A Study On Concomitant Polymorphism And Solution-mediated Phase Transformation Of L-Histidine In Antisolvent Crystallization

Polymorph has been defined as a solid crystalline phase of a given compound possessing at least two crystalline molecular arrangements of that compound in the solid state.The various solid-state forms display different chemical and physical properties.These differences would not only affect the processing performance of solid products such as fluidity and cohesion,but also cause differences in drug quality such as drug dissolution rate and stability,which in turn affects the clinical efficacy of drugs.In polymorphic systems,nucleation often play the most central role in the areas of the consumption of supersaturation,the control of the nucleation rate and nucleation outcomes,and the concomitant polymorphism as a common nucleation phenomenon in the crystallization process can have a large impact on the quality of the product.Meanwhile,the transformation between different forms also plays an indispensable role in the control of the polymorphic purity and the storage and transportation of different polymorphic products.Thus,the study on polymorphic nucleation behavior and polymorphic transformation mechanism can not only provide theoretical basis for the study of other polymorphic solid products,but also provide theoretical guidance for the control of the polymorphic crystallization process in industrial production.L-Histidine,as one of the most essential and naturally occurring amino acids,is a well-known amino acid to crystallize in two different polymorphs,with Form A being stable.In industrial production,there are obvious disadvantages such as significantly differences in the properties of polymorphs,a single preparation method of the stable form,and the low polymorphism transformation rate,which reduce the solid product quality and production efficiency.This work took L-Histidine as the research model compound,systematically studying the thermodynamics behavior of crystallization,polymorph formation and the effect of concomitant polymorphism on the subscent solution-mediated phase transformation in antisolvent crystallization.Firstly,the crystallization thermodynamics of L-Histidine was investigated.The solubility of L-Histidine Form A in three different binary solvents,including(acetone + water),(ethanol + water)and(2-propanol + water),was measured over temperatures from 283.15 K to 318.15 K by employing a gravimetric method at atmosphere pressure.The experimental data was well correlated by modified Apelblat equation,CNIBS/RK model,combined version of the Jouyban-Acree model and NRTL model,respectively.Furthermore,the mixing thermodynamic properties of L-Histidine in different binary solvent mixtures were also calculated based on the NRTL model.These thermodynamic values obtained above indicate that the mixing processes of two separate solvents and L-histidine are spontaneous.These studies provide an important basis for the selection of solvent in crystallization process and the understanding of dissolution process.Of note,L-Histidine exists two different polymorphs.In order to characterize and analyze the two forms,several characterized instruments,including PXRD,polarizing microscope,TGA,FTIR and Raman were applied,which can provide qualitative and quantitative analytical methods for the process of polymorph formation and phase transformation.Subsequently,the polymorphic nucleation of L-Histidine in different antisolvent crystallization was investigated.Furthermore,water + methanol antisolvent crystallization system was selected to study the effect of supersaturation on polymorphic crystallization.Lastly,the polymorphic transformation mechanism of L-Histidine in watermethanol antisolvent crystallization system was analyzed and explored on the basis of experimental and process monitoring experimental results.The process analytical technologies,such as FBRM,was used to monitor the nucleation with the trend of crystal number and particle size in antisolvent crystallization over time.PXRD was used to quantitative analysis the Form A in the suspended solid,and the UV spectrophotometric solution concentration was adopted to measure the concentration.In addition,the suspended solution-mediated phase transformation experiments were designed to determine the trend of the time required for complete transformation with the volume fraction of methanol in the solvent.The results obtained in this work confirmed that Form A in the concomitant nucleation has self-seeded effect on subsequent transformation experiments in antisolvent crystallization.All the contents discussed above have never been reported by any other related literatures.