Method of producing hydroxypropyl methylcellulose acetate succinate powder

Abstract

To provide a method of producing an esterified cellulose ether that achieves improved flowability of the powder, while reducing the amount of fine powder formed from the precipitated esterified cellulose ether.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 extruding the reaction solution, prepared in the esterification reaction step, into water from extruding ports of an extruder to form a precipitate, and then mincing the resultant precipitate to form a suspension containing hydroxypropyl methylcellulose acetate succinate particles.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as "HPMCAS") is a copolymer in which some of the hydrogen atoms of the hydroxyl groups of cellulose are replaced with methyl groups (-CH 3 ), hydroxypropyl group (-CH 2 CH(OH)CH 3 ), acetyl group (-COCH 3 ) and succinyl group (-COCH 2 CH 2 It is an esterified cellulose ether substituted with a total of four types of substituents, including cellulose ether, cellulose acetate, cellulose ether, and cellulose ether (COOH), and is produced by chemically modifying cellulose ether.

[0003] HPMCAS is widely used, particularly in the pharmaceutical field, for example as an enteric polymer base for coating applications and for use in solid dispersions with poorly water-soluble drugs.

[0004] 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. Examples of methods for bringing a reaction solution containing an esterified cellulose ether into contact with water include a method in which a reaction solution containing an esterified cellulose ether is joined with water, and the joined mixed solution is rotated along a peripheral wall at a point of diameter contraction in the joining channel to stir and shear (Patent Document 1); a method in which a mixture of a reaction solution containing an esterified cellulose ether and water is heated for at least 800 s; -1 A method of subjecting the mixture to a shear rate of 1000 rpm (Patent Document 2) has been reported. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 5-339382 [Patent Document 2] Special Publication No. 2015-512456 Summary of the Invention [Problem to be solved by the invention]

[0006] However, in the methods described in Patent Documents 1 and 2, the precipitated esterified cellulose ether contains a large amount of fine powder, which causes clogging of the filtration surface when impurities are washed away by filtration, leading to a decrease in the washing speed and also causing a problem that the fluidity of the final product is poor, making it difficult to handle as a powder. The present invention has been made in consideration of the above circumstances, and has an object to provide a method for producing an esterified cellulose ether in which the amount of fine powder of precipitated esterified cellulose ether generated is suppressed and the powder has improved fluidity. [Means for solving the problem]

[0007] As a result of extensive investigations aimed at solving the above problems, the inventors have discovered that in the precipitation step of a production method for HPMCAS, a reaction solution containing HPMCAS is extruded from the extrusion port of an extruder into water to cause precipitation, and then the precipitate obtained is cut, thereby making it possible to reduce the amount of fine powder generated 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 is provided the following method for producing 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 extruding the reaction solution from an extrusion port of an extruder into water to cause precipitation, and then cutting the resulting precipitate to obtain a suspension containing hydroxypropyl methylcellulose acetate succinate particles; 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] In the precipitation step, the opening area of ​​the extrusion port when the reaction solution is extruded into water is 0.120 to 1.150 mm 2 The method for producing the hydroxypropyl methylcellulose acetate succinate powder according to [1], [3] The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to [1] or [2], wherein in the precipitation step, the temperature of the reaction solution immediately before being extruded into water is 15 to 40°C. [4] The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to any one of [1] to [3], wherein the average particle size of the hydroxypropyl methylcellulose acetate succinate particles in the suspension as determined by a wet sieving test according to JIS Z8815 is 500 to 1300 μm, and the proportion of particles having a particle size of 350 μm or less to the total mass is 3.0% or less. Effect of the Invention

[0008] According to the present invention, the amount of fine powder generated in the precipitation step can be suppressed, which improves filterability in the washing step and prevents a decrease in the washing speed. Furthermore, according to the present invention, it is possible to produce an HPMCAS powder with excellent flowability, and therefore the HPMCAS powder 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]

[0009] [Figure 1] FIG. 1 is a perspective view showing an example of an extruder used in the method for producing hydroxypropyl methylcellulose acetate succinate powder of the present invention. [Figure 2A] FIG. 2 is a cross-sectional end view showing an example of an extruder used in the method for producing hydroxypropyl methylcellulose acetate succinate powder of the present invention. [Figure 2B] FIG. 2B is a front view showing an example of an extrusion outlet plate of the extruder shown in FIG. 2A. [Figure 2C] FIG. 2B is a front view showing an example of a rotary blade of the extruder shown in FIG. 2A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] [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.

[0011] <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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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 containing post-treated HPMCAS. The concentration of HPMCAS in the reaction solution containing HPMCAS is preferably 20 to 30% by mass from the viewpoints of suppressing the generation of fine powder due to the collapse of HPMCAS particles in the precipitation step while ensuring liquid transportability during extrusion. When post-treatment is performed, the HPMCAS concentration in the reaction solution containing the post-treated HPMCAS is preferably 20 to 30% by mass. 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.

[0022] <Precipitation process> Next, a precipitation step will be described in which the reaction solution containing HPMCAS is extruded from the extrusion port of an extruder into water to cause precipitation, and then the resulting precipitate is cut to obtain a suspension containing HPMCAS particles. In the precipitation step, the reaction solution containing the HPMCAS is introduced into an extruder equipped with an extrusion port, and extruded from the extrusion port of the extruder into water. As a result of various investigations, the inventors have found that when precipitation is carried out by subjecting a mixture of a reaction solution containing HPMCAS and water to shearing in the precipitation step, HPMCAS particles subjected to excessive shearing become finer, leading to an increase in fine powder. As a result of further investigation, it was found that by extruding the reaction solution containing HPMCAS from the extrusion port of an extruder into water to cause precipitation, as in the present invention, the particle size of the precipitated HPMCAS particles becomes uniform and an increase in fine powder due to the micronization of the HPMCAS particles can be suppressed.

[0023] An example of an extruder equipped with an extrusion port is shown in FIG. 1 and FIG.

[0024] The extruder in Fig. 1 is composed of two members: a container member A and a screw member B. The container member A has a cylindrical portion 1 for introducing a reaction solution containing HPMCAS, and an extrusion outlet plate 3 having an extrusion port 2. The screw member B has an extrusion plate 4, a screw portion 5, a cap 6 for connection to the cylindrical portion 1, and a handle 7.

[0025] When using the extruder of Figure 1, the reaction solution containing HPMCAS is introduced into the cylindrical portion 1, and a connection cap 6 is connected to the cylindrical portion 1. With the extrusion outlet plate 3 immersed in water, the extrusion plate 4 moves by turning the handle 7 of the screw member. The reaction solution containing HPMCAS is extruded from the extrusion outlet 2 by the moving extrusion plate 4, and then comes into contact with water to obtain a precipitate of HPMCAS. The obtained precipitate can be cut with a cutter, a rotary blade, or the like to obtain a suspension containing HPMCAS.

[0026] The extruder shown in Fig. 2A also includes a hopper 8 for introducing a reaction solution containing HPMCAS, a screw 9 for extruding HPMCAS, an extrusion outlet plate 10 having an extrusion port, a water inlet 11, and a rotary blade 12. A front view showing an example of the extrusion outlet plate 10 is shown in Fig. 2B, and a front view showing an example of the rotary blade 12 is shown in Fig. 2C.

[0027] When the extruder of Fig. 2A is used, a reaction solution containing HPMCAS is introduced into a hopper 8, and the reaction solution is discharged by a screw 9 in the direction of the downward arrow from the hopper 8, and extruded from an extrusion outlet plate 10 having an extrusion port 2. A precipitate of HPMCAS is obtained when the extruded reaction solution comes into contact with water introduced in the direction of the downward arrow from a water inlet 11. The obtained precipitate is cut with a rotary blade 12 to obtain a suspension containing HPMCAS.

[0028] 1 and 2 has one or more extrusion ports. The opening area of ​​the extrusion port is preferably 0.120 to 1.150 mm from the viewpoints of preventing a decrease in cleaning performance due to an increase in the particle size of HPMCAS and suppressing the amount of fine powder generated due to the reduction in the particle size of the HPMCAS particles. 2 , more preferably 0.135 to 1.050 mm 2 , and most preferably 0.150 to 0.950 mm 2When an extruder having an extrusion port with an opening area within the above range is used, it is preferable to operate the extruder so that the discharge from the extrusion port has a linear velocity within the range of 0.1 to 10 mm / s.

[0029] The shape of the extrusion port is not particularly limited. For example, it may be a square, rectangular, round hole, or other polygonal shape, but a round hole shape is preferable from the viewpoint of suppressing the amount of fine powder generated when the HPMCAS precipitate is cut. When the extrusion port has a round hole shape, the HPMCAS precipitate obtained by being extruded from the extrusion port and contacting with water may be cut to a cutting length of, for example, about 0.5 to 2 times the diameter of the extrusion port.

[0030] The temperature of the reaction solution containing the HPMCAS extruded into water in the precipitation step is preferably 5 to 50°C, more preferably 10 to 45°C, and most preferably 15 to 40°C, from the viewpoints of suppressing adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing energy consumption due to heating.

[0031] The viscosity of the HPMCAS-containing reaction solution used in the precipitation step at 25°C is preferably 15 to 250 Pa·s, more preferably 20 to 200 Pa·s, and even more preferably 20 to 150 Pa·s, from the viewpoints of preventing poor extrusion of the reaction solution and suppressing the amount of fine powder generated. 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.

[0032] The temperature of the water used in the precipitation step is preferably 10 to 50°C, more preferably 15 to 40°C, and most preferably 20 to 30°C, from the viewpoints of suppressing adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing energy consumption due to heating.

[0033] The average particle size of the HPMCAS particles in the suspension containing the HPMCAS particles is preferably 500 to 1300 μm, more preferably 520 to 1250 μm, and more preferably 550 to 1200 μm, from the viewpoints of suppressing the amount of fine powder generated and preventing a decrease in cleaning properties. The average particle size of the HPMCAS particles in the suspension containing the 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 sieve opening value 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% 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 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.

[0034] The mass ratio of particles having a particle size of 350 μm or less to the total mass of HPMCAS particles in the suspension containing the HPMCAS particles is preferably 3.0% or less, more preferably 2.5% or less, and most preferably 2.2% or less, from the viewpoints of suppressing clogging of the filtration surface during washing by fine powder and improving the fluidity of the finally obtained HPMCAS powder. The lower limit is not particularly limited, but is, for example, more than 0%. The mass proportion of particles having a particle size of 350 μm or less to the total mass of HPMCAS particles in the suspension containing the HPMCAS particles can be calculated from the sum of the mass of HPMCAS particles remaining on each sieve with a mesh size of 350 μm or less relative to the sum of the mass of HPMCAS particles remaining on each sieve after the wet sieving test.

[0035] <Cleaning and recovery process> Next, a washing and recovery step of washing the HPMCAS particles in the suspension containing the HPMCAS particles 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 the suspension containing the 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 viewpoints of suppressing adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing energy consumption due to heating.

[0036] 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 hydrous HPMCAS cake can be measured according to the method described in General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition. Specifically, the moisture content of the hydrous HPMCAS cake is defined as {(mass of hydrous HPMCAS cake - bone dry mass of HPMCAS) / (mass of hydrous HPMCAS cake)} x 100%, where "mass of hydrous HPMCAS cake" refers to the mass of HPMCAS precisely weighed according to General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition. Also, "bone dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition "Loss on Drying Test Method".

[0037] <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.

[0038] [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 General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition. 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 General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition. In addition, "bone dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to General Tests 2.41 of the Japanese Pharmacopoeia, 18th Edition "Loss on Drying Test Method".

[0039] 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 anhydrous glucose, and the MS of the hydroxypropyl group in HPMCAS represents the molar substitution and is the average amount of hydroxypropoxy groups per mole of anhydrous glucose. 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.

[0040] The average particle size of the HPMCAS powder as determined by a dry sieving test is preferably 350 μm to 1300 μm, more preferably 400 μm to 1250 μm, and most preferably 450 μm to 1200 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 on either side of 50% of the cumulative sieve mass and 50% of the cumulative sieve mass is taken as the average particle size of the HPMCAS powder.

[0041] The loose bulk density of the HPMCAS powder is preferably 0.3 g / mL or less, more preferably 0.25 g / mL or less, and even more preferably 0.2 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 uniformly supply a sample from above (23 cm) into a cylindrical container (material: stainless steel) with a diameter of 5.05 cm and a height of 5.05 cm (volume 100 mL), 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.

[0042] The packed bulk density of the HPMCAS powder is preferably 0.35 g / mL or less, more preferably 0.3 g / mL or less, and even more preferably 0.25 g / mL or less. The lower limit of the packed bulk density is not particularly limited, but is, for example, 0.10 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, thereby 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, 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, the sample is leveled on the top surface of the cylindrical container, and weighed, and the bulk density in this state is taken as the packed bulk density.

[0043] From the viewpoint of obtaining good flowability, the degree of compression of the HPMCAS powder is preferably 6% or less, more preferably 5% or less, even more preferably 4% or less, and most preferably 3% or less. The lower limit is not particularly limited, but is, for example, 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 The smaller the compression ratio, the more fluid the powder is.

[0044] From the viewpoint of obtaining good fluidity, the angle of repose of the HPMCAS powder is preferably 35.4° or less, more preferably 32° or less, even more preferably 30° or less, and most preferably 29° or less. The lower limit of the angle of repose is not particularly limited, but is, for example, 15° or more. The angle of repose is the angle between the horizontal plane and the slope of the mountain formed naturally by gently piling powder on a horizontal surface, and the smaller the angle of repose, the better the fluidity of the powder. The angle of repose can be calculated by using a powder property evaluation device manufactured by Hosokawa Micron Corporation to flow a sample from a height of 75 mm onto a metal disc-shaped stand with a diameter of 80 mm until the angle between the slope of the mountain formed by the powder and the stand becomes constant, and measuring the angle between the slope of the mountain formed by the deposited powder and the stand. A specific example of the powder property evaluation device is the powder property evaluation device POWDER TESTER PT-S manufactured by Hosokawa Micron Corporation. EXAMPLES

[0045] 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, the filtration rate of the HPMCAS particles after washing, and the ignition residue of the finally obtained HPMCAS particles were each measured according to the methods described below. In addition, other physical properties were measured or calculated according to the methods described above unless otherwise specified.

[0046] 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 (%). 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 the cumulative sieve mass of 50% and the cumulative sieve mass of 50% is taken as the average particle size of HPMCAS particles. The cumulative sieve mass (%) was calculated from the mass of HPMCAS particles remaining on the sieve after pouring a suspension containing HPMCAS particles into the sieve and pouring pure water over the HPMCAS particles until the liquid passing through the sieve becomes transparent. In addition, a cylindrical sieve with a diameter of 200 mm and a plain weave sieve mesh was used as the sieve. As the sieve openings, 4000 μm, 2360 μm, 1700 μm, 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, and 177 μm were adopted in Examples 1 to 3 and Comparative Example 1, and 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, 177 μm, 106 μm, and 75 μm were adopted in Example 4 and Comparative Example 2. Furthermore, as the sieving method, a manual sieving method was adopted.

[0047] ·Filtration speed The filtration rate was evaluated by measuring the time it took for 150 g of filtrate to pass through the filter, using 300 g of a slurry with a solids concentration of HPMCAS of 5% by mass. The filter used was an EBP (Electron Beam Perforation) filter (mesh size 300 μm, aperture ratio 22.7%) with a filtration surface area of ​​9.08 cm. 2 The filtration rate per unit filtration area was calculated using the following formula. Filtration rate per unit area (g / (s cm 2 )) = {filtrate volume (150 g) / time (s) required for 150 g of filtrate to pass through} / filtration area (9.08 cm 2 )

[0048] ·Ignition residue The residue on ignition was measured by the test method described in the Japanese Pharmacopoeia, 18th Edition, General Test Method 2.44 "Test method for residue on ignition." That is, a small amount of sulfuric acid was added to the HPMCAS powder, and the mixture was gradually heated at a low temperature to completely carbonize it, and then a small amount of sulfuric acid was added again and the mixture was gradually heated until no more white smoke was generated, and the residue was further heated to about 600°C to incinerate it, and the mass of the resulting residue was calculated using the following formula. Ignition residue (%) = mass of obtained residue (g) / mass of HPMCAS powder used in the test (g) × 100 The ignition residue is an impurity derived from the alkali metal element in the alkali metal carboxylate used as a catalyst in the reaction, and serves as an index of the washability in the washing step.

[0049] Synthesis Example 1 A 5 L kneader equipped with a twin-shaft stirrer was charged with 800 parts by mass 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), 1280 parts by mass of acetic acid, 561 parts by mass of acetic anhydride, 87.5 parts by mass of succinic anhydride, and 374 parts by mass of sodium acetate, and the mixture was stirred at 85°C for 5 hours to carry out an esterification reaction. After stirring for 5 hours, 1085.9 parts by mass of water was added to stop the reaction, and 4188.4 parts by mass of reaction solution-1 containing HPMCAS was obtained.

[0050] Synthesis Example 2 The same operation as in Synthesis Example 1 was carried out except that the amount of water added was 1396.1 parts by mass, thereby obtaining 4498.6 parts by mass of reaction solution-2 containing HPMCAS.

[0051] Synthesis Example 3 The same operation as in Synthesis Example 1 was carried out except that the amount of water added was 1706.4 parts by mass, to obtain 4808.9 parts by mass of reaction solution-3 containing HPMCAS.

[0052] Example 1 The reaction solution-1 containing HPMCAS at 25.1°C was extruded from the extrusion port of the extruder shown in Figure 1 into water at 22.8°C to cause precipitation, and the precipitate obtained was then cut to obtain a suspension containing HPMCAS particles. The extrusion port of the extruder had an opening area of ​​0.950 mm2 The linear velocity when extruding reaction solution-1 from the extrusion port into water was within a range of 0.1 to 10 mm / s, and the precipitate was cut to a length within a range of 0.5 to 2 times the diameter of the extrusion port. The average particle size of the HPMCAS particles in the suspension was evaluated by a wet sieving test and was found to be 1179 μm. The suspension was filtered through a 200 mesh (75 μm opening) sieve until no filtrate was discharged. The HPMCAS particles obtained by filtration were dispersed in water at 20° C., and then the procedure of filtering through a 200 mesh (75 μm opening) sieve until no filtrate was discharged was repeated three times to obtain washed HPMCAS particles. The washed HPMCAS particles were resuspended in pure water at 20°C and stirred to form a slurry. The filtration rate was evaluated by filtering with a filter. The filtration rate per unit filtration area was 4.29 g / (s cm 2 ) was. The washed HPMCAS particles were dried at 40° C. to 80° C. using a fluidized bed dryer to obtain HPMCAS powder. The physical properties of the obtained HPMCAS powder are shown in Table 1.

[0053] Example 2 The same procedure as in Example 1 was carried out to obtain HPMCAS powder, except that the reaction solution-2 containing the HPMCAS at 26.3° C. was extruded into water at 27.8° C. The physical properties of the obtained HPMCAS powder are shown in Table 1.

[0054] Example 3 The same procedure as in Example 1 was carried out to obtain HPMCAS powder, except that the reaction solution-3 containing HPMCAS at 24.2° C. was extruded into water at 25.6° C. The physical properties of the obtained HPMCAS powder are shown in Table 1.

[0055] Example 4 The reaction solution-1 containing the HPMCAS was used at 25.5° C., and the extrusion port of the extruder was set at an opening area of ​​0.159 mm 2The same procedure as in Example 1 was carried out except that the mesh sizes of the sieves used in the wet sieving test were 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, 177 μm, 106 μm, and 75 μm, and HPMCAS powders were obtained. The physical properties of the obtained HPMCAS powders are shown in Table 1.

[0056] Comparative Example 1 The reaction solution-3 containing HPMCAS at 24.8°C was introduced into a mixer (Labo-lution Pipeline Homomixer, manufactured by PRIMIX Corporation) together with water at 26.8°C, and subjected to shearing to obtain a suspension containing precipitated HPMCAS particles. The mixer has a rotor with a diameter of 27.5 mm and a stator with an inner diameter of 29 mm. The rotation speed of the rotor was 5000 rpm, the peripheral speed of the outermost blade of the rotor was 7.2 m / s, and the shear rate was 9599 s -1 The mass of the water mixed with 100 parts by mass of the HPMCAS-containing reaction solution-3 was 300 parts by mass. The average particle size of the HPMCAS particles in the suspension was evaluated by a wet sieving test and was found to be 1014 μm. The suspension was filtered through a 200 mesh (75 μm opening) sieve until no filtrate was discharged. The HPMCAS particles obtained by filtration were dispersed in water at 20° C., and then the procedure of filtering through a 200 mesh (75 μm opening) sieve until no filtrate was discharged was repeated three times to obtain washed HPMCAS particles. The washed HPMCAS particles were resuspended in pure water at 20°C and stirred to form a slurry. The filtration rate was evaluated by filtering with a filter. The filtration rate per unit filtration area was 4.29 g / (s cm 2 ) was. The washed HPMCAS particles were dried at 40° C. to 80° C. using a fluidized bed dryer to obtain HPMCAS powder. The physical properties of the obtained HPMCAS powder are shown in Table 1.

[0057] Comparative Example 2 The reaction solution-1 containing HPMCAS at 24.9°C and water at 24.9°C were used, and the rotation speed of the rotor of the mixer was set to 10,000 rpm, the peripheral speed of the outermost blade of the rotor was set to 14.4 m / s, and the shear rate was set to 19,198 s -1 The same operation as in Comparative Example 1 was carried out, except that the mass of the mixed water was 300 parts by mass per 100 parts by mass of the reaction solution-1 containing HPMCAS, and the mesh sizes of the sieves used in the wet sieving test were 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, 177 μm, 106 μm, and 75 μm, to obtain HPMCAS powders. The physical properties of the obtained HPMCAS powders are shown in Table 1.

[0058] [Table 1A] [Table 1B]

[0059] The HPMCAS particles of Examples 1 to 3 had a high slurry filtration rate and excellent washing rate due to a low proportion of fine powder with a particle size of 350 μm or less in the suspension, while having the same average particle size as the HPMCAS particles of Comparative Example 1. Furthermore, the dried HPMCAS powders of Examples 1 to 3 had a low compressibility and a small angle of repose, while having the same average particle size as the dried HPMCAS of Comparative Example 1, and thus had excellent fluidity.

[0060] Furthermore, the HPMCAS particles of Example 4 had a higher slurry filtration rate and a higher washing rate due to a lower proportion of fine powder with a particle size of 350 μm or less in the suspension, despite the same average particle size, compared to the HPMCAS particles of Comparative Example 2. Furthermore, the dried HPMCAS powder of Example 4 had a lower compressibility and a smaller angle of repose, despite the same average particle size, compared to the dried HPMCAS powder of Comparative Example 2, thus exhibiting superior fluidity. [Explanation of symbols]

[0061] A Container material B Screw member 1 Cylindrical part 2 Extrusion outlet 3 Extrusion exit plate 4 Extrusion plate 5 Threaded section 6 Connection cap 7 Handle 8. Hopper 9 Screw 10 Extrusion exit plate 11 Water inlet 12 Rotary blade

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 extruding the reaction solution from an extrusion port of an extruder into water to cause precipitation, and then cutting the resulting precipitate to obtain a suspension containing hydroxypropyl methylcellulose acetate succinate particles; 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. In the precipitation step, the opening area of ​​the extrusion port when the reaction solution is extruded into water is 0.120 to 1.150 mm 2 The method for producing hydroxypropyl methylcellulose acetate succinate powder according to claim 1,

3. The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or 2, wherein in the precipitation step, the temperature of the reaction solution immediately before being extruded into water is 15 to 40°C.

4. The method for producing a hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or 2, wherein the average particle size of the hydroxypropyl methylcellulose acetate succinate particles in the suspension is 500 to 1300 μm as determined by a wet sieving test according to JIS Z8815, and the mass ratio of particles having a size of 350 μm or less to the total mass is 3.0% or less.

Images