1. 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
September 2013, Riccione

2. 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)
B. Onida and R. Mortera, Eudermic compositions, WO 2012/ A2

3. 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).

4. 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 September - Riccione

5. 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

6. 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

7. 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 September - Riccione

8. 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 September - Riccione

9. Characterization of incorporated clotrimazole: XRD (34%)
Andrea Gignone GIC-AIZ September - Riccione

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

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

12. 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 September - Riccione

13. 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 September - Riccione

14. 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 September - Riccione