| ?-lactam antibiotics are one of the most commonly used antibacterial drugs in clinics.Due to their widespread use,bacteria have developed drug resistance,which is a major challenge in the field of anti-infective therapy.The new ?-lactamase inhibitor Avibactam sodium has a strong effect and a wide range,and it has a significant inhibitory effect on Class A,Class C and some Class D ?-lactamases.At the same time,it can be effectively restored in combination with cephalosporin antibiotics or enhance its activity,showing a good clinical application prospect.At present,there are few reports on the crystalline form and crystallization process of Avibactam sodium in China.In this paper,the crystal form and crystallization technology of Avibactam sodium were systematically studied by the method of solvent crystallization.First,three different crystal forms of Avibactam sodium were prepared by dissolution crystallization method,and the polymorphic products were analyzed and characterized by XRD,SEM,TGA,DSC,etc.In addition,the single crystal product of the crystal form ? was obtained by cultivating the crystallization-cooling coupled crystallization method.The single crystal product was analyzed and characterized to determine that it is a monoclinic crystal system,P21 space group.The thermal analysis method showed that the crystalline form ? is Avibactam sodium monohydrate,which loses a molecule crystal water at about 393.15 K and thermally decomposes at 505.15 K.Secondly,the dynamic method was used to measure the solubility of the Avibactam sodium in different proportions,and it was found that the solubility increased slowly with temperature;the empirical equation was also used to simulate the solubility data,the fitting results are better.In addition,the experiment also carried out thermodynamic analysis on the dissolution process of Avibactam sodium.Through data comparison analysis,it was proved that its dissolution in the mixed solvent system was driven by the entropy change and the enthalpy change alternately.Finally,through the single factor method,the experiment investigated the influence of the process conditions such as stirring speed,cooling rate,end temperature and crystal growth time on the product yield and particle size distribution in the crystallization process,and determined the best process conditions.Under this process condition,the product yield can be guaranteed while maintaining the uniformity of the crystal particle size,and it is of great significance to provide data support for the subsequent crystallization process research. |
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