This document summarizes a study on enhancing the shelf-life and handling properties of itraconazole drug nanoparticles by mixing them with silica at the nanoscale using rapid depressurization of supercritical suspensions (RDSS). Poorly soluble itraconazole drug flakes produced by a bottom-up approach were deagglomerated and uniformly mixed with fumed silica nanoparticles using RDSS. This resulted in improved flowability, physical stability over time, and constant drug dissolution rate compared to pure drug flakes. The presence of silica particles between itraconazole nanoflakes improved stability by preventing reaggregation.

1. Enhancement of Shelf-life and Handling
Properties of Drug Nanoparticles:
Nanoscale Mixing of Itraconazole with Silica
N l Mi i fI l i h Sili
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
Dissolution Rate = × (Cs − Cb )
h
Decreasing particle size
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
4
*ElanTechnologies
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. Materials
Itraconazole (Used as a antifungal agent)
Dosage = 200-400 mg
g g
Aqueous Solubility = 0.004-0.012 mg/ml
Dose/Solubility = 16500 > 250 ml
MP= 166.2 °C
logP =6.939
pKa =3.7
Fumed Silica (FDA approved Used as a glidant)
approved,
Surface area = 200 +15 m2/g
Tapped Density = 40 g/l
Agglomerate size = 30-44 µm
Aggregate size = 200-300 nm
Primary particle size = 9-30 nm
*Wishart, et al.,2006 Nucleic Acids Res. 1(34), * Cabot Corp. 2007. Available via www.cabot-
D668-D672. corp.com. Accessed on June 20, 2007.

8. 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
supercritical carbon dioxide. CRC Press, Boca technology for drug delivery. Taylor and Francis
Raton. Group., New York.

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
gm/min
g
Ultrasound Amplitude – 25 %
9
P. Chattopadhyay, R. B. Gupta. Int J Pharm. 228 (2001) 19-31.

10. Continued….
Production of itraconazole nanoflakes
Micronized itraconazole from Itraconazole flakes produced by SAS-EM method
supplier (Hawkins Inc.)
Particle size:~3-60 μm flakes, Particle size:~submicron-14 μm flakes with 150
Aspect ratio: 8-10 nm thickness, Aspect ratio: 1-4

11. Method for deagglomeration and mixing
Rapid Depressurization of Supercritical Suspension (RDSS)
A
B
Mixture
Beginning
*Yang et al., 2003. Adv. Powder Tech. 14, 471-93.

12. Apparatus for nanomixing
Rapid depressurization of supercritical suspension (RDSS)
Powder loading ( 1:1 w/w of Itraconazole/silica)
Pressure = 1200 psig : Temperature = 45 °C
CO2 flow rate = ~ 50 gm/min
Back pressure in expansion vessel = up to 250 psig

13. Deagglomeration and mixing by RDSS
gg g y
Agglomerated Itraconazole flakes Deagglomeration and mixing of
itraconazole with silica
RDSS
Silica

14. Continued…
Physical mixing
Drug Particles Silica

15. Handling Properties
g
Angle of Repose
Measured by flowing 25 ml powder
through firmly fixed funnel (8 mm
diameter) from height of 5 cm on flat
surface
Compressibility Index (%)
Hausner Ratio

16. Handling Properties
g p
Component or Mixture Angle of Aerated Tapped C.I. (%) Hausner
Repose (°) Density Density Ratio
(mg/ml) (mg/ml)
Silica 30 + 0.9 41.0 44.2 12.4 1.12
Itraconazole (Supplier) 41.6 + 1.0 256.9 391.4 52.4 1.52
Itraconazole ( SAS-EM) 46.3 + 0.3 36.4 55.7 52.9 1.53
Physical Mixture –
Itraconazole(SAS-EM) and 41.7 + 2.6 39.8 49.8 25.0 1.25
silica
RDSS-Itraconazole (SAS-EM)
34.7 + 1.7 105.4 120.5 14.3 1.14
and silica
Flow Character Angle of Repose C.I. (%) Hausner Ratio
(°)
Excellent 25-30 < 10 1.00-1.11
Good 31-35
31 35 11-15
11 15 1.12-1.18
1 12 1 18
Fair 36-40 16-20 1.19-1.25
Passable 41-45 21-25 1.26-1.34
Poor 46-55 36-31 1.35-1.45
Very poor 56-65 32-37 1.46-1.59
Very Very poor >66
66 >38
38 >1.60
1.60
Better handling properties !

17. Continued…
Physical Stability (by keeping samples at 90°C for 25 days)
Aggregates/Agglomerates of RDSS mixture of
Itraconazole nanoflakes after Itraconazole/silica after storage
g
storage

18. Drug Dissolution
120
Silica Particle size:~submicron-14 μm Titania 150 nm thickness,
flakes with
Aspect ratio: 1-4
p
100
80
% Drug Dissolved
d
60
Particle size:~3-60 μm flakes, Aspect ratio: 8-10
D
40
Itraconazole nanoflakes
RDSS mixture (itraconazole nanoflakes/silica nanoparticles)
20 RDSS mixture after storage (itraconazole nanoflakes/silica nanoparticles)
Itraconazole nanoflakes after storage
Micronized itraconazole from supplier
0
0 20 40 60 80 100
Time (minutes)
Improvement in shelf-life !

19. Conclusions
Pure itraconazole flakes have poor flowability and
reduced dissolution rate upon storage
Drug nanoflakes and silica nanoparticles deagglomerate
and mix at nanoscale using RDSS process
Mixture has better flowability and constant dissolution
rate upon storage
Presence of silica particles between nanoflakes
improves physical stability or shelf life

20. Acknowledgement
g
The National Science Foundation
NIRT grant DMI-0506722
Experimental assistance from Andrew Scott (a NSF
REU student)
Technical discussion on RDSS with Prof. Rajesh N.
Dave (NJIT, Newark)
Thank you !