Hydroxypropylmethylcellulose acetate succinate powder and method for producing same

Abstract

Provided is a method for producing a hydroxypropyl methyl cellulose acetate succinate powder with which it is possible to obtain an esterified cellulose ether at a high yield while preventing agglomeration between precipitated esterified cellulose ether particles and while suppressing the amount of fine powder generation. Specifically disclosed is a method for producing a hydroxypropyl methyl cellulose acetate succinate powder, which comprises at least an esterification reaction step, a precipitation step, a cleaning and recovery step and a drying step, in the precipitation step, the reaction solution obtained in the esterification reaction step and water are introduced into a mixer provided with a rotatable rotor having blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor. And a step for discharging a suspension containing the precipitated hydroxypropyl methyl cellulose acetate succinate particles through the porous plate.

Description

Technical Field

[0001] The present invention relates to hydroxypropylmethylcellulose acetate succinate powder and a preparation method thereof. Background Art

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is an esterified cellulose ether in which a portion of the hydrogen atoms of the hydroxyl group of cellulose are substituted with a total of four substituents, namely, methyl (-CH3), hydroxypropyl (-CH2CH(OH)CH3), acetyl (-COCH3) and succinyl (-COC2H4COOH), and is widely used in solid dispersions for improving the dissolution of poorly water-soluble drugs and enteric coatings for tablets.

[0003] Esterified cellulose ether represented by HPMCAS can be produced by a known method. In the known production method, the esterified cellulose ether is precipitated and the impurities are washed and removed by contacting the reaction solution containing the esterified cellulose ether with water. As a method for contacting the reaction solution containing the esterified cellulose ether with water, for example, a method of adding a large amount of water, specifically, a method of adding water 10 times the volume of the reaction solution, to the reaction solution containing the esterified cellulose ether is disclosed (Patent Document 1), a method of heating the reaction solution containing the esterified cellulose ether and water for at least 800 seconds, and a method of heating the reaction solution containing the esterified cellulose ether and water for at least 800 seconds. -1 A method of increasing the shear rate of the reaction mixture (Patent Document 2), a method of continuously or intermittently adding a reaction solution containing esterified cellulose ether to water (Patent Document 3), and the like.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: U.S. Patent No. 4226981

[0007] Patent Document 2: Japanese Patent Application No. 2015-512456

[0008] Patent Document 3: Japanese Patent Application No. 2017-501239 Summary of the invention

[0009] Problem that the invention aims to solve

[0010] However, in the method described in Patent Document 1, the precipitated esterified cellulose ether agglomerates between particles, so that the esterified cellulose ether cannot be obtained in the form of granules. In addition, in the method described in Patent Document 1, since the obtained particles agglomerate between particles, water is prevented from penetrating between particles, and therefore, impurities cannot be fully removed, and there is still room for improvement. In the method described in Patent Document 2, the precipitated esterified cellulose ether contains a large amount of fine powder, and when filtering and washing impurities, the fine powder flows out, thereby deteriorating the yield. Furthermore, there is a problem that the final product obtained by the method described in Patent Document 2 has poor fluidity and poor operability as a powder. In addition, in the method of Patent Document 3, although the amount of fine powder generated is small, the shape of the generated esterified cellulose ether particles is deformed, and the fluidity as a powder is poor. In addition, the method of Patent Document 3 requires a large amount of water in the generation of esterified cellulose ether particles, and there is a problem of increased wastewater treatment volume.

[0011] The present invention has been made in view of the above-mentioned problems, and its object is to provide a method for producing esterified cellulose ether in a high yield while preventing the aggregation of precipitated esterified cellulose ether particles and suppressing the amount of fine powder generated, and to provide esterified cellulose ether powder having improved powder fluidity.

[0012] Solutions for solving problems

[0013] As a result of intensive studies to solve the above problems, the present inventors have found that, in the precipitation step of the method for producing HPMCAS, by using a mixer including a rotatable rotor having blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, the generation of fine powder can be suppressed while preventing the aggregation of precipitated HPMCAS particles, thereby obtaining HPMCAS at a high yield and HPMCAS powder having good fluidity, thereby completing the present invention.

[0014] According to the present invention, the following method for producing hydroxypropyl methylcellulose acetate succinate powder and hydroxypropyl methylcellulose acetate succinate powder can be provided. [1]

[0016] A method for preparing hydroxypropyl methylcellulose acetate succinate powder, comprising at least:

[0017] an esterification reaction step, in which hydroxypropyl methylcellulose is subjected to an esterification reaction with an acetylating agent and a succinic acylating agent in the presence of an aliphatic carboxylic acid, thereby obtaining a reaction solution containing hydroxypropyl methylcellulose acetate succinate;

[0018] A precipitation step, wherein the reaction solution and water are introduced into a mixer having a rotatable rotor with blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and a suspension containing the precipitated hydroxypropyl methylcellulose acetate succinate particles is discharged through the porous plate;

[0019] a washing and recovery step of washing the hydroxypropyl methylcellulose acetate succinate particles in the suspension and recovering the washed hydroxypropyl methylcellulose acetate succinate particles; and

[0020] The drying step is to dry the washed hydroxypropylmethylcellulose acetate succinate particles. [2]

[0022] The method for producing hydroxypropyl methylcellulose acetate succinate powder according to [1], wherein:

[0023] Each opening of the porous plate has a diameter of 0.1 to 10.0 mm. 2 opening area. [3]

[0025] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] or [2], wherein:

[0026] The peripheral speed of the outermost portion of the blade is 5.0 to 20.0 m / s. [4]

[0028] The method for producing hydroxypropylmethylcellulose acetate succinate according to any one of [1] to [3], wherein

[0029] The amount of water added to the reaction solution is 200 to 600 parts by mass based on 100 parts by mass of the reaction solution. [5]

[0031] The method for producing hydroxypropylmethylcellulose acetate succinate according to any one of [1] to [4], wherein

[0032] When the particle size distribution of the hydroxypropylmethylcellulose acetate succinate particles in the suspension was evaluated by a wet sieving test described in JIS Z8815, the average particle size was 500 to 2000 μm, and the mass of particles of 250 μm or less accounted for 15.0% or less of the total mass. [6]

[0034] A hydroxypropyl methylcellulose acetate succinate powder, wherein:

[0035] The average particle size measured by the dry sieving test described in JIS Z8815 is greater than 300 μm and less than 1000 μm, the loose bulk density is less than 0.30 g / mL, and the compression degree (ratio of the difference between the close bulk density and the loose bulk density to the close bulk density) is less than 10%.

[0036] Effects of the Invention

[0037] According to the present invention, the amount of fine powder generated can be suppressed, HPMCAS can be produced at a high yield, and further, HPMCAS powder having good fluidity can be obtained. Therefore, the HPMCAS produced by the production method of the present invention is useful in applications such as solid dispersions for improving the dissolution of poorly water-soluble drugs and enteric coatings for tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a conceptual diagram showing a structure of a rotatable rotor having blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor.

[0039] Figure 2A This is a conceptual diagram showing an example of a perforated plate having square openings.

[0040] Figure 2B This is a conceptual diagram showing an example of a perforated plate having rectangular openings.

[0041] Figure 2C This is a conceptual diagram showing an example of a porous plate having circular hole-shaped openings.

[0042] Figure 3 This is a flow chart for classifying all particles of hydroxypropylmethylcellulose acetate succinate into four types of particles: fine particles, long fibrous particles (LF1 and LF2), short fibrous particles (SF1 and SF2), and spherical particles (S1 and S2). DETAILED DESCRIPTION

[0043] [Method for producing hydroxypropyl methylcellulose acetate succinate powder]

[0044] The method for producing hydroxypropylmethylcellulose acetate succinate powder of the present invention comprises at least an esterification reaction step, a precipitation step, a washing and recovery step, and a drying step.

[0045] <Esterification reaction step>

[0046] In the esterification reaction step, hydroxypropyl methylcellulose is subjected to an esterification reaction with an acetylating agent and a succinic acylating agent in the presence of an aliphatic carboxylic acid, thereby obtaining a reaction solution containing hydroxypropyl methylcellulose acetate succinate.

[0047] Hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") is a nonionic water-soluble cellulose ether. HPMC may be synthesized by a known method or commercially available HPMC. HPMC may be prepared by contacting a solution of an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide with, for example, a flake, fragment or powdered pulp to produce alkali cellulose, and then adding an etherifying agent such as methyl chloride or propylene oxide to cause an etherification reaction to be performed.

[0048] From the viewpoint of obtaining HPMC with a small number of insoluble fibers, the DS of the methoxyl group in HPMC is preferably 1.10 to 2.20, more preferably 1.40 to 2.00, and further preferably 1.60 to 2.00. From the viewpoint of obtaining HPMC with a small number of insoluble fibers, the MS of the hydroxypropoxyl group in HPMC is preferably 0.10 to 1.00, more preferably 0.20 to 0.80, and further preferably 0.2 to 0.65.

[0049] The so-called insoluble fiber refers to the water-insoluble part contained in HPMC. HPMC shows water solubility by partially etherifying the hydroxyl groups of cellulose, thereby weakening the hydrogen bonds within and between the molecules of cellulose. Since it is difficult to carry out etherification completely and evenly in industry, HPMC may contain a part that is insoluble in water due to insufficient degree of substitution of ether groups or uneven substitution of ether groups, that is, it may contain insoluble fibers. If a large amount of insoluble fibers is contained in the HPMCAS finally obtained, the enteric film becomes uneven, the yield of the enteric coating preparation is reduced, or the filter is frequently blocked in the filtering process of the coating solution, resulting in reduced productivity. Therefore, HPMC as a raw material of HPMCAS is preferably HPMC with a small number of insoluble fibers. The number of insoluble fibers can be obtained, for example, by analyzing the HPMC aqueous solution with a device such as a Coulter counter.

[0050] It should be noted that 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. The MS of the hydroxypropoxy group in HPMC represents the molar substitution, which is the average molar number of the hydroxypropoxy group per 1 mole of anhydrous glucose. The DS of the methoxy group in HPMC and the MS of the hydroxypropoxy group can be obtained by converting the values ​​obtained by measuring based on the 18th revised edition of the Japanese Pharmacopoeia.

[0051] From the viewpoint of kneading properties in the esterification reaction step, the viscosity of a 2 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.

[0052] The viscosity of a 2 mass % aqueous solution of HPMC at 20° C. can be measured by a capillary viscometer method in the “Viscosity Measurement Method” described in the “General Test Methods” of the 18th revised edition of the Japanese Pharmacopoeia.

[0053] 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, and acetic acid is preferred from an economical viewpoint.

[0054] From the viewpoint of increasing the reaction rate of dissolving HPMC, the amount of the aliphatic carboxylic acid used is preferably 3.00 to 10.00 mol, more preferably 4.00 to 8.00 mol, based on 1 mol of HPMC.

[0055] As the acetylating agent, acetic anhydride, acetyl chloride, etc. may be mentioned, and from the viewpoint of economy, acetic anhydride is preferred.

[0056] The amount of the acetylating agent used is not particularly limited as long as HPMC with a desired degree of substitution can be obtained, but from the viewpoint of reaction efficiency, the amount of the acetylating agent used is preferably 0.20 to 1.50 mol, more preferably 0.40 to 1.30 mol, relative to 1 mol of HPMC.

[0057] Examples of the succinic acylating agent include succinic anhydride and succinyl chloride, and succinic anhydride is preferred from an economical viewpoint.

[0058] The amount of the succinic acylating agent used is not particularly limited as long as the HPMCAS with a desired degree of substitution can be obtained. However, from the viewpoint of reaction efficiency, the amount of the succinic acylating agent used is preferably 0.10 to 1.50 mol, more preferably 0.20 to 1.20 mol, relative to 1 mol of HPMC.

[0059] The esterification reaction can be carried out in the presence of a catalyst. From an economic point of view, alkali metal carboxylates such as sodium acetate and potassium acetate are preferably used as the catalyst. As required, the catalyst can be used alone or in combination of two or more. In addition, the catalyst can use a commercially available catalyst.

[0060] The amount of the catalyst used may be arbitrarily selected in consideration of the degree of substitution with HPMCAS, but from the viewpoint of reaction efficiency, the amount of the catalyst used is preferably 0.10 to 2.00 mol, more preferably 0.30 to 1.90 mol, relative to 1 mol of HPMC.

[0061] The reaction temperature in the esterification reaction step is preferably 60 to 120°C, more preferably 60 to 100°C, from the viewpoint of reaction rate.

[0062] From the viewpoint of obtaining HPMCAS having a desired degree of substitution, the reaction time in the esterification reaction step is preferably 2 to 8 hours, more preferably 3 to 6 hours.

[0063] From the viewpoint of reaction efficiency, it is preferred to use a stirring device that can evenly disperse and mix the high-viscosity reaction raw materials for the esterification reaction. There is no particular limitation on the stirring device used in the reaction, and for example, a kneader type mixer with a double-shaft stirring blade, a vertical stirring tank with two or more stirring shafts and stirring blades, etc. can be used.

[0064] After the esterification reaction, water may be added to the reaction solution containing HPMCAS as needed to the extent that HPMCAS particles are not precipitated in order to treat unreacted acetylating agent and succinic acylating agent and control the viscosity of the reaction solution containing HPMCAS (the mixing treatment with water after the reaction is also referred to as "post-treatment"), thereby obtaining a post-treated HPMCAS reaction solution.

[0065] From the viewpoint of improving the transportability of the HPMCAS reaction solution and preventing the precipitation of HPMCAS particles, 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, more preferably 50 to 300 parts by mass, relative to 100 parts by mass of HPMC.

[0066] <Precipitation process>

[0067] Next, the precipitation step of mixing the reaction solution containing HPMCAS and water to obtain a suspension in which HPMCAS particles are precipitated will be described.

[0068] In the precipitation step, the reaction solution and water are introduced into a mixer having a rotatable rotor with blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and a suspension containing the precipitated HPMCAS particles is discharged through the porous plate.

[0069] In the precipitation process, when a mixer without a porous plate surrounding the rotor is used, the suspension may be discharged directly in the mixer in a state where the mixing action on the precipitated HPMCAS particles is not uniform. In the case of insufficient mixing action, the HPMCAS particles cause aggregation between the particles, while in the case of excessive mixing action, the precipitated HPMCAS particles are fined, resulting in an increase in fine powder.

[0070] By allowing the suspension containing the HPMCAS particles precipitated in the precipitation step to pass through the porous plate and be discharged as in the present invention, the precipitated HPMCAS particles are uniformly mixed, thereby suppressing the aggregation of the precipitated HPMCAS particles, and suppressing the refinement of the precipitated HPMCAS particles and the increase of fine powder.

[0071] An example (front view) of a mixer including a rotatable rotor having blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor is shown in FIG. Figure 1 . Figure 1 The mixer shown has a rotor 2 and blades 1 on a central axis 3. In addition, Figure 1 The mixer shown in the figure is provided with a porous plate 5 having openings 4 in a direction perpendicular to the radial direction of the rotor 2 so as to surround the rotor 2 .

[0072] There is no particular limitation on the number of blades, arrangement of blades, and shape of blades in the rotatable rotor having blades. For example, the blades may have a shape extending from the center portion of the rotor to the outer peripheral portion. The blades extending from the center portion of the rotor to the outer peripheral portion may also have a straight line shape, a streamline shape, or a discontinuous shape.

[0073] From the viewpoint of preventing aggregation of the obtained HPMCAS particles, the shortest distance between the outermost peripheral surface of the blades in the rotatable rotor having the blades and the porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor is preferably greater than 0 mm and less than 3.0 mm, more preferably greater than 0 mm and less than 1.0 mm.

[0074] From the viewpoint of suppressing the pulverization of HPMCAS particles precipitated in the mixer due to excessive mixing, precipitating the HPMCAS particles by sufficient mixing, and producing HPMCAS at a high yield, the speed (circumferential speed) of the outermost peripheral portion of the blades in 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.

[0075] From the viewpoint of suppressing the adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles, the shear rate generated by the rotational motion of the rotating rotor is preferably 800 s -1 More than 10000s, more preferably -1 More than, more preferably 15000s -1 There is no particular upper limit on the shear rate generated by the rotational motion of the rotating rotor, and it is, for example, 100,000 s -1 It should be noted that the shear rate (s -1 ) can be calculated by dividing the circumferential speed (m / s) of the front end of the blade in the rotating rotor by the shortest distance (m) between the outermost circumferential surface of the blade in the rotating rotor and the porous plate surrounding the outside of the rotor in a direction perpendicular to the radial direction of the rotor.

[0076] The porous plate has one or more openings. From the viewpoint of preventing the HPMCAS particles in the suspension containing the HPMCAS particles from adhering to each other, suppressing the generation of fine powders due to the miniaturization of the particle size of the HPMCAS particles, and improving the recovery rate of the HPMCAS, the opening area of ​​each opening is preferably 0.1 to 10.0 mm. 2 , more preferably 0.3 to 8.0 mm 2 , more preferably 0.5 to 5.0 mm 2 .

[0077] From the viewpoint of ensuring the processing rate of the reaction solution containing HPMCAS, the ratio of the opening area to the total area of ​​the porous plate (opening ratio) is preferably 1 to 90%, more preferably 10 to 90%, and even more preferably 20 to 90%.

[0078] There is no particular limitation on the shape of the openings in the porous plate. FIG. 2A to FIG. 2C As shown, it can be a square ( Figure 2A ),rectangle( Figure 2B ), round hole ( Figure 2C ) and other polygonal shapes, but from the viewpoint of suppressing the generation of fine powder and obtaining HPMCAS at a high yield, the shape is preferably a circular hole.

[0079] The temperature of the HPMCAS-containing reaction solution used in the precipitation step is preferably 10 to 60°C, more preferably 20 to 50°C, from the viewpoint of suppressing the adhesion and aggregation of the HPMCAS particles in the HPMCAS particle-containing suspension.

[0080] From the viewpoint of suppressing the generation of fine powder and obtaining HPMCAS at a high yield, the viscosity of the reaction solution containing HPMCAS used in the precipitation step is preferably 10,000 to 100,000 mPa·s at 40°C, more preferably 20,000 to 80,000 mPa·s, and even more preferably 30,000 to 50,000 mPa·s. The viscosity of the reaction solution containing HPMCAS can be measured by the viscosity measurement method using a cone-plate type rotational viscometer described in JIS Z8803 at a shear rate of 10 sec. -1 To carry out the measurement.

[0081] From the viewpoint of suppressing the adhesion and cohesion of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles, the amount of water mixed with the reaction solution containing HPMCAS is preferably 100 to 1000 parts by mass, more preferably 150 to 800 parts by mass, and even more preferably 200 to 600 parts by mass, based on 100 parts by mass of the reaction solution containing HPMCAS.

[0082] The temperature of water 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 of HPMCAS particles in a suspension containing precipitated HPMCAS particles.

[0083] From the viewpoint of suppressing the generation of fine powder and producing HPMCAS at a high yield, 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.

[0084] 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 aperture diameter (μm), the vertical axis is the cumulative mass of the oversize (%), and the value of the sieve aperture diameter at the intersection of the straight line connecting two plotted points sandwiching 50% of the cumulative mass of the oversize and 50% of the cumulative mass of the oversize when plotting the cumulative mass of the oversize of each sieve aperture diameter and the sieve of each aperture diameter is taken as the average particle size of the HPMCAS particles. It should be noted that the cumulative mass of the oversize (%) can be calculated from the mass of the HPMCAS particles remaining on the sieve after pouring the suspension containing the precipitated HPMCAS particles onto the sieve, pouring pure water on the HPMCAS particles until the liquid passing through the sieve becomes transparent, and then transferring it to a container for mass measurement.

[0085] From the viewpoint of producing HPMCAS at a high yield, the proportion of fine powder having a particle size of 250 μm or less in the total mass of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles is preferably 15.0% or less, more preferably 14.0% or less, and even more preferably 13.0% or less. The lower limit is not particularly limited, and is, for example, greater than 0%.

[0086] The ratio of the amount of fine powder having a particle size of 250 μm or less to the total mass of the HPMCAS particles in the suspension containing the precipitated HPMCAS particles can be calculated from the ratio of the total mass of the HPMCAS particles remaining on each sieve having an aperture of 250 μm or less in the wet sieving test to the total mass of the HPMCAS particles remaining on each sieve after the test.

[0087] <Cleaning and Recovery Process>

[0088] Next, the washing and recovery step of washing the HPMCAS particles in the suspension and recovering the washed HPMCAS particles will be described.

[0089] In the washing and recovery step, acetic acid, succinic acid and the like formed as by-products in the esterification reaction step are removed.

[0090] The washing method is not particularly limited, and examples thereof include a method of repeatedly removing a portion of water from a suspension containing HPMCAS particles by centrifugation, filtration, squeezing, decantation, etc., and then resuspending the particles in a clear solvent.

[0091] The type of solvent used for washing is not particularly limited, but water is preferred from an economical point of view. 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 the adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles.

[0092] After the washing and recovery step and before the drying step, the suspension containing the HPMCAS particles may be dehydrated to obtain a water-containing HPMCAS cake in order to reduce the drying load. The dehydration method is not particularly limited, and a portion of the water in the suspension containing the HPMCAS particles may be removed by centrifugal separation, pressure filtration, vacuum filtration, squeezing, etc. From the viewpoint of reducing the drying load, the water content of the water-containing HPMCAS cake is preferably 90% or less, more preferably 80% or less. The lower limit is not particularly limited, and is, for example, 20% or more.

[0093] It should be noted that the moisture content of the HPMCAS water cake can be measured according to the method described in the "General Test Methods 2. Physical Test Methods - Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. Specifically, the moisture content of the HPMCAS water cake is defined as {(mass of the HPMCAS water cake - absolute dry mass of the HPMCAS) / (mass of the HPMCAS water cake)}×100%. The so-called "mass of the HPMCAS water cake" refers to the mass of the HPMCAS when it is accurately weighed according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. In addition, the so-called "absolute dry mass of HPMCAS" refers to the mass of the HPMCAS after drying according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia.

[0094] From the viewpoint of producing HPMCAS at 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, and is, for example, less than 100%.

[0095] Specifically, the yield after the washing step is defined as (the absolute dry mass of the HPMCAS particles in the suspension containing the washed HPMCAS particles, or the absolute dry mass of the HPMCAS in the HPMCAS water-containing cake) / (theoretical yield of HPMCAS)×100%. Here, the so-called "theoretical yield of HPMCAS" refers to the theoretical yield calculated from the reaction efficiency of the esterification agent in the esterification reaction step.

[0096] <Drying process>

[0097] Next, the drying process of drying the washed HPMCAS particles is described. From the viewpoint of preventing the HPMCAS particles from agglomerating, the drying temperature (product temperature) in the drying process is preferably 20 to 100° C., more preferably 25 to 80° C. From the viewpoint of preventing the HPMCAS particles from agglomerating, the drying time in the drying process is preferably 5 hours or less, more preferably 3 hours or less. The lower limit of the drying time in the drying process is not particularly limited as long as the moisture content of the HPMCAS powder can be sufficiently reduced, and is, for example, 10 minutes or more.

[0098] The apparatus used for drying is not particularly limited, and for example, a fluidized bed dryer, a tank-type stirring dryer, a vacuum dryer, etc. can be used.

[0099] [Hydroxypropyl methylcellulose acetate succinate powder]

[0100] From the viewpoint of obtaining HPMCAS powder having good fluidity, the water content of the HPMCAS powder after drying is preferably greater than 0% and 5.0% or less, and more preferably 0.5% or more and 3.0% or less.

[0101] It should be noted that the moisture content of the HPMCAS powder can be measured according to the method described in the "General Test Methods 2. Physical Test Methods - Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. Specifically, the moisture content of the HPMCAS powder is defined as {(mass of the HPMCAS powder - absolute dry mass of the HPMCAS powder) / (mass of the HPMCAS powder)}×100%. The "mass of the HPMCAS powder" refers to the mass of the HPMCAS powder when it is accurately weighed according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. In addition, the "absolute dry mass of HPMCAS" refers to the mass of the HPMCAS after drying according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia.

[0102] 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.

[0103] The DS of the acetyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.20 to 0.80.

[0104] The DS of the succinyl group in HPMCAS is preferably 0.10 to 2.50, more preferably 0.10 to 1.00, and even more preferably 0.10 to 0.60.

[0105] 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.

[0106] It should be noted that the DS of the methoxy, acetyl and succinyl groups in HPMCAS represents the degree of substitution, which is the average number of methoxy, acetyl and succinyl groups per unit of anhydrous glucose, and the MS of the hydroxypropoxy group in HPMCAS represents the molar substitution, which is the average molar number of the hydroxypropoxy group per 1 mole of anhydrous glucose.

[0107] It should be noted that the DS of the methoxyl group, acetyl group, succinyl group, and the MS of the hydroxypropoxy group in HPMCAS can be converted from the values ​​obtained by the method described in the pharmaceutical article "Hydroxypropylmethylcellulose acetate succinate" of the 18th revised edition of the Japanese Pharmacopoeia.

[0108] The average particle size of the HPMCAS powder measured by the dry sieving test is preferably greater than 300 μm and less than 1000 μm, more preferably greater than 350 μm and less than 950 μm, and further preferably greater than 350 μm and less than 900 μm. It should be noted that the average particle size measured by the dry sieving test can be measured by the dry sieving test described in JIS Z8815. That is, the horizontal axis is the sieve aperture diameter (μm), the vertical axis is the cumulative mass of the oversize (%), and when plotting the cumulative mass of the oversize (%) of each sieve aperture diameter and the sieve of each aperture diameter, the value of the sieve aperture diameter at the intersection of the straight line connecting the two plotted points sandwiching the cumulative mass of the oversize of 50% and the cumulative mass of the oversize of 50% is taken as the average particle size of the HPMCAS powder.

[0109] The loose bulk density in the HPMCAS powder is preferably 0.5 g / mL or less, more preferably 0.45 g / mL or less, further preferably 0.35 g / mL or less, and most preferably 0.30 g / mL or less. There is no particular restriction on the lower limit of the loose bulk density, for example, it is 0.10 g / mL or more. The so-called loose bulk density refers to the bulk density in a loosely filled state, which can be measured by using a powder property evaluation device, allowing the sample to pass through a sieve with an aperture of 1 mm from above (23 cm) and evenly supply it to a cylindrical container (material: stainless steel) with a diameter of 5.05 cm and a height of 5.05 cm (volume of 100 ml), and scraping the upper surface to weigh it. As a specific example of a powder property evaluation device, a powder property evaluation device POWDER TESTER PT-S manufactured by Hosokawa Micron Ltd. can be cited.

[0110] The close packing density in the HPMCAS powder is preferably 0.5 g / mL or less, more preferably 0.45 g / mL or less, further preferably 0.40 g / mL or less, and most preferably 0.35 g / mL or less. There is no particular restriction on the lower limit of the close packing density, for example, it is 0.15 g / mL or more. The so-called close packing density refers to the packing density when the cylindrical container is tapped and tightly filled. The so-called tapping refers to the operation of repeatedly dropping the cylindrical container filled with the sample from a certain height, applying a slight impact to the bottom, and making the sample tightly filled. In fact, as with the determination of the loose bulk density, the sample is filled into the cylindrical container, and after the upper surface is scraped flat and weighed, the lid is further put on the cylindrical container, and the sample is added to the upper edge of the lid, and then 180 free fall heights of 1.8 cm are tapped. After the tapping is completed, the lid is removed, the sample is scraped flat on the upper surface of the cylindrical container and weighed, and the bulk density of this state is taken as the close packing density.

[0111] From the viewpoint of obtaining good fluidity, the compression degree of the HPMCAS powder is preferably 10% or less, more preferably 8% or less, further preferably 6% or less, and most preferably 5% or less. There is no particular restriction on the lower limit, but it is greater than 0%. It should be noted that the so-called compression degree is a value obtained by the following formula from the values ​​of the loose bulk density and the close bulk density.

[0112] Compression (%) = {(close packing density - loose packing density) / close packing density} × 100

[0113] In this specification, HPMCAS powder is classified into four types of particles: "long fibrous particles", "short fibrous particles", "spherical particles" and "fine particles". Figure 3 The present invention is a flowchart summarizing the method of classifying "all particles A" of HPMCAS powder into four types of particles, namely "fine particles B", "long fibrous particles (LF1 and LF2)", "short fibrous particles (SF1 and SF2)" and "spherical particles (S1 and S2)". The volume fraction of each particle in the HPMCAS powder can be calculated by the dynamic image analysis method by measuring the following shape parameters such as fiber length (LEFI), fiber diameter (DIFI), elongation, aspect ratio and circularity. The dynamic image analysis method is a method of obtaining the particle size or particle shape by continuously taking images of particles dispersed in a fluid such as a gas or a solvent and performing binarization analysis. For example, the dynamic image analysis type particle size distribution measuring device QICPIC / R16 (manufactured by Sympatec) can be used for measurement.

[0114] All particles (A) are divided into particles (C) with a fiber length (LEFI) of 40 μm or more and microparticles (B) with a fiber length of less than 40 μm. LEFI is defined as the length between the two ends of a particle, which is the longest path from one end to the other end of the particle contour. It should be noted that since the detection limit of QICPIC / R16 when equipped with an M7 lens is 4.7 μm, particles smaller than 4.7 μm are not detected, but since the volume of particles with LEFI smaller than 4.7 μm accounts for a very small proportion of the entire HPMCAS powder, they can be ignored for the purpose of the present invention.

[0115] Particles (C) with a LEFI of 40 μm or more are divided into first spherical particles (S1) having a ratio of fiber diameter (DIFI) to LEFI (DIFI / LEFI), i.e., elongation of 0.5 or more, and particles (D) having a ratio of fiber diameter (DIFI) to LEFI (DIFI / LEFI), i.e., elongation of less than 0.5. DIFI is defined as the minor diameter of the particle, which can be calculated by dividing the projected area of ​​the particle by the total length of all fiber branches.

[0116] Particles (D) having a LEFI of 40 μm or more and an elongation of less than 0.5 are divided into particles (E) having a ratio (Fmin / Fmax) of the minimum Feret diameter (Fmin) to the maximum Feret diameter (Fmax), i.e., an aspect ratio of less than 0.5, and particles (F) having a ratio (Fmin / Fmax) of the minimum Feret diameter (Fmin) to the maximum Feret diameter (Fmax), i.e., an aspect ratio of 0.5 or more. The aspect ratio of any particle is a value greater than 0 and less than 1. The Feret diameter is the distance between two parallel tangents sandwiching the particle, the maximum Feret diameter (Fmax) is the distance between two tangents sandwiching the particle, and refers to the maximum diameter when the direction changes from 0° to 180°, and the minimum Feret diameter (Fmin) is the distance between two tangents sandwiching the particle, and refers to the minimum diameter when the direction changes from 0° to 180°.

[0117] Fibrous particles (E) having a LEFI of 40 μm or more, an elongation 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.

[0118] Particles (F) having a LEFI of 40 μm or more, an elongation of less than 0.5, and an aspect ratio of 0.5 or more are classified into second spherical particles (S2) having a circularity of 0.7 or more and fibrous particles (G) having a circularity of less than 0.7. Circularity is the circumference (P) of a circle having the same area as the projected area (Ap) of the particle. EQPC ) and the actual particle circumference (P real ) and is defined by the following formula. The circularity of any particle is a value greater than 0 and less than 1. The smaller the circularity, the more irregular the shape of the particle. EQPC is defined as the diameter of a circle of equal projection area, that is, the diameter of a circle with the same area as the projection area of ​​the particle, also known as the Hey wood diameter.

[0119] Formula 1

[0120]

[0121] Fibrous particles (G) having a LEFI of 40 μm or more, an elongation 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.

[0122] By assuming that the microparticles are spheres with a diameter of EQPC, the volume (V) of the microparticles in HPMCAS can be calculated by the following formula: m ).

[0123] V m =(π / 6)×(EQPC) 3 ×N m

[0124] Among them, N m is the number of fine particles in the sample, and EQPC is the median EQPC of the 50% cumulative value of the cumulative particle size distribution curve based on the number of fine particles.

[0125] In this specification, based on the LEFI, elongation, aspect ratio and circularity which are the shape parameters of the above-mentioned particles, microparticles with a LEFI of less than 40 μm are excluded from all particles, and only particles with a LEFI of more than 40 μm are classified into "long fibrous particles", "short fibrous particles" and "spherical particles", and are distinguished from each other.

[0126] <Long fibrous particles>

[0127] Particles that satisfy either LF1 or LF2 as defined below are classified as "long fibrous particles".

[0128] LF1: Particles with an elongation of less than 0.5, an aspect ratio of less than 0.5, and a LEFI (fiber length) of more than 200 μm

[0129] LF2: Particles with an elongation 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

[0130] The volume of the long fibrous particles in HPMCAS (V LF ) can be calculated by the following formula by assuming that the long fibrous particles are cylinders with a bottom diameter of DIFI and a height of LEFI.

[0131] V LF =(π / 4)×(DIFI) 2 ×(LEFI)×N LF

[0132] Among them, N LF is the number of long-fibrous particles in the sample, DIFI is the median DIFI of 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 of the 50% cumulative value of the cumulative particle size distribution curve based on the number of long-fibrous particles.

[0133] It should be noted that the volume of each particle satisfying the above-mentioned definitions of LF1 and LF2 is calculated by the above-mentioned formula, and the total volume value of the two is the volume value of the long-fibrous particles in the HPMCAS powder.

[0134] <Short fibrous particles>

[0135] Particles that satisfy either SF1 or SF2 as defined below are classified as "short fibrous particles".

[0136] SF1: Particles having an elongation 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

[0137] SF2: Particles having an elongation 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

[0138] The volume of short fibrous particles in HPMCAS (V SF ), similar to the above-mentioned long-fiber particles, the short-fiber particles can be assumed to be cylinders with a bottom diameter of DIFI and a height of LEFI, and calculated using the following formula.

[0139] V SF =(π / 4)×(DIFI) 2 ×(LEFI)×N SF

[0140] Among them, N SF is the number of short fibrous particles in the sample, DIFI is the median DIFI of the 50% cumulative value of the cumulative particle size distribution curve equivalent to the number of short fibrous particles, and LEFI is the median LEFI of the 50% cumulative value of the cumulative particle size distribution curve equivalent to the number of short fibrous particles.

[0141] It should be noted that the volumes of the particles satisfying the above-mentioned definitions of SF1 and SF2 are calculated by the above-mentioned formula, and the value of the total volume of the two is the value of the volume of the short fibrous particles in the HPMCAS powder.

[0142] <Spherical particles>

[0143] Particles that satisfy either S1 or S2 of the following definitions are classified as "spherical particles".

[0144] S1: Particles having an elongation of 0.5 or more and a LEFI (fiber length) of 40 μm or more

[0145] S2: Particles having an elongation of less than 0.5, an aspect ratio of 0.5 or more, a circularity of 0.7 or more, and a LEFI (fiber length) of 40 μm or more

[0146] The volume of spherical particles in HPMCAS (V S ) can be calculated by assuming that the spherical particles are spheres with a diameter of EQPC using the following formula.

[0147] V S =(π / 6)×(EQPC) 3 ×N S

[0148] Among them, N Sis 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.

[0149] It should be noted that the volume of each particle satisfying the above-mentioned S1 and S2 is calculated by the above-mentioned formula, and the value of the total volume of the two is the value of the volume of the spherical particles in the HPMCAS powder.

[0150] The volume fractions of various particles in the HPMCAS powder can be obtained by m 、Volume V LF 、Volume V SF and volume V S Calculate according to the following formulas.

[0151] Volume fraction of microparticles = {V m / (V m +V LF +V SF +V S )}×100

[0152] Volume fraction of long fibrous particles = {V LF / (V m +V LF +V SF +V S )}×100

[0153] Volume fraction of short fibrous particles = {V SF / (V m +V LF +V SF +V S )}×100

[0154] Volume fraction of spherical particles = {V S / (V m +V LF +V SF +V S )}×100

[0155] The volume fraction of various particles (long fibrous particles, short fibrous particles, spherical particles and microparticles) was measured using a dynamic image analysis particle size distribution measuring device QICPIC / R16 (manufactured by Sympatec) equipped with a quantitative feeder VIBRI / L, an airflow disperser RODOS / L and an M7 lens, under the conditions of a frame rate of 500Hz, an injector of 4mm and a dispersion pressure of 1bar, and the image of the captured particles was analyzed by the analysis software WINDOX5Version: 5.9.1.1 to obtain the median EQPC of the number standard, the median LEFI of the number standard, the median DIFI of the number standard, the elongation, the aspect ratio and the circularity of the various particles, and the volume fraction of the various particles was calculated based on the values ​​by the calculation formula described above. It should be noted that M7 was used for the division during the analysis.

[0156] From the viewpoint of obtaining HPMCAS powder having good fluidity, 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. The upper limit is not particularly limited, and is, for example, less than 100%.

[0157] [Example]

[0158] Hereinafter, the present invention will be described in detail by way of Examples and Comparative Examples, but the present invention is not limited to these Examples at all.

[0159] 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 following method.

[0160] In addition, other physical properties were measured or calculated according to the above-mentioned methods unless otherwise specified.

[0161] Average particle size of HPMCAS particles in the suspension containing the precipitated HPMCAS particles

[0162] The average particle size of the HPMCAS particles was measured by a wet sieving test described in JIS Z8815. That is, the horizontal axis is the sieve aperture diameter (μm), the vertical axis is the cumulative mass of the oversize (%), and the value of the sieve aperture diameter at the intersection of the straight line connecting two plotted points sandwiching 50% of the cumulative mass of the oversize and 50% of the cumulative mass of the oversize when plotting the cumulative mass of the oversize of each sieve aperture diameter and each sieve aperture diameter is taken as the average particle size of the HPMCAS particles. It should be noted that the cumulative mass of the oversize (%) is calculated by pouring a suspension containing HPMCAS particles on a sieve, pouring pure water on the HPMCAS particles until the liquid passing through the sieve becomes transparent, and then transferring it to a container for mass measurement, and the mass of the HPMCAS particles remaining on the sieve. In addition, as a sieve, a cylindrical sieve with a diameter of 200 mm and a plain weave sieve was used. As the apertures of the sieves, 4000 μm, 1700 μm, 1000 μm, 500 μm, 250 μm, 177 μm, 150 μm, 106 μm, and 75 μm were used. In addition, as the sieving method, a manual wet sieving method was used.

[0163] ·Water content and cleaning yield of water-containing HPMCAS filter cake

[0164] The moisture content of the HPMCAS water cake obtained in the cleaning and recovery process was measured according to the method described in the "General Test Methods 2. Physical Test Methods - Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. Specifically, the moisture content of the HPMCAS water cake is defined as {(total mass of the HPMCAS water cake - absolute dry mass of the HPMCAS) / (total mass of the HPMCAS water cake)}×100%. The so-called "total mass of the HPMCAS water cake" refers to the mass of the HPMCAS water cake when it is accurately weighed according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia. In addition, the so-called "absolute dry mass of HPMCAS" refers to the mass of the HPMCAS after drying according to the "Loss on Drying Test Method" of the 18th revised edition of the Japanese Pharmacopoeia.

[0165] The washing yield was calculated by the following formula from the theoretical yield calculated from the amount of raw materials charged, the mass of the HPMCAS water-containing cake obtained after the washing step, and the water content.

[0166] Washing yield (%) = {HPMCAS water-containing filter cake mass × (100-HPMCAS water content of the filter cake) / 100} / theoretical yield

[0167] Synthesis example 1

[0168] 700 g of HPMC having a methoxy DS of 1.87, a hydroxypropoxy MS of 0.24, and a viscosity of 3.4 mPa·s in a 2% by mass aqueous solution 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 added to a 5L kneader having a double-shaft stirrer, and stirred for 5 hours at 85° C. to carry out an esterification reaction. After stirring for 5 hours, 1471 g of water was added to the kneader to stop the reaction, thereby obtaining 4146 g of a reaction solution containing HPMCAS-1. The equivalent relationship in the esterification reaction is shown in Table 1.

[0169] Synthesis example 2

[0170] The same operation as in Example 1 was performed except that the amount of acetic anhydride was adjusted to 485 g, the amount of succinic anhydride was adjusted to 74 g, and the amount of water added was adjusted to 1480 g, thereby obtaining 4171 g of a reaction solution containing HPMCAS-2. The equivalent relationship in the esterification reaction is shown in Table 1.

[0171] Table 1

[0172]

[0173] Example 1

[0174] The reaction solution containing the HPMCAS-1 was adjusted to 40°C (shear rate was 10 sec -1 The viscosity at the time was 45000 mPa·s) was introduced into a mixer (liquid continuous mixer 200 L type, manufactured by Silverson Nippon Co., Ltd.) equipped with a rotor and a perforated plate at a rate of 2.4 kg / min together with cold water at 10° C., thereby obtaining a suspension containing the precipitated HPMCAS particles.

[0175] The mixer has the following structure: a rotor with a diameter of 50.8 mm and linear blades that can rotate on its own, and a plurality of openings with a diameter of 1.5 mm (the opening area of ​​each opening is 1.8 mm) in a direction perpendicular to the radial direction of the rotor. 2 The rotor is surrounded by a porous plate with a circular hole-shaped opening. The rotation speed of the rotor is 2400 rpm, the peripheral speed of the outermost periphery of the blades in the rotor is 6.4 m / s, and the shear speed generated by the rotation of the rotor is 31900 s -1 In addition, the mass of the cold water mixed was 540 parts by mass with respect to 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0176] The average particle size of the HPMCAS particles in the suspension and the ratio of the mass of fine powder with a particle size of 250 μm or less to the mass of the HPMCAS particles contained in the suspension were evaluated by wet sieving. The average particle size was 1175 μm and the ratio of the fine powder was 5.4% by mass.

[0177] The suspension was filtered through a sieve of 83 mesh (pore size 180 μm) until the filtrate was no longer discharged. After the HPMCAS particles obtained by filtration were suspended again in water at 20° C., the filtration through a sieve of 83 mesh (pore size 180 μm) was repeated three times for washing until the filtrate was no longer discharged, thereby obtaining a water-containing filter cake of HPMCAS. At this time, the water content of the water-containing filter cake of HPMCAS was 68.0%, and the yield was 90.2%.

[0178] The HPMCAS water cake 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 2A and Table 2B.

[0179] Example 2

[0180] HPMCAS powder was obtained by the same operation as in Example 1 except that the mass of the cold water to be mixed was adjusted to 300 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0181] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0182] Example 3

[0183] HPMCAS powder was obtained by the same operation as in Example 1 except that the mass of the cold water to be mixed was adjusted to 250 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0184] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0185] Example 4

[0186] In addition to adjusting the rotation speed of the mixer rotor to 3600 rpm, the peripheral speed of the outermost periphery of the blades in the rotor was adjusted to 9.6 m / s, and the shear speed generated by the rotation of the rotor was adjusted to 47900 s -1HPMCAS powder was obtained by performing the same operation as in Example 1 except that the mass of the cold water to be mixed was adjusted to 580 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0187] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0188] Example 5

[0189] In addition to adjusting the rotation speed of the mixer rotor to 3600 rpm, the peripheral speed of the outermost periphery of the blades in the rotor was adjusted to 9.6 m / s, and the shear speed generated by the rotation of the rotor was adjusted to 47900 s -1 HPMCAS powder was obtained by the same operation as in Example 1 except that the mass of the cold water to be mixed was adjusted to 420 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0190] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0191] Example 6

[0192] In addition to adjusting the opening of the porous plate to a diameter of 1.0 mm (the opening area of ​​each opening is 0.8 mm 2 ), and the same operation as in Example 1 was performed except that the mass of the cold water mixed was adjusted to 390 parts by mass relative to 100 parts by mass of the reaction solution containing the HPMCAS-1, thereby obtaining HPMCAS powder.

[0193] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0194] Example 7

[0195] In addition to adjusting the opening of the porous plate to a diameter of 2.5 mm (the opening area of ​​each opening is 4.9 mm 2 ), and the same operation as in Example 1 was performed except that the mass of the cold water to be mixed was adjusted to 330 parts by mass relative to 100 parts by mass of the reaction solution containing the HPMCAS-1, thereby obtaining HPMCAS powder.

[0196] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0197] Example 8

[0198] In addition to using a mixer with a rotor diameter of 69.9 mm (Liquid Continuous Mixer 275L, manufactured by Silverson Nippon Co., Ltd.), the openings of the perforated plate were adjusted to a diameter of 1.0 mm (the opening area of ​​each opening was 0.8 mm 2 ), the rotation speed of the rotor of the mixer was adjusted to 3600 rpm, the peripheral speed of the outermost periphery of the blades in the rotor was adjusted to 13.1 m / s, and the shear speed generated by the rotation of the rotor was adjusted to 65500 s -1 HPMCAS powder was obtained by the same operation as in Example 1 except that the mass of the cold water to be mixed was adjusted to 400 parts by mass relative to 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0199] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0200] Example 9

[0201] In addition to adjusting the opening of the porous plate to a square with a side length of 1.5 mm (the opening area of ​​each opening is 2.3 mm 2 ), and the same operation as in Example 1 was performed except that the mass of the cold water mixed was adjusted to 300 parts by mass relative to 100 parts by mass of the reaction solution containing the HPMCAS-1, thereby obtaining HPMCAS powder.

[0202] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0203] Example 10

[0204] HPMCAS powder was obtained by the same operation as in Example 1 except that the opening of the porous plate was adjusted to a rectangular shape with a width of 1.5 mm and the mass of the cold water to be mixed was adjusted to 300 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0205] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0206] Embodiment 11

[0207] In addition to using the reaction solution containing the HPMCAS-2 adjusted to 40°C (shear rate of 10 sec -1 The same operation as in Example 1 was carried out except that the viscosity at the time was 37000 mPa·s, thereby obtaining HPMCAS powder.

[0208] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0209] Example 12

[0210] HPMCAS powder was obtained by the same operation as in Example 1 except that the reaction solution containing the HPMCAS-2 adjusted to 40° C. was used and the mass of the cold water to be mixed was adjusted to 290 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-2.

[0211] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0212] Embodiment 13

[0213] HPMCAS powder was obtained by the same operation as in Example 1 except that the reaction solution containing the HPMCAS-2 adjusted to 40° C. was used and the mass of the cold water to be mixed was adjusted to 200 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-2.

[0214] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0215] Comparative Example 1

[0216] The reaction solution containing HPMCAS-1 adjusted to 40°C was introduced into a mixer without a perforated plate (LABOLUTION PIPELINE-HOMO MIXER, manufactured by PRIMIX Corporation) at a rate of 2.4 kg / min together with 10°C cold water to obtain a suspension containing precipitated HPMCAS particles.

[0217] The mixer has a rotor and a stator with a diameter of 28.0 mm, but there is no opening on the stator, and the suspension containing HPMCAS particles is discharged from the clearance between the rotor and the stator. The rotor has straight blades. The rotation speed of the rotor is 4360 rpm, the peripheral speed of the outermost periphery of the blades in the rotor is 6.4 m / s, and the shear speed generated by the rotation of the rotor is 8667 s -1 In addition, the mass of the cold water mixed was 400 parts by mass with respect to 100 parts by mass of the reaction solution containing the HPMCAS-1.

[0218] The average particle size of the HPMCAS particles in the suspension and the ratio of the mass of fine powder of 250 μm or less to the mass of the HPMCAS particles contained in the suspension were evaluated by wet sieving. The average particle size was 1218 μm and the ratio of the fine powder was 17.8% by mass.

[0219] The suspension was filtered through a sieve of 83 mesh (pore size 180 μm) until the filtrate was no longer discharged. After the HPMCAS particles obtained by filtration were suspended again in water at 20° C., the filtration through a sieve of 83 mesh (pore size 180 μm) was repeated three times for washing until the filtrate was no longer discharged, thereby obtaining a water-containing filter cake of HPMCAS. At this time, the water content of the water-containing filter cake of HPMCAS was 70.0%, and the yield was 79.1%.

[0220] The HPMCAS water cake 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 2A and Table 2B.

[0221] Comparative Example 2

[0222] In addition to adjusting the rotation speed of the rotor of the mixer to 6550 rpm, adjusting the peripheral speed of the outermost periphery of the blades in the rotor to 9.6 m / s, and adjusting the shear speed generated by the rotation of the rotor to 12800 s -1 The same operation as in Comparative Example 1 was carried out except for the above, thereby obtaining HPMCAS powder.

[0223] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0224] Comparative Example 3

[0225] In addition to adjusting the rotation speed of the rotor of the mixer to 8930 rpm, adjusting the peripheral speed of the outermost periphery of the blades in the rotor to 13.1 m / s, and adjusting the shear speed generated by the rotation of the rotor to 17467 s -1 The same operation as in Comparative Example 1 was carried out except for the above, thereby obtaining HPMCAS powder.

[0226] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0227] Comparative Example 4

[0228] 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.

[0229] The other operations were carried out in the same manner as in Comparative Example 1 to obtain HPMCAS powder.

[0230] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0231] Comparative Example 5

[0232] HPMCAS powder was obtained by performing the same operation as in Comparative Example 1, except that the reaction solution containing the HPMCAS-2 adjusted to 40° C. was used in the mixer without the perforated plate, and the mass of the cold water to be mixed was adjusted to 210 parts by mass based on 100 parts by mass of the reaction solution containing the HPMCAS-2.

[0233] The average particle size of the HPMCAS particles in the suspension, the ratio of the fine powder, the washing yield, and the physical properties of the finally obtained HPMCAS powder are shown in Table 2A and Table 2B.

[0234] Table 2A

[0235]

[0236] Table 2B

[0237]

[0238] In the precipitation step, the HPMCAS particles of Examples 1 to 13 precipitated using a mixer having a rotating rotor and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor had a smaller 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 Comparative Example 5 precipitated using a mixer without a porous plate. In addition, in the HPMCAS powder after drying, Examples 1 to 13 showed a lower degree of compression than Comparative Examples 1 to 5, and obtained a powder having good fluidity.

[0239] Description of Reference Numerals

[0240] 1- Blade

[0241] 2-Rotor

[0242] 3-Center Axis

[0243] 4-Opening

[0244] 5-Multiwell plate.

Claims

1. A method for producing hydroxypropyl methylcellulose acetate succinate powder, wherein: At least: an esterification reaction step, in which hydroxypropyl methylcellulose is subjected to an esterification reaction with an acetylating agent and a succinic acylating agent in the presence of an aliphatic carboxylic acid, thereby obtaining a reaction solution containing hydroxypropyl methylcellulose acetate succinate; A precipitation step, wherein the reaction solution and water are introduced into a mixer having a rotatable rotor with blades and a porous plate surrounding the rotor in a direction perpendicular to the radial direction of the rotor, and a suspension containing the precipitated hydroxypropyl methylcellulose acetate succinate particles is discharged through the porous plate; a washing and recovery step of washing the hydroxypropyl methylcellulose acetate succinate particles in the suspension and recovering the washed hydroxypropyl methylcellulose acetate succinate particles; and The drying step is to dry the washed hydroxypropylmethylcellulose acetate succinate particles.

2. The method for producing hydroxypropylmethylcellulose acetate succinate powder according to claim 1, wherein: Each opening of the porous plate has a diameter of 0.1 to 10.0 mm. 2 opening area.

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

4. The method for producing hydroxypropylmethylcellulose acetate succinate powder according to claim 1 or claim 2, wherein: The amount of water added to the reaction solution is 200 to 600 parts by mass based on 100 parts by mass of the reaction solution.

5. The method for producing hydroxypropylmethylcellulose acetate succinate powder according to claim 1 or claim 2, wherein: When the particle size distribution of the hydroxypropylmethylcellulose acetate succinate particles in the suspension was evaluated by a wet sieving test described in JIS Z8815, the average particle size was 500 to 2000 μm, and the mass of particles of 250 μm or less accounted for 15.0% or less of the total mass.

6. A hydroxypropyl methylcellulose acetate succinate powder, wherein: The average particle size measured by the dry sieving test described in JIS Z8815 is greater than 300 μm and less than 1000 μm, the loose bulk density is less than 0.30 g / mL, and the compression ratio, i.e., the difference between the close bulk density and the loose bulk density, to the close bulk density is less than 10%.

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