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.
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
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
Abstract: Amorphous solid dispersion (ASD) formulations are widely used to delivery poorly soluble drugs for dissolution enhancement and bioavailability improvement. When administered, ASDs often exhibit fast dissolution to yield supersaturated solutions. The physical chemistry of these supersaturated solutions is not well understood. This review will discuss the concepts of solubility, supersaturation, and the connection to membrane transport rate. Liquid-liquid phase separation (LLPS), which occurs when the amorphous solubility is exceeded, leading to solutions with interesting properties is extensively discussed as a phenomenon that is relevant to all enabling formulations. The multiple physical processes occurring during dissolution of the ASD and during oral absorption are analyzed. The beneficial reservoir effect of a system that has undergone LLPS is demonstrated, both experimentally and conceptually. It is believed that formulations that rapidly supersaturate and subsequently undergo LLPS, with maintenance of the supersaturation at this maximum value throughout the absorption process, i.e. those that exhibit “spring and plateau” behavior, will give superior performance in terms of absorption.
Pub.: 22 Mar '16, Pinned: 30 Dec '17
Abstract: Ordered mesoporous silica (OMS) has been recognized as promising adsorbent material for drug molecules with low aqueous solubility. The release of drug molecules from OMS upon contact with aqueous environment enhances their oral bioavailability. The release is governed by a complex interplay of adsorption, diffusion, and intermolecular interaction inside OMS pores. The presence of water hampers in situ FT-IR investigation of the behavior of the drug molecules upon release. The poorly water-soluble etravirine molecule having two nitrile functions was selected for an in situ FT-IR spectroscopic investigation of the release process. The stretching vibration of the nitrile organic function (υ(CN)) is a spectral feature that is accessible to FT-IR even in the presence of water. Etravirine depending on the loading was found to be present in SBA-15 pores as isolated adsorbed molecules, solvated molecules, and aggregates with intermolecular interaction similar to the crystalline state, each with a different spectroscopic fingerprint. Etravirine evacuation from the SBA-15 pores was shown to proceed in the solvated state. Surprisingly, the etravirine clusters inside pores were converted more readily into solvated molecules compared to individually adsorbed molecules.
Pub.: 21 Dec '12, Pinned: 30 Dec '17
Abstract: Aqueous solubility of an active pharmaceutical ingredient is an important consideration to ensure successful drug development. Mesoporous materials have been investigated as an amorphous drug delivery system owing to their nanosized capillaries and large surface areas. The complex interactions of crystalline compounds with mesoporous media and their implication in drug delivery are not well understood. Molecules interacting with porous media behave very differently than those in bulk phase. Their altered dynamics and thermodynamics play an important role in the properties and product performance of the amorphous system. In this review, application of mesoporous silicon dioxide and silicates in drug amorphization is the main focus. First, as background, the nature of gas-porous media interactions is summarized. The synthesis of various types of mesoporous silica, which are used by many investigators in this field, is described. Second, the behavior of molecules confined in mesopores is compared with those in bulk, crystalline phase. The molecular dynamics of compounds due to confinement, analyzed using various techniques, and their consequences in drug delivery are discussed. Finally, the preparation and performance of drug delivery systems using mesoporous silica are examined.
Pub.: 07 Oct '11, Pinned: 30 Dec '17
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