| The research and development of drugs is a key point in the field of life and health.The insoluble drugs,due to their special molecular structure containing polar groups,usually have intermolecular interactions dominated by hydrogen bonding,and are prone to crystallization under hydrogen bonding-induced action,which in turn leads to poor water solubility and low bioavailability of the drugs.This defect seriously hinders the promotion and application of related drugs.Accordingly,the technology of solid dispersion has been widely adopted in the drug preparation process,which can reduce the particle size of insoluble drugs and make them easy to be dispersed in the matrix by miscible solubility of hydrophilic excipients and drugs to produce powder products.At present,the preparation,characterization and performance testing of solid dispersions have achieved multifaceted and multidimensional development.However,most of the studies on solid dispersions of insoluble drugs rely on trial-and-error experimental methods,and there are deficiencies of insufficient quantitative analysis at the micro-molecular level,such as excipient material screening,evaluation criteria,material and formulation design,etc.,and the exploration of their theoretical mechanisms still needs to be improved.Therefore,this project adopts the multi-scale molecular simulation technology and combines the experimental characterization means to analyze,screen and design the molecular structure of excipients composed of solid dispersions for the different characteristics of the molecular structure of difficult-to-solve drugs,with a view to improving the solubility of the drug specimens.The specific research includes the following five parts:(1)A combination of experimental and molecular simulation methods was used to investigate the microscopic mechanisms and properties of the interactions between the solid dispersions formed by myricetin(MYR)and three polymer excipients(polyvinylpyrrolidone(PVP),hydroxypropylmethylcellulose(HPMC),and poly(ethylene glycol)(PEG))with the aim of screening out the optimal excipients.The enhancement of drug dispersibility by solid dispersion modification techniques was demonstrated by experimental means such as Differential Scanning Calorimetry(DSC),X-ray Diffractometry(XRD),and Scanning Electron Microscopy(SEM).Monte Carlo(MC)and molecular dynamics(MD)simulations were used to analyse the micro-mechanisms,and it was found that the effects of promoting the dispersibility of MYR were PVP>HPMC>PEG in descending order.Based on the qualitative analysis method of Fourier infrared(FT-IR),for the study of intermolecular interactions,the quantitative analysis of the energy and concentration of intermolecular hydrogen bonding in the three systems was carried out by combining quantum mechanical(QM)and MD simulation,and the results were obtained to be consistent with the order of the effect of dispersibility of MYR.The energy and concentration of intermolecular hydrogen bonds were calculated,and results consistent with the order of effect of dispersibility were obtained.The reliability of the simulation results and microscopic mechanism analysis is further confirmed by relevant experiments such as dissolution testing,cell activity and reactive oxygen species(ROS)level detection in solid dispersions.This work is expected to explain the solubilization mechanism of solid dispersions at the molecular level and provide a theoretical basis for the screening of polymer excipient materials for solid dispersions.(2)Some commercial polymer excipients for improving the solubility of highly crystalline insoluble drugs have been widely used,but they still cannot cover all types of insoluble drugs.For this reason,this section of the work takes the antiepileptic drug phenytoin(PNT)as the research target,and combines the relevant theories and methods in(1)to design the molecular structure of the polymer excipient for phenytoin.The optimal structures,No.5(Ni PAm)and No.11(HEAm),were identified from 11copolymer units by QM simulation method based on molecular activity,associative dimer conformation,and thermodynamic parameters of hydrogen bond dissociation.On this foundation,the compatibility was analysed using MC simulation method to define the copolymerization ratio of the designed polymer excipients and the molecular structure of the final material,P(N-co-H),was made clear.MD simulation was used to predict the properties from the perspectives of molecular mobility,binding energy,and the strength of hydrogen bonding,which proved that the binding energy of the designed P(N-co-H)with PNT was higher than that of the commercial PVP with PNT,and it was expected to improve the dispersibility of PNT.This part relies on simulation methods at different scales of QM,MD and MC to complete the molecular structure design of the target drug excipients.(3)The experimental validation was carried out for the polymer excipient P(N-co-H)designed in(2).Firstly,the target polymers were synthesized by free radical polymerization method.The successful synthesis of P(N-co-H)was evidenced by the test results of Fourier infrared spectroscopy(FT-IR),nuclear magnetic resonance hydrogen spectroscopy(~1H NMR)and gel resonance chromatography(GPC).Afterwards,it was mixed with the target drug phenytoin(PNT)to prepare solid dispersions,which were characterized by XRD,DSC and SEM,confirming that PNT modified by the synthesized polymer P(N-co-H)was transformed from crystalline to amorphous state.The results of the performance tests showed that the solid dispersion prepared with P(N-co-H)was superior to the samples containing PVP in terms of drug solubility and cell membrane permeability,which was in accordance with the simulation results of(2).The results of this experiment confirm the effectiveness of the molecular simulation method to assist the molecular structure design of polymer excipients.(4)From the related studies of(1)-(3),it can be seen that the preparation of solid dispersions by mixing insoluble drugs with polymers is the main method to improve the aqueous solubility of drugs.Meanwhile,some researchers have introduced the third component of organic small molecules into this binary solid dispersion,and this method further improves the solubility of the drug by modulating the intermolecular hydrogen bonding in the system.In this part of the study,the antiepileptic drug carbamazepine(CBZ)was used as the target drug and polyvinylpyrrolidone(PVP)as the polymer matrix of the solid dispersion.According to the principle of similarity of solubility parameters,the third component was screened from 13 organic small molecules that were more compatible with the binary solid dispersion.The hydrogen bonding parameters and dissociation Gibbs free energy of the organic small molecule-CBZ dimer were calculated by QM simulation,and the optimal organic small molecule third component of tryptophan(Try)for this system was clarified.The mobility and binding strength of CBZ drugs in binary and ternary systems were analysed by MD simulation methods.Subsequently,on the basis of this theoretical study,the corresponding solid dispersions were prepared by solvent method and subjected to microstructural characterisation and solubility analysis,and it was verified that the solid dispersion samples with the addition of Try as the third component of organic small molecules had better solubility,which was in agreement with the simulation prediction.(5)In addition to the carrier types discussed in(1)-(4),related studies have shown that different ratios of drug to excipient within the solid dispersion also have an effect on the performance of the solid dispersion for practical applications.In this regard,CBZ/PVP solid dispersions with carbamazepine CBZ content ranging from 10%to 50%were prepared,and XRD,DSC,and FT-IR experimental tests confirmed that the higher the drug content,the more crystalline the solid dispersion was,and the glass transition temperature was shifted to a lower temperature.On this point,a combination of QM and MD simulation methods was used to simulate the energy transfer of hydrogen bond dissociation,radial distribution function,and molar concentration of intermolecular hydrogen bonding from parameters such as molecular point of view,which confirmed that the proportion of hydrogen bonding between drug-drug(CBZ-CBZ)molecules increased with the increase of CBZ content in the solid dispersions,whereas the proportion of CBZ-PVP intermolecular hydrogen bonding decreased,which in turn led to the crystallization of the drug.The simulation results quantify the different crystallization phenomena caused by solid dispersions with different drug contents,and provide theoretical support for the formulation design of solid dispersions of insoluble drugs. |
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