Studies On The Stability Of Amorphous Probucol After Pressure,Annealing And Mixing Treatments

Amorphous drugs,which have good apparent solubility and bioavailability,is a hot topics in the amorphous field in recent years.A key issue for the application of amorphous drugs is the thermodynamics stability.Especially the pressurization of the tablet preparation process often induces recrystallization.The above structural instability phenomenon will cause the reduction in the efficacy of the drug.Existing studies have pointed out that thermodynamic and kinetic parameters can affect the stability of amorphous drugs.However,the problem of recrystallization of amorphous drugs under pressure has not been resolved,and there is a lack of specific parameters and measurement standards that could accurately control and guide the stability of amorphous drugs.Aiming at the problem that the stability of the amorphous probucol would greatly reduced after pressure production,this thesis used the differential scanning calorimeter(DSC)and the broadband dielectric spectrometer(BDS)as the measurement methods to compare and study pressure,annealing,and mixing drug processing methods affect the structure instability of amorphous probucol.The aging experiment was carried out at315 K,and the isothermal crystallization kinetic analysis showed that recrystallization behavior occurred after the amorphous probucol was prepared into tablets with a pressure of 10 MPa,and the crystallization time was 84 min.The stability was greatly reduced.By changing the value of the pre-pressure during preparation,it was found that the crystallization time of tablets prepared with a larger pressure of 14 MPa was the longest,reaching 147 minutes,and the stability of the tablet was improved;After annealing below room temperature,the crystallization time was prolonged,and the stability of the agent was improved.By changing the temperature of thermodynamic parameters of annealing,it is found that annealing at a lower temperature of 230 K has the longest crystallization time,and the stability of the tablet was not completely crystallized at 240 minutes;Acetaminophen,a drug with the same glass transition temperature,was added into a binary mixture system(molar ratio 3:1),it was found that the tablets did not appear to be crystallized,and the stability was significantly improved;In addition,the tablets prepared at different pressures were processed by analyzing the relaxation kinetics and non-isothermal crystallization kinetics,the relationship between the crystallization activation energy(E_a)and the JGβrelaxation strength(ε″β)and the stability of the amorphous probucol was constructed,that is,as the stability increases,E_a became larger,ε″βbecame smaller,and it has been verified in the annealing and mixing processing methods,which can be used as an important parameter to measure the stability of the tablet probucol.This thesis systematically evaluated the inhibition effect of the three treatments of pressure,annealing and mixing on the crystallization of the amorphous probucol tableting process,among which the mixing effect was the best;And through the experimental data and theoretical analysis,the amorphous probucol were established the stability was linearly related to the JGβrelaxation strength 1/ε″_β.The above work provides theoretical supported for optimizing the stability of amorphous drugs,and brings more amorphous drugs into industrial production one step closer.