Screening Of Cosolvents For Poorly Soluble Drugs And Research On Their Interactions

The therapeutic effect of a drug depends on its bioavailability and ultimately on the solubility of the drug molecule.The solubility of a drug is one of the important parameters to achieve the required drug concentration in the systemic circulation to exert its pharmacological effects.Due to poor water solubility,currently more than 40% of lipophilic drug candidates cannot be marketed.Therefore,this experiment selected four poorly water-soluble drugs: chloramphenicol,indomethacin,ibuprofen,riboflavin,and theophylline were selected as model drugs,and arginine,meglumine,nicotinamide,urea,glycine and sodium salicylate were used as cosolvent.The solubilization effect of each cosolvent on each drug was studied by phase solubility,and the better cosolvent for model drug was selected.Differential scanning calorimetry,X-ray diffraction,Fourier infrared chromatography were used to characterize and study the interaction between the drug and the cosolvent.Finally,by measuring the apparent oil-water partition coefficient of the drug in different p H phosphate buffers,the effect of the cosolvent on the fat solubility of the drug in the gastrointestinal tract was investigated.Part one Screening of poorly soluble drug co-solventsObjectives: Screen out the cosolvent with better dissolving effect on poorly soluble drugs.Methods: Excessive IBU,IN,RIB,THEO were added to different concentrations of Arg,MEG,NIC,UR,Gly,SS in aqueous solutions,stirred for 24 h,then filtered,and UV spectrophotometry was used to determine the drug at different concentrations,and the curve of drug solubility and cosolvent concentration was drawn;the p H values of different concentrations of co-solvents were measured,and the relationship between drug solubility and co-solvent concentration and p H was plotted.Results: The solubility of IN increases with the concentration of Arg,MEG,NIC,UR,Gly,etc.Among them,Arg and MEG have better solubilizing effects on IN;the solubility of IBU increases with the increase of Arg and MEG concentration.Moreover,these two co-solvents have better dissolving effects on IBU;Arg,MEG,NIC,UR,Gly,SS have poor dissolving effects on riboflavin;the solubility of THEO varies with Arg,MEG,NIC,UR,Gly,SS Increase with the increase of concentration.Among them,Arg,MEG,NIC,and SS have better solubilizing effects on THEO;the solubility of IN,IBU,THEO increases with the increase of the p H value of Arg and MEG,and the solubility of THEO increases with the decrease of the p H value of NIC.Conclusion: The results showed that Arg and MEG had better solubilization effect on IN and IBU,and Arg,MEG,NIC and SS had better solubilization effect on THEO,the solubility of the drug is related to the p H of the co-solvent.Part two Study on the interaction between poorly soluble drugs and cosolventsObjectives: Characterize the drug cosolvent complex,and study the mechanism of the solubilization effect of the cosolvent on poorly soluble drugs.Methods: The drug cosolvent complex powder was prepared by freeze-drying method,and the formation mechanism of the complex was analyzed by X-ray diffraction method,differential scanning calorimetry,Fourier infrared chromatography.Results: The XRD,DSC also indicates that IN and Arg and MEG have generated new amorphous substances in water;IBU interacts with Arg and MEG in water to form new amorphous substance;THEO interacts with Arg in water to form new substance;THEO and MEG have generated new amorphous substances in water;THEO interacts with NIC in water to form new eutectic substance;THEO interacts with SS in water to form a new substance.The results of FTIR showed that both IN and IBU reacted with Arg and MEG to form amorphous substance,which improved the solubility;THEO and Arg formed THEO-Arg complex through the conjugation effect between purine of THEO and guanidine of Arg;the hydrogen bond between THEO and MEG formed amorphous THEO-MEG complex;purine of THEO reacted with pyridine ring of NIC and benzene ring of SS has a π-π conjugate effect to form THEO-NIC、THEO-SS complex.Conclusion: In this part,XRD,DSC and FTIR were used to determine that the mechanism of cosolvent improving the solubility of insoluble drugs is mainly related to the cosolvent and the functional groups in the molecular structure of the drug itself.The appropriate cosolvent can be selected according to the acidity and basicity of the functional groups of the drug itself and whether there are aromatic rings.Part three Determination of the apparent oil-water partition coefficient of poorly soluble drugs and drug-cosolvent complexesObjectives: Determine the apparent oil-water partition coefficient of drugs and drug cosolvent complexes in different p H phosphate buffer solutions.Methods: The mass concentration of the drug was determined by high performance liquid chromatography,and the apparent oil-water partition coefficient of the drug and drug co-solvent complex was determined by the constant temperature shaking-shaking flask method in a water bath.Results: At 37℃,the lg P values of indomethacin and its complexes with arginine and meglumine in the range of ph1-8 phosphate buffer were-1.08～1.72;at 37℃,the lg P values of ibuprofen and its complexes with arginine and meglumine in the range of ph1-8 phosphate buffer were-0.37～1.49;at 37℃,the lg P values of theophylline and its complexes with arginine,meglumine,nicotinamide and sodium salicylate were-0.37～1.49 The LGP value in the range of phosphate buffer was-0.06～0.32.Conclusion: Indomethacin,ibuprofen,and theophylline are all fat-soluble drugs,and the apparent oil-water partition coefficients of ibuprofen and indomethacin in phosphate buffer solution are all related to the p H value of the medium,and decrease with the increase of the p H value of the medium.The use of cosolvents arginine,meglumine,nicotinamide,and sodium salicylate will not reduce the fat solubility of indomethacin,ibuprofen,and theophylline in the gastrointestinal tract.