| The poor solubility of the drug in water severely affects its clinical use.It is of great importance to measure and improve the solubility of poorly soluble drugs in the field of biomedicine.It is also necessary to choose different methods to improve the solubilities of insoluble drugs according to their own characteristics and applications.In the pharmaceutical industry,excipients are often used to increase the solubility of poorly soluble drugs.Excipients can be either polymers or drug molecules.Additionally,a huge amount of manpower,material and financial resources can be saved through a small amount of the determined solubility data to predict solubility under other conditions,or through theoretical analysis to design the solubilization strategy.In this work,aspirin,berberine and folic acid are selected as model drugs,and the experimental measurements,thermodynamics models and molecular dynamics(MD)simulations are employed to systematically investigate the solubilization of excipients,the prediction of solubility and the preparation of self-assembled nanodrugs,respectively.The main contents are as follows:1.The solubility of aspirin is experimentally determined in aqueous solutions in the presence of various polymeric excipients with different polymer contents at five temperatures.It is found that the solubility of aspirin has a positive correlation with the temperature and polymer concentration.All of five polymers(polyethylene glycol(PEG)6000,PEG 400,Polyvinylpyrrolidone(PVP)K25,hydroxypropyl methylcellulose(HPMC)E3 and Poloxamer188)show solubilization abilities,of which the solubilizing ability of poloxamer 188 is most affected by temperature and PVP K25 owns the best solubilizing capability.This can be ascribed to the strong capability of PVP K25 to establish hydrogen bonding with aspirin according to the density functional theory(DFT)calculation results.2.The solubility of aspirin in different systems is predicted based on solid-liquid equilibrium theory and thermodynamic model.The experimental solubility data of aspirin in binary systems and ternary systems is used to regress the interaction parameters of Wilson,NRTL and UNIQUAC models successfully.The average ARDs of Wilson,NRTL,and UNIQUAC models are 0.0300,0.0318,0.0305 for the binary aspirin-solvent systems,respectively,and those are 0.4214,0.1166,0.0861 for the ternary aspirin-polymer-water systems.In general,the UNIQUAC model has excellent prediction accuracy in both binary and ternary systems.3.The interaction between berberine(BBR)and folic acid(FA)is explored by MD simulations and DFT calculations.The theoretical feasibility of self-assembled nanodrugs of BBR and FA is systematically studied based on the analysis of solvent accessible surface area,hydrogen bond,structural properties,interaction energy,electrostatic potential distribution,and reduced density gradient.MD simulation results show that BBR and FA molecules can form stable aggregates in a short time;DFT calculations show that π-π stacking interactions play a dominant role in the process of aggregation of BBR and FA,and the electrostatic effect also shows a promoting effect.As a whole,it is theoretically possible to obtain self-assembled nanodrugs of BBR-FA.4.The anti-solvent method is applied to prepare BBR-FA self-assembled nanodrugs.The effects of p H,the addition order of alkali,and the ratio of BBR and FA on the preparation of assembled nanodrugs are investigated.The BBR-FA self-assembled nanodrugs are characterized by nuclear magnetic resonance hydrogen spectroscopy,scanning electron microscopy and dynamic light scattering methods.The results show that with BBR-FA molar ratio of 1:1,adding alkali first and adjusting the p H to around 7～8,then the prepared spherical nanodrug has the most uniform particle size(about 160 nm),and can be stored stably for at least one week without precipitation,which significantly improves the solubility of both two insoluble drugs. |
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