Study On The Controllable Crystallization Process Of Carbamazepine Crystal Form Induced By SAMS

Controlling polymorphism of drug is one of the core demands of polymorphic drug crystallization process.In recent years,more and more scholars have paid attention to novel control methods of crystal form.Induced crystallization of SAMs with different groups is an effective method.However,the methods lack theoretical process research.At present,there is no online analysis method for this process.The commonly used online monitoring instruments only interfere with the crystallization process of the solution as heterophase.Therefore,a in-situ method that supports SAMs to induce crystallization and offers online monitoring function will attract wide attentions.First,QCM crystal plate is used as the support substrate for SAMs modification and the medium for online monitoring of the crystal nucleation process in this paper.MUA(11-Mercaptoundecanoic acid),2-MBT(mercaptobenzothiazole),MUOH(11-Mercapto-1-undecanol)were self-assembly on the QCM chip through S-Au bond respectively.The modified SAMs have been characterized by using cyclic voltammetry(CV)test and physical methods.These results verified the complete coverage and compositional characteristics of the functionalized interface.The whole modification process of the of SAMs on the substrate were online monitored.Then,the above three kinds of SAMs-modified crystal oscillators were used as the inducing medium for inducing and in-situ monitoring the nucleation process online respectively.The nucleation temperature was significantly earlier than that of the bare QCM chip.The crystals grown at the interfaces of SAMs were qualitatively determined by PXRD and Raman.As a results,form II was induced on the SAMs modified by MUA and 2MBT.Form I was induced on the SAM modified by MUOH.Then,cooling crystallization was carried out in different initial concentrations of carbamazepine solutions.The results of the metastable zone of carbamazepine solutions induced by different SAMs-modified were obtained.Last,the Hirshfeld surface analysis and the binding energy between SAMs and different crystal forms were simulated respectly.And the mechanism of the polymorphism selection induced by the SAMs was discussed.The simulation results showed that there are differences in the internal bonding of the obtained crystal forms,which may be due to the regulation of the functionalized interface to change the internal arrangement.Moreover,the SAMs modified by MUA and 2MBT have better affinity for CBZ crystal form II(1,-1,-1)and the SAM modified by MUOH have better affinity for CBZ crystal form I(0,1,1).The simulation results were in good agreement with the experimental results.This work explored the formation process of functionalized heterogeneous nucleation and the phenomenon of nucleation,which could provide a reliable new idea for online analysis of induced nucleation and crystal form control.