1) The document describes a study that used supercritical carbon dioxide to adsorb the poorly water-soluble drug fenofibrate onto silica particles to enhance its dissolution rate.
2) Two formulations were produced - Formulation A at 174 bar and 40°C resulted in an amorphous structure, while Formulation B at 174 bar and 50°C resulted in a slightly crystalline structure.
3) In vitro dissolution tests found that both formulations significantly increased fenofibrate's dissolution rate compared to the raw drug. However, stability tests found that the more crystalline Formulation B was more stable in storage over time.
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Dissolution-rate enhancement of fenofibrate by adsorption onto silica using supercritical carbon dioxide
1. Dissolution-rate enhancement of fenofibrate
by adsorption onto silica using supercritical
carbon dioxide
b di id
Ganesh P Sanganwar and Ram B Gupta
P. B.
Department of Chemical engineering
Auburn University, Auburn, AL
2. Poorly water soluble drugs
Tablet Granules
Stomach
Particles
Rate of Dissolution << Rate of absorption
ointestinal Tract
Drug in
systemic circulation
Gastro
2
Transit
3. Dissolution-rate enhancement
Noyes-Whitney Equation A.D
Di l ti n R t =
Dissolutio Rate × (Cs − Cb )
Decreasing particle size h
A – Surface area
Increasing surface area (by
D –Diffusion coefficient
Diff i ffi i t
solid dispersion, adsorption of
h- Boundary layer thickness
drug onto high surface area Cs – Saturation solubility
carrier) Cb – Bulk concentration
Decreasing crystallinity
Complexing with cyclodextrin
Salt formation
3
4. Available methods
Micronization
- High agglomeration tendency of p
g gg y particles
- Caking, poor flowability, segregation, content non homogeneity
in tablets, loss in bioavailability of drugs , etc.
Solid dispersion
- At high loading of drug, crystallization of drug takes place
leading to instability of formulation
Complexing with Cyclodextrin
- Higher molar ratio
Adsorption onto high surface area carrier using organic solvents
-A l
Agglomeration prevention
ti ti
- Residue solvent
Adsorption onto high surface area carrier using supercritical fluid
- No residual solvent
4
5. Dissolution-rate enhancement by adsorption
Example: Drug- Carbamazepine onto silica (an anti-convulsant and mood
stabilizing drug)
100
80
% Drug Released
60 Carbamezapine
PEG 400
R
2‐pyrrolidone
40 methanol
20 drug from supplier
0
0 20 40 60 80
Time (minutes) 5
H. Friedrich et al., Eur J Pharm Biopharm. 62 (2006) 171-7.
6. Supercritical Carbon dioxide
Environmentally benign non-
polar solvent
Cheap, inert and non-
flammable
Tunable properties (density
changes with pressure)
Mild critical point
(Pc = 73.7 bar Tc =31 1 °C)
73 7 bar, =31.1 C)
100 fold more diffusive than
liquids
*Gupta, R. B. and Shim, JJ., 2007. Solubility in *Gupta, R. B. and Kompella, U. B., 2006. Nanoparticle
6
supercritical carbon dioxide. CRC Press, Boca Raton. technology for drug delivery. Taylor and Francis Group.,
New York.
7. Solubility in supercritical CO2
y
200 308 K
318 K
328 K
Naproxen, a non-steroidal 338 K
348 K
anti-inflammatory drug 150
6
y x 10
100
50
0
100 200 300 400
P (bar)
( )
*Gupta, R. B. and Shim, JJ., 2007. Solubility in 7
supercritical carbon dioxide. CRC Press, Boca Raton.
8. Materials
Fenofibrate (Used as a lipid regulating agent)
MW = 360.831
Molecular formula =C20H21ClO4
MP= 80.5
MP 80 5 °C
logP =5.5
Tg= -20 °C
Dosage = 40-120 mg
Aqueous Solubility = 0.0003 mg/ml
Dose/Solubility = 4,00000 > 250 ml
*
8
Wishart, et al., Nucleic Acids Res. 1(34), D668-
D672.
9. Continued….
Hydrophilic Silica (FDA approved, Used as a glidant)
Surface area = 200 +15 m2/
S f /g
Tapped Density = 40 g/l
Agglomerate size = 30-44 µm
Aggregate size = 200-300 nm
200 300
Primary particle size = 9-30 nm
100 nm
10 µm
9
* Cabot Corp. 2007. Available via www.cabot-
corp.com. Accessed on June 20, 2007.
10. Apparatus for drug adsorption onto silica
Pressure
Gauge Pressure = 174 bar
Temperature = 40/50 °C
Formulation A = 174 bar/40 °C
Formulation B = 174 bar/50 °C
C
Pump
Chiller Preheater
Pressure
Temperature
e pe atu e
Gauge
G
Controller
Vent
Filter
Heating Tape
CO2 Gas cylinder
High Pressure
Vessel
V l
10
11. Procedure
CO2
pressurization
Drug particles Silica particles
CO2
depressurization
11
14. X-ray Diffraction
unts)
ntensity (Cou
Fenofibrate
In
10 20 30 40 50 60 70 80
Degree (2theta)
Intensity (Counts)
Formulation B
y
Formulation A
Silica
10 20 30 40 50 60 70 80
14
Degree (2theta)
15. X-ray Diffraction
s)
tensity (Counts
Formulation B -1 month
Formulation A -1 month
Formulation B
Int
Formulation A
Silica
10 20 30 40 50 60 70 80
Degree (2theta)
Processing temperature affects crystallinity ! 15
16. Reasons for increase in crystallinity
3.E+07
T − Tg
Molccular mobility (1/ζ, s-1)
Reduced Temperature = 2.E+07
2 E+07
Tm − Tg
2.E+07
T – crystallization temperature
m
Tg –glass transition temperature 1.E+07
Tm- melting temperature
5.E+06
0.E+00
Reduced temperature > 0.6
0 0.2 0.4 0.6 0.8
Very high molecular mobility ! (T-Tg)/(Tm-Tg)
Formulation A ( 174 bar, 40°C) = 27.5 wt % drug = 1.25 nm (drug layer thickness)
Formulation B ( 174 bar, 50°C) = 25.0 wt % drug = 1.13 nm (drug layer thickness)
16
A. Zhou et al., J. Pharma. Sci. 1 (2002) 1863-72.
17. Drug Dissolution
g
100
Formulations A and B
90
80
sed
70
% Drug Releas
60
50
40
30
Fenofibrate
20 Formulation A
Formulation A
Formulation B
10
0
0 20 40 60 80
Time (minutes)
17
18. Drug Stability and Dissolution
g y
100
Formulations A and B
90
80
Drug Particles Silica
70
ase
% Dru Relea
60
50
ug
40
30
20
10
0
0 20 40 60 80
Time (minutes)
18
Better stability of formulation B !
19. Conclusions
Adsorption of fenofibrate on high-surface area silica
significantly increases drug dissolution
Adsorption of fenofibrate from supercritical CO2 does
not leave any residual solvent in the final formulation
Amorphous formulation A (174 bar/40°C)found to be
more unstable in storage condition.
Slightly crystalline formulation B (174 bar/50°C) found
to be stable in storage condition
19
20. Acknowledgement
g
The National Science Foundation
NIRT grant DMI-0506722
20