WO2017140074A1 - Nouvelle forme cristalline et formulation de chlorhydrate de cefménoxime - Google Patents

Nouvelle forme cristalline et formulation de chlorhydrate de cefménoxime Download PDF

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Publication number
WO2017140074A1
WO2017140074A1 PCT/CN2016/085307 CN2016085307W WO2017140074A1 WO 2017140074 A1 WO2017140074 A1 WO 2017140074A1 CN 2016085307 W CN2016085307 W CN 2016085307W WO 2017140074 A1 WO2017140074 A1 WO 2017140074A1
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WIPO (PCT)
Prior art keywords
cefmenoxime hydrochloride
crystalline form
cefmenoxime
hydrochloride
hydrochloric acid
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PCT/CN2016/085307
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English (en)
Chinese (zh)
Inventor
陶灵刚
王静康
尹秋响
郝红勋
Original Assignee
海南灵康制药有限公司
天津大学
陶灵刚
王静康
尹秋响
郝红勋
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Application filed by 海南灵康制药有限公司, 天津大学, 陶灵刚, 王静康, 尹秋响, 郝红勋 filed Critical 海南灵康制药有限公司
Publication of WO2017140074A1 publication Critical patent/WO2017140074A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medical technology, and particularly relates to a novel crystalline form compound and preparation of cefmenoxime hydrochloride using molecular assembly and morphology optimization technology of particle process crystal products.
  • Cefmenoxime hydrochloride its chemical name is: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-[[ 1-methyl-1H-tetrazol-5-yl)-sulfo]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-A Acid hydrochloride (2:1), molecular formula: C 16 H 17 N 9 O 5 S 3 ⁇ 1/2HC1, molecular weight: 529.79, structural formula:
  • Cefmenoxime Hydrochloride is a third-generation cephalosporin developed by Takeda, Japan. It was first introduced in Japan in 1983 and is a broad-spectrum antibiotic that achieves bactericidal action by inhibiting the biosynthesis of bacterial cell walls.
  • cefmenoxime hydrochloride prepared by the above method on the market has poor purity, poor color grade and poor stability, thereby affecting the quality of the preparation.
  • the conventional crystal form of cefmenoxime hydrochloride has poor stability and is unstable to heat, acid environment and alkaline environment. It is characterized by easy discoloration, reduced content and degradation products. To solve this problem, it is necessary to develop a new crystallization production technology to optimize process parameters such as solvent, temperature, reaction time, additives, etc., so that crystallization can be carried out under suitable conditions to ensure product quality.
  • the invention mainly aims at the above problems of cefmenoxime hydrochloride, and on the basis of sufficient investigation of factors such as solvent, temperature, external force and additives in the crystal formation process, the molecular assembly and morphology optimization technology of the particle process crystal product obtains a high purity. , good color grade, good fluidity, good stability, cefmenoxime hydrochloride
  • the new crystal form compound, the synthesis step is more focused on the control of the reagents and parameters in the synthesis process than the previous preparation process, the steps are simple, the raw materials used are all cheap, non-toxic or low-toxic products, and are suitable for industrial scale production.
  • Formulations made using the compounds described in the present invention have better stability than previous formulations.
  • a first object of the present invention is to provide a novel crystalline form of cefmenoxime hydrochloride, which is prepared by molecular assembly and morphology optimization technology of a particle process crystal product, and has the characteristics of high purity, good color grade and good stability.
  • the new crystalline form of cefmenoxime hydrochloride according to the present invention is determined by X-ray powder diffraction, and the X-ray powder diffraction pattern represented by the 2 ⁇ diffraction angle is 6.25° ⁇ 0.2°, 13.04° ⁇ 0.2°, 14.31° ⁇ 0.2°, 17.21° ⁇ 0.2°, 18.18° ⁇ 0.2°, 19.95° ⁇ 0.2°, 22.77° ⁇ 0.2°, 23.76° ⁇ 0.2°, 25.88° ⁇ 0.2°, 29.19° ⁇ 0.2°, showing characteristic diffraction peaks, as shown in the attached drawing 1 is shown.
  • the preparation of the new crystalline form of cefmenoxime hydrochloride according to the present invention comprises the following steps:
  • the weight ratio of the 7-ATCA ⁇ HCl to the AE active ester is 1:1 to 1:3. More preferably, the weight ratio is 1:2.
  • the hydrochloric acid concentration in the step (1) is 5-8 mol/L. More preferably, the hydrochloric acid concentration is 6 mol/L.
  • the hydrochloric acid adjusted pH in the step (1) is 1-3. More preferably, the pH is 2.5.
  • the alkali liquid described in the step (2) is an aqueous solution of 8 to 12% sodium hydrogencarbonate. More preferably, the lye is a 10% aqueous solution of sodium hydrogencarbonate.
  • the lye adjusted pH in the step (2) is 6-8. More preferably, the pH is 7.0.
  • the crystal growth time in the step (2) is 2 to 4 hours. More preferably, the crystal growth time is from 3 to 3.5 hours.
  • a second object of the present invention is to provide a cefmenoxime hydrochloride pharmaceutical composition comprising the novel crystalline form of cefmenoxime hydrochloride of the present invention, which is simple in operation and has better stability than the prior products. The side effects are small.
  • the cefmenoxime hydrochloride pharmaceutical composition of the present invention comprises, by weight fractions, the following components by weight: 40-80 parts of cefmenoxime hydrochloride (calcium cefprozil) and 20-60 parts of sodium hydrogencarbonate.
  • Fig. 1 X-ray powder diffraction pattern of a new crystalline form of cefmenoxime hydrochloride, and the 2 ⁇ values corresponding to the diffraction peak numbers in the figure are shown in Table 1.
  • X-ray powder diffraction was used to study and characterize the new crystalline form of cefmenoxime hydrochloride.
  • the X-ray powder diffraction pattern of the product of Example 1 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19. See Figure 1 of the specification for details.
  • the aqueous phase was combined, decolorized by activated carbon at room temperature, filtered, and the carbon layer was washed with ethanol, and the washings were combined.
  • the pH was adjusted to 2.0 with 8 mol/L hydrochloric acid, and the crystal was maintained for 3 hours.
  • the filtrate was washed with water and dried under vacuum at 40 ° C to obtain crude cefmenoxime hydrochloride.
  • the X-ray powder diffraction pattern of the product of Example 2 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.
  • the X-ray powder diffraction pattern of the product of Example 3 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.
  • cefmenoxime hydrochloride compound was prepared according to the procedure of Example 1, and the raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.
  • cefmenoxime hydrochloride compound was prepared according to the method described in CN 102675344 A.
  • the aqueous phase was combined and the aqueous phase was stripped with dichloromethane.
  • the aqueous phase was adjusted to pH 6-7 with acid, 0.5 g of activated carbon was added for 20 min, filtered, and the filter cake was washed with 70 ml of water.
  • 20 ml of acetone and 90 ml of 35% concentrated hydrochloric acid were added to the other reaction flask, and the filtrate was added dropwise to the mixture, and the temperature was controlled at 35 ° C to precipitate a white solid.
  • the crystals were crystallized at 25 ° C for 2 h, suction filtered, washed with 100 ml of water, washed with 120 ml of acetone, and dried by suction filtration to give 50 g.
  • the cefmenoxime hydrochloride compound was prepared in the same manner as in Comparative Example 1.
  • the raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.
  • the inventors conducted a purity test on the cefmenoxime hydrochloride compound prepared in Example 1 of the present invention and Comparative Example 1.
  • the conditions of investigation were temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%. After 6 months of storage, samples were taken at the end of 0, 1, 2, 3, and 6 months, respectively.
  • the indicators were traits, clarity, solution color, pH, content and related substances. See Table 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne un nouveau composé cristallin de chlorhydrate de cefménoxime et un procédé de préparation par cristallisation correspondant; ledit nouveau composé cristallin de chlorhydrate de cefménoxime est formé à l'aide d'un traitement particulaire pour l'assemblage moléculaire et l'optimisation morphologique d'un produit cristallin. Le présent composé présente des caractéristiques de pureté élevée, de bonne fluidité et de bonne stabilité. L'invention concerne également une formulation de chlorhydrate de cefménoxime utilisée pour une injection, fabriquée à l'aide du composé de chlorhydrate de cefménoxime décrit.
PCT/CN2016/085307 2016-02-18 2016-06-08 Nouvelle forme cristalline et formulation de chlorhydrate de cefménoxime WO2017140074A1 (fr)

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Application Number Priority Date Filing Date Title
CN201610089927.6A CN105566352A (zh) 2016-02-18 2016-02-18 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂
CN201610089927.6 2016-02-18

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CN114540454A (zh) * 2022-03-09 2022-05-27 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体

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CN105566352A (zh) * 2016-02-18 2016-05-11 海南灵康制药有限公司 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂
CN109134504A (zh) * 2017-06-16 2019-01-04 陈立平 一种1/2水盐酸头孢甲肟化合物及其药物组合物制剂
CN112661776A (zh) * 2020-12-29 2021-04-16 苏州盛达药业有限公司 一种盐酸头孢甲肟的制备方法

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Publication number Priority date Publication date Assignee Title
CN114540454A (zh) * 2022-03-09 2022-05-27 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体
CN114540454B (zh) * 2022-03-09 2023-10-17 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体

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