Fenofibrate Dissolution Enhancement-AIChE\' 08

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Fenofibrate Dissolution Enhancement-AIChE\' 08

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 11. Procedure CO2 pressurization Drug particles Silica particles CO2 depressurization 11
  12. 12. SEM Agglomerated Fenofibrate Adsorption of fenofibrate onto silica Drug Particles Adsorption Silica 12
  13. 13. FT-IR Spectroscopy Silica ce nsmittanc Physical Mixture-Silica/Fenofibrate Tran Fenofibrate adsorbed onto silica 0 1000 2000 3000 4000 5000 Wavenumber(cm-1) 13
  14. 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. 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. 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. 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. 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. 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. 20. Acknowledgement g The National Science Foundation NIRT grant DMI-0506722 20

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