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CN-116178363-B - Method for preparing beta-crystal form aztreonam

CN116178363BCN 116178363 BCN116178363 BCN 116178363BCN-116178363-B

Abstract

The application provides a method for preparing beta-crystal form aztreonam, which comprises the following steps of (1) dissolving alpha-crystal form aztreonam in absolute ethyl alcohol or a mixed solution of absolute ethyl alcohol and acetone, recrystallizing to obtain beta-crystal form aztreonam wet product, and (2) drying the beta-crystal form aztreonam wet product in drying equipment with the relative humidity kept between 70 and 100 percent at 40-70 ℃ for 2-10 hours under normal pressure or for 2-18 hours under vacuum to obtain beta-crystal form aztreonam with the ethanol content lower than 0.5 percent. According to the application, the humidity of the drying environment is controlled when the product is dried, and under the condition of keeping a certain moisture content of the aztreonam wet product, the ethanol can be effectively baked out, so that the ethanol content in the aztreonam product is reduced, the requirement that the ethanol content of ICH guide Q3C is not more than 0.5 weight percent is met, and the safety of clinical medication of aztreonam is greatly improved.

Inventors

  • ZOU XIN
  • WANG TINGSHENG
  • LI JIE
  • ZENG LINGTAO
  • YANG MINGTAO

Assignees

  • 广安凯特制药有限公司

Dates

Publication Date
20260512
Application Date
20230306

Claims (9)

  1. 1. A process for preparing aztreonam in the beta crystalline form, comprising the steps of: (1) Dissolving alpha crystal form aztreonam in absolute ethyl alcohol or mixed solution of absolute ethyl alcohol and acetone, recrystallizing to obtain beta crystal form aztreonam wet product, and (2) Drying the beta-crystal form aztreonam wet product in a drying device with the relative humidity kept between 70 and 100 percent at 40 to 70 ℃ for 2 to 10 hours under normal pressure, or Drying the beta-crystal form aztreonam wet product in a rotary vacuum drier for 1-3 hours in a rotary vacuum way at 40-70 ℃, then keeping the relative humidity of the drier to be 80% -100% for 30 minutes-1 hour through humidification under normal pressure, stopping humidification, then drying in the rotary vacuum way for 1-3 hours, repeating the process for 3-5 times, and finally drying in the rotary vacuum way for 1-3 hours, Beta-crystal aztreonam with ethanol content lower than 0.5 wt% is obtained, In the step (1), alpha-crystal form aztreonam is dissolved in absolute ethyl alcohol at the temperature of 1-10 ℃ or a mixed solution of absolute ethyl alcohol and acetone, stirred for 1-3 hours, then heated to 30-35 ℃ for crystallization for 2-3 hours, and filtered to obtain beta-crystal form aztreonam wet product.
  2. 2. The method of claim 1, wherein in step (2), the relative humidity in the drying apparatus is controlled by ultrasonic humidification or by shallow water pan humidification.
  3. 3. The method of claim 1, wherein in step (2), the drying apparatus is a rotary vacuum dryer or an atmospheric drying oven.
  4. 4. The method according to claim 1, wherein in step (2), the atmospheric drying temperature is 50 ℃ to 70 ℃.
  5. 5. The method of claim 4, wherein the atmospheric drying temperature is 60 ℃ to 70 ℃.
  6. 6. The method according to claim 1, wherein in step (2), the vacuum drying temperature is 40 ℃ to 70 ℃.
  7. 7. The method of claim 6, wherein the vacuum drying temperature is 40-50 ℃.
  8. 8. The method according to any one of claims 1 to 7, wherein in step (1), in the case of using a mixed solution of absolute ethanol and acetone, the volume ratio of absolute ethanol and acetone is 5:1 to 2:1.
  9. 9. The method of claim 8, wherein the volume ratio of the anhydrous ethanol to the acetone is 3:1 to 2:1.

Description

Method for preparing beta-crystal form aztreonam Technical Field The invention relates to the field of pharmaceutical chemicals, and in particular relates to a method for preparing beta-crystal form aztreonam with low ethanol content. Background Aztreonam (Aztreonam) is an artificially synthesized monocyclic beta-lactam antibiotic with antibacterial activity against gram-negative bacteria. Molecular formula C 13H17N5O8S2 molecular weight 435.43 Some references report the preparation of aztreonam, for example, U.S. Pat. Nos. 4,775,670 and 5,194,606. Aztreonam is polymorphic and US4,826,973 reports four different crystals of aztreonam, namely alpha, beta, gamma and delta. The alpha crystal form is an aqueous crystal, usually containing 7-15% water, and has poor stability. Therefore, the beta-form is converted into the beta-form, and the beta-form has the characteristics of no water, no moisture absorption, good fluidity, smaller surface area, better stability and the like, and is more suitable for medicines. However, the beta crystalline form typically contains about 2.5% ethanol, exceeding 0.5% by weight required by the ICH guidelines standard. U.S. Pat. No. 4,946,838 reports a process for the preparation of aztreonam in the beta form by adding crystals of the alpha form to absolute ethanol at 55-60 ℃ for crystallization, under which conditions the alpha form may be temporarily dissolved in ethanol and then crystallized to form aztreonam in the beta form. The ethanol content of the resulting beta crystalline form is typically about 2.5%, far exceeding the requirements of the ICH guidelines of not more than 0.5% by weight. U.S. patent US7,452,991B2 reports a preparation method of beta-crystalline aztreonam with low ethanol content, namely, crystallization is carried out under the condition of rapid stirring (rotating speed of 500-700 rmp) at the low temperature of-60-5 ℃ to obtain beta-crystalline aztreonam with ethanol content lower than 2.5%, and the method has low reaction temperature and too high rotating speed, cannot meet the requirement in production, and therefore cannot be used for large-scale industrial production. CN101195618a discloses a process for the production of crystalline beta form anhydrous aztreonam by crystallizing the filtered solution at a lower temperature, i.e. by lowering the crystallization temperature, to achieve a reduction of the ethanol content in the product crystalline beta form aztreonam. Disclosure of Invention The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the application. The application provides a method for preparing beta-crystal form aztreonam. According to the application, the humidity of the drying environment is controlled when the beta-crystal form aztreonam wet product is dried, so that the beta-crystal form aztreonam wet product keeps certain moisture content, and ethanol can be effectively baked out, so that the ethanol content in the beta-crystal form aztreonam product is reduced, and the requirement that the ethanol content of the ICH guide Q3C is not more than 0.5 weight percent is met. Thus, the present application enables large-scale industrial production of beta-crystalline aztreonam having an ethanol content of less than 0.5 wt%. The application provides a method for preparing beta-crystal form aztreonam, which comprises the following steps: (1) Dissolving alpha crystal form aztreonam in absolute ethyl alcohol or mixed solution of absolute ethyl alcohol and acetone, recrystallizing to obtain beta crystal form aztreonam wet product, and (2) Drying the beta-crystal form aztreonam wet product in drying equipment with the relative humidity kept between 70 and 100 percent at 40 to 70 ℃ for 2 to 10 hours under normal pressure or 2 to 18 hours under vacuum to obtain the beta-crystal form aztreonam with the ethanol content lower than 0.5 weight percent. In an embodiment of the present application, in step (2), the relative humidity in the dryer is controlled to be 70% -100% by ultrasonic humidification or by shallow water tray humidification. In an embodiment of the present application, in step (2), the drying apparatus is a rotary vacuum dryer or an atmospheric drying oven. In an embodiment of the application, in step (2), the atmospheric drying temperature is 50 ℃ to 70 ℃, preferably 60 ℃ to 70 ℃. In an embodiment of the application, in step (2), the vacuum drying temperature is 40 ℃ to 70 ℃, preferably 40 ℃ to 50 ℃. In an embodiment of the application, in step (2), the relative humidity inside the drying apparatus is kept between 70% and 100%, preferably between 80% and 100%. In the embodiment of the application, in the step (2), the beta-crystal form aztreonam wet product is dried in a rotary vacuum dryer in a rotary vacuum way for 1-3 hours at 40-70 ℃, then the humidity in the dryer is 80-100% for 30 minutes-1 hour through humidification under normal pressure, the humidification