Method for producing hydroxypropyl methyl cellulose acetate succinate powder

Abstract

Provided is a method for producing an esterified cellulose ether in which the amount of fine powder of the precipitated esterified cellulose ether is reduced and the flowability of the powder is improved. The method for producing an esterified cellulose ether is a method for producing a hydroxypropyl methyl cellulose acetate succinate powder comprising at least an esterification reaction step, a precipitation step, a cleaning and recovery step, and a drying step, and a precipitation step for obtaining a suspension containing hydroxypropyl methyl cellulose acetate succinate particles by extruding the reaction solution obtained in the esterification reaction step into water from the extrusion port of the extruder to precipitate the reaction solution, and then cutting the obtained precipitate.

Description

Technical Field

[0001] The invention relates to a method for preparing hydroxypropylmethylcellulose acetate succinate powder. Background Art

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is an esterified cellulose ether in which a part of the hydrogen atoms of the hydroxyl group of cellulose is substituted with a total of four substituents, namely, methyl (-CH3), hydroxypropyl (-CH2CH(OH)CH3), acetyl (-COCH3) and succinyl (-COCH2CH2COOH), and is produced by chemically modifying cellulose ether.

[0003] HPMCAS is used as an enteric polymer substrate for coating purposes or used together with poorly water-soluble drugs in solid dispersions, and is particularly widely used in the pharmaceutical field.

[0004] Esterified cellulose ether represented by HPMCAS can be produced by a known method. In the known production method, the reaction solution containing esterified cellulose ether is brought into contact with water to precipitate the esterified cellulose ether and to clean and remove impurities. As a method for bringing a reaction solution containing esterified cellulose ether into contact with water, for example, there is disclosed a method of causing a reaction solution containing esterified cellulose ether to merge with water, and causing the merged mixed liquid to rotate along the peripheral wall at a diameter-reduced portion in the merged path to stir and shear (Patent Document 1); subjecting a combination of a reaction solution containing esterified cellulose ether and water to agitation and shearing for at least 800 seconds. -1 The method of shear rate (Patent Document 2) etc.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Laid-Open No. 5-339382

[0008] Patent Document 2: Japanese Patent Application No. 2015-512456 Summary of the invention

[0009] Problem that the invention aims to solve

[0010] However, in the methods described in Patent Documents 1 and 2, since the precipitated esterified cellulose ether contains a lot of fine powder, there is a problem that the filter surface is blocked when the impurities are washed by filtration, resulting in a decrease in the washing speed, and the fluidity of the final product is also deteriorated, and the handleability as a powder is poor.

[0011] The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide a method for producing esterified cellulose ether in which the amount of fine powder of precipitated esterified cellulose ether produced is suppressed and the fluidity of the powder is improved.

[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 in the production method of HPMCAS, by extruding a reaction solution containing HPMCAS from an extruder outlet into water to precipitate, and then cutting the obtained precipitate, the amount of fine powder generated can be suppressed and an HPMCAS powder having good fluidity can be obtained, thereby completing the present invention.

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

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

[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 of extruding the reaction solution into water from an extruder to precipitate the reaction solution, and then cutting the precipitate to obtain a suspension containing hydroxypropylmethylcellulose acetate succinate particles;

[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] 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 . [3]

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

[0026] In the precipitation step, the temperature of the reaction solution immediately before being extruded into water is 15 to 40°C. [4]

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

[0029] The hydroxypropylmethylcellulose acetate succinate particles in the suspension have an average particle size of 500 to 1300 μm as measured by a wet sieving test described in JIS Z8815, and the mass of particles of 350 μm or less accounts for 3.0% or less of the total mass.

[0030] Effects of the Invention

[0031] According to the present invention, the amount of fine powder generated in the precipitation process can be suppressed, thereby improving the filterability in the washing process and preventing a decrease in the washing speed.

[0032] In addition, the present invention enables the production of HPMCAS powder having excellent fluidity. 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 coatings for tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a perspective view showing an example of an extruder used in the method for producing hydroxypropylmethylcellulose acetate succinate powder of the present invention.

[0034] Figure 2A This is a cut-off end view showing an example of an extruder used in the method for producing hydroxypropylmethylcellulose acetate succinate powder of the present invention.

[0035] Figure 2B To express in Figure 2A A front view of an example of an extrusion outlet plate of an extruder shown in FIG.

[0036] Figure 2C To express in Figure 2A A front view of an example of a rotary blade of an extruder shown in FIG. DETAILED DESCRIPTION

[0037] [Method for producing hydroxypropyl methylcellulose acetate succinate powder]

[0038] 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.

[0039] <Esterification reaction step>

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] As the acetylating agent, acetic anhydride, acetyl chloride, etc. may be mentioned, and from the viewpoint of economy, acetic anhydride is preferred.

[0050] 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.

[0051] Examples of the succinic acylating agent include succinic anhydride and succinyl chloride, and succinic anhydride is preferred from an economical viewpoint.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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-containing reaction solution.

[0059] From the viewpoint of suppressing the generation of fine powder caused by the disintegration of HPMCAS particles in the precipitation step and ensuring the liquid feeding property during extrusion, the concentration of HPMCAS in the reaction solution containing the HPMCAS is preferably 20 to 30% by mass. When post-treatment is performed, the concentration of HPMCAS in the reaction solution containing the post-treated HPMCAS is preferably set to 20 to 30% by mass.

[0060] 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.

[0061] <Precipitation process>

[0062] Next, the precipitation step of obtaining a suspension containing HPMCAS particles by extruding the reaction solution containing HPMCAS from an extruder port into water to precipitate the reaction solution and then cutting the obtained precipitate will be described.

[0063] 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.

[0064] As a result of various studies, the inventors have found that when a mixture of a reaction solution containing HPMCAS and water is sheared to precipitate in the precipitation step, excessively sheared HPMCAS particles are fined, resulting in an increase in fine powder.

[0065] Furthermore, as a result of further studies, the inventors found that, by extruding the reaction solution containing HPMCAS from the extrusion port of an extruder into water to precipitate it, as in the present invention, the particle size of the precipitated HPMCAS particles becomes uniform, and the increase of fine powder due to the refinement of the HPMCAS particles can be suppressed.

[0066] An example of an extruder equipped with an extrusion port is shown in Figure 1 and Figure 2A to Figure 2C .

[0067] Figure 1 The extruder is composed of two components, namely, a container component A and a screw component B. The container component A includes a cylindrical portion 1 for introducing a reaction solution containing HPMCAS and an extrusion outlet plate 3 having an extrusion outlet 2. In addition, the screw component B includes an extrusion plate 4, a screw portion 5, a connection cap 6 connected to the cylindrical portion 1, and a handle 7.

[0068] In use Figure 1 In the case of an extruder, a reaction solution containing HPMCAS is introduced into a cylindrical portion 1, and a connecting cap 6 is connected to the cylindrical portion 1. The extrusion plate 4 is moved by rotating a handle 7 of a screw member while the extrusion outlet plate 3 is placed in water. After the reaction solution containing HPMCAS is extruded from the extrusion outlet 2 by the moving extrusion plate 4, it is brought into contact with water to obtain a precipitate of HPMCAS. The obtained precipitate is cut using a cutter or a rotary blade to obtain a suspension containing HPMCAS.

[0069] in addition, Figure 2AThe extruder shown in the figure 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 introduction portion 11, and a rotating blade 12. A front view showing an example of the extrusion outlet plate 10 is shown in FIG. Figure 2B A front view showing an example of the rotating blade 12 is shown in Figure 2C .

[0070] In use Figure 2A In the case of an extruder, a reaction solution containing HPMCAS is introduced into a hopper 8, and the reaction solution is transported from the hopper 8 in the direction of a downward arrow by a screw 9, and extruded from an extrusion outlet plate 10 having an extrusion port 2. The extruded reaction solution is brought into contact with water introduced in the direction of a downward arrow from a water introduction portion 11, thereby obtaining a precipitate of HPMCAS. The obtained precipitate is cut by a rotating blade 12, thereby obtaining a suspension containing HPMCAS.

[0071] Figure 1 and Figure 2A , Figure 2B The extrusion outlet plate shown has one or more extrusion outlets. From the viewpoint of preventing the decrease in cleaning performance caused by the increase in the particle size of HPMCAS and suppressing the amount of fine powder generated due to the miniaturization of the particle size of HPMCAS particles, the opening area of ​​the extrusion outlet is preferably 0.120 to 1.150 mm 2 , more preferably 0.135 to 1.050 mm 2 , the most preferred is 0.150 to 0.950 mm 2 When using an extruder having an extrusion port with an opening area within the above range, it is preferred to operate the extruder so that the linear velocity of discharge from the extrusion port is within a range of 0.1 to 10 mm / s.

[0072] The shape of the extrusion port is not particularly limited. For example, it may be a square, a rectangle, a circular hole, or other polygonal shapes. However, from the viewpoint of suppressing the amount of fine powder generated when the HPMCAS precipitate is cut, a circular hole shape is preferred. When the shape of the extrusion port is a circular hole shape, for example, the HPMCAS precipitate obtained by extruding from the extrusion port and contacting with water can be cut at a cutting length of about 0.5 to 2 times the diameter of the extrusion port.

[0073] From the viewpoint of suppressing the adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing the energy consumption due to heating, 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.

[0074] From the viewpoint of preventing the reaction solution from being extruded poorly and suppressing the amount of fine powder generated, the viscosity of the reaction solution containing HPMCAS used in the precipitation step is preferably 15 to 250 mPa·s, more preferably 20 to 200 mPa·s, and even more preferably 20 to 150 Pa·s at 25°C. 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.

[0075] From the viewpoint of suppressing the adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing the energy consumption due to heating, 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.

[0076] From the viewpoint of suppressing the generation of fine powder and preventing a decrease in cleaning properties, 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 even more preferably 550 to 1200 μm.

[0077] 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 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 by pouring the suspension containing the HPMCAS particles onto 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.

[0078] From the viewpoint of suppressing clogging of the filter surface during washing caused by the fine powder and improving the fluidity of the finally obtained HPMCAS powder, the mass ratio of particles having a particle size of 350 μm or less in the total mass of the 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. The lower limit is not particularly limited, and is, for example, more than 0%.

[0079] The mass ratio of the particles having a particle size of 350 μm or less in the total mass of the HPMCAS particles in the suspension containing the HPMCAS particles can be calculated from the ratio of the total mass of the HPMCAS particles remaining on each sieve having an aperture of 350 μm or less in the wet sieving test to the total mass of the HPMCAS particles remaining on each sieve after the test.

[0080] <Cleaning and Recovery Process>

[0081] Next, the 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.

[0082] In the washing and recovery step, acetic acid, succinic acid and the like formed as by-products in the esterification reaction step are removed.

[0083] 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.

[0084] The type of solvent used for washing is not particularly limited, but water is preferred from an economical point of view. From the viewpoint of suppressing the adhesion and aggregation of the HPMCAS particles in the suspension containing the HPMCAS particles and suppressing the energy consumption due to heating, the temperature of the solvent used for washing is preferably 5 to 50° C., more preferably 10 to 40° C.

[0085] 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 filter 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 centrifugation, pressure filtration, vacuum filtration, squeezing, etc. From the viewpoint of reducing the drying load, the water content of the water-containing HPMCAS filter cake is preferably 90% or less, more preferably 80% or less. There is no particular limitation on the lower limit, but it is, for example, 20% or more.

[0086] It should be noted that the moisture content of the hydrous HPMCAS filter cake can be measured according to the method described in the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41. Specifically, the moisture content of the hydrous HPMCAS filter cake is defined as {(mass of the hydrous HPMCAS filter cake-absolute dry mass of HPMCAS) / (mass of the hydrous HPMCAS filter cake)}×100%. The so-called "mass of the hydrous HPMCAS filter cake" refers to the mass of HPMCAS accurately weighed according to the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41. In addition, the so-called "absolute dry mass of HPMCAS" refers to the mass of HPMCAS after drying according to the "loss on drying test method" of the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41.

[0087] <Drying process>

[0088] Next, the drying process for 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.

[0089] 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.

[0090] [Hydroxypropyl methylcellulose acetate succinate powder]

[0091] 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.

[0092] It should be noted that the moisture content of the HPMCAS powder can be measured according to the method described in the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41. 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 accurately weighed according to the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41. In addition, the "absolute dry mass of HPMCAS" refers to the mass of the HPMCAS after drying according to the 18th revised edition of the Japanese Pharmacopoeia General Test Method 2.41 "Loss on Drying Test Method".

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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 amount of hydroxypropoxy groups per 1 mole of anhydrous glucose.

[0098] It should be noted that the DS of the methoxyl group, acetyl group, succinyl group, and the MS of the hydroxypropoxyl 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.

[0099] The average particle size of the HPMCAS powder measured by the dry sieving test is preferably 350 μm or more and 1300 μm or less, more preferably 400 μm or more and 1250 μm or less, and further preferably 450 μm or more and 1200 μm or less. It should be noted that the average particle size obtained 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 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% when plotting the graph of 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 powder.

[0100] The loose bulk density in the HPMCAS powder is preferably less than 0.3 g / mL, more preferably less than 0.25 g / mL, and further preferably less than 0.2 g / mL. There is no particular restriction on the lower limit of the loose bulk density, for example, it is greater than 0.10 g / mL. 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 to uniformly supply the sample from above (23 cm) 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 scrape the upper surface flat for weighing. 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.

[0101] The close packing density in the HPMCAS powder is preferably 0.35 g / mL or less, more preferably 0.3 g / mL or less, and further preferably 0.25 g / mL or less. There is no particular restriction on the lower limit of the close packing density, for example, it is 0.10 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 packing 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 packing density of this state is taken as the close packing density.

[0102] From the viewpoint of obtaining good fluidity, the compression degree of the HPMCAS powder is preferably 6% or less, more preferably 5% or less, further preferably 4% or less, and most preferably 3% or less. There is no particular restriction on the lower limit, and it is, for example, 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.

[0103] Compression (%) = {(close packing density - loose packing density) / close packing density} × 100

[0104] In other words, the smaller the compression degree, the better the flowability of the powder.

[0105] 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, further preferably 30° or less, and most preferably 29° or less. There is no particular restriction on the lower limit of the angle of repose, for example, it is 15° or more. The so-called angle of repose refers to the angle between the inclined surface of the pile formed naturally by stably piling the powder on the horizontal plane and the horizontal plane, that is, 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 Ltd., allowing the sample to flow down from a height of 75 mm onto a metal disc-shaped table with a diameter of 80 mm until the angle between the inclined surface of the pile formed by the powder and the table becomes stable and constant, and measuring the angle between the inclined surface of the pile formed by the deposited powder and the table. 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.

[0106] [Example]

[0107] 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.

[0108] 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 measured by the following method.

[0109] In addition, other physical properties were measured or calculated according to the above-mentioned methods unless otherwise specified.

[0110] Average particle size of HPMCAS particles in the suspension containing the precipitated HPMCAS particles

[0111] 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 pure water on the HPMCAS particles after pouring a suspension containing HPMCAS particles on the sieve until the liquid passing through the sieve becomes transparent. In addition, as the sieve, a cylindrical sieve with a diameter of 200 mm and a plain weave sieve was used. As the aperture of the sieve, 4000 μm, 2360 μm, 1700 μm, 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm and 177 μm were used 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 used in Example 4 and Comparative Example 2. In addition, as the screening method, a manual wet screening method was used.

[0112] Filtration speed

[0113] In the evaluation of the filtration rate, 300 g of HPMCAS slurry with a solid content concentration of 5% by mass was used, and the time required for 150 g of filtrate to pass through the filter was measured. As the filter, an EBP (Electron Beam Perforation) filter (pore size of 300 μm, opening rate of 22.7%) was used, and the filtration area of ​​the filtration surface was set to 9.08 cm 2 The filtration rate per unit filtration area was calculated using the following formula.

[0114] Filtration rate per unit area (g / (s·cm 2 )) = {amount of filtrate (150 g) / time required until 150 g of filtrate passes through the filter ( S )} / filtration area (9.08cm 2 )

[0115] Ignition residue

[0116] The ignition residue was measured according to the test method described in the 18th revised edition of the Japanese Pharmacopoeia General Test Methods 2.44 "Ignition Residue Test Method". That is, a small amount of sulfuric acid was added to the above HPMCAS powder, and it was slowly heated at low temperature to completely carbonize it. Then, a small amount of sulfuric acid was added again, and it was slowly heated until no white smoke was generated. Then, it was heated at about 600°C to ashed the residue, and the mass of the obtained residue was calculated according to the following formula.

[0117] Ignition residue (%) = mass of obtained residue (g) / mass of HPMCAS powder used for the test (g) × 100.

[0118] The ignition residue is an impurity derived from the alkali metal element in the alkali metal salt of carboxylic acid used as a catalyst in the reaction, and serves as an indicator of the cleaning property in the cleaning step.

[0119] Synthesis example 1

[0120] 800 parts by mass 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., 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 were added to a 5L kneader equipped with a biaxial stirrer and stirred for 5 hours at 85° C. to carry out an esterification reaction. After stirring for 5 hours, 1085.9 parts by mass of water was added to the kneader to stop the reaction, thereby obtaining 4188.4 parts by mass of a reaction solution-1 containing HPMCAS.

[0121] Synthesis example 2

[0122] The same operation as in Synthesis Example 1 was carried out except that the amount of water added was adjusted to 1396.1 parts by mass, thereby obtaining 4498.6 parts by mass of a reaction solution-2 containing HPMCAS.

[0123] Synthesis example 3

[0124] The same operation as in Synthesis Example 1 was carried out except that the amount of water added was adjusted to 1706.4 parts by mass, thereby obtaining 4808.9 parts by mass of a reaction solution-3 containing HPMCAS.

[0125] Example 1

[0126] The reaction solution containing the HPMCAS at 25.1°C was Figure 1 The suspension containing HPMCAS particles was obtained by extruding the mixture into water at 22.8°C through the extruder opening shown in the figure to precipitate the mixture, and then cutting the precipitate. The extruder opening had an opening area of ​​0.950 mm2 It should be noted that the linear speed when the reaction solution-1 was extruded from the extrusion port into the water was set in the range of 0.1 to 10 mm / s, and the precipitate was cut at a length in the range of 0.5 to 2 times the diameter of the extrusion port.

[0127] When the average particle size of the HPMCAS particles in the suspension was evaluated by a wet sieving test, the average particle size was 1179 μm.

[0128] The suspension was filtered through a 200-mesh (pore size 75 μm) sieve until the filtrate was no longer discharged. The HPMCAS particles obtained by filtration were dispersed in 20° C. water, and then filtered through a 200-mesh (pore size 75 μm) sieve three times until the filtrate was no longer discharged to wash the particles, thereby obtaining washed HPMCAS particles.

[0129] The washed HPMCAS particles were suspended again in pure water at 20°C and stirred to prepare a slurry. When the filtration rate was evaluated in the filter, the filtration rate per unit filtration area was 4.29 g / (s·cm 2 ).

[0130] 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 1A and Table 1B.

[0131] Example 2

[0132] HPMCAS powder was obtained by performing the same operation as in Example 1 except that the reaction solution-2 containing the HPMCAS at 26.3° C. was extruded into water at 27.8° C.

[0133] The physical properties of the obtained HPMCAS powder are shown in Table 1A and Table 1B.

[0134] Example 3

[0135] HPMCAS powder was obtained by performing the same operation as in Example 1 except that the reaction solution-3 containing the HPMCAS at 24.2° C. was extruded into water at 25.6° C.

[0136] The physical properties of the obtained HPMCAS powder are shown in Table 1A and Table 1B.

[0137] Example 4

[0138] In addition to using the reaction solution-1 containing the HPMCAS at 25.5°C, the extruder opening was adjusted to have an opening area of ​​0.159 mm 2 The reaction solution-1 was extruded into water at 22.7° C., and the same operation as in Example 1 was performed except that the aperture of the sieve used in the wet sieving test was adjusted to 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, 177 μm, 106 μm, and 75 μm, thereby obtaining HPMCAS powder. The physical properties of the obtained HPMCAS powder are shown in Tables 1A and 1B.

[0139] Comparative Example 1

[0140] The reaction solution-3 containing the HPMCAS at 24.8°C was introduced into a mixer (LABOLUTIO PIPELINE-HOMO MIXER, manufactured by PRIMIX Co., Ltd.) together with water at 26.8°C, thereby obtaining a suspension containing HPMCAS particles precipitated by shearing. The mixer had 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 circumferential speed of the outermost periphery of the blades in the rotor was 7.2 m / s, and the shear speed was 9599 s. -1 In addition, the mass of the water mixed was 300 parts by mass with respect to 100 parts by mass of the reaction solution-3 containing the HPMCAS.

[0141] When the average particle size of the HPMCAS particles in the suspension was evaluated by a wet sieving test, the average particle size was 1014 μm.

[0142] The suspension was filtered through a 200-mesh (pore size 75 μm) sieve until the filtrate was no longer discharged. The HPMCAS particles obtained by filtration were dispersed in 20° C. water, and then filtered through a 200-mesh (pore size 75 μm) sieve three times until the filtrate was no longer discharged for washing, thereby obtaining washed HPMCAS particles.

[0143] The washed HPMCAS particles were suspended again in pure water at 20°C and stirred to prepare a slurry. When the filtration rate was evaluated in the filter, the filtration rate per unit filtration area was 4.29 g / (s·cm 2 ).

[0144] 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 1A and Table 1B.

[0145] Comparative Example 2

[0146] In addition to using the reaction solution-1 containing the HPMCAS at 24.9° C. and water at 24.9° C., the rotation speed of the rotor of the mixer was adjusted to 10,000 rpm, the peripheral speed of the outermost periphery of the blades in the rotor was adjusted to 14.4 m / s, and the shear rate was adjusted to 19198 s -1 HPMCAS powder was obtained by the same operation as in Comparative Example 1 except that the mass of the water mixed was adjusted to 300 parts by mass relative to 100 parts by mass of the reaction solution-1 containing the HPMCAS and the aperture of the sieve used in the wet sieving test was adjusted to 1400 μm, 1000 μm, 710 μm, 500 μm, 350 μm, 177 μm, 106 μm and 75 μm. The physical properties of the obtained HPMCAS powder are shown in Tables 1A and 1B.

[0147] [Table 1A]

[0148]

[0149] [Table 1B]

[0150]

[0151] Although the average particle size of the HPMCAS particles of Examples 1 to 3 is about the same as that of the HPMCAS particles of Comparative Example 1, the proportion of fine powder with a particle size of 350 μm or less in the suspension of Examples 1 to 3 is small, so the slurry filtering speed is fast and the washing speed is excellent. In addition, although the average particle size of the HPMCAS powders after drying of Examples 1 to 3 is about the same as that of the HPMCAS powders after drying of Comparative Example 1, the HPMCAS powders after drying of Examples 1 to 3 show low compression and small angle of repose, and are excellent in fluidity.

[0152] In addition, although the average particle size of the HPMCAS particles of Example 4 is about the same as that of the HPMCAS particles of Comparative Example 2, the proportion of fine powder with a particle size of 350 μm or less in the suspension of Example 4 is small, so the slurry filtering speed is fast and the washing speed is excellent. In addition, although the average particle size of the HPMCAS powder after drying of Example 4 is about the same as that of the HPMCAS powder after drying of Comparative Example 2, the HPMCAS powder after drying of Example 4 shows a low compression degree and a small angle of repose, and is excellent in fluidity.

[0153] Description of Reference Numerals

[0154] A-Container component

[0155] B-Screw element

[0156] 1-Cylinder

[0157] 2-Extrusion port

[0158] 3-Extrusion outlet plate

[0159] 4-Extrusion plate

[0160] 5-Threaded part

[0161] 6-Connection cover

[0162] 7-Handle

[0163] 8-Hopper

[0164] 9-Screw

[0165] 10-Extrusion outlet plate

[0166] 11- Water inlet

[0167] 12- Rotating knife.

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 of extruding the reaction solution into water from an extruder to precipitate the reaction solution, and then cutting the precipitate to obtain a suspension containing hydroxypropylmethylcellulose acetate succinate particles; 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: 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 .

3. The method for producing hydroxypropyl methylcellulose acetate succinate powder according to claim 1 or claim 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 hydroxypropylmethylcellulose acetate succinate powder according to claim 1 or claim 2, wherein: The hydroxypropylmethylcellulose acetate succinate particles in the suspension have an average particle size of 500 to 1300 μm as measured by a wet sieving test described in JIS Z8815, and the mass of particles of 350 μm or less accounts for 3.0% or less of the total mass.

Images