A pinboard by
Tahnee Dening

PhD Candidate, University of South Australia


Characterising drug release and supersaturation of ritonavir from mesoporous silica

My research focuses on investigating mesoporous silica drug delivery systems and their ability to generate and maintain drug supersaturation in the gastrointestinal tract. Mesoporous materials are materials that are porous, with high surface areas and very small pores in the size range of 2-50 nanometres.

Poorly water-soluble drugs are not well absorbed from the gastrointestinal tract into the bloodstream, since they do not dissolve well in the watery gut environment. Simply, if a drug does not dissolve, it cannot be absorbed. Importantly, recent estimates suggest that up to 90% of all new drug molecules under development are poorly water-soluble.

Drug crystals are often very large i.e. hundreds of microns in diameter and take a long time to dissolve if a drug is poorly water-soluble. To overcome this issue, drugs may be dissolved in organic solvents and loaded into the pores of mesoporous materials. The very small mesopores restrict the drug molecules (one drug molecule is often a few nanometres in size) from reforming drug “crystals” when the solvent is removed, due to space restrictions. Thus, drug in mesoporous delivery systems does not need to dissolve as it is in the non-crystalline form, and absorption from the gut into the bloodstream is improved. This leads to enhanced drug efficacy.

Since mesoporous drug delivery systems are gaining popularity for improving poorly water-soluble drug delivery, fundamental studies into the ability of these systems to generate drug supersaturation (i.e. drug dissolved at levels higher than the crystalline drug solubility, which drives drug absorption) are important for progressing their application and commercial success. In my research, we have found that mesoporous silica is capable of generating supersaturated solutions of the poorly water-soluble drug, ritonavir, in simulated intestinal fluids. This increased drug concentration in solution relative to crystalline drug material results in a higher transfer rate of drug across an artificial membrane that mimics the gut. Accordingly, an increased rate and extent of drug absorption into the bloodstream can be expected for drug loaded in mesoporous silica. Importantly, we also observed that drug release from mesoporous silica is always incomplete. A percentage of drug remains irreversibly bound to the silica surface, due to strong hydrogen bonding interactions. Various studies have been undertaken to characterise the nature of interaction between drug and silica.


Role of drug adsorption onto the silica surface in drug release from mesoporous silica systems.

Abstract: Factors contributing to incomplete drug release from a number of mesoporous silica formulations are not well understood. This study aims to address this gap in knowledge by exploring the role of drug adsorption onto silica substrates during the drug release process in dissolution media. Adsorption isotherms were generated to understand drug adsorption behaviour onto the silica surface. Two silica materials were selected (SBA-15 (mesoporous) and Aerosil®200 (non-porous)) to investigate the influence of porous architecture on the adsorption/dissolution processes. The ability of the dissolution medium to wet the silica surface, particularly the porous network, was investigated by the addition of a surfactant to the dissolution medium. The results demonstrated that a larger amount of drug was bound/m2 to the non-porous surface than to the mesoporous material. Adsorption isotherms proved useful in understanding drug adsorption/release behaviour for the non-porous silica formulation. However, the quantity of drug remaining on the mesoporous silica surface after dissolution was significantly higher than the amount predicted using adsorption isotherm data. These results suggest that a fraction of loaded drug molecules were tightly bound to the silica surface or attached to sites which are inaccessible for the dissolution media. The presence of surfactant, sodium dodecyl sulphate, in the media enhanced drug release from the silica surface. This behaviour can be attributed to both the improved wetting characteristics of the media and adsorption of the surfactant to the silica surface. The findings of this study reinforce the significance of the role that silica porous architecture plays in the dissolution process and indicates that accessible surface area is an important parameter to consider for mesoporous systems in relation to drug release.

Pub.: 09 Dec '17, Pinned: 30 Dec '17

Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs.

Abstract: Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies.

Pub.: 03 Jan '14, Pinned: 30 Dec '17