Study On Process Control And Analytical Technology For Shaping Crystal Size Distribution And Improving Polymorphism Quantification

Crystallization is one of the most important separation unit operations,which has a significant influence on product quality.But crystallization is a complex process and there is not a detailed model to describe it.Therefore,it is important to focus on process control for improving product quality.Recently,besides the purity,we are paying more attention on pharmecutical polymorphism.Pharmeceutical polymorphism quantification is also an important project in the field of pharmaceutical research and patent protection as different polymorph has a significantly different stability,solubility and bioavalibility.Currently,we mainly use off-line and destructive analysis.However,in the presence of excipients,it is difficult to quantify quickly and precisely.With the development of process analytical technology(PAT),on-line and intact pharmecutical polymorphism quantification technologies are feasible and in demand.In this context,we choose supersaturation control strategy for improving product crystal size distribution;combining Raman spectroscopy with on-line platform,we achieve API polymorph intact quantification.First,Triethylenediamine(TEDA)is an important foaming catalyst in the field of polyurethane.A uniform crystal size distribution has an effect on its following filtration,drying,and catalyst packing.We investigate the effect of main impurity piperazine from raw material on thermodynamic behavior and nucleation process.Combined with molecular simulation and classical nucleation theory,we try to explain improved solubility and narrowed nucleation barrier in the presence of piperazine under different conditions.From a perspective of supersaturation control strategy,we propose a one-step crystallization technology for the production of TEDA with a higher purity and larger crystal size distribution,which can provide a guideline for industrial scale up.Second,Raman spectroscopy is considered as a new PAT tool for polymorph quantification test in pharmaceutical manufacturing.Vortioxetine hydrobromide is an antidepressant drug.Itsαform andβform are different in pharmaceutical activity and patent protection.We combine portable Raman device with a movable platform for the purpose of rapid and non-destructive quantitative analysis.Novel chemometric algorithems are introduced to extract analytical information from raw tablet’s Raman and eliminate errors from inhomogeneous distribution on the surface and fluoresce effects from excipients.With the aid of modern computer technology,we also modify software in order to overcome environmental disturbance and achieve continuous operation.Compared with traditional calculation methods,such as Lamb-Beer equation and partial least square regression,predicted results precision R~2 improves significantly from 0.60 to 0.98,which can provide technology and model support for fast and stable polymorph quantification in the future.All the contents discussed above have never been reported by any other related literatures.