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Dipyridamole Nanomixing- AIChE\' 08

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  • 1. Nano-mixing of Dipyridamole Drug and Excipient Nanoparticles by Sonication in Liquid CO2 q 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. Improvement in bioavailability by nanosizing 100 nm 500 nm 2000 nm 5000 nm Bioavailability = % drug absorbed = Area under the curve Bi il bilit d b b d A d th *ElanTechnologies 4 http://www.elan.com/EDT/nanocrystal_technology/
  • 5. Importance of deagglomeration and mixing Reason for agglomeration Van der Waals attractions +Electrostatic force +Capillary force > Gravitational force p y Van der Waals attractions α d ; Gravitational force α d3 Effect of agglomeration gg Caking, poor flowability, segregation, content non homogeneity in tablets, loss in bioavailability of drugs , etc. 90 80 19-27 µm 70 Drug Dissolved (%) 60 50 40 10-38 µm 30 20 3-108 µm 10 0 0 10 20 30 40 5 Time (minutes) *De Villiers, M. M., 1996.. Int. J. Pharm. 136, 175-179.
  • 6. Available mixers Currently available mixers are not effective in deagglomeration of particles smaller than 10 micron Require very high shear or impaction Rotary and vibratory ball mill can be used for fine powders but may affect crystal lattice of particles. Tumbler, most common mixer, is not effective if deagglomeration is required. gg q 6
  • 7. Method for deagglomeration and mixing Mechanism: Mixing by cavitation in liquid CO2 7
  • 8. Materials Dipyridamole (Used as an anti-thrombosis agent) Dosage = 25 75 mg D 25-75 Aqueous Solubility = 0.012 mg/ml Dose/Solubility = 5000 > 250 ml MP= MP 163 °C logP =1.5 pKa =6.4 Excipients Hydrophobic and Hydrophilic silica (primary particle size = 9-30 nm) Lactose monohydrate (D50 ≤ 5 µm , D90 ≤ 10 µm) * Wishart, et al., Nucleic Acids Res. 1(34), D668-D672. 8
  • 9. Dipyridamole Nano-flakes by bottom-up approach Supercritical antisolvent-enhanced mass transfer (SAS-EM) Drug Solution Flow rate – 1 ml/min Drug concentration – 5 mg/ml in DCM Antisolvent Flow rate (CO2) – 10-15 gm/min g Ultrasound Amplitude – 25-40 % 9 P. Chattopadhyay, R. B. Gupta. Int J Pharm. 228 (2001) 19-31.
  • 10. Continued…. Production of dipyridamole nanoflakes 10 µm 2 µm Drug from supplier (Sigma-Aldrich) Dipyridamole flakes produced by SAS-EM 45 Drug  from SAS‐EM method 40 35 Length (µm) 30 25 20 15 10 5 0 10 0 5 10 15 20 Width (µm)
  • 11. Apparatus for nanomixing Sonication in Liquid CO2 Pressure = 1100 psig Temperature = 5-10 °C T t 5 10 11
  • 12. Deagglomeration gg Deagglomeration and Mixing by Sonication Agglomerated Dipyridamole flakes Deagglomeration and mixing of dipyridamole with lactose Drug Particles 2 µm Sonication Lactose 12
  • 13. Drug homogeneity g g y 5 Sample weight = 10 mg S l i ht 4 Silica n=10 n 3 1 ∑ (C − Ci ) i =1 RSD % RSD = C n −1 2 1 0 0 1 2 3 4 5 6 Drug content (wt%) 13 Low RSD is indicator of better mixing quality!
  • 14. Drug Dissolution g 120 100 Drug Dissolved (%) 80 60 D 40 Nanomixed -drug nanoflakes/lactose (5 wt%) Physical Mixture - drug nanoflakes/lactose (5 wt% drug) 20 Drug Nanoflakes Supplier Drug 0 0 15 30 45 60 75 90 Time (minutes) 14 Higher dissolution rate for nanomixed mixture!
  • 15. Deagglomeration and mixing by sonication gg g y Silica Nanomixed-silica/drug nanoflakes Drug Particles Sonication Dipyridamole flakes 2 µm 15
  • 16. Handling Properties g p Component or Mixture Aerated Tapped C.I. (%) Hausner Density Density Ratio (mg/ml) (mg/ml) Silica (Hydrophobic) 37.13 45.97 19.2 1.23 Dipyridamole ( SAS-EM) 36.4 55.7 52.9 1.53 Sonication-Dipyridamole (SAS-EM) and silica 150.3 167 10.0 1.11 Flow Character C.I. (%) Hausner Ratio Compressibility Index (%) Excellent < 10 1.00-1.11 Good 11-15 1.12-1.18 Fair 16-20 1.19-1.25 Passable 21-25 1.26-1.34 Poor 36-31 1.35-1.45 Hausner Ratio Very poor 32-37 1.46-1.59 Very Very poor >38 >1.60 Better handling properties ! 16
  • 17. Conclusions Effective deagglomeration and mixing of drug nanoparticles with excipients Potential use of this method in deagglomeration and mixing for low drug strength dosage ( g g g (RSD of 3.8 % for 0.14 wt% drug) Nanomixed drug-lactose mixture shows higher dissolution drug lactose rate than agglomerated drug nanoflakes Drug-silica Drug silica mixture has better flowability as compared to pure drug nanoflakes Presence of excipient particles b t P f i i t ti l between nanoflakes can fl k improve physical stability or shelf life 17
  • 18. Acknowledgement g The National Science Foundation NIRT grant DMI-0506722 Technical discussion on sonication with Prof. Rajesh N. N Dave (NJIT Newark) (NJIT, Thank you ! 18

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