INCORPORATION OF CLOTRIMAZOLE IN ORDERED MESOPOROUS SILICA BY SUPERCRITICAL CO2 Andrea Gignone, Barbara Onida, Silvia Ronchetti, Luigi Manna XVII National Congress of Catalysis GIC 2013 and XI National Congress of Zeolites Science and Technology 15 - 18 September 2013, Riccione

The context Ordered mesoporous silica for drug delivery of molecule poorly soluble in water Clotrimazole: antifungal, dermatological application R. Mellaerts, R. Mols, J.A.G. Jammaer, C.A. Aerts, P.Annaert, J. Van Humbeeck, G.V. Mooter, P. Augustijns, G. Van den Mooter, J.A. Martens, Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica, Eu. J. Pharma. Biopharmaceutics 69 (2008) 223-230. B. Onida and R. Mortera, Eudermic compositions, WO 2012/007906 A2

Supercritical CO2 Supercritical fluids have many advantages: low viscosity high diffusivity near-zero surface tension green solvent solubility parameter is a function of P & T 1- M. Hiroshi, M. Takesue, R.L. Smith Jr., Green chemical processes with supercritical fluids: Properties, materials, separation and energy, Journal of Supercritical Fluids 60 (2011) 2-11. 2- M. Ni, Q-Q. Xu, and J-Z. Yin: Preparation of controlled release nanodrug ibuprofen supported on mesoporous silica using supercritical carbon dioxide, J. Mater. Res. 27, 2902 (2012).

The ordered mesoporous silica used for this study Commercial from Sigma-Aldritch: MSU-H type, cylindrical pores, hexagonal symmetry Volume 0,900 cm3/g Surface area 596 m2/g Pore diameter 8,5 nm Particle size ~ 400 nm Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Incorporation of clotrimazole Two ways: Adsorption from solution Supercritical CO2 (homemade setup) Incorporation of clotrimazole Glass Wool Clotrimazole Filter paper Silica Process Conditions Solvent Ethanol CO2 Temperature 25°C 100°C Pressure 1 bar 250 bar drug:silica weight ratio 3:1 1:1

Preliminary study: effects of scCO2* on the OMS SSA (m2/g) Volume (cm3/g) Microporous volume (cm3/g) Pore diameter (nm) OMS 596 0,900 0,073 8,4 OMS after SCF-CO2 358 0,780 0,031 -13% -57% * Supercritical process conditions: 100°C, 250 bar, 12 h

Possible role of humidity ? Effects of dehydration prior to scCO2 Volume (cm3/g) Microporous volume (cm3/g) SSA (m2/g) Pore diameter (nm) OMS as such 0,900 0,073 596 8,4 OMS after scCO2 0,780 0,031 358 OMS dehydrated scCO2 0,863 0,082 605 Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Effects of process parameters Time Pressure Temperature Incorporation time Temperature (°C) Pressure (bar) Drug-OMS ratio Incorporated quantity Exp 1 6h 100 250 1:1 12 % Exp 2 12h 30 % Exp 3 500 34 % Exp EtOH 24h 25 1 3:1 9 % Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Characterization of incorporated clotrimazole: XRD (34%) Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Characterization of incorporated clotrimazole: FT-IR (34%) 1 2 1 2 3 Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione Characterization of incorporated clotrimazole: N2 adsorption (34%) Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Model of pore occupation as a monolayer Model of Monolayer Calculated Distribution 𝑽 𝟎 = 𝝅 𝟒 ∙ 𝒅 𝟎 𝟐 𝑽 𝟏 = 𝝅 𝟒 ∙ 𝒅 𝟏 𝟐 ⇒ 𝑽 𝟎 𝑽 𝟏 = 𝒅 𝟎 𝟐 𝒅 𝟏 𝟐 𝑽 𝟏 = 𝒅 𝟏 𝟐 𝒅 𝟎 𝟐 ∙ 𝑽 𝟎 𝒅 𝟏 = 𝒅 𝟎 −𝟐 𝒅 𝒄𝒍𝒐 ⇒ 𝑽 𝟏 = (𝒅 𝟎 − 𝟐 𝒅 𝒄𝒍𝒐 ) 𝟐 𝒅 𝟎 𝟐 ∙ 𝑽 𝟎 Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione The process of incorporation of clotrimazole into OMS with supercritical CO2 is promising. Incorporation by supercritical CO2 has been observed to be more efficient than adsorption from solution (for instance: higher incorporated amount using a lower drug:silica weight ratio). The incorporated drug can be considered in the form of a monolayer. Conclusions Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione

Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione Associazione Italiana Zeoliti Prof. Barbara Onida Prof. Luigi Manna Prof. Silvia Ronchetti Thank you all for your kind attention I would like to say a special word of thanks and appreciation to the organizing committee for the magnificent work he has done and Acknowledgements Andrea Gignone GIC-AIZ 2013 15-18 September - Riccione