Cocrystal Design And Its Solid-state Chemical Properties Investigation Of Two Natural Products

Natural products are the secondary metabolites isolated from driven plants and microorganisms.Natural products are widely applied in the fields of food and pharmaceutics,because of their wide variety of biological activities.Over the past three decades,more than 50%of the small molecule drugs approved by the U.S.Food and Drug Administration are natural products and their derivatives.However,the further applications of natural products are limited by their poorly physicochemical properties,such as solubility,chemical stability and so on.Chronic respiratory disease is an increasingly serious public health problem,and is a serious threat to human health.In this context,the development of drugs for respiratory diseases is imperative.Natural products with extensive pharmacological activities and fewer side effects are very popular in the treatment of respiratory diseases,which have attracted extensive attention from researchers in recent years.Herein,natural products for bergenin(BGN)and theophylline(THP)are usually utilized to treat respiratory diseases according to Chinese Pharmacopoeia.However,anhydrate of BGN and THP are unstable in a high humidity environment and will be transformed into monohydrate,which will cause drug safety problems.In addition,the common side effects of THP,such as central stimulation,cardiac arrhythmias,and so on,limit the linical application of THP.Hence,in this work,BGN and THP were selected as model natural products to improve their physicochemical properties.BGN and THP cocrystal were designed and synthesized by introducing supramolecular synthons.The relationship between the solid-state and physicochemical properties of BGN and THP was fully explored.This work may point to futuristic directions for the development of natural products.To resolve the problems of BGN and THP,firstly,based on the crystal engineering method,the possible cocrystals of BGN and THP were designed.Secondly,based on the principle of supramolecular chemistry,new cocrystals were synthesized and characterized for the first time.1.(1)For BGN,BGN-4-Aminobenzamide and BGNIsonicotinamide cocrystal significantly increased the solubility.Especially BGN-4Aminobenzamide cocrystal,increased the solubility of BGN about 9.5～32.7 times in water and buffer solutions with different pH values(1.2～6.8).(2)Based on the solubility product(Ksp)and solution binding constant(K11),the solubility phase diagrams of BGN cocrystals in ethanol,isopropanol and ethyl acetate were drawn.The results show that there is a complex dissolution dynamic equilibrium reaction in the organic solvents.The established dissolution equation can effectively predict the solubility of BGN cocrystals.(3)The DFT results show that compared with BGN monohydrate,the number of hydrophilic groups on mian crystal plane with water of BGN-4-Aminobenzamide cocrystal is dominant and BGN-4-Aminobenzamide cocrystal is relatively stable in thermodynamics.(4)BGN cocrystals can maintain higher phase stability in a high humidity environment(RH=80%),according to the hygroscopicity experiment.2.(1)THP anhydrate(THPa)and monohydrate(THPm)have significant differences in mechanical properties.In this study,we found that the fundamental reason lies in the mechanical properties of their single crystal.The single crystal of THPa shows good plasticity,while THPm presents elasticity.(2)The results of experiments and theoretical calculations reveal that the difference of slip plane andπ…π interaction are the main reasons for their different mechanical properties.(3)A new cocrystal of THP and ferulic acid(FA)and its polymorphs were synthesized,and the new cocrystal has better hygroscopic stability than THP and FA.Under the guidance of supramolecular chemistry theory and the concept of green chemistry,this paper focused on the solid forms and properties of BGN and THP,two natural products with therapeutic effects on respiratory diseases.New cocrystals present better physicochemical properties than raw materials.And the relationship between their properties and crystal structure was fully explored.To sum up,this work will provide theoretical and practical applications to the further development and properties regulation of natural products.