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EP-4650373-B1 - METHOD FOR PRODUCING HYDROXYPROPYL METHYLCELLULOSE ACETATE SUCCINATE

EP4650373B1EP 4650373 B1EP4650373 B1EP 4650373B1EP-4650373-B1

Inventors

  • INADA, Shinnosuke
  • MIKI, KENTARO
  • KITAGUCHI, Taishi
  • KITAMURA, AKIRA
  • NARIITA, Mitsuo

Dates

Publication Date
20260513
Application Date
20250516

Claims (6)

  1. A method for producing hydroxypropyl methylcellulose acetate succinate comprising: 1) a liquid removal step of a) allowing hydroxypropyl methylcellulose, an acetylating agent, and a succinoylating agent to react with each other in the presence of a catalyst to produce a reaction solution, b) mixing water with the reaction solution to obtain a suspension of hydroxypropyl methylcellulose acetate succinate, and c) removing liquid from the suspension of hydroxypropyl methylcellulose acetate succinate to obtain liquid-removed hydroxypropyl methylcellulose acetate succinate; 2) a first drying step of drying the liquid-removed hydroxypropyl methylcellulose acetate succinate using a fluid-bed dryer until it reaches a water content of 30% by mass while maintaining the product temperature at 28°C or lower to obtain first dried hydroxypropyl methylcellulose acetate succinate; and 3) a second drying step of further drying the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate.
  2. The method according to claim 1, wherein the hydroxypropyl methylcellulose acetate succinate in the first drying step 2) has a product temperature of 5 to 28°C.
  3. The method according to claim 1 or 2, wherein the first drying step 2) involves an inlet air temperature of 5 to 70°C.
  4. The method according to any one of claims 1 to 3, wherein a fluid-bed dryer is used as a dryer for use in the second drying step 3).
  5. The method according to any one of claims 1 to 4, wherein the liquid-removed hydroxypropyl methylcellulose acetate succinate immediately before being subjected to the first drying step 2) has a water content of 55 to 80% by mass.
  6. The method according to any one of claims 1 to 5, wherein the hydroxypropyl methylcellulose acetate succinate has a water content of 5% by mass or lower.

Description

BACKGROUND OF THE INVENTION Field of the invention The present invention relates to a method for producing hydroxypropyl methylcellulose acetate succinate. Background art Hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS") is widely known as an enteric polymer which is synthesized by introducing in total four types of substituent groups of which two types of substituents-methyl groups (-CH3) and hydroxypropyl groups (-CH2CH(OH)CH3)-are introduced into a cellulose backbone to form an ether structure and the other two types of substituents -acetyl groups (-COCH3) and succinyl groups (-COC2H4COOH)-are introduced into the cellulose backbone to form an ester structure. HPMCAS is widely used for the purposes of, for example, coating a tablet, controlling drug release, and preparing a solid dispersion for use together with a water-insoluble drug through hot melt extrusion or spray dry. Typically, when coating or a spray drying process is performed, HPMCAS, either alone or combined with a drug, needs to be first dissolved in a solvent. In this case, there is a problem that dissolution of HPMCAS takes a significantly long time, and therefore, there has been a long-standing demand for producing the HPMCAS with improved solubility. JP-A-2017-501239 proposes a method for enhancing the solubility of HPMCAS that includes a process of continually or intermittingly pouring an HPMCAS-containing reaction solution into water to produce particles. US 2023/340162, US 2020/031954, and US 2018/116968 disclose preparation methods for HPMCAS comprising drying in a fluid bed dryer. They are silent on drying while maintaining the product temperature at 28°C or lower. SUMMARY OF THE INVENTION However, the method described in JP-A-2017-501239 requires the addition of water in an amount of 12 to 20 times the total weight of the reaction medium into the reaction solution after the reaction before performing the precipitation step. This method produces a large amount of drainage leading to issues with production costs and environmental burden. Additionally, the method has room for improvement in the solubility of the HPMCAS particles obtained by this manufacturing method. The present invention has been made in view of these circumstances, and it is an object of the present invention to provide a method for producing hydroxypropyl methylcellulose acetate succinate by which particle density increment is suppressed and a method for producing hydroxypropyl methylcellulose acetate succinate by which the dissolution time is reduced. The inventors of the present invention diligently conducted studies to solve the aforementioned problems, and have found that a method having two drying steps including a first drying step of drying HPMCAS using a fluid-bed dryer until the water content is reduced to 30% by mass so that the product temperature does not exceed 28°C to obtain a first dried HPMCAS; and a second drying step of further drying the first dried HPMCAS to obtain HPMCAS can suppress increment in particle density after being dried without any careful management of the materials and manufacturing, and improves dissolution time for dissolving HPMCAS into a solvent, thus completing the invention. The present invention provides a method for producing hydroxypropyl methylcellulose acetate succinate as defined below. <1> A method for producing hydroxypropyl methylcellulose acetate succinate including: a liquid removal step of allowing hydroxypropyl methylcellulose, an acetylating agent, and a succinoylating agent to react with each other in the presence of a catalyst to produce a reaction solution,mixing water with the reaction solution to obtain a suspension of hydroxypropyl methylcellulose acetate succinate, andremoving liquid from the suspension of hydroxypropyl methylcellulose acetate succinate to obtain liquid-removed hydroxypropyl methylcellulose acetate succinate;a first drying step of drying the liquid-removed hydroxypropyl methylcellulose acetate succinate using a fluid-bed dryer until it reaches a water content of 30% by mass while maintaining the product temperature at 28°C or lower to obtain first dried hydroxypropyl methylcellulose acetate succinate; anda second drying step of further drying the first dried hydroxypropyl methylcellulose acetate succinate to obtain hydroxypropyl methylcellulose acetate succinate.<2> The method according to <1>, wherein the hydroxypropyl methylcellulose acetate succinate in the first drying step has a product temperature of 5 to 28°C.<3> The method according to <1> or <2>, wherein the first drying step involves an inlet air temperature of 5 to 70°C.<4> The method according to any one of <1> to <3>, wherein a fluid-bed dryer is used as a dryer for use in the second drying step.<5> The method according to one of <1> to <4>, wherein the liquid-removed hydroxypropyl methylcellulose acetate succinate immediately before being subjected to the first drying step has a water