| Salicylic acid drugs are widely used in clinical practice because of their good antipyretic,analgesic,anti-inflammatory,anti-tuberculosis,anti-rheumatism and other effects.However,the solubility of most salicylic acid drugs is very low,which greatly limits their drug absorption and clinical application effect.Drug cocrystals,as a relatively new form of drug,improves drug efficacy by introducing ligand molecules to modify the physical and chemical properties of drugs,such as solubility.The detection and characterization of drug cocrystals is an important step in the process of drug development.In addition,salicylic acid drugs have similar structure,even some drugs have similar appearance,but their uses are not the same,and there may be misuse and abuse in the actual use process.Therefore,it is of great significance to establish a convenient and efficient nondestructive testing technology for the detection and characterization of salicylic acid drugs with similar structures and their drug cocrystals.As a new spectral detection method,terahertz time-domain spectroscopy(THz-TDS),with its advantages of strong penetrability,high spectral resolution,convenience,efficiency,safety and nondestructive,is extremely sensitive to molecular configuration,molecular vibration,and intermolecular interaction.It has broad application prospects in drug molecular detection,and also provides a feasible means for the detection and characterization of drug cocrystals.In this paper,six salicylic acid drugs,including salicylic acid,acetylsalicylic acid,4-aminosalicylic acid,5-aminosalicylic acid,4-hydroxysalicylic acid and 5-hydroxysalicylic acid,are taken as the research object.Combining THz-TDS technology and quantum chemical calculation methods,the absorption spectral characteristics of six salicylic acid drugs in the terahertz frequency band are studied,and the formation mechanism of the spectral characteristic absorption peak is deeply explored.On this basis,in order to improve the drug solubility,4-aminosalicylic acid nicotinamide and acetylsalicylic acid nicotinamide were prepared by grinding cocrystals method,and were detected and characterized by terahertz spectroscopy.The specific research contents and results are as follows:(1)Terahertz spectrum experiment and theoretical calculation of drugs.The terahertz experimental spectra of six salicylic acid drugs were measured by THz-TDS,and the fingerprints of these drugs in the terahertz low frequency band were supplemented.Terahertz spectroscopy is sensitive to molecular structure,which can effectively identify similar substances or isomers,providing a research basis for the detection and characterization of drug cocrystals.In view of the problem that the weak intermolecular interaction is ignored in the single molecular structure,the theoretical simulation of the single molecule and unit cell structure of the drug is carried out through the quantum chemical calculation method.In contrast,the unit cell structure considers the weak intermolecular interaction,and its simulation calculation is more consistent with the experimental measurement results.To solve the problem of theoretical calculation accuracy,B3LYP,M06-2X and PBE methods were used to optimize the geometry and calculate the frequency of drug cell structure respectively.The analysis results showed that B3LYP method had better accuracy.(2)Study on vibration characteristics and weak interaction.In order to understand the formation mechanism of the spectral characteristic absorption peak,this paper studied the vibration characteristics and weak interaction of drug molecules.The vibration characteristics of the system were analyzed by potential energy distribution method,and the vibration modes corresponding to each characteristic absorption peak of the THz spectrum of six drugs were identified and assigned.In order to comprehensively and accurately investigate the weak intermolecular interactions in salicylic acid drug systems,a method based on the interaction region indicator(IRI)and energy decomposition analysis based on force field(EDA-FF)was proposed to conduct qualitative and quantitative analysis of the weak intermolecular interactions,and to visually display the types of weak interactions between drug molecules in the form of charts action position and relative strength,etc.The IRI method shows all kinds of interactions in the molecular structure of six drugs more intuitively and comprehensively in the form of iso-surface combined with scatter diagram.The EDA-FF method mainly decomposes the total interaction energy between fragments into energy terms with physical significance,so as to quantitatively investigate the weak interaction in the system.The results of IRI and IEDA-FF analysis showed that there were van der Waals interaction,hydrogen bond and other weak interactions in the six drug systems,and van der Waals interaction was dominant in quantity.There are electrostatic interaction,mutual exclusion and dispersive interaction with different intensities in the system of six drugs,among which electrostatic interaction is mainly attributed to hydrogen bond,and dispersive interaction is mainly contributed by carbon,oxygen and nitrogen atoms.(3)Application of drug cocrystals.Weak intermolecular interactions,especially hydrogen bonds,are the basis for the formation of drug cocrystals.Analyze the groups contained in drug molecules and cocrystals ligand molecules,and preliminarily judge the possibility of forming hydrogen bonds and other weak interactions between selected target drug molecules and ligand molecules according to the types and numbers of hydrogen bond donors and receptors in the molecules.In this paper,4-aminosalicylic acid,nicotinamide and acetylsalicylic acid,nicotinamide cocrystals were prepared by grinding cocrystals method with 4-aminosalicylic acid and acetylsalicylic acid as active components and nicotinamide as cocrystals ligand,which enriched the solid morphology of drugs.THz-TDS was used to measure the cocrystals of two drugs.According to the new characteristic absorption peak,the formation of drug cocrystals was indicated,providing a novel and effective identification method for the detection and characterization of drug cocrystals.At the same time,the unit cell structure of drug cocrystals is simulated with quantum chemical calculation method,which provides evidence for the experimental results,and the cause of the characteristic absorption peak is analyzed from the perspective of vibration characteristics.Qualitative and quantitative analysis of the weak interaction in the two drug cocrystals and ligand nicotinamide system showed that the van der Waals effect in the nicotinamide molecular system was weak,which was not conducive to the stable binding of internal molecules;The strong hydrogen bond between drug molecules and ligand molecules in the two drug cocrystals systems is conducive to the synthesis of cocrystals.Finally,through the determination of drug solubility,the solubility of 4-ASA has increased by about 20 times,and that of ASP has increased by nearly 10 times,the results show that drug cocrystals has a significant increase in drug solubility. |
