Study On The Formation Mechanism And Properties Of Norfloxacin Solid Dispersion

Solid dispersion(SD)technology,as an effective means to control drug dissolution and improve the bioavailability of drugs,has been widely concerned.However,the mechanism of SDs' formation and performance is still in the exploration stage.Besides,there is still a lack of reasonable and effective carrier screening strategies.In this work,Norfloxacin(NFX)was used as a model drug,and PVP,HPMC and HPMCP were selected as carriers to form SDs.By investigating the drug-polymer miscibility and interaction of NFX/polymer systems,we laid the foundation of SD's preliminary design from a molecular perspective.The solid form,physical stability and dissolution properties of SDs in simulated gastric-intestinal media were explored.The relationship among these factors was further investigated to reveal the formation mechanism of NFX/polymer SDs,and to achieve a deep understanding of the structure(drug-carrier miscibility and intermolecular interaction)-performance(physical stability and dissolution behavior)relationship.The key to the development of SD carrier screening strategy and molecular design theory is to understand the interaction of drug-carrier.The miscibility of NFX with three polymers was evaluated qualitatively and quantitatively through Hansen solubility paramerter and Flory-Huggins interaction parameter.The the rank ordering of drugcarrier miscibility was NFX-HPMCP > NFX-HPMC > NFX-PVP.PXRD and FT-IR were combined to study the drug-carrier interaction within NFX/polymer SDs.When PVP and HPMC were used as carriers,NFX interacted with polymer in the form of hydrogen bonds,while when HPMCP was used,the drug-carrier interaction was dominated by ionic bonds.The the strength of interactions can be NFX-HPMCP >NFX-HPMC > NFX-PVP.It is concluded that there is a close relationship between drug-carrier miscibility and intermolecular interaction.By employing molecular dynamics simulation approach,a promising carrier screening method for NFX/polymer SDs was developed,which provides theoretical basis for molecular design of SDs.To solve the problem that the formation mechanism of solid dispersion is unclear,the different dispersion forms of drug in carriers were explored from the molecular level.Combined with PXRD,VT-PXRD,TGA-DSC,fluorescence,XPS and FT-IR spectra techniques,different dispersion forms of NFX in carriers(amorphous state,hydrated state and crystalline state)was observed in SDs with various formula and proportion.Based on the drug-carrier interaction and radial distribution function(RDF),a drugwater-carrier model was constructed.It was found that the key factors affecting the dispersion form of the drug includes: NFX-polymer hydrogen bonds/ionic interactions,water-NFX-NFX protonation,and NFX-NFX association.The formation of different SDs of NFX/polymer depends on the competition among the above interactions.Different microscopic characteristics of drug/polymer system may lead to different performances of SDs.It was observed that the rank ordering of robustness to crystallization of three NFX/polymr SDs was NFX/HPMCP > NFX/HPMC >NFX/PVP.Induced by water molecules,NFX molecules were self-protonated,and the formed NFX-NFX ionic interactions competed with drug-carrier interaction,which leads to the aging of SDs.In the simulated gastric media,it was found that three polymers did not improve or even delay the drug release.The drug release from SDs was influenced by the properties of the polymer,the drug-carrier compatibility and the interactions,performing a non-classical drug release phenomenon.In the simulated small intestinal liquid,NFX shows excellent supersaturation maintenance ability in the presence of HPMCP,followed by HPMC and PVP.The key factor was found to be the specific form of drug-carrier interaction.