Hydroxypropyl methylcellulose acetate succinate and method for producing hydroxypropyl methylcellulose acetate succinate

Abstract

To provide a method for producing hydroxypropyl methylcellulose acetate succinate that is capable of efficient industrial production and allows for a controlled pore volume of particles obtained.SOLUTION: A method for producing hydroxypropyl methylcellulose acetate succinate includes at least an esterification step, a precipitation step, a deliquoring step, a pulverization step, and a drying step, wherein a screw press is used in the deliquoring step.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Hydroxypropylmethylcellulose acetate succinate (hereinafter referred to as "HPMCAS") is a widely known enteric polymer. It is a polymer that incorporates two substituents, a methyl group (-CH3) and a hydroxypropyl group (-C3H6OH), into the cellulose backbone to form an ether structure, and two more, an acetyl group (-COCH3) and a succinyl group (-COC2H4COOH), to form an ester structure, for a total of four types of substituents.

[0003] HPMCAS is widely used in tablet coatings, drug release control applications, and in the preparation of solid dispersions of poorly water-soluble drugs by hot-melt extrusion or spray drying.

[0004] HPMCAS is industrially produced by esterifying hydroxypropyl methylcellulose in the presence of a catalyst, followed by precipitation, deliquoring, drying, and, if necessary, pulverization. However, from the perspective of production efficiency, there was a need to shorten the drying time. For example, a method for reducing the drying time by reducing the loss on drying of the wet mass after the deliquoring step has been reported (Patent Document 1). Specifically, the method reported involves deliquoring a suspension whose temperature has been adjusted to at least 28°C using a filtration device, a filter centrifuge, or a decanter centrifuge in a step corresponding to the deliquoring step. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2016-532725 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the dehydration method using a filtration device or centrifugal dehydrator described in Patent Document 1 makes it difficult to sufficiently reduce the moisture content of the HPMCAS suspension, resulting in a high loss on drying during the drying process and reduced production efficiency. Furthermore, the filtration device used in Patent Document 1 is not suitable for industrial production because it is limited in the amount of liquid it can remove at one time. Furthermore, when filter paper is used, there is a risk of filter paper fibers being mixed in as impurities when peeling the dehydrated HPMCAS from the filter paper, making industrial use difficult. Furthermore, centrifugal dehydration methods, such as those described in Patent Document 1, have difficulty reducing the pore volume within the particles due to the weak force acting on the HPMCAS particles. The pore volume within the particles affects, for example, when HPMCAS is used in hot-melt extrusion or spray-drying. When HPMCAS is used in hot-melt extrusion, the presence of air trapped within the pores of the HPMCAS particles can reduce the uniformity of mixing with the drug. This reduced uniformity reduces the drug dissolution rate in the resulting solid dispersion, resulting in insufficient efficacy. Furthermore, when HPMCAS is used in spray-drying, the trapped air generates a large number of bubbles during the preparation of the HPMCAS solution, requiring a long degassing time and significantly reducing production efficiency. However, despite these issues regarding the pore volume within HPMCAS particles, no optimized manufacturing method for HPMCAS has been developed to address these issues, and an urgent solution is needed to address these issues. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing hydroxypropyl methylcellulose acetate succinate, which includes a draining step and can be produced industrially and efficiently, and a method for producing hydroxypropyl methylcellulose acetate succinate in which the pore volume in HPMCAS particles is controlled. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above problems, the inventors have discovered that by using a screw press as a draining device in a method for producing HPMCAS, the moisture content of the HPMCAS after draining can be reduced, thereby achieving a reduction in the loss on drying of the HPMCAS during the drying step, i.e., shortening the drying time. Furthermore, the inventors have surprisingly discovered that the HPMCAS produced through the draining step using a screw press has a high loose bulk density due to the compaction of the particles, resulting in a reduced pore volume and reduced bubble generation when HPMCAS is mixed with a solvent and stirred, which led to the completion of the present invention. According to the present invention, there are provided the following method for producing hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose acetate succinate. [1] an esterification step of reacting hydroxypropyl methylcellulose with an esterifying agent in the presence of a catalyst to obtain a reaction solution; a precipitation step of mixing the reaction solution with water to obtain a suspension of hydroxypropyl methylcellulose acetate succinate by precipitation of crude hydroxypropyl methylcellulose acetate succinate; a deliquifying step of deliquifying the hydroxypropyl methylcellulose acetate succinate suspension using a screw press to obtain deliquified hydroxypropyl methylcellulose acetate succinate; a grinding step of grinding the deliquorized hydroxypropyl methylcellulose acetate succinate in a grinder to obtain ground hydroxypropyl methylcellulose acetate succinate; and a drying step of drying the ground hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate. [2] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] further comprises, between the precipitation step and the deliquoring step, a washing step of washing the crude hydroxypropyl methylcellulose acetate succinate in the hydroxypropyl methylcellulose acetate succinate suspension obtained in the precipitation step to obtain a hydroxypropyl methylcellulose acetate succinate suspension to be used in the deliquoring step. [3] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] or [2] further comprises a preliminary deliquifying step between the precipitation step and the deliquifying step, in which the hydroxypropyl methylcellulose acetate succinate suspension obtained in the precipitation step is preliquified using a dehydrator to obtain preliquified hydroxypropyl methylcellulose acetate succinate to be used in the deliquifying step. [4] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [3], wherein the mill used in the milling step is a feather mill. [5] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [4], wherein the temperature at the inlet of the screw shaft of the screw press in the deliquoring step is 0 to 80°C. [6] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [5], wherein the deliquorized hydroxypropyl methylcellulose acetate succinate has a water content of 25 to 60 mass %. [7] Loose bulk density is 0.6g / cm 3 Super Hydroxypropyl methylcellulose acetate succinate. [Effects of the Invention]

[0008] According to the present invention, the moisture content of HPMCAS after dewatering can be reduced, thereby shortening the drying time in the HPMCAS production method. Furthermore, according to the present invention, it is possible to produce hydroxypropyl methylcellulose acetate succinate that can reduce the generation of bubbles when stirring and mixing HPMCAS with a solvent in applications such as preparing a solid dispersion by spray drying. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 2 is a schematic diagram showing an example of a screw press used in the liquid removal step. DETAILED DESCRIPTION OF THE INVENTION

[0010] The method for producing HPMCAS of the present invention comprises at least an esterification step, a precipitation step, a deliquification step, a grinding step, and a drying step, and is characterized by using a screw press in the deliquification step. The method for producing HPMCAS of the present invention may also comprise a washing step and / or a preliminary deliquification step, as necessary. A screw press is a device that performs solid-liquid separation by utilizing the compressive force generated by utilizing the volume change between the deliquified raw material inlet and the deliquified product outlet.

[0011] [Esterification process] In the esterification step, hydroxypropylmethylcellulose is reacted with an esterifying agent (for example, succinic anhydride and acetic anhydride) in the presence of a catalyst to obtain a reaction solution.

[0012] We will explain how to obtain hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC"), the raw material for HPMCAS. HPMC may be obtained by a known method or may be a commercially available product. HPMC can be obtained, for example, by contacting pulp in the form of a sheet, chips, or powder with a solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide to form alkali cellulose, and then adding an etherifying agent such as methyl chloride and propylene oxide to react with the resulting cellulose.

[0013] The alkali metal hydroxide solution used in preparing alkali cellulose is not particularly limited as long as it can produce alkali cellulose of the desired composition, but from an economical viewpoint, an aqueous solution of sodium hydroxide or potassium hydroxide is preferred. The concentration of the solution is 23 to 60 mass %, more preferably 35 to 55 mass %, from the viewpoints of stabilizing the composition of the alkali cellulose and ensuring the transparency of the cellulose ether.

[0014] After the alkali cellulose is produced, an etherifying agent such as methyl chloride and propylene oxide is added to the alkali cellulose in a conventional manner to cause an etherification reaction, thereby obtaining HPMC.

[0015] 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 0.20 to 0.65. Insoluble fiber refers to the portion of HPMC that does not dissolve in water. HPMC exhibits water solubility by partially etherifying the hydroxyl groups of cellulose, weakening the intramolecular and intermolecular hydrogen bonds of cellulose. Because completely uniform etherification is difficult industrially, HPMC may contain insoluble portions, i.e., insoluble fiber, due to insufficient or uneven ether group substitution. If the final HPMCAS contains a large amount of insoluble fiber, the enteric coating becomes nonuniform, reducing the yield of enteric-coated formulations and frequently clogging filters during the filtration process of the coating solution, reducing productivity. Therefore, it is preferable that the HPMC used as the raw material for HPMCAS contains a small amount of insoluble fiber. The amount of insoluble fiber can be determined by analyzing an aqueous HPMC solution using a device such as a Coulter counter. The DS of the methoxy group in HPMC represents the degree of substitution and is the average number of methoxy groups per unit of anhydroglucose, and the MS of the hydroxypropoxy group in HPMC represents the molar substitution and is the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The DS of the methoxy group and the MS of the hydroxypropoxy group in HPMC can be determined by converting values ​​obtained by measurement based on the 18th Edition of the Japanese Pharmacopoeia.

[0016] The viscosity of a 2% by mass aqueous solution of HPMC at 20°C is preferably 2.2 to 7.2 mPa·s, more preferably 3.0 to 3.5 mPa·s, from the viewpoint of kneading properties during the esterification reaction. The viscosity of a 2% by mass HPMC aqueous solution at 20°C is measured in accordance with the capillary viscometer method of the 18th edition of the Japanese Pharmacopoeia.

[0017] From the viewpoint of economy, the catalyst for the esterification step is preferably an alkali metal carboxylate such as sodium acetate. The amount of catalyst is preferably 0.1 to 1.5, more preferably 0.6 to 1.1, in terms of molar ratio relative to the starting HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS.

[0018] Among the esterifying agents used in the esterification step, acetylating agents include acetic anhydride and acetyl chloride, with acetic anhydride being preferred from the viewpoint of economy. The amount of the acetylating agent is preferably 0.1 to 1.5, more preferably 1.1 to 1.3, in terms of molar ratio relative to the raw material HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS. Of the esterifying agents used in the esterification step, examples of the succinoylating agent include succinic anhydride and succinyl chloride, with succinic anhydride being preferred from the viewpoint of economy. The amount of succinoylating agent is preferably 0.1 to 1.0, more preferably 0.3 to 0.5, in terms of molar ratio relative to the starting HPMC, from the viewpoints of the composition (degree of substitution) and yield of the resulting HPMCAS.

[0019] The esterification step may be carried out in the presence of a solvent, preferably one that can dissolve HPMC, the esterifying agent, and the catalyst, and examples of the solvent include acetic acid, propionic acid, and butyric acid, with acetic acid being preferred from an economical viewpoint. From the viewpoint of reaction rate, the amount of the solvent used is preferably 1.0 to 3.0, more preferably 1.2 to 2.0, and even more preferably 1.5 to 1.8, in terms of mass ratio relative to HPMC. The reactor used for the esterification reaction in the esterification step may be a twin-shaft agitator capable of kneading a highly viscous fluid to form a uniform mixture. Specifically, agitators generally available on the market under the names of kneaders, internal mixers, etc. may be used. The reaction temperature in the esterification step is preferably 60 to 100° C., more preferably 80 to 90° C., from the viewpoint of increasing the reaction rate or viscosity. The reaction time in the esterification step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of obtaining HPMCAS with the desired degree of substitution.

[0020] After the esterification reaction, water may be added to the reaction solution to treat any unreacted acetylating agent and succinoylating agent (the treatment of mixing with water after the esterification reaction is also referred to as "post-treatment"). The amount of water added to the reaction solution in the esterification step for the purpose of post-treatment is preferably 0.8 to 1.5, more preferably 1.0 to 1.3, in mass ratio relative to HPMC.

[0021] [Precipitation process] In the precipitation step, the reaction solution obtained in the esterification step is mixed with water to precipitate crude HPMCAS, thereby obtaining an HPMCAS suspension. The amount of water to be mixed with the reaction solution in the precipitation step is preferably 8.0 to 50.0, more preferably 12.0 to 35.0, in mass ratio relative to the HPMC used in the esterification reaction, from the viewpoints of the degree of precipitation of HPMCAS and the treatment time. The temperature of the water mixed with the reaction solution in the precipitation step is preferably 0 to 40°C, more preferably 0 to 30°C, from the viewpoint of controlling the particle size of the HPMCAS particles in the HPMCAS suspension. The temperature of the reaction solution immediately before mixing with water is preferably 10 to 80°C, more preferably 10 to 50°C, from the viewpoint of controlling the particle size of the HPMCAS particles in the HPMCAS suspension.

[0022] The average particle size of the suspended particles in the HPMCAS suspension obtained in the precipitation step is preferably 150 μm or more, more preferably 150 to 4000 μm, and even more preferably 150 to 2000 μm, from the viewpoint of reducing the water content of the deliquified HPMCAS after the deliquifying step described below. The average particle size of the suspended particles can be adjusted to fall within the above range by carrying out the esterification step and the precipitation step under the above conditions. The average particle size of HPMCAS particles in a suspension containing precipitated HPMCAS particles can be measured by the wet sieving test described in JIS Z8815. Specifically, the horizontal axis represents sieve opening (μm) and the vertical axis represents cumulative sieve mass (%). A plot of each sieve opening and the cumulative sieve mass (%) for each sieve opening is made. The average particle size of the HPMCAS particles is determined by the intersection of a line connecting two points on either side of 50% of the cumulative sieve mass with the 50% cumulative sieve mass. The cumulative sieve mass (%) can be calculated by pouring the suspension containing precipitated HPMCAS particles into a sieve, pouring pure water over the HPMCAS particles until the liquid passing through the sieve becomes transparent, transferring the liquid to a container for mass measurement, and then calculating the mass of the HPMCAS particles remaining on the sieve.

[0023] The concentration of the HPMCAS suspension obtained in the precipitation step (the ratio of the mass of suspended particles per unit mass of suspension) is not particularly limited, but is preferably 20% by mass or less, more preferably 15% by mass or less, from the viewpoint of the tendency of suspended particles to aggregate in the subsequent deliquoring step. The lower limit of the concentration of the HPMCAS suspension obtained in the precipitation step is not particularly limited, but is 0.1% by mass from the viewpoint of productivity. The amount of water added in the precipitation step is appropriately adjusted so that the concentration of the HPMCAS suspension falls within the aforementioned range; however, the amount of water in the suspension may also be appropriately adjusted before the HPMCAS suspension is subjected to the deliquoring step so that the concentration of the HPMCAS suspension falls within the aforementioned range.

[0024] Furthermore, in consideration of factors such as the tendency for suspended particles to aggregate in the subsequent deliquoring step, it is preferable to adjust the temperature of the HPMCAS suspension obtained in the precipitation step to preferably 80° C. or lower, more preferably 60° C. or lower, and even more preferably 40° C. or lower before subjecting it to the deliquoring step. There are no particular restrictions on the lower limit of the temperature of the HPMCAS suspension, but from the viewpoint of operability and the like, it is 0° C.

[0025] [Cleaning process] The obtained HPMCAS suspension may contain residual impurities such as salts, free acetic acid, free succinic acid, etc. Since the use of a screw press is also expected to have a washing effect, the obtained HPMCAS suspension can be directly deliquored using a screw press, but if necessary, a washing step can be included between the precipitation step and the deliquoring step, in which crude HPMCAS in the HPMCAS suspension obtained in the precipitation step is washed to obtain an HPMCAS suspension to be used in the deliquoring step. The HPMCAS suspension may be washed by removing water from the suspension by filtration or other methods, followed by resuspending the HPMCAS in a clean solvent. In the washing step, the removal of water from the suspension by filtration or other methods and resuspension in a solvent may be repeated multiple times. The solvent used to wash the HPMCAS includes water. Typically, this washing step involves washing the crude HPMCAS with, for example, water, using a filter such as a batch-type agitated filter, a continuous rotary pressure filter, a continuous horizontal vacuum filter, a horizontal plate filter, or a horizontal belt filter.

[0026] The HPMCAS suspension used in the draining step obtained after the washing step preferably has the same average particle size of suspended particles, concentration, and temperature as the HPMCAS suspension obtained in the precipitation step. Furthermore, water may be added appropriately after the washing step so that the concentration of the HPMCAS suspension obtained after the washing step and used in the dewatering step falls within the above range.

[0027] [Preliminary draining process] For the purpose of reducing the water content of the deliquified HPMCAS obtained by the deliquifying step, a preliminary deliquifying step can be included, as necessary, between the washing step and the deliquifying step, or between the precipitation step and the deliquifying step if a washing step is not performed, in which the HPMCAS suspension is deliquified using a dehydrator to obtain preliminary deliquified HPMCAS. Generally, a dehydrator such as a centrifugal dehydrator or a decanter-type centrifuge can be used in this preliminary deliquoring step.

[0028] The moisture content of the pre-deliquified HPMCAS is not particularly limited, but from the viewpoint of obtaining deliquified HPMCAS with a low moisture content in the subsequent deliquifying step using a screw press, it is preferably 75% by mass or less, more preferably 65% ​​by mass or less, and from the viewpoint of productivity, etc., it is preferably more than 60% by mass. Furthermore, the degree of preliquitonization may be adjusted or water may be added appropriately after the preliquitonization step so that the water content of the preliquitonized HPMCAS obtained after the preliquitonization step and used in the deliquitonization step falls within the above-mentioned range.

[0029] The preliminarily deliquified HPMCAS obtained after the preliquifying step and used in the deliquifying step preferably has the same average particle size and temperature as the HPMCAS suspension obtained in the precipitation step.

[0030] [Deliquoring process] After the precipitation step, washing step, or pre-draining step, a deliquification step is carried out in which the HPMCAS suspension or pre-drained HPMCAS is deliquified using a screw press. Previously, the use of a screw press for the dewatering process in HPMCAS manufacturing had not been considered. This was due to the belief that the high shear stress applied to the HPMCAS particles during the dewatering process would make it difficult to obtain particles with the desired powder properties. Surprisingly, however, we discovered that powerful dewatering of HPMCAS suspensions using a screw press enables the continuous and stable production of high-density HPMCAS particles, which was previously unattainable using conventional methods. High-density HPMCAS particles have extremely small void volumes within the particles, which improves mixing uniformity with drugs during heat melting and suppresses bubble formation during solution preparation. Furthermore, their high packability increases the shipping efficiency of HPMCAS products. Furthermore, dewatering using a screw press offers advantages over other dewatering devices, including energy efficiency, continuous production capacity, ease of maintenance, and independence from the condition of the wet powder or suspension being dewatered, thereby potentially improving HPMCAS production efficiency.

[0031] A screw press is a device that separates solids and liquids using a compressive force generated by utilizing the volumetric change between the deliquified raw material inlet and the deliquified product outlet. Figure 1 shows a schematic diagram of an example of a screw press used in the deliquifying process. The screw press 1 is equipped with a filter cylinder 2 that is approximately cylindrical and has slits or holes formed by punching or the like for discharging the liquid, and a screw that is concentrically arranged inside the filter cylinder 2. The screw is composed of a screw shaft 4 and screw blades 3 welded to the periphery thereof. The screw shaft 4 is connected to a deliquified raw material input section 5 and a deliquified product discharge section 8. Xu The volume gradually increases. The screw shaft 4 can adjust the temperature by passing a liquid or a gas from the temperature-adjusting liquid inlet 6 to the temperature-adjusting liquid outlet 10. The screw shaft 4 also includes a straight section 12 (without screw blades 3) in front of the deliquified product discharge section 8, in order to extend the residence time of the deliquified raw material A in the device and enhance the deliquifying performance. Specifically, the deliquified raw material A transported from the deliquified raw material inlet 5 to the deliquified product discharge section 8 while being deliquified due to a change in volume resides in the straight section 12 (without screw blades 3). This applies pressure from the deliquified product discharge section 8 to the deliquified raw material A subsequently transported from the deliquified raw material inlet 5, further reducing the moisture content of the deliquified product B. The length of the straight section 12 is called the straight length (or plug length), and this length can be adjusted by moving the screw, which can move parallel to the main axis. The deliquified product discharge section 8 is equipped with a truncated cone-shaped back pressure plate 11 arranged concentrically with the screw shaft 4, and the opening of the back pressure plate 11 can be adjusted. Furthermore, pressure can be applied from the deliquified product discharge section 8 side to the deliquified raw material input section 5 side by an air cylinder 9 (hereinafter also referred to as "back pressure"). The compressed liquid C, which is the liquid component compressed by the screw press 1, passes through the pores of the filter cylinder 2 and is discharged from the compressed liquid discharge section 7. Examples of the screw press include the FKC screw press (manufactured by Fukoku Kogyo Co., Ltd.), the ISGKV hybrid press-fit screw press (manufactured by Ishigaki Co., Ltd.), and the YSP screw press dehydrator (manufactured by Yamato Sangyo Co., Ltd.).

[0032] A method for deliquifying an HPMCAS suspension or pre-deliquified HPMCAS using a screw press will be described based on the screw press 1 illustrated in FIG. First, if necessary, select a screw that will achieve the desired compression ratio. The compression ratio of a screw is the ratio of the area between the thickest part of the screw shaft 4 and the inner diameter of the filter cylinder 2 to the area between the thinnest part of the screw shaft 4 and the inner diameter of the filter cylinder 2. Next, the desired screw speed, straight length, back pressure plate opening, back pressure, and screw shaft inlet temperature are set. After setting these parameters, the screw press 1 is operated to rotate the screw shaft 4. After the screw speed reaches the desired speed, HPMCAS suspension or preliminarily deliquified HPMCAS is introduced as deliquified feedstock A through the deliquified feedstock inlet 5. Deliquified feedstock A supplied through the deliquified feedstock inlet 5 undergoes gravity filtration through the holes in the filter tube 2 directly below the deliquified feedstock inlet 5, resulting in solid-liquid separation of a portion of the liquid component. The partially solid-liquid separated deliquified feedstock A is transported by the rotating screw to the deliquified product discharge section 8. During this process, deliquification occurs due to volume changes between the deliquified feedstock inlet 5 and the deliquified product discharge section 8. Deliquified product B, i.e., deliquified HPMCAS, is in the form of a wet powder or wet lump. It either falls from the deliquified product discharge section 8 under its own weight or falls from the deliquified product discharge section 8 after being roughly crushed by collision with the back pressure plate 11. The compressed liquid C, which is the liquid component obtained by solid-liquid separation, is discharged through the holes in the filter cylinder 2 and recovered from the compressed liquid discharge section 7.

[0033] The screw rotation speed is preferably 0.1 to 6 rpm, more preferably 0.2 to 3 rpm, from the viewpoint of obtaining deliquescence HPMCAS with a low moisture content while maintaining high production efficiency.

[0034] If the screw shaft inlet temperature is high, the viscosity of the water in the HPMCAS suspension decreases, and the HPMCAS softens, facilitating drainage from the interior of the HPMCAS suspension particles. However, the particle shape of the HPMCAS, a thermoplastic material, is not maintained. On the other hand, if the screw shaft inlet temperature is low, the viscosity of the water in the HPMCAS suspension increases, and the water freezes, potentially causing equipment failure. From the above perspectives, the screw shaft inlet temperature is preferably 0 to 80°C, more preferably 10 to 70°C, and even more preferably 10 to 60°C.

[0035] The straight length is not particularly limited, but from the viewpoint of obtaining deliquified HPMCAS with a low moisture content, it is 0 to 300 mm, preferably 50 to 200 mm.

[0036] The compression ratio is not particularly limited, but from the viewpoint of obtaining deliquified HPMCAS with a low moisture content, it is 1.1 to 3.0, preferably 1.1 to 2.0.

[0037] The back pressure is not particularly limited, but from the viewpoint of obtaining deliquified HPMCAS with a low moisture content, it is preferably 0 to 0.5 MPa, more preferably 0 to 0.4 MPa, and even more preferably 0.1 to 0.4 MPa. Note that the opening of the back pressure plate is preferably 10 mm or more, since if it is too narrow, the dehydrated product will not be discharged.

[0038] The moisture content of the deliquified HPMCAS obtained after the deliquification step is not particularly limited, but is preferably 5 to 90% by mass, more preferably 10 to 80% by mass, even more preferably 15 to 70% by mass, particularly preferably 20 to 60% by mass, and most preferably 25 to 35% by mass, from the viewpoint of drying efficiency and the like. The moisture content of deliquified HPMCAS can be measured by the method described in "General Test Methods, 2. Physical Test Methods, Loss on Drying Test" in the Japanese Pharmacopoeia, Eighteenth Edition. Specifically, the moisture content of HPMCAS is defined as {(Total Mass of HPMCAS - Bone-Dry Mass of HPMCAS) / (Total Mass of HPMCAS)} × 100%. Here, "Total Mass of HPMCAS" refers to the mass of HPMCAS precisely weighed according to the "Loss on Drying Test" in the Japanese Pharmacopoeia, Eighteenth Edition. Furthermore, "Bone-Dry Mass of HPMCAS" refers to the mass of HPMCAS after drying according to the "Loss on Drying Test" in the Japanese Pharmacopoeia, Eighteenth Edition. When measuring the "moisture content of deliquified HPMCAS," the "moisture content of deliquified HPMCAS" can be measured and calculated by replacing "HPMCAS" in the above with "deliquified HPMCAS." The moisture content of HPMCAS in each step, such as the moisture content of dried HPMCAS described below, can also be measured in the same manner.

[0039] [Crushing process] Depending on the operating conditions of the screw press, deliquified HPMCAS may be obtained as a cake-like product. In such cases, it is necessary to crush or pulverize the product into particles with a large specific surface area and high fluidity in order to efficiently carry out the subsequent drying step. In the pulverization step, the deliquified HPMCAS obtained in the deliquifying step is pulverized in a pulverizer to obtain pulverized HPMCAS. The pulverizer used in the pulverization step is not particularly limited, but from the viewpoint of obtaining pulverized HPMCAS of the desired particle size, a cone crusher, impact crusher, hammer mill, feather mill, or the like is preferred. From the viewpoint of powder flowability, the average particle size (D50) of the pulverized HPMCAS is preferably 70 to 5000 μm, more preferably 150 to 3000 μm, and even more preferably 300 to 1500 μm. The average particle size (D50) of the pulverized HPMCAS can be measured by dry laser diffraction (for example, using a Mastersizer manufactured by Malvern Instruments, UK).

[0040] [Drying process] In the drying step, the pulverized HPMCAS obtained in the pulverization step is dried to a desired moisture content (for example, 0.1 to 5.0% by mass). The drying temperature is not particularly limited, but is preferably from room temperature (20±15°C) to 120°C, more preferably from 50°C to 90°C, from the viewpoint of drying capacity and discoloration (quality) of the dried product. The dryer is not particularly limited, but examples thereof include a fluidized bed dryer and a flash dryer.

[0041] [Hydroxypropyl methylcellulose acetate succinate] The degree of substitution of HPMCAS obtained by the production method of the present invention will now be described. 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 even more 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 even more 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, more preferably 0.80 to 3.70. 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 anhydroglucose, and the MS of the hydroxypropoxy groups in HPMCAS represents the molar substitution, which is the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The DS of the methoxy group, acetyl group, and succinyl group and the MS of the hydroxypropoxy group in HPMCAS can be calculated from the values ​​obtained by the method described in the pharmaceutical articles "Hypromellose acetate succinate" in the 18th Edition of the Japanese Pharmacopoeia.

[0042] The average particle size (D50) of the HPMCAS obtained in this manner is preferably 70 to 2000 μm, more preferably 150 to 1750 μm, and even more preferably 300 to 1500 μm, from the viewpoints of powder fluidity and miscibility with drugs. The average particle size (D50) of the HPMCAS can be measured by dry laser diffraction (for example, using a Mastersizer manufactured by Malvern Pharmaceuticals, UK).

[0043] The HPMCAS obtained by the production method of the present invention has a reduced pore volume and a high loose bulk density, which reduces the generation of bubbles when HPMCAS is mixed with a solvent and stirred. The loose bulk density and packed bulk density of the HPMCAS thus obtained will now be described. The loose bulk density is preferably 0.3 to 0.85 g / cm from the viewpoint of suppressing the generation of bubbles. 3 , more preferably more than 0.6 to 0.85 g / cm 3 "Loose bulk density" refers to the bulk density in a loosely packed state, and is measured by passing a sample through a 24-mesh sieve into a cylindrical container 5.03 cm in diameter and 5.03 cm in height (volume 100 mL) and uniformly feeding the sample from 23 cm above the cylindrical container, then leveling off the top surface and weighing the sample. The packed bulk density is preferably 0.3 to 0.90 g / cm from the viewpoint of suppressing the generation of bubbles.3 , more preferably more than 0.6 to 0.9 g / cm 3 "Packed bulk density" is the bulk density when the sample is tightly packed by tapping. Tapping is a procedure in which a cylindrical container filled with the sample is repeatedly dropped from a certain height to apply a light impact to the bottom, causing the sample to be tightly packed. In practice, the sample is filled into a cylindrical container in the same manner as for measuring loose bulk density, and the top is leveled off and weighed. Then, a cap is placed on the cylindrical container, the sample is added up to the top edge, and tapping is performed 180 times at a tapping height of 1.8 cm. After tapping is complete, the cap is removed and the sample is leveled off at the top of the cylindrical container and weighed; the bulk density in this state is taken as the packed bulk density. The "packed bulk density" and the "loose bulk density" can be measured using a powder tester manufactured by Hosokawa Micron Corporation.

[0044] The specific surface area of ​​the dried HPMCAS thus obtained is preferably 0.5 to 5.0 m from the viewpoint of suppressing the generation of bubbles during dissolution. 2 / g, more preferably 0.5 to 3.0 m 2 / g. Specific surface area is measured by adsorbing molecules with known adsorption areas onto the powder particle surface at liquid nitrogen temperature (-196°C), and then determining the specific surface area of ​​the sample from the amount of adsorption. The BET method (BET multipoint method) using low-temperature, low-humidity physical adsorption of an inert gas can be used. For example, measurements can be made using the TriStar II 3020 automatic specific surface area / pore distribution analyzer (manufactured by Micromeritics). [Example]

[0045] EXAMPLES 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.

[0046] Example 1 12 kg of glacial acetic acid was weighed into a 50 L kneader equipped with a twin-shaft stirrer, and 7.5 kg of hydroxypropyl methylcellulose, which has a methoxy group DS of 1.87, a hydroxypropoxy group MS of 0.24, and a viscosity of a 2% by mass aqueous solution at 20°C of 3.4 mPa·s, was added and dissolved. Next, 2.3 kg of succinic anhydride, 4.3 kg of acetic anhydride, and 3.6 kg of sodium acetate were added to the 50 L kneader and reacted at 85°C for 5 hours. After that, 8.4 kg of water was added to the reaction solution in the 50 L kneader and stirred to obtain a reaction solution. Water (20°C) in an amount 20 times the mass of HPMC was gradually added to the reaction solution at 40°C to precipitate crude HPMCAS, thereby obtaining an HPMCAS suspension. The crude HPMCAS in the HPMCAS suspension was filtered using a horizontal plate filter and washed with water. The obtained HPMCAS was mixed with water to obtain HPMCAS suspension-1 at a temperature of 12°C and with an HPMCAS concentration of 6% by mass. HPMCAS suspension-1 was deliquified (solid-liquid separation) using a screw press (FKC screw press SHX-200 x 1500L, Fukoku Kogyo Co., Ltd., compression ratio 1.4) at a screw rotation speed of 2 rpm, a screw shaft inlet temperature of 13°C, a back pressure plate opening of 20 mm, a back pressure of 0 MPa, and a straight length of 50 mm to obtain deliquified HPMCAS. The moisture content of the deliquified HPMCAS was 55.21% by mass. Next, the deliquified HPMCAS was pulverized using a Feather Mill (FM-1F manufactured by Hosokawa Micron Corporation) at a rotation speed of 3833 rpm with a mesh size of 5.0 mm to obtain pulverized HPMCAS. The resulting pulverized HPMCAS was then dried at 80°C using a fluidized bed dryer until the moisture content after the drying step was less than 5%, yielding dried HPMCAS. The drying time of the pulverized HPMCAS was 0.80, compared with 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator in Comparative Example 1. The resulting dried HPMCAS was then sieved through a 7.5 mesh (opening: 2360 μm) sieve. The degree of substitution of the obtained HPMCAS was as follows: DS of methoxy group: 1.87, MS of hydroxypropoxy group: 0.24, DS of acetyl group: 0.46, and DS of succinyl group: 0.38. The resulting HPMCAS (20.4 g) was added to purified water (175 g) in a stirring vessel and dispersed by stirring at 300 rpm for 5 minutes. A 10% by mass aqueous ammonia solution (5.07 g) was added, sufficient to neutralize the carboxyl groups in the HPMCAS. After stirring at 700 rpm for an additional 150 minutes, the stirring blades were stopped. The resulting aqueous ammonia solution of HPMCAS was allowed to stand for 30 minutes, and the bubble volume was calculated from the bubble height above the liquid surface and the cross-sectional area of ​​the stirring vessel. The bubble volume was 0.7, compared to the bubble volume of the aqueous ammonia solution prepared using the HPMCAS of Comparative Example 1, which was dewatered using a filtration-type centrifugal dehydrator (1.0). Furthermore, the average particle size (D50), loose bulk density, packed bulk density, and specific surface area (hereinafter collectively referred to as powder properties) of the sieved HPMCAS were measured using the methods described above. The results are shown in Table 1.

[0047] Example 2 HPMCAS was obtained in the same manner as in Example 1, except that the draining conditions in the screw press were a back pressure of 0.4 MPa and a rotation speed of 0.25 rpm. The drying time of the pulverized HPMCAS was 0.41, compared to 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated during the preparation of an aqueous ammonia solution using HPMCAS was 0.4, compared to the bubble volume of 1.0 for the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0048] Example 3 HPMCAS was obtained in the same manner as in Example 2, except that the grinding conditions in the feather mill were changed to a mesh size of 3.0 Φmm. The drying time of the pulverized HPMCAS was 0.40, compared to the drying time of 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated during the preparation of an aqueous ammonia solution using HPMCAS was 0.4, compared to the bubble volume of 1.0 for the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0049] Example 4 HPMCAS was obtained in the same manner as in Example 1, except that the deliquoring conditions in the screw press were a screw rotation speed of 1 rpm and a screw shaft inlet temperature of 30°C. The drying time of the pulverized HPMCAS was 0.33, compared to 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated when preparing an aqueous ammonia solution using HPMCAS was 0.3, compared to the volume of bubbles generated in the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1, which was 1.0. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0050] Example 5 HPMCAS was obtained in the same manner as in Example 2, except that a Victory Mill was used as the grinder. The drying time of the pulverized HPMCAS was 0.44, compared to 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated during the preparation of an aqueous ammonia solution using HPMCAS was 0.4, compared to the bubble volume of 1.0 for the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0051] Example 6 HPMCAS was obtained in the same manner as in Example 2, except that a force mill was used as the pulverizer. The drying time of the pulverized HPMCAS was 0.47, compared to 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated during the preparation of an aqueous ammonia solution using HPMCAS was 0.4, compared to the bubble volume of 1.0 for the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0052] Example 7 12 kg of glacial acetic acid was weighed into a 50 L kneader equipped with a twin-shaft stirrer, and 7.5 kg of hydroxypropyl methylcellulose, which has a methoxy group DS of 1.89, a hydroxypropoxy group MS of 0.24, and a viscosity of a 2% by mass aqueous solution at 20°C of 3.4 mPa·s, was added and dissolved. Next, 0.8 kg of succinic anhydride, 5.3 kg of acetic anhydride, and 3.5 kg of sodium acetate were added to the 50 L kneader and reacted at 85°C for 5 hours. After that, 8.4 kg of water was added to the reaction solution in the 50 L kneader and stirred to obtain a reaction solution. Water (20°C) in an amount 20 times the mass of HPMC was gradually added to the reaction solution at 40°C to precipitate crude HPMCAS, thereby obtaining an HPMCAS suspension. The crude HPMCAS in the HPMCAS suspension was filtered using a horizontal plate filter and washed with water. The obtained HPMCAS was mixed with water to obtain HPMCAS suspension-2 at a temperature of 12°C and with an HPMCAS concentration of 6% by mass. HPMCAS suspension-2 was subjected to deliquification (solid-liquid separation) using a screw press (FKC screw press SHX-200×1500L, manufactured by Fukoku Kogyo Co., Ltd., compression ratio 1.4) at a screw rotation speed of 2 rpm, a screw shaft inlet temperature of 55°C, a back pressure plate opening of 20 mm, a back pressure of 0 MPa, and a straight length of 50 mm to obtain deliquified HPMCAS. The moisture content of the deliquified HPMCAS was 25.01% by mass. Next, the deliquified HPMCAS was pulverized using a Feather Mill (FM-1F manufactured by Hosokawa Micron Corporation) at a rotation speed of 3833 rpm with a mesh size of 5.0 mm to obtain pulverized HPMCAS. The resulting pulverized HPMCAS was then dried at 80°C using a fluidized bed dryer until the moisture content after the drying step was less than 5%, yielding dried HPMCAS. The drying time of the pulverized HPMCAS was 0.32, compared with 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator in Comparative Example 1. The resulting dried HPMCAS was then sieved through a 7.5 mesh (opening: 2360 μm) sieve. The degree of substitution of the obtained HPMCAS was as follows: DS of methoxy group: 1.87, MS of hydroxypropoxy group: 0.23, DS of acetyl group: 0.66, and DS of succinyl group: 0.18. The resulting HPMCAS (20.4 g) was added to purified water (178 g) in a stirring vessel and dispersed by stirring at 300 rpm for 5 minutes. A 10% by mass aqueous ammonia solution (2.57 g) was added, sufficient to neutralize the carboxyl groups in the HPMCAS. The mixture was stirred at 700 rpm for an additional 150 minutes, after which the impeller was stopped. The resulting aqueous ammonia solution of HPMCAS was allowed to stand for 30 minutes, and the bubble volume was calculated from the bubble height above the liquid surface and the cross-sectional area of ​​the stirring vessel. The bubble volume was 0.4, compared to the bubble volume of the aqueous ammonia solution prepared using HPMCAS in Comparative Example 1, which was 1.0. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0053] Comparative Example 1 The HPMCAS suspension-1 obtained in Example 1 was subjected to deliquification using a centrifugal dehydrator (top-discharge centrifuge H-130A model manufactured by Kokusan Co., Ltd.) instead of a screw press, at a centrifugal effect of 1200 G. After discharge of liquid from the device's drain outlet was no longer observed, deliquification was continued for 2 minutes. Deliquification was continued for an additional 2 minutes, but the water content did not decrease, so the deliquification process was terminated and deliquified HPMCAS with a water content of 67.8% by mass was obtained. HPMCAS was obtained in the same manner as in Example 1, except that the obtained deliquified HPMCAS was dried without being subjected to a pulverization process. In the same manner as in Example 1, the bubble volume was calculated from the bubble height and the cross-sectional area of ​​the stirring vessel. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0054] Comparative Example 2 HPMCAS was obtained in the same manner as in Example 1, except that the centrifugal dehydrator described in Comparative Example 1 was used instead of the screw press. The drying time of the pulverized HPMCAS was 0.98, compared to 1.00 for the deliquified HPMCAS deliquified using the filtration-type centrifugal dehydrator of Comparative Example 1. The volume of bubbles generated when preparing an aqueous ammonia solution using HPMCAS was 1.0, compared to the volume of bubbles generated when preparing an aqueous ammonia solution using HPMCAS in Comparative Example 1, which was 1.0. The powder properties of the sieved HPMCAS were investigated and the results are shown in Table 1.

[0055] [Table 1]

[0056] The results of Examples 1 to 7 and Comparative Examples 1 and 2 show that the drying time of the HPMCAS suspension could be shortened by dewatering it using a screw press and then pulverizing it. The powder properties of the resulting HPMCAS differed significantly depending on the type of dehydrator used in the dewatering step, and the use of HPMCAS obtained by the manufacturing method of the present invention reduced the amount of bubbles generated during solution preparation. Furthermore, the results of Examples 2 and 3 confirmed that the average particle size of HPMCAS can be adjusted by changing the mesh size of the pulverizer. Furthermore, the results of Examples 1 and 4 confirmed that the moisture content of deliquified HPMCAS can be significantly reduced by increasing the screw shaft inlet temperature of the screw press. In addition, the results of Examples 2, 5 and 6 confirmed that when a pulverizer other than a feather mill was used, the same effects as when a feather mill was used could be obtained. Finally, the results of Examples 1 and 7 confirmed that even when the amount of esterifying agent used in the esterification step was changed and the degree of substitution of the resulting HPMCAS was different, the drying time of the HPMCAS could be shortened and the amount of air bubbles generated could also be reduced. [Explanation of symbols]

[0057] 1. Screw press 2 Filter cylinder 3 screw blades 4 screw shaft 5 Deliquified raw material input section 6 Temperature control liquid inlet 7. Squeezed liquid discharge section 8 Deliquid product discharge section 9 Air Cylinder 10 Temperature control liquid outlet 11 Back pressure plate 12 Straight section A Deliquified raw material B Delicious product C. Pressed liquid D Temperature control liquid to be added E Discharged temperature control liquid

Claims

1. an esterification step of reacting hydroxypropyl methylcellulose with an esterifying agent in the presence of a catalyst to obtain a reaction solution; a precipitation step of mixing the reaction solution with water to obtain a suspension of hydroxypropyl methylcellulose acetate succinate by precipitation of crude hydroxypropyl methylcellulose acetate succinate; a deliquifying step of deliquifying the hydroxypropyl methylcellulose acetate succinate suspension using a screw press to obtain deliquified hydroxypropyl methylcellulose acetate succinate; a grinding step of grinding the deliquorized hydroxypropyl methylcellulose acetate succinate in a grinder to obtain ground hydroxypropyl methylcellulose acetate succinate; and a drying step of drying the ground hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate.

2. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, further comprising, between the precipitation step and the deliquoring step, a washing step of washing the crude hydroxypropyl methylcellulose acetate succinate in the hydroxypropyl methylcellulose acetate succinate suspension obtained in the precipitation step to obtain a hydroxypropyl methylcellulose acetate succinate suspension to be used in the deliquoring step.

3. 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, further comprising a preliminary deliquifying step between the precipitation step and the deliquifying step, in which the hydroxypropyl methylcellulose acetate succinate suspension obtained in the precipitation step is preliqui- dized by a dehydrator to obtain preliqui- dized hydroxypropyl methylcellulose acetate succinate to be used in the deliquifying step.

4. The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of claims 1 to 3, wherein the grinding machine used in the grinding step is a feather mill.

5. The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of claims 1 to 3, wherein the temperature at the inlet of the screw shaft of the screw press in the deliquoring step is 0 to 80°C.

6. The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of claims 1 to 3, wherein the deliquorized hydroxypropyl methylcellulose acetate succinate has a water content of 25 to 60 mass%.

7. Loose bulk density 0.6 g / cm ３ Super Hydroxypropyl methylcellulose acetate succinate.

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