| Cefaclor belongs to the second generation of cephalosporin antibiotics,which has a significant therapeutic effect on respiratory tract infection.At present,the domestic product of cefaclor usually has the quality problem,such as uncertain product crystal form between batches and poor stability.For different solvates,their formation and phase transformation can affect their physicochemical properties.Therefore,in this paper,the solvates of cefaclor along with their discovery,characterization,interconversion and stability were studied,which can provide a theoretical basis for future production and research.First of all,the screening,preparation and characterization of cefaclor solvates were studied.Cefaclor hemihydrate and cefaclor water-methanol solvate were obtained by suspension in a water-methanol mixed solvent.Cefaclor 2.5 hydrate was obtained by the isoelectric crystallization method of rapidly dropping ammonia in aqueous solution.The three selected cefaclor solvates were all channel solvates,and their solid form,crystal habit,thermodynamic property and hygroscopicity were different.Then,we studied the formation and transition of cefaclor solvates.The formation mechanism of the spherulite of cefaclor 2.5 hydrate was spherical growth using online and offline methods.The solubility of different cefaclor solvates in water-methanol solvent was determined by dynamic method,which provided basic data for the study of phase conversion.It was determined that the solvent-mediated phase transition process of dihydrate to hemihydrate was nucleation-growth control,and the transition time increased with the mass of dihydrate added.The phase transition process of hemihydrate to water-methanol solvate was growth control,and the transition time was independent of the mass of the added dihydrate.In addition,increasing the temperature and speeding up the stirring rate can shorten the transition time for both phase transition processes.The study of its formation and transition process can guide the production process of obtaining the most stable solid form.The solution and solid stability of cefaclor solvates were studied.In the study of the stability of cefaclor solution,it was found that under low temperature,solution p H=3～4 and low methanol content,the solution degradation rate was low.As for the solid stability of cefaclor solvates,it was found that hemihydrate has better stability than existing solvates.The above research has guiding significance for the optimization and design of the crystallization process of cefaclor solvates. |
