Method for producing hydroxypropyl methylcellulose acetate succinate

Abstract

To provide a method capable of efficiently producing, even after reducing the amount of aliphatic carboxylic acid used, hydroxypropyl methylcellulose acetate succinate (HPMCAS) with an equivalent level of molecular weight as compared to before reducing the amount of the aliphatic carboxylic acid.SOLUTION: A production method for hydroxypropyl methylcellulose acetate succinate includes at least an esterification reaction step of yielding a hydroxypropyl methylcellulose acetate succinate-containing reaction solution by subjecting hydroxypropyl methylcellulose, an acetylating agent, and a succinoylating agent to an esterification reaction under the presence of aliphatic carboxylic acid and polyalcohol.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is a widely known enteric polymer. It is a polymer that has four types of substituents introduced into the cellulose backbone: two substituents, a methyl group (-CH3) and a hydroxypropyl group (-C3H6OH), to form an ether structure, and two substituents, an acetyl group (-COCH3) and a succinyl group (-COC2H4COOH), to form an ester structure. HPMCAS, an enteric polymer, is widely used as a solid dispersion and enteric coating base to improve the dissolution of poorly water-soluble drugs.

[0003] Enteric-coated preparations are one of the important preparations that are widely used when administering acid-labile drugs, for the purpose of protecting the gastric mucosa, etc. One known method for producing HPMCAS involves an esterification reaction using acetic anhydride as an acetylating agent, succinic anhydride as a succinoylating agent, and glacial acetic acid as an aliphatic carboxylic acid in the presence of sodium acetate as a catalyst, at a ratio (mass ratio) of glacial acetic acid to hydroxypropyl methylcellulose (hereinafter also referred to as "HPMC") of 2.2 (Patent Document 1). Another known production method is to carry out an esterification reaction in a kneader reactor equipped with multiple stirring blades that revolve while rotating, using acetic anhydride as an acetylating agent, succinic anhydride as a succinoylating agent, and glacial acetic acid as an aliphatic carboxylic acid in the presence of sodium acetate as a catalyst, under conditions where the ratio (mass ratio) of glacial acetic acid to HPMC is 1.6 (Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2017-505847 [Patent Document 2] Patent Publication No. 2021-070789 Summary of the Invention [Problem to be solved by the invention]

[0005] In the production of HPMCAS, increasing the amount of aliphatic carboxylic acid as described in Patent Document 1 can reduce the viscosity of the reaction solution during synthesis, but this limits the amount of HPMC that can be charged per batch, making it difficult to improve production efficiency. Conversely, reducing the amount of aliphatic carboxylic acid used reduces the amount of solvent, allowing the amount of HPMC to be increased accordingly and improving production efficiency. However, reducing the amount of aliphatic carboxylic acid causes cellulose chains to react with each other, resulting in a very high molecular weight of HPMCAS and a high viscosity of the HPMCAS solution. Furthermore, Patent Document 2 describes that the viscosity of an HPMCAS solution can be adjusted by producing HPMCAS in a kneader reactor equipped with multiple stirring blades that revolve while rotating on their own axes. However, this requires the use of a reactor equipped with a specific stirring mechanism, and therefore existing reactors cannot be used as is. Thus, there is a need for a method for producing HPMCAS with high productivity without changing the reactor, while suppressing the increase in molecular weight that accompanies the reduction of aliphatic carboxylic acid. 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 HPMCAS with high productivity, even when the amount of aliphatic carboxylic acid used is reduced, and which has the same molecular weight as before the reduction of the amount of aliphatic carboxylic acid. [Means for solving the problem]

[0006] As a result of extensive research conducted by the present inventors in order to achieve the above-mentioned object, they discovered that in the reaction step for producing HPMCAS, an esterification reaction of HPMC with an acetylating agent and a succinoylating agent is carried out in the presence of an aliphatic carboxylic acid and a polyhydric alcohol, thereby enabling the synthesis of HPMCAS to be carried out using a reduced amount of aliphatic carboxylic acid without increasing the molecular weight of HPMCAS, thereby improving production efficiency per batch, and thereby completing the present invention.

[0007] In one embodiment of the present invention, there is provided a method for producing hydroxypropyl methylcellulose acetate succinate, which includes at least an esterification reaction step of carrying out an esterification reaction between hydroxypropyl methylcellulose, an acetylating agent, and a succinoylating agent in the presence of an aliphatic carboxylic acid and a polyhydric alcohol to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate. The present invention also provides the following method for producing hydroxypropyl methylcellulose acetate succinate. [1] A method for producing hydroxypropyl methylcellulose acetate succinate includes at least an esterification reaction step in which hydroxypropyl methylcellulose is esterified with an acetylating agent and a succinoylating agent in the presence of an aliphatic carboxylic acid and a polyhydric alcohol to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate. [2] In addition to the esterification reaction step, there is further included a precipitation step of mixing the reaction solution with water to obtain a suspension in which hydroxypropyl methylcellulose acetate succinate is precipitated; and washing, dewatering, and drying the hydroxypropyl methylcellulose acetate succinate in the suspension. [3] The method for producing hydroxypropyl methylcellulose acetate succinate according to [1] or [2], wherein the mass ratio of the aliphatic carboxylic acid to the hydroxypropyl methylcellulose (aliphatic carboxylic acid / hydroxypropyl methylcellulose) is 1.1 to 1.5. [4] The method for producing hydroxypropyl methylcellulose acetate succinate according to any one of [1] to [3], wherein the polyhydric alcohol is at least one of sugar alcohol, glycerin, and alkylene glycol. [Effects of the Invention]

[0008] According to the present invention, even if the amount of aliphatic carboxylic acid used in the production of HPMCAS is reduced, the amount of HPMC charged to the reactor can be increased without increasing the molecular weight of the HPMCAS. This makes it possible to produce HPMCAS with a molecular weight equivalent to that of conventional methods with good productivity without increasing the size or modifying the reactor. Furthermore, no polyhydric alcohol or esterified polyhydric alcohol remains in the HPMCAS. [Brief explanation of the drawings]

[0009] [Figure 1] 1 shows the results of gas chromatographic analysis of the ethanol extracts of HPMCAS from Examples 1, 2, 3, 5, and 6 and the Comparative Example, as well as glycerin, triacetin, propylene glycol, propylene glycol diacetate, and acetic acid for comparison. [Figure 2] 1 shows the results of gas chromatographic analysis of the acid hydrolysis solutions of HPMCAS of Examples 1, 2, 3, 5, and 6 and the Comparative Example, as well as glycerin, triacetin, propylene glycol, propylene glycol diacetate, and acetic acid for comparison. [Figure 3] 1 shows the results of gas chromatographic analysis of alkaline hydrolysis solutions of HPMCAS from Examples 1, 2, 3, 5, and 6 and the Comparative Example, as well as glycerin, triacetin, propylene glycol, propylene glycol diacetate, and acetic acid for comparison. [Figure 4]Figure 1 shows the results of high-performance liquid chromatographic analysis of the ethanol extract, acid hydrolysis solution, and alkaline hydrolysis solution of HPMCAS from Example 4, as well as sorbitol, ethanol (extraction solvent), acetic acid, succinic acid, and sodium chloride (produced in the neutralization step after hydrolysis) for comparison. DETAILED DESCRIPTION OF THE INVENTION

[0010] First, an esterification reaction step will be described in which a reaction solution containing HPMCCAS is obtained by carrying out an esterification reaction between HPMC, an acetylating agent, and a succinoylating agent in the presence of an aliphatic carboxylic acid and a polyhydric alcohol.

[0011] HPMC is a nonionic water-soluble cellulose ether. From the viewpoint of obtaining HPMC having a small number of insoluble fibers, the degree of substitution (DS) of methoxy groups in HPMC is preferably 0.73 to 2.83, more preferably 1.25 to 2.37, and even more preferably 1.60 to 2.00. From the viewpoint of obtaining HPMC having a small number of insoluble fibers, the molar substitution number (MS) of hydroxypropoxy groups is preferably 0.10 to 1.90, more preferably 0.12 to 0.95, and even more preferably 0.15 to 0.65. Insoluble fiber refers to the portion of HPMC that does not dissolve in water. As described below, HPMC exhibits water solubility by partially etherifying the hydroxyl groups of cellulose, weakening the intramolecular and intermolecular hydrogen bonds. Because completely uniform etherification is difficult to achieve industrially, HPMC contains portions that are insoluble in water due to insufficient or uneven ether group substitution, i.e., insoluble fiber. If 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 low 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 degree of substitution of methoxy groups (DS) refers to the degree of substitution and refers to the average number of methoxy groups per unit of anhydroglucose. The molar substitution number of hydroxypropoxy groups (MS) refers to the average number of moles of hydroxypropoxy groups per mole of anhydroglucose. The degree of substitution of methoxy groups (DS) and the molar substitution number of hydroxypropoxy groups (MS) in HPMC can be determined by measuring the methoxy group content and the hydroxypropoxy group content according to the method described in the section on "hypromellose" in the 18th Edition of the Japanese Pharmacopoeia, and converting the results.

[0012] The viscosity of a 2% by mass aqueous solution of HPMC at 20° C. is preferably 1.5 to 30.0 mPa·s, more preferably 2.0 to 20.0 mPa·s, and even more preferably 2.5 to 15.0 mPa·s, from the viewpoint of kneading properties in the esterification step. The viscosity of a 2% by mass aqueous solution of HPMC at 20°C can be measured in accordance with the capillary viscometer method in the "Viscosity Measurement Method" described in the "General Test Methods" of the 18th Edition of the Japanese Pharmacopoeia. HPMC produced by a known method or commercially available HPMC may be used. HPMC can be obtained, for example, by contacting sheet-like, chip-like, or powdery pulp 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 or propylene oxide to cause a reaction.

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

[0014] After producing alkali cellulose, an etherifying agent such as methyl chloride or propylene oxide is added to carry out an etherification reaction in a conventional manner, and HPMC is obtained by optionally undergoing steps such as washing, dehydration, drying, pulverization, and depolymerization.

[0015] Examples of aliphatic carboxylic acids include aliphatic carboxylic acids having 2 to 4 carbon atoms, such as acetic acid, propionic acid, and butyric acid, with acetic acid being preferred from an economical standpoint.

[0016] The amount of aliphatic carboxylic acid used is determined based on the esterification reaction efficiency, the viscosity of the reaction solution, the amount of HPMC obtained, and the amount of the carboxylic acid used. AS From the viewpoint of molecular weight, the mass ratio of the aliphatic carboxylic acid to the mass of HPMC (mass of aliphatic carboxylic acid / mass of HPMC) is preferably 1.0 to 2.0 times, more preferably 1.1 to 1.8 times, and even more preferably 1.1 to 1.5 times. If the amount of aliphatic carboxylic acid is too large, the efficiency of the esterification reaction decreases, while if it is too small, the amount of polyhydric alcohol required to suppress the increase in molecular weight of HPMCAS becomes very large, which is undesirable from an economic standpoint. The effect of suppressing the increase in molecular weight by adding a polyhydric alcohol is particularly pronounced when the amount of aliphatic carboxylic acid used is small, such as in the above mass ratio of 1.1 to 1.5 times.

[0017] Examples of polyhydric alcohols include sugar alcohols such as sorbitol, and alkylene glycols such as glycerin and propylene glycol. From the viewpoints of safety and ease of removal of by-products, sorbitol, glycerin, and propylene glycol are preferred, glycerin and propylene glycol are more preferred, and glycerin is even more preferred. The amount of polyhydric alcohol used is preferably 0.01 to 0.30 mol, more preferably 0.02 to 0.26 mol, and even more preferably 0.03 to 0.22 mol per mol of HPMC, from the viewpoints of controlling the molecular weight of HPMCAS and esterification efficiency. From the viewpoint of suppressing an increase in the molecular weight of HPMCAS, it is preferable to add the polyhydric alcohol before the acetylating agent and the succinoylating agent.

[0018] Examples of the acetylating agent include acetic anhydride and acetyl chloride, with acetic anhydride being preferred from an economical point of view. The amount of the acetylating agent used is preferably 0.2 to 1.8 mol, more preferably 0.4 to 1.7 mol, and even more preferably 0.6 to 1.6 mol per mol of HPMC, from the viewpoint of the degree of substitution and yield of the resulting HPMCAS.

[0019] Examples of succinoylating agents include succinic anhydride and succinyl chloride, with succinic anhydride being preferred from an economical point of view. The amount of succinoylating agent used is preferably 0.1 to 1.0 mol, more preferably 0.1 to 0.8 mol, and even more preferably 0.3 to 0.5 mol per mol of HPMC, from the viewpoint of the degree of substitution and yield of the resulting HPMCAS.

[0020] The esterification reaction may be carried out in the presence of a catalyst. From an economical viewpoint, alkali metal carboxylates such as sodium acetate are preferred as the catalyst. The catalyst may be used alone or in combination of two or more types, as needed. Commercially available catalysts may also be used. The amount of the catalyst used is preferably 0.8 to 1.5 mol, more preferably 0.9 to 1.1 mol, per mol of HPMC, from the viewpoint of the degree of substitution and the yield.

[0021] For example, a reaction solution containing HPMCAS can be obtained by adding a polyhydric alcohol, an acetylating agent, a succinoylating agent, and, if necessary, a catalyst to a solution obtained by dissolving HPMC in an aliphatic carboxylic acid. The method for adding the acetylating agent and succinoylating agent is not particularly limited, but it is believed that when succinyl groups formed by the reaction of the succinoylating agent with HPMC further react with other HPMC, the molecules are crosslinked, increasing the molecular weight of HPMCAS. Therefore, from the viewpoint of preventing an excessive increase in molecular weight, it is preferable to add the succinoylating agent in two or more divided portions rather than adding the entire amount at the start of the reaction.

[0022] In the esterification reaction, a twin-shaft agitator suitable for uniformly mixing a highly viscous fluid can be used. Specifically, commercially available devices such as kneaders and internal mixers can be used. The reaction temperature in the esterification reaction step is preferably 60 to 100° C., more preferably 80 to 90° C., from the viewpoint of optimizing the reaction rate or the viscosity of the reaction solution. The reaction time in the esterification reaction step is preferably 2 to 8 hours, more preferably 3 to 6 hours, from the viewpoint of the yield or productivity.

[0023] After the esterification reaction, water can be added to the reaction mixture as needed to treat unreacted acetic anhydride and succinic anhydride and to adjust the viscosity of the reaction mixture. The amount of water added is preferably 0.8 to 1.5 times, more preferably 1.0 to 1.3 times, the mass of HPMC.

[0024] In the precipitation step, the reaction solution is mixed with water to obtain a suspension in which HPMCAS is precipitated. The amount of water to be mixed is preferably 3.3 to 8.5 times, and more preferably 3.8 to 6.5 times, the mass of the suspension, in terms of the degree of precipitation and treatment time. When water is added after the esterification reaction as described above, the amount of water to be mixed in the precipitation step is preferably 1.7 to 7.7 times, and more preferably 2.5 to 5.5 times, the mass of the suspension. The temperature of the water mixed in the precipitation step is preferably 5 to 40° C., more preferably 5 to 30° C. The temperature of the suspension immediately before being mixed with water in the precipitation step is preferably 10 to 40° C., more preferably 10 to 35° C., and even more preferably 15 to 30° C. In order to keep the temperature of the reaction liquid within the above range immediately before contact with water, cooling may be performed using a jacket on the reaction vessel.

[0025] The precipitated HPMCAS can be washed, deliquified, and dried as necessary. In the washing, deliquifying, and drying steps, the precipitate is thoroughly washed with water to remove free acetic acid, free succinic acid, and their metal salts, residual polyhydric alcohol, and esterified polyhydric alcohols. The precipitate is then deliquified by filtration using a sieve or the like, and dried at preferably 60 to 100°C, more preferably 70 to 80°C, for preferably 1 to 5 hours, more preferably 2 to 3 hours. This allows high-purity HPMCAS to be obtained.

[0026] Next, the physical properties of the obtained HPMCAS will be explained. <Degree of substitution and viscosity> The degree of substitution (DS) of methoxy groups in HPMCAS is preferably 0.73 to 2.83, more preferably 1.25 to 2.37, and even more preferably 1.60 to 2.00. The molar substitution number (MS) of hydroxypropyl groups is preferably 0.10 to 1.90, more preferably 0.12 to 0.95, and even more preferably 0.15 to 0.65. The degree of substitution (DS) of acetyl groups is preferably 0.09 to 2.30, more preferably 0.18 to 1.07, and even more preferably 0.20 to 0.80. The degree of substitution (DS) of succinyl groups is preferably 0.07 to 1.78, more preferably 0.08 to 0.62, and even more preferably 0.10 to 0.60. 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, respectively. 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 degrees of substitution (DS) of methoxy groups, acetyl groups, and succinyl groups and the number of moles of hydroxypropoxy groups (MS) in HPMCAS can be determined by measuring the contents of methoxy groups, acetyl groups, succinyl groups, and hydroxypropoxy groups according to the method described in the section on "Hypromellose acetate succinate" in the 18th Edition of the Japanese Pharmacopoeia, and converting the results obtained.

[0027] The viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C is preferably 1.0 to 10.0 mPa s, and more preferably 1.5 to 5.0 mPa s. The viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C can be measured by the method described in the section on "Hypromellose acetate succinate" in the 18th Edition of the Japanese Pharmacopoeia.

[0028] The viscosity of a 10% by mass acetone solution of HPMCAS at 20°C is preferably 150 mPa·s or less, more preferably 10 to 100 mPa·s, and even more preferably 10 to 80 mPa·s, from the viewpoint of increasing the HPMCAS concentration in a coating solution when HPMCAS is used as a coating base. The viscosity of a 10% by mass acetone solution of HPMCAS at 20°C can be determined by the capillary viscometer method described in the section "General Test Methods" of the 18th Edition of the Japanese Pharmacopoeia.

[0029] <Molecular weight (Mw, Mn) and polydispersity> The weight-average molecular weight (Mw), number-average molecular weight (Mn), and polydispersity (Mw / Mn) of HPMCAS can be determined by an absolute molecular weight measurement method that combines size exclusion chromatography (SEC), such as gel permeation chromatography (GPC), with multi-angle light scattering (MALS) (e.g., Journal of Pharmaceutical and Biomedical Analysis 56 (2011) 743-748).

[0030] When HPMCAS is used as a coating base, the Mw of HPMCAS is preferably 80,000 to 350,000 daltons, more preferably 80,000 to 300,000 daltons, and even more preferably 80,000 to 280,000 daltons, from the viewpoint of the balance between the concentration of HPMCAS in the enteric coating solution and the viscosity of the coating solution.

[0031] When HPMCAS is used as a coating base, the Mn of HPMCAS is preferably 20,000 to 50,000 daltons, more preferably 22,000 to 48,000 daltons, and even more preferably 25,000 to 45,000 daltons, from the viewpoint of the balance between the concentration of HPMCAS in the enteric coating solution and the viscosity of the coating solution.

[0032] The polydispersity (Mw / Mn) of HPMCAS is preferably 3.8 to 8.0, more preferably 3.8 to 7.0, and even more preferably 3.8 to 6.0.

[0033] The absence of impurities derived from polyhydric alcohols in the HPMCAS obtained by the method of the present invention can be confirmed by analyzing HPMCAS that has been pretreated by an appropriate method using gas chromatography, high-performance liquid chromatography, or the like. The polyhydric alcohol-derived impurities mainly include residual polyhydric alcohols and esterified polyhydric alcohols. The presence or absence of the residual polyhydric alcohols and esterified polyhydric alcohols can be confirmed, for example, by dispersing HPMCAS in a solvent in which the polyhydric alcohols and esterified polyhydric alcohols are soluble, for example, a monohydric alcohol such as water or ethanol, performing an extraction operation, and then analyzing the solvent to determine whether the polyhydric alcohols and esterified polyhydric alcohols are present by gas chromatography, high-performance liquid chromatography, or the like. The absence of polyhydric alcohol binding to HPMCAS can be confirmed by hydrolyzing HPMCAS in an acidic or basic aqueous solution, followed by analyzing the hydrolyzed solution by gas chromatography, high-performance liquid chromatography, or the like. [Example]

[0034] EXAMPLES The present invention will be explained in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0035] Example 1 A 5 L horizontal kneader reactor (PNV-5T model, manufactured by Irie Shokai Co., Ltd.) equipped with a biaxial impeller (PNV-5T Z-type impeller, made of SUS316L, manufactured by Irie Shokai Co., Ltd.) was charged with 910 g of glacial acetic acid. 700 g of HPMC (HPMC) with a methoxy group DS of 1.87, a hydroxypropoxy group MS of 0.24, and a viscosity of 3.4 mPa s as a 2% by mass aqueous solution at 20°C), 30.2 g of glycerin, 400 g of acetic anhydride, 68 g of succinic anhydride, and 306 g of sodium acetate were added, and the mixture was stirred at 85°C with the impeller rotating at 43 rpm for 1 hour. After stirring for an additional 4 hours, 68 g of succinic anhydride was added, and the mixture was subjected to an esterification reaction. Water was added to the resulting HPMCAS-containing reaction solution to terminate the reaction, and then 20°C water was gradually added in an amount 5.0 times the mass of the reaction solution to obtain a suspension containing precipitated HPMCAS. The precipitated HPMCAS was filtered through an 80-mesh sieve to obtain crude HPMCAS. The resulting crude HPMCAS was resuspended in 30°C water in an amount 20 times the mass of the raw HPMC, stirred for 10 minutes, and then filtered through an 80-mesh sieve. This procedure was repeated eight times to obtain washed HPMCAS. Finally, the mixture was dried at 80°C for 3 hours to obtain HPMCAS. The reaction conditions for the esterification reaction step are shown in Table 1.

[0036] To assess the usefulness of the HPMCAS for enteric coating, the viscosity of the resulting 10% by weight acetone solution at 20°C was measured. 198.0 g of acetone was placed in a glass bottle and stirred at 200 rpm for 5 minutes using a stirring blade. 22.0 g of HPMCAS was added, and the mixture was stirred at the same speed for an additional 60 minutes, after which the stirring was stopped. The viscosity of the resulting 10% by weight acetone solution at 20°C was measured using an Ubbelohde viscometer in accordance with the capillary viscometer method described in the "General Test Methods" section of the 18th Edition of the Japanese Pharmacopoeia. Table 2 shows the degree of substitution of HPMCAS, the viscosity at 20°C of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS, and the viscosity at 20°C of an acetone solution containing 10% by mass of HPMCAS.

[0037] <Molecular weight measurement method> An aqueous buffer solution was prepared by adding 7.20 g of anhydrous sodium dihydrogen phosphate (Kanto Chemical, special grade) and 10.2 g of sodium nitrate (Fujifilm Wako Pure Chemical Industries, special grade) to 1.2 L of purified water and stirring at room temperature until completely dissolved. 1.2 L of the aqueous buffer solution was mixed with 800 mL of acetonitrile (Kanto Chemical, high-performance liquid chromatography grade). After stirring at room temperature for 3 hours, the pH was adjusted to 8.0 with 10 M NaOH (Sigma-Aldrich). The mobile phase was then filtered through a 0.45 μm pore size hydrophilic PTFE (polytetrafluoroethylene) filter. HPMCAS was weighed into a glass vial, and an amount of mobile phase corresponding to the mass of HPMCAS was added. The mixture was stirred at room temperature for 3 hours using a magnetic stirrer to prepare a 2 mg / mL HPMCAS solution. The prepared HPMCAS solution was passed through a hydrophilic PTFE syringe filter with a pore size of 0.45 μm before use.

[0038] The GPC measurement equipment used was a Prominence HPLC system (Shimadzu Corporation), a DAWN NEON 18-angle laser light scattering detector (Wyatt Technology), and an OPTILABrex NEON differential refractive index detector (Wyatt Technology). The analytical column was TSK-GEL (registered trademark) GMPW. XL A 300 x 7.8 mm column (Tosoh Corporation) was used, and the analytical column was operated at 25 ± 2°C, the refractive index detector at 25°C, and the mobile phase flow rate was 0.5 mL / min. HPMCAS measurements were performed after instrument calibration using a 5 mg / mL solution of polyethylene oxide 20K (Agilent Technologies) as the standard substance. The measured data was analyzed using Wyatt Astra6 software (Wyatt Technology, version 7.3.2.19) under the condition of dn / dc = 0.120 mL / g for HPMCAS, and the molecular weight (Mw, Mn) and polydispersity (Mw / Mn) of HPMCAS were determined. The measurement results are shown in Table 2.

[0039] <Impurity analysis> 1.0 g of HPMCAS was weighed into a glass vial and 10.0 g of ethanol was added. The mixture was stirred at room temperature for 6 hours using a magnetic stirrer to extract ethanol-soluble impurities. The HPMCAS ethanol dispersion was centrifuged at 3000 rpm for 5 minutes to separate the solid and liquid, and the supernatant was filtered through a hydrophilic PTFE syringe filter with a pore size of 0.45 μm to prepare an ethanol extract of HPMCAS.

[0040] 1.0 g of HPMCAS was weighed into a glass vial and 20.0 g of 5% by weight hydrochloric acid was added. The mixture was stirred using a magnetic stirrer at 60°C for 4 hours to perform acid hydrolysis of the HPMCAS. The solution was cooled to room temperature and then neutralized with 1 mol / L aqueous sodium hydroxide until the pH reached approximately 5.0. The neutralized dispersion was centrifuged at 3,000 rpm for 5 minutes, and the supernatant was filtered through a hydrophilic PTFE syringe filter with a pore size of 0.45 μm to prepare an acid hydrolysis solution of HPMCAS.

[0041] 1.0 g of HPMCAS was weighed into a glass vial and 20.0 g of 1 mol / L aqueous sodium hydroxide solution was added. The mixture was stirred using a magnetic stirrer at 60°C for 4 hours to perform alkaline hydrolysis of the HPMCAS. The solution after alkaline hydrolysis was cooled to room temperature and then neutralized with 5% by mass hydrochloric acid until the pH reached approximately 7.0. The neutralized solution was centrifuged at 3,000 rpm for 5 minutes, and the supernatant was filtered through a hydrophilic PTFE syringe filter with a pore size of 0.45 μm to prepare an alkaline hydrolysis solution of HPMCAS.

[0042] Impurity analysis was performed using a gas chromatograph GC-2010 (Shimadzu Corporation) and a DB-WAX analytical column (column length 30 m, column inner diameter 0.25 mm, capillary thickness 0.25 μm, Agilent Technologies). Helium was used as the carrier gas, and the carrier gas was flowed at a constant flow rate of 35 cm / s. The sample injection volume was 1 μL, the sample inlet temperature was set to 250 °C, and the sample was introduced into the column with a split ratio of 20:1. The column oven was held at 100 °C for 1 min, then heated to 250 °C at a rate of 10 °C / min, and then held at 250 °C for 4 min. The sample passing through the analytical column was detected using a flame ionization detector (FID) set at 250 °C.

[0043] The ethanol extract, acid hydrolysis solution, and alkaline hydrolysis solution of HPMCAS were each analyzed by gas chromatography. The results of the gas chromatography analysis of the ethanol extract, acid hydrolysis solution, and alkaline hydrolysis solution of HPMCAS are shown in Figures 1 to 3, along with the results of the gas chromatography analysis of glycerin, a comparative polyhydric alcohol, triacetin, an esterified product of polyhydric alcohol, and acetic acid produced by hydrolysis of the acetyl group. In the gas chromatograms of Example 1 in Figures 1 to 3, no peaks for glycerin or esterified products of glycerin such as triacetin were detected, confirming that the polyhydric alcohol and esterified products of polyhydric alcohol were removed by the washing procedure and that no polyhydric alcohol was bound to HPMCAS. As a result of the impurity analysis by gas chromatography, if no peaks of polyhydric alcohols or esterified products of polyhydric alcohols were confirmed, it was evaluated as "not detected," and if the respective peaks were confirmed, it was evaluated as "detected." The evaluation results are shown in Table 3 as the results of the impurity analysis.

[0044] Example 2 HPMCAS was obtained by the same procedure as in Example 1, except that the amounts of glacial acetic acid, glycerin, acetic anhydride, and succinic anhydride added at one time were changed to 770 g, 45.3 g, 423 g, and 69 g, respectively, during the synthesis of HPMCAS. Table 1 shows the reaction conditions for the esterification reaction step. Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity at 20°C of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS, and the viscosity and molecular weight at 20°C of an acetone solution containing 10% by mass of HPMCAS. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3, along with the gas chromatography analysis results of glycerin, a comparative polyhydric alcohol, triacetin, an esterified product of a polyhydric alcohol, and acetic acid produced by hydrolysis of the acetyl group.

[0045] Example 3 HPMCAS was obtained by the same procedure as in Example 1, except that the polyhydric alcohol used in synthesizing HPMCAS was changed to propylene glycol and the amount added was increased to 37.8 g. Table 1 shows the reaction conditions for the esterification reaction step. Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity at 20°C of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS, and the viscosity and molecular weight measurement results at 20°C of an acetone solution containing 10% by mass of HPMCAS. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3, along with the gas chromatography analysis results of propylene glycol (a comparative polyhydric alcohol), propylene glycol diacetate (an ester of the polyhydric alcohol), and acetic acid produced by hydrolysis of the acetyl group.

[0046] Example 4 HPMCAS was obtained by the same procedure as in Example 1, except that the polyhydric alcohol used in synthesizing HPMCAS was changed to sorbitol. Table 1 shows the reaction conditions in the esterification reaction step, and Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C, and the viscosity and molecular weight of an acetone solution containing 10% by mass of HPMCAS at 20°C.

[0047] Because sorbitol has a high boiling point and is difficult to analyze by gas chromatography, high performance liquid chromatography was used for the analysis of impurities in Example 4. The liquid delivery unit was a Prominence HPLC system (manufactured by Shimadzu Corporation), and the analytical column was a Rezex RCM-Monosaccharin Ca. +2 A 300 x 7.8 mm (8%) column (Phenomenex) was used, and a RID-10A (Shimadzu) refractive index detector was used. The analytical column was set at 85 ± 2°C, the refractive index detector at 40°C, and the mobile phase flow rate was 0.5 mL / min. Distilled water was used as the mobile phase.

[0048] The ethanol extract, acid hydrolysis solution, and alkaline hydrolysis solution of HPMCAS were each analyzed by high-performance liquid chromatography. Figure 4 shows the high-performance liquid chromatography results for the ethanol extract, acid hydrolysis solution, and alkaline hydrolysis solution of HPMCAS, along with the results for the comparative polyhydric alcohol sorbitol, the extraction solvent ethanol, acetic acid produced by hydrolysis of acetyl groups, succinic acid produced by hydrolysis of succinyl groups, and sodium chloride produced by the neutralization step after hydrolysis. (Because water-soluble sorbitol esters were not commercially available, chromatograms of the polyhydric alcohol esters are not shown.) The high-performance liquid chromatogram for Example 4 in Figure 4 did not detect a sorbitol peak, confirming that the polyhydric alcohol and its esters were removed by the washing step and that no polyhydric alcohols were bound to HPMCAS. As a result of the impurity analysis by high performance liquid chromatography, if no polyhydric alcohol peak was confirmed, it was evaluated as "not detected," and if the same peak was confirmed, it was evaluated as "detected." The evaluation results are shown in Table 3 as the results of the impurity analysis.

[0049] Example 5 HPMCAS was obtained by the same procedure as in Example 1, except that the amount of acetic anhydride used in synthesizing HPMCAS was 560 g and the amount of succinic anhydride added at one time was 48 g. Table 1 shows the reaction conditions for the esterification reaction step. Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity at 20°C of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS, and the viscosity at 20°C and molecular weight measurement results of an acetone solution containing 10% by mass of HPMCAS. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3, along with the gas chromatography analysis results of glycerin, a comparative polyhydric alcohol, triacetin, an esterified product of a polyhydric alcohol, and acetic acid produced by hydrolysis of the acetyl group.

[0050] Example 6 HPMCAS was obtained by the same procedure as in Example 1, except that the amount of acetic anhydride used in synthesizing HPMCAS was 410 g and the amount of succinic anhydride added at one time was 114 g. Table 1 shows the reaction conditions for the esterification reaction step. Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity at 20°C of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS, and the viscosity and molecular weight measurement results at 20°C of an acetone solution containing 10% by mass of HPMCAS. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3, along with the gas chromatography analysis results of glycerin, a comparative polyhydric alcohol, triacetin, an esterified product of a polyhydric alcohol, and acetic acid produced by hydrolysis of the acetyl group.

[0051] Comparative Example 1 HPMCAS was obtained by the same procedure as in Example 1, except that the amounts of glacial acetic acid, acetic anhydride, and succinic anhydride added per addition were 1,120 g, 354 g, and 62 g, respectively, and no glycerin was added during the synthesis of HPMCAS. Table 1 shows the reaction conditions in the esterification reaction step, while Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C, and the viscosity and molecular weight of an acetone solution containing 10% by mass of HPMCAS at 20°C. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3.

[0052] Comparative Example 2 HPMCAS was obtained by the same procedure as in Example 1, except that the amount of glacial acetic acid used in synthesizing HPMCAS was 910 g and glycerin was not added. Table 1 shows the reaction conditions in the esterification reaction step, Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of HPMCAS at 20°C, and the viscosity and molecular weight of an acetone solution containing 10% by mass of HPMCAS at 20°C, and the results of the impurity analysis are shown in Figures 1 to 3 and Table 3.

[0053] Comparative Example 3 HPMCAS was obtained by the same procedure as in Comparative Example 1, except that the amount of acetic anhydride used in synthesizing HPMCAS was 508 g and the amount of succinic anhydride added at one time was 41 g. Table 1 shows the reaction conditions in the esterification reaction step, while Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity of a 0.43 mass% aqueous sodium hydroxide solution containing 2 mass% HPMCAS at 20°C, and the viscosity and molecular weight of an acetone solution containing 10 mass% HPMCAS at 20°C. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3.

[0054] Comparative Example 4 HPMCAS was obtained by the same procedure as in Comparative Example 1, except that the amount of acetic anhydride used in synthesizing HPMCAS was 373 g and the amount of succinic anhydride added at one time was 97 g. Table 1 shows the reaction conditions in the esterification reaction step, while Table 2 shows the degree of substitution of the obtained HPMCAS, the viscosity of a 0.43 mass% aqueous sodium hydroxide solution containing 2 mass% HPMCAS at 20°C, and the viscosity and molecular weight of an acetone solution containing 10 mass% HPMCAS at 20°C. The results of the impurity analysis are shown in Figures 1 to 3 and Table 3.

[0055] [Table 1]

[0056] [Table 2]

[0057] [Table 3]

[0058] As shown in Examples 1 and 2, when HPMCAS was synthesized with the addition of glycerin, even though the amount of aliphatic carboxylic acid (glacial acetic acid) used was reduced compared to Comparative Example 1, HPMCAS was obtained with a degree of substitution, a viscosity at 20°C of a 0.43% by weight sodium hydroxide solution containing 2% by weight HPMCAS, a molecular weight, and a viscosity at 20°C of an acetone solution containing 10% by weight HPMCAS, similar to those of the HPMCAS obtained in Comparative Example 1. Furthermore, since the various viscosities were similar, it was confirmed that the handleability of the HPMCAS solution in the enteric coating operation was also comparable. Furthermore, by reducing the amount of aliphatic carboxylic acid used in this way, the amount of HPMC charged per batch could be increased, which is thought to lead to improved production efficiency. As shown in Examples 3 and 4, it was found that when HPMCAS was synthesized with the addition of propylene glycol or sorbitol, the same effect as when glycerin was added was obtained, regardless of the type of polyhydric alcohol. The results of Example 1 and Comparative Example 1, Example 5 and Comparative Example 3, and Example 6 and Comparative Example 4 confirmed that, regardless of the degree of substitution of HPMCAS, by synthesizing HPMCAS in the coexistence of a polyhydric alcohol, even when the amount of aliphatic carboxylic acid used is reduced, HPMCAS can be produced that exhibits physical properties equivalent to those before the amount of aliphatic carboxylic acid is reduced.

[0059] As shown in Comparative Example 2, when the amount of aliphatic carboxylic acid (glacial acetic acid) used was reduced without adding a polyhydric alcohol, the molecular weight and the viscosity of an acetone solution containing 10% by mass of HPMCAS at 20°C became significantly higher, and it was confirmed that the handleability of the HPMCAS solution during enteric coating operations was reduced. This confirmed that by synthesizing HPMCAS in the presence of a polyhydric alcohol, it is possible to efficiently produce HPMCAS that exhibits physical properties equivalent to those obtained before the amount of aliphatic carboxylic acid was reduced, even when the amount of aliphatic carboxylic acid used was reduced.

Claims

1. The method includes at least an esterification reaction step of esterifying hydroxypropyl methylcellulose with an acetylating agent and a succinoylating agent in the presence of an aliphatic carboxylic acid and a polyhydric alcohol to obtain a reaction solution containing hydroxypropyl methylcellulose acetate succinate, the polyhydric alcohol is at least one of a sugar alcohol, glycerin, and an alkylene glycol; the esterification reaction is an esterification reaction in the presence of a catalyst, and the catalyst is sodium acetate; Method for producing hydroxypropyl methylcellulose acetate succinate.

2. In addition to the esterification reaction step, there is further included a precipitation step of mixing the reaction solution with water to obtain a suspension in which hydroxypropyl methylcellulose acetate succinate is precipitated; 2. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, further comprising at least the steps of washing, dewatering and drying the hydroxypropyl methylcellulose acetate succinate in the suspension.

3. The method for producing hydroxypropyl methylcellulose acetate succinate according to claim 1, wherein the mass ratio of the aliphatic carboxylic acid to the hydroxypropyl methylcellulose (aliphatic carboxylic acid / hydroxypropyl methylcellulose) is 1.1 to 1.5.

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