Investigation On Co-Crystals Preparation And Dissolution Thermodynamics Of Insoluble Drugs

During the stage of drug design,in order to improve the biological activity of drugs,they are usually designed as structures which can form a variety of interactions with target receptor,therefore the solubility of these drugs is getting worse and worse.It is particularly important to solve the problem of poor water solubility of drugs to improve bioavailability.This paper takes the design of co-crystal structure as the starting point,focuses on the problem of poor bioavailability of insoluble drugs,and regulates the drug crystal structure through co-crystal strategy to solve the solubility problem of insoluble oral drugs.Actarit and fenbufen were selected as the objects of study.The dissolution thermodynamics and mechanism of actarit or fenbufen,the design and formation mechanism of co-crystals,the phase equilibrium and complexation mechanism of co-crystals,the dissolution performance and dissolution mechanism of co-crystals in vitro were studied.(1)The phase equilibrium system of actarit or fenbufen was constructed by isothermal equilibrium method,it was found that there was a cosolvency phenomenon in acetone + water mixed solvent.The analysis results of intermolecular interaction showed that polarity,hydrogen-bonding interaction and steric hindrance were important factors affecting the dissolution of actarit and fenbufen.The changes of solute-solvent and solvent-solvent interactions lead to the cosolvency phenomenon of actarit and fenbufen in acetone + water mixed solvent.The analysis results of solvent effect showed that hydrogen-bonding interaction and dipole interactions were the main factors to promote its dissolution.Preferential solvation analysis clarified the dissolution mechanism of actarit or fenbufen: Water molecules form a cage structure around the hydrophobic aromatic groups of actarit or fenbufen by hydrogen bonds.It is difficult for the cosolvents to approach the solute molecules.At this time,actarit or fenbufen are dissolved by water preferentially.The continuous increase of cosolvents destroys the cage structure of water molecules,which makes the cosolvents can interact with solute.Then actarit or fenbufen are dissolved by cosolvents preferentially.The analysis of thermodynamic properties showed that the dissolution process of actarit or fenbufen is an entropy increase and endothermic process,and the dissolution enthalpy played a major role in dissolution Gibbs free energy.(2)The actarit-nicotinamide co-crystal,actarit-isonicotinamide co-crystal,fenbufennicotinamide co-crystal and fenbufen-isonicotinamide co-crystal based on hydrogen-bonding interaction were designed and prepared.The optimal crystallization process was determined by the analysis of host and guest functional groups,the optimization of solvent systems and the molar ratio of host to guest molecules.The properties were characterized by NMR,PXRD and DSC,which showed that these co-crystals had better purity and lower melting point.Crystal structure analysis showed that hydrogen-bonding interaction was the main interaction of each component in co-crystals.Hirsheld surface analysis and Laplacian electron density analysis confirmed the formation mechanism of these co-crystals: the host and guest are connected and extended by hydrogen bonds to obtain an ordered crystal structure.Density functional theory calculation showed that when the electrons of these co-crystals were transferred from the ground state to the excited state,the electron cloud on actarit or fenbufen molecules was mainly transferred to the atomic orbitals on co-formers,which indicated that these co-crystals were charge transfer co-crystals.(3)The ternary phase equilibrium systems of four co-crystals at different temperatures were established.The ternary phase diagrams were constructed,and the stable phase regions of every co-crystal were determined.The phase diagram analysis showed that the crystallization region of pure co-crystals decreased with the increase of temperature,which was not conducive to the formation of co-crystals.The analysis of solubility product determined that the complex form of actarit-isonicotinamide co-crystal was 2:1(mole ratio)in solution,while the complex form of other co-crystal was 1:1(mole ratio)in solution.The effects of temperature on solubility product and complexation constant were investigated.The hydrogen-bonding interactions between co-crystals and solvent molecules increased with the increase of temperature,which resulted in increased solubility product and decreased complexation constant.These had guiding significance for the design of co-crystal and the prediction of its formation.(4)The dissolution performance of actarit and its co-crystals,fenbufen and its co-crystals in vitro in water,simulated intestinal fluid,simulated duodenal fluid and simulated gastric fluid were evaluated.The results showed that the formation of co-crystals can improve the dissolution rates of API significantly.According to the characteristics of dissolution curves and the analysis of co-crystals structure,the mechanism of increasing dissolution rates of actarit or fenbufen co-crystals was clarified: the dissolution of drug co-crystals goes through the process of the dissolution of hydrogen bond,the dissolution and escape of guest molecules,the "collapse" of co-crystals skeleton,the release of amorphous drug and slow crystallization of amorphous drugs.It provided a better method for the co-crystal strategy to solve the dissolution problem of other insoluble drugs.