| Drugs are an indispensable part of the global healthcare system,and help prevent and treat diseases.According to statistics,approximately 80-90% of candidate drugs in the research and development pipeline,as well as 40% of marketed drugs,belong to insoluble drugs,which seriously limits the development of Class II and Class IV drugs in the Biopharmaceutical Classification System(BCS).How to improve the solubility and dissolution rate of insoluble drugs,and further improve their bioavailability is one of the key challenges to be solved in pharmaceutical and chemical industries.To improve the solubility of insoluble drugs,drug solid state chemistry(solid dispersion and cocrystal)is the most potential and representative strategy.The recrystallization problem in the storage process of solid dispersants and the rapid desaturation problem in the microenvironment of drug release are important factors limiting their development.Compared with amorphous materials,cocrystal materials have stronger stability and are an effective way to avoid patent protection in original research.Cocrystal synthons typically choose functional groups with hydrogen bond receptors and donors.It is very important to select synthons intelligently from the huge cocrystal synthon library and control the physical and chemical properties of cocrystal purposefully.The research commonness of drug solid state chemistry method is the problem of stability between drugs and excipients.The scientific problem is the thermodynamic multi phase equilibrium between drugs and multi excipients,and the problem of drug transfer at the solid-liquid interface in complex systems at nanoscale and microscale.In this work,firstly,through the coupling of solid-liquid phase equilibrium theory and perturbed chain statistical associative fluid theory(PC-SAFT),the phase diagrams of drugs in binary and ternary systems were established,and the effects of polymers,humidity,and small molecular compounds on drug phase equilibrium were explained to guide the design and storage of solid dispersion.Then,two types of oxaprozin cocrystal molecules were prepared to enhance the solubility of the insoluble drug oxaprozin.Lastly,based on the principle of nonequilibrium thermodynamics,a two-step chemical potential gradient model was established to discuss the mass transfer mechanism of drug crystallization,and determine the speed control steps of crystal growth.The specific research content is as follows:(1)Differential scanning calorimetry(DSC)and PC-SAFT were used to determine and model the phase diagrams of drugs(mesalazine and allopurinol)in binary systems with polymer excipients(PEG,PVP and HPMC),respectively,and density functional theory(DFT)was used to explore the drug and polymer interaction mechanisms.The research shows that PVP,HPMC and PEG can increase the solubility of mesalazine and allopurinol solid dispersions,in which PVP and HPMC have better effects than PEG.DFT calculations found that hydrogen bonding is the key noncovalent bond affecting the physical stability of solid dispersions.Solid liquid equilibrium theory and PC-SAFT coupling to model the drug thermodynamic phase behavior in polymer excipient binary systems and further accurately predicte the drug solubility in polymer/water ternary systems,where the mesalazine and allopurinol system prediction ARD were less than 8% and 6%,respectively.This theoretical approach is expected to predict drug dissolution in ternary systems.It can be used to guide solid dispersion excipient screening to achieve poorly soluble drug solubilization purpose and reduce massive human,material,and financial consumption.It is an effective way to realize smart design of pharmaceutical formulations in the future.(2)The effects of different temperatures,relative humidity(RH),and polymers on the long-term stability of solid dispersions were explored by powder X-ray diffractometer(PXRD),and DFT was used to explore the interactions between drugs and polymers.The research shows that the moisture uptake of solid dispersions increases significantly with increasing RH.The risk of drug crystallization increases significantly with increasing drug loading in the solid dispersion under the same storage environment.DFT calculations show that drugs and polymers can spontaneously generate mutual attraction,and hydrogen bond is one of the important factors affecting the physical stability of solid dispersions.PC-SAFT and Gordon-Taylor equation were used to predict the phase behavior of drugs and the glass transition temperature of solid dispersion under different RH,which was basically consistent with the stability of solid dispersion measured experimentally.This theoretical approach helps aid in the design of solid dispersion drug loading and the selection of a drug storage environment to extend the stability(expiration)of drug formulations.(3)Five types of oxaprozin eutectic compounds were designed and prepared,namely oxaprozin-isoniazid,oxaprozin-isoniazid,oxaprozin-maleic acid,oxaprozin-aspirin,and oxaprozin-pyrazinamide.The experiments show that the melting point of oxaprozin decreases by 41 ℃,30 ℃,44 ℃,45 ℃,and 24 ℃,respectively.The PC-SAFT model established above accurately calculates the eutectic phase behavior,and the average relative deviation is less than 5%,indicating that PC-SAFT is suitable for solid dispersion with polymer and small molecular compound as the carrier.The solubility of eutectic oxaprozin-isoniazid,oxaprozinisoniazid,and oxaprozin-pyrazinamide in pure water was increased by 58%,24%,and 8%,respectively,compared to oxaprozin.The solubility in p H 6.8 buffer was increased by 6%,6%,and 15%,respectively.This indicates that eutectic is an effective solubilization strategy.Molecular dynamics(MD)calculations indicate that the hydrogen bond ratio between oxaprozin and compound molecules is higher than that of oxaprozin itself,indicating that hydrogen bonding is the driving force for solubilization of eutectic compounds.(4)Two types of oxaprozin eutectic were designed and prepared.Compared with oxaprozin,the solubility of oxaprozin-nicotinamide and oxaprozin-benzoamide increased by11% and 2% in pure water,and increased by 15% and 27% in p H 6.8 buffer.Eutectic compounds oxaprozin-isonicotinamide and oxaprozin-isoniazid increased permeability by 26%and 14%,respectively,while cocrystal oxaprozin-nicotinamide and oxaprozin-benzoamide increased permeability by 26% and 16%,respectively.Release kinetics studies have shown that eutectic compounds(oxaprozin-isonicotinamide,oxaprozin-isoniazid,and oxaprozinpyrazinamide)and cocrystal compounds(oxaprozin-nicotinamide and oxaprozin-benzoamide)significantly increase the release rate of oxaprozin in pure water systems.Two step chemical potential gradient model analysis shows that the eutectic and cocrystal release are mainly controlled by the surface reaction,indicating that small molecular compounds can enhance the surface reaction stage of drug release process.The two-step chemical potential gradient model based on non-equilibrium thermodynamics can analyze the speed control steps of drug release process and reveal the drug release mechanism.(5)The effects of PVP,PGE,and HPMC on the crystallization kinetics of allopurinol were studied using a cooling method.Research has shown that the inhibition rate of 0.5%HPMC on allopurinol growth is 20.9%,much higher than 2% PVP(12.1%),2% PEG 6000(11.5%),and 2% PEG 400(15.2%).A two-step chemical potential gradient model was established to study the crystal growth mechanism of allopurinol and mesalazine.The research results indicate that the crystal growth of allopurinol and mesalazine is controlled by surface reactions in both pure water and polymer containing systems,and the surface reaction order significantly increases with the increase of inhibition.In addition,the two-step chemical potential gradient model successfully predicted the crystal growth kinetics of allopurinol and mesalazine at a certain temperature and stirring rate,and the average relative errors between the prediction results and the experimental data were 6.5% and 2.5%,respectively.The two-step chemical potential gradient model based on non-equilibrium thermodynamics combined with accurate kinetic experimental data can describe,predicte and regulate crystal growth rate. |
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