Elsevier

Journal of Controlled Release

Volume 307, 10 August 2019, Pages 186-199
Journal of Controlled Release

Application of an adsorption isotherm to explain incomplete drug release from ordered mesoporous silica materials under supersaturating conditions

https://doi.org/10.1016/j.jconrel.2019.06.028Get rights and content

Abstract

Ordered mesoporous silica (OMS) materials have received significant attention in recent years for use as effective supersaturating oral delivery systems for poorly water-soluble drugs. Whilst OMS materials are indeed capable of generating drug supersaturation, previous research has demonstrated incomplete drug release to always be a feature of OMS formulations. A dynamic adsorption equilibrium between drug adsorbed to OMS and free drug in solution has been hypothesized as the underlying cause of incomplete release. Therefore, the aim of this study was to characterize the adsorption of hydrophobic ritonavir (as a model poorly water-soluble drug) to OMS from supersaturated solutions. Importantly, this study represents the first report of drug adsorption by mesoporous materials under supersaturating conditions. Extensive adsorption of ritonavir from solution by mesoporous SBA-15 silica was observed for the concentration range spanning below the crystalline solubility to slightly above the amorphous solubility of ritonavir, with the extent of drug adsorption increasing with the extent of supersaturation. The Brunauer-Emmett-Teller (BET) isotherm equation (adapted for solution phase adsorption) provided the best fit to the adsorption data (R2 = 0.94) and afforded important mechanistic insights. Hydrogen bonding between ritonavir and SBA-15 surface silanols drives adsorption from subsaturated/saturated solutions, whereas the increased thermodynamic activity of the drug drives adsorption from supersaturated solutions. These observations account for the incomplete release of drug molecules from OMS materials under both dilute and supersaturating conditions. In summary, the high surface free energy of OMS materials and high reactivity of surface silanol moieties leads to incomplete drug release under a wide range of dissolution conditions. The findings described herein have significant implications for the application of OMS materials for oral drug delivery, especially for poorly water-soluble drugs which rely on supersaturation for adequate exposure in vivo.

Introduction

Recent estimates suggest that up to 90% of all drug candidates in development possess low aqueous solubility and/or high hydrophobicity characteristics [1,2]. Many enabling formulation strategies are available to increase oral bioavailability, and of these, ordered mesoporous silica (OMS) materials have become an increasingly popular delivery system given their ability to increase drug dissolution and absorption from the gastrointestinal tract [[3], [4], [5], [6]]. OMS materials, such as MCM-41 and SBA-15, possess very large specific surface areas (SSA) in the range of 500–1000 m2/g because of their mesoporous nature [5]. The adsorption of poorly water-soluble drug molecules within the small mesopores of OMS materials (mean pore diameter 2–30 nm) allows the drug to exist in a non-crystalline and thermodynamically stable form, owing to an overall decrease in the Gibbs free energy of the system [[6], [7], [8], [9]]. Under non-sink conditions, OMS delivery systems can rapidly release encapsulated drug cargo and generate supersaturated solutions due to displacement of drug molecules from the silica surface by water [6,[10], [11], [12], [13], [14]]. It is this ability of OMS to increase the rate and extent of drug dissolution and generate supersaturation that has led to significant interest in the utility of these unique delivery systems [10].

In a recent study by our group, the ability of OMS materials to generate and maintain drug supersaturation was comprehensively investigated for the first time [6]. Dissolution of ritonavir, when loaded into mesoporous SBA-15 silica, led to supersaturated drug solutions in both phosphate buffer and fasted state simulated intestinal fluid (FaSSIF). However, as the formulation dose and theoretical supersaturation ratio (S) was increased, percentage drug release from SBA-15 decreased significantly. Further, complete release of encapsulated drug cargo was never achieved. A dynamic adsorption equilibrium between drug adsorbed to SBA-15 and free drug in the supersaturated solution was hypothesized, in which the equilibrium shifts towards greater drug adsorption at higher formulation doses (which lead to higher S) and incomplete drug release occurs:Adsorbed drug+solvent in solutionAdsorbed solvent+drug in solution

Our observations were supported by previous research that also demonstrated incomplete drug release from OMS under supersaturating conditions [3,[12], [13], [14], [15], [16], [17], [18]], and likewise, proposed a dynamic adsorption equilibrium to be responsible [12]. Given that the solution is supersaturated, the equilibrium between OMS and poorly water-soluble drug is a metastable equilibrium, since a lower energy state can be achieved via drug crystallization. The large SSA of OMS leads to a high surface free energy, and the equilibrium shift as S increases is likely attributable to a reduction in solute chemical potential as drug molecules adsorb to OMS in a more thermodynamically stable state [[7], [8], [9], [10]]; it should be noted that adsorption thus provides an alternate pathway to crystallization to lower the solute chemical potential. In the context of developing effective supersaturating drug delivery systems that enhance drug absorption in vivo, this adsorption phenomenon has important implications for the use of OMS materials. Further investigations are therefore warranted.

Importantly, several studies have characterized the physical state of drug molecules loaded in OMS materials, as well as the specific molecular interactions between drug molecules and silica in the solid state [[19], [20], [21], [22]]. However, the thermodynamics of drug-loaded OMS formulations in solution are poorly explored/understood. Few studies have examined the adsorption of drug molecules from solution by SBA-15 in the context of oral drug delivery. A recent study by McCarthy et al. explored the role of drug adsorption by porous (SBA-15) and nonporous (Aerosil 200) silica during in vitro dissolution under sink conditions [23], and Bui et al. examined the adsorption of five select drug molecules from solution by SBA-15 particles [24]. Both studies reported incomplete drug dissolution/desorption, supporting the notion that drug adsorption by SBA-15 is not completely reversible due to strong interactions with the silica surface. Critically, both of these studies examined drug adsorption by SBA-15 at a range of concentrations below the equilibrium crystalline solubility of the drug i.e. under “sink” conditions. To the best of our knowledge, drug adsorption from solution by OMS materials under supersaturating conditions has not been investigated. Given that these dosage forms are increasingly being employed for poorly water-soluble drug delivery, and that a major mechanism behind improved bioavailability is thought to be supersaturation generation, this is a key gap in our understanding of OMS delivery systems.

In this study, the adsorption of ritonavir from solution by SBA-15 particles under supersaturating conditions was studied by generating an adsorption isotherm, and Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) techniques were employed to gain insights into the adsorption mechanism(s) between ritonavir molecules and the SBA-15 silica surface. The aim was to characterize the adsorption phenomenon between hydrophobic drug molecules and OMS under supersaturating conditions. The hypothesis to be tested was that incomplete drug release under supersaturating conditions is due to adsorption to the OMS material, which becomes more favorable as the supersaturation increases. The influence of dissolution medium composition on drug release was also investigated; dissolution studies under supersaturating conditions in the presence of monomeric/micellar concentrations of neutral and anionic surfactants were undertaken. Here, the hypothesis to be tested was that surfactant molecules will compete for adsorption and displace adsorbed ritonavir molecules from the SBA-15 silica surface, thereby increasing the extent of drug release into solution.

Section snippets

Materials

Ritonavir was purchased from ChemShuttle (Hayward, CA). SBA-15 material with pore diameter 7.1 nm, pore volume 0.80 cm3/g and SSA 586 m2/g was supplied by Glantreo (Cork, Ireland). Vitamin E polyethylene glycol succinate (Vit E TPGS), sodium dodecyl sulfate (SDS), pyrene and urea were purchased from Sigma-Aldrich (St. Louis, MO). Buffer salts and analytical grade solvents were obtained from Fisher Chemical (Fair Lawn, NJ). The aqueous media used in all experiments was 50 mM sodium phosphate

Crystalline and amorphous solubility measurements

The crystalline and amorphous solubility of ritonavir in 50 mM phosphate buffer pH 6.8 in the presence of Vit E TPGS or SDS was determined as described previously [6]. To determine crystalline solubility, an excess of crystalline ritonavir (polymorph form II) was equilibrated in 15 mL medium using an agitating water bath (Dubnoff metallic shaking incubator, PGC Scientific, Palm Desert, CA) set at 37 °C for 48 h. Samples were then centrifuged at 21,100 ×g for 30 min (37 °C) to separate the

Crystalline and amorphous solubility

The crystalline solubility of ritonavir in 50 mM phosphate buffer pH 6.8 was previously determined to be 3.6 ± 0.6 μg/mL [6]. To assess the impact of the solubilizing additives, Vit E TPGS and SDS, on the degree of supersaturation, the crystalline solubility of ritonavir was measured in the presence of the surfactants (Table 1). The critical micelle concentration (CMC) values for Vit E TPGS and SDS in water are 212 μg/mL and 2.4 mg/mL, respectively [29,30]. Both additives were assessed at a

Adsorption of ritonavir from solution by SBA-15

In an earlier study by our group, it was demonstrated that incomplete ritonavir release was always a feature of OMS formulations when dosed under supersaturating conditions during in vitro dissolution or diffusive flux experiments [6]. Importantly, incomplete drug release persisted even when samples were diluted to at “sink” conditions. The major concept underlying the use of OMS as a supersaturating formulation is that drug is confined within the OMS mesopores in the amorphous form, with

Conclusions

In this study, extensive adsorption of ritonavir from supersaturated aqueous drug solutions by mesoporous SBA-15 silica was observed, with the extent of drug adsorption increasing with the extent of supersaturation. The adsorption isotherm, which was best fit by the Brunauer-Emmett-Teller (BET) isotherm equation, supported the presence of a significant driving force for ritonavir adsorption by SBA-15 from supersaturated solutions. This driving force was based on the increased thermodynamic

Acknowledgements

The Australian Government Endeavour Scholarships and Fellowships Program is gratefully acknowledged for the Endeavour Postgraduate Scholarship of Tahnee J. Dening. Mitulkumar Patel is acknowledged for his assistance in conducting ATR FTIR experiments, and Siddhi S. Hate is acknowledged for her assistance in collecting fluorescence data.

Declarations of interest

None.

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    Present address: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66047, United States.

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