| Azlocillin(ALPC)is a broad-spectrum antibiotic that is highly active when used alone and is also used as a pharmaceutical intermediate for the production of azlocillin sodium.At present,domestic enterprises have problems such as low product content,high impurity and residual solvent,poor dispersibility and low process yield in the production process of ALPC.Crystallization,as a key process in the production process of ALPC,will greatly affect the quality indicators such as crystal form,crystal habit and purity.Therefore,it is particularly important to conduct in-depth discussion and research on the development process of crystallization process of ALPC.Firstly,the crystallization thermodynamics study of ALPC was carried out in this work.The solubility data of ALPC in nine pure solvents and two mixed solvents were determined by the gravimetric method;the modified Apelblat equation,λh equation,CNIBS/R-K model and NRTL model were applied to simulate the experimental solubility data and the fitting results were good;and the mixing and dissolution properties of ALPC in the studied systems were also determined and analyzed by using the NRTL model.Secondly,in this work,a new crystal form(Form II),different from the existing crystal form(Form I)of ALPC,was successfully prepared by cooling crystallization in n-butanol.The crystal morphology,structure and related properties of polymorphs of ALPC were analyzed by the optical microscopy,X-ray powder diffraction(XRPD),infrared and Raman spectroscopy,and thermogravimetric analyzer(TGA).Moreover,the relative stability of the two crystal forms was investigated,and the stability of Form I was better than that of Form II.Finally,we studied the crystallization process of ALPC in this work.The solvent systems involved in the crystallization process of ALPC were determined and the best operating conditions for the new process were determined by controlling some key parameters,such as the dropping method,solvent system,crystallization temperature,concentration of hydrochloric acid and stirring rate.The product of Form I of ALPC obtained by the optimized process has a long rod shape;the average particle size is about 47.5 μm;the purity can reach 99.5%;the product indexes are superior to the original technology,and fully meet the requirements of the relevant cooperative enterprises.The above research content in this paper has not been reported in the literatures. |
