Mesoporous silica-based formulations of poorly soluble drugs may exhibit incomplete drug release due to drug remaining adsorbed on the silica surface. The goal of this study was (1) to evaluate the adsorption tendency of atazanavir from aqueous solution onto mesoporous silica (SBA-15) and (2) to determine if the drug release from mesoporous silica formulations was promoted by the presence of an absorptive compartment during dissolution testing.
Atazanavir (ATZ) formulations with different drug loadings were prepared by incipient impregnation. The solid-state properties of the formulations were analyzed by X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectroscopy and thermogravimetric analysis. Drug release was compared for closed compartment versus absorptive dissolution testing at gastric and intestinal pH.
XRD and DSC showed that all formulations were amorphous. Infrared spectra indicated intermolecular interactions between silanol groups in SBA-15 and carbonyl groups in atazanavir. Nanoconfinement of drug in silica mesopores was suggested by thermal analysis. Closed compartment dissolution testing showed incomplete drug release, largely due to the adsorption tendency of ATZ. However, coupled dissolution-absorption studies showed complete release over a 240 min time period. This suggested that the depletion of drug in the dissolution medium due to drug diffusion across the membrane promotes drug release. Drug release was further improved when the formulation was first added to fasted state gastric pH conditions followed by pH-shift to intestinal conditions, which was attributed to the higher solubility of atazanavir at low pH. However, ATZ mesoporous silica formulations showed a poorer overall absorption behavior relative to a polymer-based amorphous solid dispersion formulation.
This study highlights that absorptive dissolution conditions promote drug desorption from the silica surface and hence, enhance drug release. Further, the influence of solution pH on drug release underscores the need to consider how variations in physiological conditions may impact the performance of mesoporous silica-based formulations.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Amorphous Solid Dispersions
Differential Scanning calorimeter
Fourier Transform Infrared Spectroscopy
High pressure liquid chromatography
Liquid-Liquid Phase Separation
Mesoporous Silica-based Drug Delivery Systems
Powder X-ray Diffraction
Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315 LP–499.
Taylor LS, Zhang GGZ. Physical chemistry of supersaturated solutions and implications for Oral absorption. Adv Drug Deliv Rev. 2016;101:122–42.
Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: I. a thermodynamic analysis. J Pharm Sci. 2010;99(3):1254–64.
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited Oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.
Vallet-Regi M, Ramila A, Del Real RP, Pérez-Pariente J. A new property of MCM-41: drug delivery system. Chem Mater. 2001;13(2):308–11.
Vallet-Regí M, Balas F, Arcos D. Mesoporous materials for drug delivery. Angew Chemie Int Ed. 2007;46(40):7548–58.
Speybroeck, M. Van; Barillaro, V.; Thi, T. Do; Mellaerts, R.; Martens, J.; Humbeeck, J. Van; Vermant, J.; Annaert, P.; Den Mooter, G. Van; Augustijns, P. Ordered Mesoporous silica material SBA-15: a broad-Spectrum formulation platform for poorly soluble drugs. J Pharm Sci 2009, 98 (8), 2648–2658.
Vallet-Regí M, Colilla M, Izquierdo-Barba I, Manzano M. Mesoporous silica nanoparticles for drug delivery: current insights. Molecules. 2018;23(1):47.
Zhao D, Sun J, Li Q, Stucky GD. Morphological control of highly ordered Mesoporous silica SBA-15. Chem Mater. 2000;12(2):275–9.
Florek, J.; Guillet-Nicolas, R.; Kleitz, F. Ordered mesoporous silica: synthesis and applications. Funct. Mater. Energy, Sustain. Dev. Biomed. Sci. ed. M. Leclerc R. Gauvin, Gruyter 2014, 61–100.
Kurdyukov DA, Eurov DA, Kirilenko DA, Kukushkina JA, Sokolov VV, Yagovkina MA, et al. High-surface area spherical micro-Mesoporous silica particles. Microporous Mesoporous Mater. 2016;223:225–9.
Wang S. Ordered Mesoporous materials for drug delivery. Microporous Mesoporous Mater. 2009;117(1–2):1–9.
Ahern RJ, Hanrahan JP, Tobin JM, Ryan KB, Crean AM. Comparison of Fenofibrate–Mesoporous silica drug-loading processes for enhanced drug delivery. Eur J Pharm Sci. 2013;50(3):400–9.
Mellaerts R, Jammaer JAG, Van Speybroeck M, Chen H, Van Humbeeck J, Augustijns P, et al. Physical state of poorly water soluble therapeutic molecules loaded into SBA-15 ordered Mesoporous silica carriers: a case study with Itraconazole and ibuprofen. Langmuir. 2008;24(16):8651–9.
Prasad BR, Lele S. Stabilization of the amorphous phase inside carbon nanotubes: solidification in a constrained geometry. Philos Mag Lett. 1994;70(6):357–61.
Rengarajan GT, Enke D, Steinhart M, Beiner M. Stabilization of the amorphous state of Pharmaceuticals in Nanopores. J Mater Chem. 2008;18(22):2537–9.
Xia X, Zhou C, Ballell L, Garcia-Bennett AE. In vivo enhancement in bioavailability of Atazanavir in the presence of proton-pump inhibitors using Mesoporous materials. ChemMedChem. 2012;7(1):43–8.
Alcoutlabi M, McKenna GB. Effects of confinement on material behaviour at the nanometre size scale. J Phys Condens Matter. 2005;17(15):R461–524.
Jackson CL, McKenna GB. Vitrification and crystallization of organic liquids confined to Nanoscale pores. Chem Mater. 1996;8(8):2128–37.
Strømme M, Brohede U, Atluri R, Garcia-Bennett AE. Mesoporous silica-based Nanomaterials for drug delivery: evaluation of structural properties associated with release rate. Wiley Interdiscip Rev Nanomedicine Nanobiotechnology. 2009;1(1):140–8.
Zhang Y, Zhi Z, Jiang T, Zhang J, Wang Z, Wang S. Spherical Mesoporous silica nanoparticles for loading and release of the poorly water-soluble drug Telmisartan. J Control Release. 2010;145(3):257–63.
Andersson J, Rosenholm J, Areva S, Lindén M. Influences of material characteristics on ibuprofen drug loading and release profiles from ordered micro-and Mesoporous silica matrices. Chem Mater. 2004;16(21):4160–7.
Azaïs T, Tourné-Péteilh C, Aussenac F, Baccile N, Coelho C, Devoisselle J-M, et al. Solid-state NMR study of ibuprofen confined in MCM-41 material. Chem Mater. 2006;18(26):6382–90.
Horcajada P, Ramila A, Perez-Pariente J, Vallet-Regı M. Influence of pore size of MCM-41 matrices on drug delivery rate. Microporous Mesoporous Mater. 2004;68(1–3):105–9.
Vallet-Regí M, Balas F, Colilla M, Manzano M. Bioceramics and pharmaceuticals: a remarkable synergy. Solid State Sci. 2007;9(9):768–76.
Rosenholm JM, Sahlgren C, Lindén M. Towards multifunctional, targeted drug delivery systems using Mesoporous silica nanoparticles–opportunities & challenges. Nanoscale. 2010;2(10):1870–83.
Mellaerts R, Mols R, Jammaer JAG, Aerts CA, Annaert P, Van Humbeeck J, et al. Increasing the Oral bioavailability of the poorly water soluble drug Itraconazole with ordered Mesoporous silica. Eur J Pharm Biopharm. 2008;69(1):223–30.
Van Speybroeck M, Mellaerts R, Mols R, Do Thi T, Martens JA, Van Humbeeck J, et al. Enhanced absorption of the poorly soluble drug Fenofibrate by tuning its release rate from ordered Mesoporous silica. Eur J Pharm Sci. 2010;41(5):623–30.
Mellaerts R, Mols R, Kayaert P, Annaert P, Van Humbeeck J, Van den Mooter G, et al. Ordered Mesoporous silica induces PH-independent Supersaturation of the basic low solubility compound Itraconazole resulting in enhanced Transepithelial transport. Int J Pharm. 2008;357(1–2):169–79.
McCarthy CA, Ahern RJ, Devine KJ, Crean AM. Role of drug adsorption onto the silica surface in drug release from Mesoporous silica systems. Mol Pharm. 2017;15(1):141–9.
Jambhrunkar S, Qu Z, Popat A, Yang J, Noonan O, Acauan L, et al. Effect of surface functionality of silica nanoparticles on cellular uptake and cytotoxicity. Mol Pharm. 2014;11(10):3642–55.
Jambhrunkar S, Qu Z, Popat A, Karmakar S, Xu C, Yu C. Modulating in vitro release and solubility of Griseofulvin using functionalized Mesoporous silica nanoparticles. J Colloid Interface Sci. 2014;434:218–25.
Paris JL, Colilla M, Izquierdo-Barba I, Manzano M, Vallet-Regí M. Tuning Mesoporous silica dissolution in physiological environments: a review. J Mater Sci. 2017;52(15):8761–71.
Qu F, Zhu G, Huang S, Li S, Sun J, Zhang D, et al. Controlled release of captopril by regulating the pore size and morphology of ordered Mesoporous silica. Microporous Mesoporous Mater. 2006;92(1–3):1–9.
Munoz B, Ramila A, Perez-Pariente J, Diaz I, Vallet-Regi M. MCM-41 organic modification as drug delivery rate regulator. Chem Mater. 2003;15(2):500–3.
Mellaerts, R.; Aerts, C. A.; Van Humbeeck, J.; Augustijns, P.; Van den Mooter, G.; Martens, J. A. Enhanced release of itraconazole from ordered mesoporous SBA-15 Silica Materials. Chem. Commun. 2007, No. 13, 1375–1377.
Smirnova I, Mamic J, Arlt W. Adsorption of drugs on silica aerogels. Langmuir. 2003;19(20):8521–5.
Song S-W, Hidajat K, Kawi S. Functionalized SBA-15 materials as carriers for controlled drug delivery: influence of surface properties on matrix− drug interactions. Langmuir. 2005;21(21):9568–75.
Yang P, Gai S, Lin J. Functionalized Mesoporous silica materials for controlled drug delivery. Chem Soc Rev. 2012;41(9):3679–98.
Kumar D, Sailaja Chirravuri SV, Shastri NR. Impact of surface area of silica particles on dissolution rate and Oral bioavailability of poorly water soluble drugs: a case study with Aceclofenac. Int J Pharm. 2014;461(1):459–68.
McCarthy CA, Ahern RJ, Devine KJ, Crean AM. Role of drug adsorption onto the silica surface in drug release from Mesoporous silica systems. Mol Pharm. 2018;15(1):141–9.
Van Speybroeck M, Mols R, Mellaerts R, Thi T. Do; Martens, J. a.; Humbeeck, J. van; Annaert, P.; Mooter, G. van den; Augustijns, P. combined use of ordered Mesoporous silica and precipitation inhibitors for improved Oral absorption of the poorly soluble Weak Base Itraconazole. Eur. J Pharm Biopharm. 2010;75(3):354–65.
Limnell T, Santos HA, Mäkilä E, Heikkilä T, Salonen J, Murzin DY, et al. Drug delivery formulations of ordered and nonordered Mesoporous silica: comparison of three drug loading methods. J Pharm Sci. 2011;100(8):3294–306.
Dening TJ, Taylor LS. Supersaturation potential of ordered Mesoporous silica delivery systems. Part 1: dissolution performance and drug membrane transport rates. Mol. Pharm. 2018;15(8):3489–501.
Hate SS, Reutzel-Edens SM, Taylor LS. Absorptive dissolution testing: an improved approach to study the impact of residual Crystallinity on the performance of amorphous formulations. J Pharm Sci. 2019.
Florek J, Caillard R, Kleitz F. Evaluation of Mesoporous silica nanoparticles for Oral drug delivery – current status and perspective of MSNs drug carriers. Nanoscale. 2017;9(40):15252–77.
Vialpando M, Smulders S, Bone S, Jager C, Vodak D, Van Speybroeck M, et al. Evaluation of three amorphous drug delivery technologies to improve the Oral absorption of Flubendazole. J Pharm Sci. 2016;105(9):2782–93.
Hate, S. S.; Reutzel-Edens, S. M.; Taylor, L. S. Absorptive dissolution testing of supersaturating systems: Impact of absorptive sink conditions on solution phase behavior and mass transport. Mol. Pharm. 2017.
Hate, S. S.; Reutzel-Edens, S. M.; Taylor, L. S. Insight into amorphous solid dispersion performance by coupled dissolution and membrane mass transfer measurements. Mol Pharm. 2018.
Braun K, Pochert A, Beck M, Fiedler R, Gruber J, Lindén M. Dissolution kinetics of Mesoporous silica nanoparticles in different simulated body fluids. J Sol-Gel Sci Technol. 2016;79(2):319–27.
Dening TJ, Zemlyanov D, Taylor LS. Application of an adsorption isotherm to explain incomplete drug release from ordered Mesoporous silica materials under supersaturating conditions. J Control Release. 2019;307:186–99.
Parfitt GD, Rochester CH. Adsorption from solution at the solid/liquid Interface. Academic press London. 1983;122.
Brunauer S, Emmett PH, Teller E. Adsorption of gases in multimolecular layers. J Am Chem Soc. 1938;60(2):309–19.
Fu Y, Hansen RS, Bartell FE. Thermodynamics of adsorption from solutions. I. The molality and activity co-efficient of adsorbed layers. J Phys Colloid Chem. 1948;52(2):374–86.
McMillan WG, Teller E. The assumptions of the BET theory. J Phys Chem. 1951;55(1):17–20.
Ebadi A, Mohammadzadeh JSS, Khudiev A. What is the correct form of BET isotherm for modeling liquid phase adsorption? Adsorption. 2009;15(1):65–73.
Weng C-H, Pan Y-F. Adsorption characteristics of methylene blue from aqueous solution by sludge ash. Colloids Surfaces A Physicochem Eng Asp. 2006;274(1):154–62.
Foo KY, Hameed BH. Insights into the modeling of adsorption isotherm systems. Chem Eng J. 2010;156(1):2–10.
Kara S, Aydiner C, Demirbas E, Kobya M, Dizge N. Modeling the effects of adsorbent dose and particle size on the adsorption of reactive textile dyes by Fly ash. Desalination. 2007;212(1–3):282–93.
Sivaraj R, Namasivayam C, Kadirvelu K. Orange Peel as an adsorbent in the removal of acid violet 17 (acid dye) from aqueous solutions. Waste Manag. 2001;21(1):105–10.
Xu Y, Ohki A, Maeda S. Adsorption and removal of antimony from aqueous solution by an activated alumina: 1. Adsorption capacity of adsorbent and effect of process variables. Toxicol Environ Chem. 2001;80(3–4):133–44.
Yapar S, Özbudak V, Dias A, Lopes A. Effect of adsorbent concentration to the adsorption of phenol on Hexadecyl Trimethyl ammonium-Bentonite. J Hazard Mater. 2005;121(1–3):135–9.
Pradhan J, Das SN, Thakur RS. Adsorption of hexavalent chromium from aqueous solution by using activated red mud. J Colloid Interface Sci. 1999;217(1):137–41.
Ellison CJ, Torkelson JM. The distribution of glass-transition temperatures in Nanoscopically confined glass formers. Nat Mater. 2003;2(10):695–700.
Park J-Y, McKenna GB. Size and confinement effects on the glass transition behavior of polystyrene/o-Terphenyl polymer solutions. Phys Rev B. 2000;61(10):6667–76.
Tang XC, Pikal MJ, Taylor LS. A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in Dihydropyridine Calcium Channel blockers. Pharm Res. 2002;19(4):477–83.
Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86(1):1–12.
Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12(6):799–806.
Ahlneck C, Zografi G. The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. Int J Pharm. 1990;62(2–3):87–95.
Cheng S, McKenna GB. Nanoconfinement effects on the glass transition and crystallization behaviors of nifedipine. Mol Pharm. 2019;16(2):856–66.
Jackson CL, McKenna GB. The melting behavior of organic materials confined in porous solids. J Chem Phys. 1990;93(12):9002–11.
Babonneau F, Yeung L, Steunou N, Gervais C, Ramila A, Vallet-Regi M. Solid state NMR characterisation of encapsulated molecules in Mesoporous silica. J Sol-gel Sci Technol. 2004;31(1–3):219–23.
Catlow CRA, Van Speybroeck V, van Santen R. Modelling and simulation in the science of micro-and meso-porous materials: Elsevier; 2017.
Paolone A, Palumbo O, Rispoli P, Cantelli R, Autrey T, Karkamkar A. Absence of the structural phase transition in Ammonia Borane dispersed in Mesoporous silica: evidence of novel thermodynamic properties. J Phys Chem C. 2009;113(24):10319–21.
Antonino RS, Ruggiero M, Song Z, Nascimento TL, Lima EM, Bohr A, et al. Impact of drug loading in Mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency. Int J Pharm X. 2019;1:100026.
Yang S, Liu Z, Jiao Y, Liu Y, Ji C, Zhang Y. New insight into PEO modified inner surface of HNTs and its Nano-confinement within nanotube. J Mater Sci. 2014;49(12):4270–8.
Chen K, Wilkie CA, Vyazovkin S. Nanoconfinement revealed in degradation and relaxation studies of two structurally different polystyrene−Clay Systems. J Phys Chem B. 2007;111(44):12685–92.
Rosenholm JM, Lindén M. Towards establishing structure–activity relationships for mesoporous silica in drug delivery applications. J Control release. 2008;128(2):157–64.
Sulpizi M, Gaigeot M-P, Sprik M. The silica–water Interface: how the Silanols determine the surface acidity and modulate the water properties. J Chem Theory Comput. 2012;8(3):1037–47.
Delle Piane, M.; Corno, M.; Ugliengo, P. Chapter 9 - Ab Initio Modeling of Hydrogen Bond Interaction at Silica Surfaces With Focus on Silica/Drugs Systems; Catlow, C. R. A., Van Speybroeck, V., van Santen, R. A. B. T.-M. and S. in the S. of M. M.-P. M., Eds.; Elsevier, 2018; pp 297–328.
Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9.
Pham AL-T, Sedlak DL, Doyle FM. Dissolution of Mesoporous silica supports in aqueous solutions: implications for Mesoporous silica-based water treatment processes. Appl Catal B Environ. 2012;126:258–64.
Joos P, Serrien G. The principle of Braun—Le Châtelier at surfaces. J Colloid Interface Sci. 1991;145(1):291–4.
Indulkar AS, Box KJ, Taylor R, Ruiz R, Taylor LS. PH-dependent liquid–liquid phase separation of highly supersaturated solutions of weakly basic drugs. Mol Pharm. 2015;12(7):2365–77.
Tao Q, Xu Z, Wang J, Liu F, Wan H, Zheng S. Adsorption of humic acid to Aminopropyl functionalized SBA-15. Microporous Mesoporous Mater. 2010;131(1–3):177–85.
Indulkar AS, Gao Y, Raina SA, Zhang GGZ, Taylor LS. Exploiting the phenomenon of liquid–liquid phase separation for enhanced and sustained membrane transport of a poorly water-soluble drug. Mol Pharm. 2016;13(6):2059–69.
Achenbach CJ, Darin KM, Murphy RL, Katlama C. Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults. Future Virol. 2011;6(2):157–77.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hate, S.S., Reutzel-Edens, S.M. & Taylor, L.S. Interplay of Adsorption, Supersaturation and the Presence of an Absorptive Sink on Drug Release from Mesoporous Silica-Based Formulations. Pharm Res 37, 163 (2020). https://doi.org/10.1007/s11095-020-02879-9
- adsorption isotherm
- membrane absorption
- mesoporous silica-based formulations