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

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