 0.5 are divided into first long fibrous particles (LF1) having a LEFI of 200 μm or more and first short fibrous particles (SF1) having a LEFI of less than 200 μm.

[0048] Particles (F) with a LEFI of 40 μm or more, an elongation ratio of less than 0.5, and an aspect ratio of 0.5 or more are divided into second spherical particles (S2) with a circularity of 0.7 or more, and fibrous particles (G) with a circularity of less than 0.7. Circularity is calculated by dividing the perimeter (P) of a circle having the same area as the projected area (Ap) of the particle. EQPC ) and the actual particle perimeter (P real ) and is defined by the following formula. For any particle, the circularity is greater than 0 and less than 1. The smaller the circularity, the more irregular the particle shape. EQPC is defined as the Diameter of a Circle of Equal Projection Area, i.e., the diameter of a circle having an area equal to the projected area of ​​the particle, and is also called the Hey wood diameter.

[0049]

number

[0050] Fibrous particles (G) having a LEFI of 40 μm or more, an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, and a circularity of less than 0.7 are divided into second long fibrous particles (LF2) having a LEFI of 200 μm or more and second short fibrous particles (SF2) having a LEFI of less than 200 μm.

[0051] The volume of fine particles in HPMCAS (V m ) can be calculated by the following formula, assuming that the microparticle is a sphere with a diameter of EQPC: V m =(π / 6) × (EQPC) 3 ×N m Here, N m is the number of particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of particles.

[0052] In this specification, particles having a LEFI of 40 μm or more, excluding fine particles having a LEFI of less than 40 μm from all particles, are classified and distinguished from one another as "long fiber particles," "short fiber particles," and "spherical particles" based on the above-mentioned particle shape parameters, namely, LEFI, elongation ratio, aspect ratio, and circularity.

[0053] <Long fiber particles> Particles that meet either definition LF1 or LF2 below are classified as "long fibrous particles". LF1: Particles with an elongation ratio of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (fiber length) of 200 μm or more LF2: Particles with an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, a circularity of less than 0.7 and a LEFI (fiber length) of 200 μm or more The volume of long fibrous particles in HPMCAS (V LF ) can be calculated by the following formula by assuming that the long fibrous particle is a cylinder with a base diameter of DIFI and a height of LEFI. V LF =(π / 4) × (DIFI) 2 ×(LEFI)×N LF Here, N LF is the number of long fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of long fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of long fibrous particles. The volume of each of the particles that satisfy the definitions of LF1 and LF2 is calculated using the above formula, and the sum of these volumes is the volume of the long fibrous particles in the HPMCAS powder.

[0054] <Short fiber particles> Particles that meet either definition SF1 or SF2 below are classified as "short fibrous particles". SF1: Particles with an elongation ratio of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (fiber length) of 40 μm or more and less than 200 μm SF2: Particles having an elongation ratio of less than 0.5, an aspect ratio of 0.5 or more, a circularity of less than 0.7, and a LEFI (fiber length) of 40 μm or more and less than 200 μm The volume of short fibrous particles in HPMCAS (V SF ) can be calculated by the following formula by assuming the short fibrous particles as cylinders with a base diameter of DIFI and a height of LEFI, similarly to the above long fibrous particles. V SF =(π / 4) × (DIFI) 2 ×(LEFI)×N SF Here, N SF is the number of short fibrous particles in the sample, DIFI is the median DIFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of short fibrous particles, and LEFI is the median LEFI corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of short fibrous particles. The volume of each of the particles that meet the definitions of SF1 and SF2 above is calculated using the above formula, and the sum of these volumes is the volume of the short fiber particles in the HPMCAS powder.

[0055] <Spherical particles> Particles that meet either definition S1 or S2 below are classified as "spherical particles". S1: Particles with an elongation ratio of 0.5 or more and a LEFI (fiber length) of 40 μm or more S2: Elongation ratio less than 0.5, aspect ratio more than 0.5, circularity more than 0.7 and 40 Particles with LEFI (fiber length) of μm or more The volume of spherical particles in HPMCAS (V S ) can be calculated by the following formula, assuming that the spherical particles are spheres with a diameter of EQPC. V S =(π / 6) × (EQPC) 3 ×N S Here, N S is the number of spherical particles in the sample, and EQPC is the median EQPC corresponding to the 50% cumulative value of the cumulative particle size distribution curve based on the number of spherical particles. The volume of each particle that satisfies the definitions of S1 and S2 above is calculated using the above formula. The sum of these values ​​is the volume of the spherical particles in the HPMCAS powder.

[0056] The volume fraction of each type of particle in the HPMCAS powder is determined by the volume V defined above. m , V LF , V SF and V S can be calculated using the following formulas. Volume fraction of fine particles = {V m / (V m +V LF +V SF +V S )}×100 Volume fraction of long fiber particles = {V LF / (V m +V LF +V SF +V S )}×100 Volume fraction of short fiber particles = {V SF / (V m +VLF +V SF +V S )}×100 Volume fraction of spherical particles = {V S / (V m +V LF +V SF +V S )}×100

[0057] The volume fractions of various particles (long fiber particles, short fiber particles, spherical particles, and fine particles) were measured using a quantitative feeder VIBRI / L, an airflow type disperser RODOS / L, and a dynamic image analysis type particle size distribution analyzer QICPIC / R16 (manufactured by Sympatec Co., Ltd.) equipped with an M7 lens at a frame rate of 500Hz, an injector of 4mm, and a dispersion pressure of 1bar. The captured particle images were analyzed using analysis software WINDOX5 Version:5.9.1.1 to determine the number-based median EQPC, number-based median LEFI, number-based median DIFI, elongation ratio, aspect ratio, and circularity of various particles, and were calculated using the above-mentioned formula based on these values. Note that M7 was used as the classification during the analysis.

[0058] From the viewpoint of obtaining an HPMCAS powder having good flowability, the volume fraction of spherical particles in the HPMCAS powder is preferably 50% or more, more preferably 60% or more, and even more preferably 65% ​​or more. There is no particular upper limit, but it is, for example, less than 100%. EXAMPLES

[0059] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples in any way. The average particle size of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles after the precipitation step, and the water content and washing yield of the water-containing HPMCAS cake obtained in the washing and recovery step were measured or calculated according to the methods described below. In addition, other physical properties were measured or calculated according to the methods described above unless otherwise specified.

[0060] Average particle size of HPMCAS particles in suspension containing precipitated HPMCAS particles The average particle size of HPMCAS particles was measured by a wet sieving test described in JIS Z8815. That is, the horizontal axis is the sieve opening (μm) and the vertical axis is the cumulative sieve mass (%), and the sieve opening and the cumulative sieve mass (%) of each sieve opening are plotted. The value of the sieve opening at the intersection of the straight line connecting two points that sandwich the cumulative sieve mass of 50% and the cumulative sieve mass of 50% was taken as the average particle size of the HPMCAS particles. The cumulative sieve mass (%) was calculated from the mass of the HPMCAS particles remaining on the sieve after pouring a suspension containing HPMCAS particles into a sieve, pouring pure water over the HPMCAS particles until the liquid passing through the sieve becomes transparent, and transferring the liquid to a container for mass measurement. In addition, a cylindrical sieve with a diameter of 200 mm and a plain weave sieve mesh was used as the sieve. The sieve openings used were 4000 μm, 1700 μm, 1000 μm, 500 μm, 250 μm, 177 μm, 150 μm, 106 μm, and 75 μm. Furthermore, the sieving method used was a manual wet sieving method.

[0061] - Moisture content and washing yield of wet HPMCAS cake The moisture content of the hydrous HPMCAS cake obtained in the washing and recovery step was measured by the method described in the Japanese Pharmacopoeia, 18th Edition, "General Test Methods, 2. Physical Test Methods, Loss on Drying Test Method." Specifically, the moisture content of the HPMCAS hydrous cake is defined as {(total mass of HPMCAS hydrous cake - bone dry mass of HPMCAS) / (total mass of HPMCAS hydrous cake)} x 100%. Here, "total mass of HPMCAS hydrous cake" refers to the mass of the HPMCAS hydrous cake precisely weighed according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method." In addition, "bone dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to the Japanese Pharmacopoeia, 18th Edition, "Loss on Drying Test Method." The washing yield was calculated from the theoretical yield calculated from the amount of the raw material charged, and the mass and moisture content of the HPMCAS water cake obtained after the washing step using the following formula. Washing yield (%) = {HPMCAS wet cake mass × (100 - moisture content of HPMCAS wet cake) / 100} / theoretical yield

[0062] Synthesis Example 1 In a 5 L kneader equipped with a biaxial stirrer, 700 g of HPMC (having a methoxy group DS of 1.87, a hydroxypropoxy group MS of 0.24, and a 2 mass% aqueous solution viscosity of 3.4 mPa s at 20°C), 1120 g of acetic acid, 358 g of acetic anhydride, 185 g of succinic anhydride, and 312 g of sodium acetate were charged and stirred at 85°C for 5 hours to carry out an esterification reaction. After stirring for 5 hours, 1471 g of water was added to the kneader to stop the reaction, and 4146 g of a reaction solution containing HPMCAS-1 was obtained. The equivalent relationship in the esterification reaction is shown in Table 1.

[0063] Synthesis Example 2 The same procedure as in Example 1 was carried out except that the amount of acetic anhydride was 485 g, the amount of succinic anhydride was 74 g, and the amount of water added was 1480 g, to obtain 4171 g of a reaction solution containing HPMCAS-2. The equivalent relationship in the esterification reaction is shown in Table 1.

[0064] [Table 1]

[0065] Example 1 The reaction solution containing the HPMCAS-1 was adjusted to 40°C (shear rate 10 sec -1 The HPMCAS suspension (viscosity at 45,000 mPa s) was introduced into a mixer equipped with a rotor and a perforated plate (In-Line Mixer Model 200 L, manufactured by Silverson Nippon Co., Ltd.) at a rate of 2.4 kg / min together with cold water at 10°C, to obtain a suspension containing precipitated HPMCAS particles. The mixer has a rotor with a diameter of 50.8 mm that can rotate on its own and is equipped with straight blades. In the direction perpendicular to the radial direction of the rotor, the rotor is rotated by a diameter of 1.5 mm (the opening area per opening is 1.8 mm 2The rotor was surrounded by a perforated plate having a plurality of round hole-shaped openings. The rotor had a rotation speed of 2400 rpm, a peripheral speed of the outermost blade of the rotor of 6.4 m / s, and a shear rate generated by the rotation of the rotor of 31900 s -1 The mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 540 parts by mass. The average particle size of the HPMCAS particles in the suspension and the proportion of the mass of fine powder having a particle size of 250 μm or less to the mass of the HPMCAS particles contained in the suspension were evaluated by a wet sieving method, and the average particle size was 1175 μm and the proportion of fine powder was 5.4 mass%. The suspension was filtered through a 83 mesh (180 μm opening) sieve until no filtrate was discharged. The HPMCAS particles obtained by filtration were suspended again in water at 20° C., and then the procedure of filtering through a 83 mesh (180 μm opening) sieve until no filtrate was discharged was repeated three times for washing, to obtain a hydrous cake of HPMCAS. The moisture content of the hydrous cake was 68.0%, and the yield was 90.2%. The wet cake of HPMCAS was dried at 50°C using a fluidized bed dryer to obtain HPMCAS powder. The physical properties of the obtained HPMCAS powder are shown in Table 2.

[0066] Example 2 The same operation as in Example 1 was carried out except that the amount of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 300 parts by mass, to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0067] Example 3 The same operation as in Example 1 was carried out except that the amount of the cold water mixed with 250 parts by mass per 100 parts by mass of the reaction solution containing HPMCAS-1 was changed to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0068] Example 4 The rotation speed of the rotor of the mixer was 3600 rpm, the peripheral speed of the outermost blade of the rotor was 9.6 m / s, and the shear rate generated by the rotational motion of the rotor was 47900 s -1 The same operation as in Example 1 was performed except that the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 580 parts by mass, to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0069] Example 5 The rotation speed of the mixer rotor is 3600 rpm, the peripheral speed of the outermost blade of the rotor is 9.6 m / s, and the shear rate generated by the rotation of the rotor is 47900 s -1 The same operation as in Example 1 was performed except that the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 420 parts by mass, to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0070] Example 6 The apertures in the perforated plate are 1.0 mm in diameter (the opening area per aperture is 0.8 mm 2 ) and the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 390 parts by mass, the same operation as in Example 1 was performed to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0071] Example 7 The openings in the perforated plate are 2.5 mm in diameter (the opening area per opening is 4.9 mm 2 ) and the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 330 parts by mass, the same operation as in Example 1 was performed to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0072] Example 8 A mixer with a rotor diameter of 69.9 mm (In-Line Mixer Model 275LS, Silverson Nippon Co., Ltd.) was used, and the openings in the perforated plate were 1.0 mm in diameter (opening area per opening: 0.8 mm 2 The rotor speed of the mixer was 3600 rpm, the peripheral speed of the outermost blade of the rotor was 13.1 m / s, and the shear rate generated by the rotational motion of the rotor was 65500 s -1 The same operation as in Example 1 was performed except that the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 400 parts by mass, to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0073] Example 9 The openings of the perforated plate are squares with sides of 1.5 mm (the opening area per opening is 2.3 mm 2 ) and the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 300 parts by mass, the same operation as in Example 1 was performed to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0074] Example 10 The same operation as in Example 1 was carried out, except that the opening of the perforated plate was a rectangle having a width of 1.5 mm, and the mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 300 parts by mass, to obtain HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0075] Example 11 The reaction solution containing the HPMCAS-2 adjusted to 40°C (shear rate 10 sec -1 The same procedure as in Example 1 was carried out except that a HPMCAS powder (viscosity at 37,000 mPa·s) was used, to obtain HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0076] Example 12 The same operation as in Example 1 was carried out, except that the reaction solution containing HPMCAS-2 adjusted to 40°C was used, and the mass of the cold water mixed with 290 parts by mass per 100 parts by mass of the reaction solution containing HPMCAS-2 was changed to an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0077] Example 13 The same operation as in Example 1 was carried out, except that the reaction solution containing HPMCAS-2 adjusted to 40°C was used, and the mass of the cold water mixed with 200 parts by mass per 100 parts by mass of the reaction solution containing HPMCAS-2 was changed to an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0078] Comparative Example 1 The reaction solution containing the HPMCAS-1, adjusted to 40°C, was introduced into a mixer without a perforated plate (Labo-lution Pipeline Homomixer, manufactured by PRIMIX Corporation) at a rate of 2.4 kg / min together with cold water at 10°C, to obtain a suspension containing precipitated HPMCAS particles. The mixer had a rotor and a stator with a diameter of 28.0 mm, but the stator had no openings, and the suspension containing HPMCAS particles was discharged from the gap (clearance) between the rotor and the stator. The rotor had straight blades. The rotation speed of the rotor was 4360 rpm, the peripheral speed of the outermost blade of the rotor was 6.4 m / s, and the shear rate generated by the rotational motion of the rotor was 8667 s -1 The mass of the cold water mixed with 100 parts by mass of the reaction solution containing HPMCAS-1 was 400 parts by mass. The average particle size of the HPMCAS particles in the suspension and the proportion of fine powder of 250 μm or less by mass to the mass of the HPMCAS particles contained in the suspension were evaluated by a wet sieving method, and the average particle size was 1218 μm and the proportion of fine powder was 17.8%. The suspension was filtered through a 83 mesh (180 μm opening) sieve until no filtrate was discharged. The HPMCAS particles obtained by filtration were suspended again in water at 20° C., and then the procedure of filtering through a 83 mesh (180 μm opening) sieve until no filtrate was discharged was repeated three times for washing, to obtain a hydrous cake of HPMCAS. The moisture content of the hydrous cake was 70.0%, and the yield was 79.1%. The wet cake of HPMCAS was dried at 50°C using a fluidized bed dryer to obtain HPMCAS powder. The physical properties of the obtained HPMCAS powder are shown in Table 2.

[0079] Comparative Example 2 The rotation speed of the rotor of the mixer was 6550 rpm, the peripheral speed of the outermost blade of the rotor was 9.6 m / s, and the shear rate generated by the rotational motion of the rotor was 12800 s -1 The same operation as in Comparative Example 1 was carried out except for the above, to obtain HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0080] Comparative Example 3 The rotation speed of the rotor of the mixer was 8930 rpm, the peripheral speed of the outermost blade of the rotor was 13.1 m / s, and the shear rate generated by the rotational motion of the rotor was 17467 s -1 The same operation as in Comparative Example 1 was carried out except for the above, to obtain HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0081] Comparative Example 4 1.0 kg of the reaction solution containing the HPMCAS-1 adjusted to 50° C. was added to 4.0 kg of water at 20° C. to form particles. Other operations were carried out in the same manner as in Comparative Example 1 to obtain an HPMCAS powder. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0082] Comparative Example 5 An HPMCAS powder was obtained by carrying out the same operation as in Comparative Example 1, except that the reaction solution containing HPMCAS-2 adjusted to 40°C was used in the mixer without a perforated plate, and the mass of the cold water mixed with 210 parts by mass per 100 parts by mass of the reaction solution containing HPMCAS-2 was changed to 100 parts by mass of the reaction solution containing HPMCAS-2. The average particle size of the HPMCAS particles in the suspension, the proportion of fine powder, the washing yield, and the physical properties of the final HPMCAS powder are shown in Table 2.

[0083] [Table 2A] [Table 2B]

[0084] In the precipitation step, the HPMCAS particles of Examples 1 to 13, which were precipitated using a mixer equipped with a rotating rotor and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, had a lower proportion of fine powder of 250 μm or less in the suspension and a higher washing yield than the HPMCAS particles of Comparative Examples 1 to 3 and 5, which were precipitated using a mixer not equipped with a perforated plate. Furthermore, the HPMCAS powders of Examples 1 to 13 showed a lower degree of compression after drying than those of Comparative Examples 1 to 5, and powders with good flowability were obtained. [Explanation of symbols]

[0085] 1 Blade 2 Rotors 3 center axis 4 Openings 5 Perforated plate

Claims

1. an esterification reaction step of carrying out an esterification reaction between hydroxypropyl methylcellulose, an acetylating agent and a succinoylating agent in the presence of an aliphatic carboxylic acid to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate; a precipitation step of introducing the reaction solution and water into a mixer having a rotatable rotor with blades and a perforated plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and passing a suspension containing precipitated hydroxypropyl methylcellulose acetate succinate particles through the perforated plate and discharging the suspension; a washing and recovering step of washing the hydroxypropyl methylcellulose acetate succinate particles in the suspension and recovering the washed hydroxypropyl methylcellulose acetate succinate particles; a drying step of drying the washed hydroxypropyl methylcellulose acetate succinate particles; A method for producing a hydroxypropyl methylcellulose acetate succinate powder comprising at least

2. The perforated plate has an opening of 0.1 to 10.0 mm 2 The method for producing hydroxypropyl methylcellulose acetate succinate powder according to claim 1, wherein the opening area is 0.01 to 0.05 mm.

3. The method for producing hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or 2, wherein the peripheral speed of the outermost periphery of the blade is 5.0 to 20.0 m / s.

4. The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or 2, wherein the amount of water added to the reaction solution is 200 to 600 parts by mass per 100 parts by mass of the reaction solution.

5. The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or 2, wherein, when the particle size distribution of the hydroxypropyl methylcellulose acetate succinate particles in the suspension is evaluated by a wet sieving test according to JIS Z8815, the average particle size is 500 to 2000 μm, and the mass ratio of particles having a size of 250 μm or less to the total mass is 15.0% or less.

6. Hydroxypropyl methylcellulose acetate succinate powder having an average particle size of more than 300 μm and not more than 1000 μm as measured by a dry sieving test according to JIS Z8815, a loose bulk density of 0.30 g / mL or less, and a compressibility (the ratio of the difference between the loose bulk density and the packed bulk density to the packed bulk density) of 10% or less.

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