Dissolution-rate enhancement of fenofibrate by adsorption onto silica using supercritical
b di idcarbon dioxide
Ganesh P Sanganwar and Ram B GuptaGanesh P. Sanganwar and Ram B. GuptaDepartment of Chemical engineering
Auburn University, Auburn, AL
Poorly water soluble drugs
GranulesTablet
StomachParticles
Tra
ct
Rate of Dissolution << Rate of absorption
oint
estin
al
Drug in
systemic circulation
2TransitG
astr
o
Dissolution-rate enhancement
Noyes-Whitney Equation)(.R tDi l ti CCDA
Decreasing particle size
Increasing surface area (by
)(Raten Dissolutio bs CCh
−×=
A – Surface area
D Diff i ffi i tsolid dispersion, adsorption of
drug onto high surface area
D –Diffusion coefficient
h- Boundary layer thickness
Cs – Saturation solubility
carrier)
Decreasing crystallinity
Cb – Bulk concentration
Complexing with cyclodextrin
Salt formation
3
Available methods
Micronization - High agglomeration tendency of particlesg gg y p- Caking, poor flowability, segregation, content non homogeneity in tablets, loss in bioavailability of drugs , etc.Solid dispersionSolid dispersion- At high loading of drug, crystallization of drug takes place leading to instability of formulationComplexing with CyclodextrinComplexing with Cyclodextrin
- Higher molar ratio Adsorption onto high surface area carrier using organic solventsA l ti ti- Agglomeration prevention
- Residue solvent Adsorption onto high surface area carrier using supercritical fluid
- No residual solvent4
Dissolution-rate enhancement by adsorption
Example: Drug- Carbamazepine onto silica (an anti-convulsant and mood stabilizing drug)
100
80
100
60
Rele
ased
CarbamezapinePEG 400
40
% D
rug
R 2‐pyrrolidonemethanol
0
20% drug from supplier
H. Friedrich et al., Eur J Pharm Biopharm. 62 (2006) 171-7.
5
0 20 40 60 80Time (minutes)
Supercritical Carbon dioxide
Environmentally benign non-polar solventpolar solventCheap, inert and non-flammableTunable properties (densityTunable properties (density changes with pressure)Mild critical point (P = 73 7 bar T =31 1 °C)(Pc = 73.7 bar, Tc =31.1 C)100 fold more diffusive than liquids
*Gupta, R. B. and Shim, JJ., 2007. Solubility insupercritical carbon dioxide. CRC Press, Boca Raton.
*Gupta, R. B. and Kompella, U. B., 2006. Nanoparticletechnology for drug delivery. Taylor and Francis Group.,New York.
6
Solubility in supercritical CO2
200 308 K
y 2
150
200 308 K318 K328 K338 K348 K
Naproxen, a non-steroidal anti-inflammatory drug
100
y x
106
50
0100 200 300 400
P (bar)( )
7*Gupta, R. B. and Shim, JJ., 2007. Solubility insupercritical carbon dioxide. CRC Press, Boca Raton.
Materials
Fenofibrate (Used as a lipid regulating agent)
MW = 360.831
Molecular formula =C20H21ClO4
MP 80 5 °CMP= 80.5 °C
logP =5.5
Tg= -20 °Cg
Dosage = 40-120 mg
Aqueous Solubility = 0.0003 mg/ml
Dose/Solubility = 4,00000 > 250 ml
* Wishart, et al., Nucleic Acids Res. 1(34), D668-D672.
8
Continued….
Hydrophilic Silica (FDA approved, Used as a glidant)
S f 200 +15 2/Surface area = 200 +15 m2/gTapped Density = 40 g/lAgglomerate size = 30-44 µmAggregate size = 200-300 nmAggregate size 200 300 nmPrimary particle size = 9-30 nm
100 nm100 nm10 µm
* Cabot Corp. 2007. Available via www.cabot-corp.com. Accessed on June 20, 2007.
9
Apparatus for drug adsorption onto silica
Pressure = 174 barPressure Gauge
Temperature = 40/50 °C
Formulation A = 174 bar/40 °C
Formulation B = 174 bar/50 °CFormulation B 174 bar/50 CPump
Chiller Preheater
Temperature Pressure G
FilterVent
e pe atu eController Gauge
CO2 Gas cylinderHeating Tape
High Pressure V lVessel
10
Procedure
CO2pressurization
Drug particles Silica particles
CO22depressurization
11
SEMAgglomerated Fenofibrate
Adsorption of fenofibrate onto silica
Adsorption
Drug Particles
Adsorption
SilicaSilica
12
FT-IR Spectroscopy
Silica
cens
mitt
anc
Physical Mixture-Silica/Fenofibrate
Tran
Fenofibrate adsorbed onto silica
0 1000 2000 3000 4000 5000Wavenumber(cm-1)
13
X-ray Diffraction
unts)
ntens
ity (C
ou
Fenofibrate
10 20 30 40 50 60 70 80
In
Degree (2theta)
y (Co
unts)
Formulation B
Inten
sity
Silica
Formulation A
Formulation B
1410 20 30 40 50 60 70 80
Degree (2theta)
Silica
X-ray Diffractions)
(Cou
nts
Formulation B -1 month
tens
ity
Formulation A -1 month
Formulation B
Int
Formulation A
Silica
10 20 30 40 50 60 70 80Degree (2theta)
Silica
Degree (2theta)Processing temperature affects crystallinity ! 15
Reasons for increase in crystallinity
gTT −=eTemperaturReduced 2 E+07
3.E+07
s-1)
gm TT −eTemperatur Reduced
T – crystallization temperature2.E+07
2.E+07
mob
ility
(1/ζ
,
Tg –glass transition temperature
Tm- melting temperature5.E+06
1.E+07
Mol
ccul
ar m
Reduced temperature > 0.6
Very high molecular mobility !
0.E+00
0 0.2 0.4 0.6 0.8(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)
16A. Zhou et al., J. Pharma. Sci. 1 (2002) 1863-72.
Drug Dissolution
90100
Formulations A and B
g
7080
sed
405060
Rele
as
203040
% D
rug
Fenofibrate
Formulation A
01020% Formulation A
Formulation B
17
0 20 40 60 80Time (minutes)
Drug Stability and Dissolutiong y
90100
Formulations A and B
Drug Particles Silica
607080
ase
405060
ug R
elea
2030
% D
ru
010
0 20 40 60 80
Better stability of formulation B !18
Time (minutes)
Conclusions
Adsorption of fenofibrate on high-surface area silica significantly increases drug dissolution
Adsorption of fenofibrate from supercritical CO2 doesAdsorption 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
Acknowledgementg
The National Science FoundationNIRT grant DMI-0506722
20