Volitaki, Charitini; (2023) Electrospraying as a Means of Loading Itraconazole onto Mesoporous Silica for Enhanced Dissolution. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mesoporous silica particles (MSPs) have been investigated as potential carriers to increase poorly water-soluble drugs' apparent solubility and dissolution rate. It is important to understand both these systems' solid-state characteristics and performance profiles to develop optimised and robust dissolution systems. In addition, the drug loading method plays a critical role in drug loading degree, distribution and solid state, making it challenging to produce mesoporous silica particles loaded with a drug in the amorphous state at high drug loading. In this study, the use of electrospraying as a means of producing amorphous drug-loaded MSPs at high drug loading was explored. Itraconazole (ITZ) a poorly soluble drug, and Syloid 244FP were selected for this research. The solid state of the drug in all formulations was assessed using Powder X- ray diffraction (PXRD) and Differential Scanning Calorimetry (DSC). The drug release profiles were determined by a comparative in vitro drug release test. A physical stability assay was performed for the drug-loaded MSPs produced by electrospraying and rotary evaporation. A range of concentrations of silica suspension that can be electrosprayed in a suitable solvent was determined. Electrospraying was effective in loading itraconazole in MSPs in the amorphous state at low (10% w/v) and high (30% w/v) drug loadings, which presented release profiles with prolonged supersaturation. Additionally, the drug loading concentration significantly affected the duration and degree of supersaturation. Adding polyvinylpyrrolidone K 30 (PVP K30) at a low concentration resulted in a drug- loaded MSP formulation at high drug loading and itraconazole in the amorphous state with prolonged supersaturation. Increasing the concentration of the polymer did not result in a proportional increase in precipitation inhibition. In comparison, the use of rotary evaporation was ineffective in loading MSPs with high amounts of amorphous itraconazole, as the crystalline drug was present at the highest drug-loaded formulation. Furthermore, most formulations prepared by rotary evaporation presented the same burst release followed by precipitation on their drug release regardless of their drug loading. The results suggested that electrospraying is a more efficient method compared to rotary evaporation in producing amorphous ITZ-loaded Syloid 244FP formulations even at relatively low drug loading (concentration and ratio). What is more, drug loading concentration appears to be a key factor in determining the drug release profiles of the formulations due to either the varying distribution of itraconazole in the formulations or the difference in drug release from physically entrapped and molecularly bound drug molecules. Above a certain drug loading concentration, the drug-to-carrier ratio influences the extent of the supersaturation. Synchrotron PXRD-DSC analysis revealed that itraconazole existed in one physical form (polymorph I) in the formulations prepared by rotary evaporation. High drug-loaded MSPs with itraconazole in the amorphous state were successfully prepared by electrospraying. This proved that it is a more effective technique in achieving this than rotary evaporation. What is more, release profiles of prolonged supersaturation were achieved by adding PVP K30 polymer at a low concentration. The advanced characterisation technique of synchrotron PXRD-DSC allowed for the elucidation of the physical form of ITZ in the formulations. This research highlights the importance of drug loading concentration for achieving desired drug release profile for poorly water- soluble drugs.

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