Research On Polymorphs And Its Regulation Of Avibactam Sodium

Avibactam sodium is the most promisingβ-lactamase inhibitor,which is used to treat complex intra-abdominal infections and other diseases.Avibactam sodium has polymorphism.There are several problems of anhydrates including small particle size,poor fluidity,and high hygroscopicity.However,the hydrates of Avibactam sodium may undergo dehydration transformation under certain conditions,which will affect its stability and efficacy.To understand and solve these problems,the crystal packing modes of polymorphs and the transformation relationship of different solid forms were investigated in detail.First of all,five crystal forms of Avibactam sodium were prepared by various crystallization methods:Form A(monohydrate),Forms B,C and D(anhydrates)and Form E(dihydrate).These five polymorphs were fully characterized by powder X-ray diffraction,polarizing microscope,thermal analysis,Raman spectroscopy and Fourier transform infrared spectroscopy.In addition,the dissolution rate of five polymorphs and the thermodynamic stabilities were studied by the direct powder tablet method,and the results showed that all crystal forms have good bioavailability.Secondly,crystallization thermodynamics of Avibactam sodium was studied.Solubility of Form D in binary solvent of methanol and ethanol as well as solubility of Forms A,B and E in binary solvent of water and 1-propanol was measured by static method.The simplified Apelblat equation,Vant’Hoff model and Jouyban-Acree model were used to correlate the solubility data.In addition,the ideal dissolution thermodynamic properties including the Gibbs energy change,entropy and enthalpy,were calculated based on the Vant’Hoff model and experimental solubility data,which provide basic data for design of crystallization process.The results showed that the dissolution process is endothermic and entropy driven.Then,the single crystals of four crystal forms of Avibactam sodium were obtained successfully by single crystal cultivation experiments,including Forms A,B,D and E.These four crystal structures were resolved using single crystal X-ray diffraction.The crystal assembly modes of the four crystal types were compared in detail,and the intermolecular interactions were analyzed using Hirshfeld Surface Analysis.The results show that the introduction of water molecules in the crystal lattice lead to stronger hydrogen bonds and more stable structure.Morever,the crystal habit of these four polymorphs were predicted by AE model,which are consistent with the morphology of experimental crystals.Finally,basing on analysis of crystal structure and crystallization thermodynamics of Avibactam sodium,the form transformation processes were studied in detail.The hydration of Form B was investigated to understand the integration of water molecules by measuring the critical hydration water activities(a_w)in the mixed solvent system of water and 1-propanol.The results proved that temperature and moisture are all critical factors which deterimine the interagartion of water molecules in crystal lattice.Moreover,to probe the disintegration of water molecules,the dehydration processes of dihydrate were investigated in detail by on-line and off-line equipments.Based on the above research,two-step dehydration and one-step dehydration+recrystallization mechanisms of these different pathways were proposed,which provide molecular mechanism of form transformation.