Spectral Analysis About The Pharmaceutical Cocrystal Formation Of Piracetam

Pharmaceutical cocrystal can improve physical and chemical properties and increase the bioavailability of active pharmaceutical ingredient(API).This feature has shown great potential in improving the pharmaceutical’s properties and characteristics.Piracetam is γ-aminobutyric acid derivatives and its molecule contains amino and carbonyl functional groups which can form hydrogen bonds. Amino group of piracetam acts as hydrogen donor while carbonyl group acts as hydrogen acceptor.Therefore, piracetam can be used as a typical model system for in-depth investigating the cocrystal formed by hydrogen bonding effect and also the corresponding physicochemical properties of cocrystals.In the study, piracetam was chosen as API while 2-, 3-, 4-hydroxybenzoic acid(HBA), 2,3-, 2,4-, 3,4-,3,5-dihydroxybenzoic acid(DHBA) were used as the cocrystal formers(CCF). Cocrystals were prepared by solvent evaporation and grinding methods and were characterized with Fourier transform infrared(FT-IR), Raman and Terahertz(THz) spectroscopy. The results of three techniques show the structural and vibrational information of cocrystals from different aspects, which provide a basis for discrimination between different molecular structures. Through spectral analysis, the formation of cocrystal is due to hydrogen bond formation between the amide group of piracetam and the carboxyl group of the CCF.Selecting the cocrystal formed by piracetam and 3HBA as an example, we analyzed the vibrational spectra of starting materials and cocrystal, and also assigned their molecular vibrational modes. The dynamic process of piracetam-3HBA cocrystal formation is investigated in-depth with Raman and THz spectra. Piracetam-3HBA cocrystal is formed pretty fast in first several minutes, and then the formation rate becomes slow. After 35 minutes, such formation process has been completed.The Gaussian 03 software was chosen to simulate the molecule structures and vibrational frequencies of piracetam, 3HBA and their cocrystal. The experimental and simulated results were analyzed and their molecular vibrational modes were assigned.Experimental results were in good agreement with the simulation. In such study,intramolecular and intermolecular interactions of piracetam and 3HBA were investigated by combining theoretical and experimental spectra. These offer theexperimental and theoretical benchmark for identifying pharmaceutical cocrystals and also further studying the intramolecular and intermolecular interactions with spectroscopic technologies.The solubilities of piracetam, 3HBA and their cocrystal in water were determined by UV-visible spectrophotometry. A theoretical model between the concentration and absorbance coefficient of cocrystal was established based on Lambert-Beer law. The result showed that the dissolution of the cocrystal was changed with around 19 times smaller than that of piracetam.To established spectrum analysis model of these cocrystals, the molecular vibration of a series cocrystal about of piracetam was studied in this thesis. The dynamic process of the cocrystal formation was established with the quantitative analysis model, which offers the theoretical benchmark and unique means for real-time monitoring pharmaceutical cocrystal formation and also the corresponding quantitative analysis in the pharmaceutical field. The work, through the mechanism of cocrystal formation by theory and experiment, also provides a theoretical basis for identifying pharmaceutical cocrystals from molecular structure changes with spectroscopic technologies.