Terahertz Spectroscopy And Density Functional Calculations Of The Carbamazepine Cocrystals

As we all know,carbamazepine has poor solubility and drug stability.In order to improve drug performance,drug cocrystals are considered to be a promising drug development method in recent years.The design and synthesis of drug cocrystals have certain advantages in improving the physical and chemical properties of drug substances.Against the background of this drug cocrystals,the carbamazepine cocrystal has attracted widespread attention.In this dissertation,terahertz time-domain spectroscopy,PXRD and DFT calculations are used to study the low-frequency motion of three cocrystals formed by carbamazepine with nicotinamide,saccharin and fumaric acid.PXRD and terahertz time-domain spectroscopy were used to determine the position of the absorption peak,which proved the formation of carbamazepine cocrystals.In this work,for the first time,the absorption peak at low frequency of carbamazepine cocrystals is found,which fills the gap of carbamazepine cocrystals in the terahertz database.In the theoretical simulation work,based on the plane-wave pseudopotential dispersion-corrected density functional theory simulation,under fixed unit cell parameters(DFT-FC)and unfixed unit cell parameters(DFT-VC),the following conclusions are obtained:(1)Compared with the experimental cell parameter,the cell volume optimized by the DFT-VC method is reduced by 1.83-6.15%.This method systematically underestimates the unit cell parameters of all crystals.Because,we did not consider the influence of temperature on the atomic position in the calculation process using DFT.Comparing the two calculated spectra with the experimental spectra,it was found that the simulated terahertz spectrum successfully reproduced the characteristics of all crystals in the experimental spectrum.In principle,the functional of DFT-FC is better than that of DFT-VC.(2)Non-covalent bonds formed by cocrystals,such as hydrogen bonds,are critical in the low frequency region.The vibration modes of characteristic peaks before and after carbamazepine cocrystals are discussed in this thesis.Compared with its pure carbamazepine vibration mode,the carbamoyl group of carbamazepine molecule has lower kinetic activity in the cocrystals.(3)We further analyzed the influence of lattice vibration on co-crystallization.Although different crystals show a certain degree of similarity in the spectral range,their energy contribution intensity is quite different Based on the contribution ratio of the crystal energy in the terahertz band,it is observed that the thermal energy contribution of the low-frequency vibration is greater than the zero point energy,and the increase of the thermal energy is beneficial to the formation of the cocrystal.Among them,CBZ-FUM crystal is the most stable.The research in this thesis shows that the cocrystal is beneficial to the improvement of the physicochemical properties of carbamazepine,and provides a reference for the development and design of drug cocrystals.