Structural Investigation Of The Cocrystal Of Typical Antiviral Drugs Based On THz And Raman Spectroscopic Techniques

Terahertz time-domain spectroscopy(THz-TDS),a technique which has the characteristic of high sensitivity,is a promising tool in studying molecular configuration and inter-molecular effects.Raman spectroscopy has been demonstrated to be an effective probe in analyzing intra-molecular vibrational modes and functional groups.Pharmaceutical cocrystal,the structure which formed between active pharmaceutical ingredient(API)and cocrystal former(CCF)by effects of non-covalent interaction,such as hydrogen bonding effect,has the most obvious feature that it could lead to a variation of physiochemical properties whereas the API of this drug is generally not influenced.So,pharmaceutical cocrystal forms have more advantages and potential marketing values in the process of pharmaceutical research when compared to the traditional drugs.The antiviral drug 5-fluorocytosine(5-FC)has several kinds of polymorphs and it is prone to crystalline transformation phenomenon in the case of high humidity and brings so much trouble to the production and storage.THz-TDS and Raman spectroscopic techniques were used to detect and analyze the substance formed between 5-FC and fumaric acid(FA)by grinding method and then results of vibrational spectra were achieved.The structure of the above substance formed between 5-FC and FA was inferred as the cocrystal form successfully by combining density functional theory(DFT)calculations and experimental results together,which overthrew the previous conclusion that the structure of this substance being the salt form provided by Cecília C.P.da Silva group(Crystal Growth & Design,2013,13(15):4315-4322).It is found that vibrational spectroscopic techniques,especially THz spectroscopy,have great advantages over other traditional detection methods in structure analysis of different materials.Acyclovir(ACV),the most commonly used antiviral drug,has problems in solubility and bioavailability and it is necessary to study this drug.ACV molecule,cocrystal between ACV and FA,and cocrystal between ACV and chiral molecules tartaric acid(TA)were detected and analyzed by vibrational spectroscopy.Theoretical and experimental results of vibrational spectra showed that vibrational spectroscopy could accurately identify the structure of ACV and different cocrystals between ACVand CCF,and then the spectral models of ACV molecule and ACV cocrystals were also established.This thesis mainly verifies that the advantages of vibrational spectroscopic techniques when compared with traditional detection methods and the great value of application of vibrational spectroscopy in analysis of different structures of pharmaceutical cocrystal.According to the characteristics that API could react with CCFs to form cocrystal structure by hydrogen bonding effects,the vibrational spectra of experimental results and DFT calculations are combined together in order to study influences which affected by hydrogen bonding in pharmaceutical molecules and structure of the cocrystal.It shows the great application prospect of vibrational spectroscopic techniques in detection and analysis of different materials.