Enhancement of Shelf-life and Handling Properties of Drug Nanoparticles:

N l Mi i f I l i h SiliNanoscale Mixing of Itraconazole with Silica

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 )(.bs CCDAn RateDissolutio −×=

Decreasing particle size

Increasing surface area (by A – Surface area

D Diff i ffi i t

)( bsh

solid 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

Improvement in bioavailability by nanosizing

100 nm

500 nm

2000 nm2000 nm

5000 nm

Bi il bilit % d b b d A d th

*ElanTechnologieshttp://www.elan.com/EDT/nanocrystal_technology/

Bioavailability = % drug absorbed = Area under the curve4

Importance of deagglomeration and mixing

Reason for agglomeration Van der Waals attractions +Electrostatic force +Capillary force > Gravitational forcep y

Effect of agglomeration

Van der Waals attractions α d ; Gravitational force α d3

ggCaking, poor flowability, segregation, content non homogeneity in tablets, loss in bioavailability of drugs , etc.

80

90

50

60

70

80lv

ed (%

)19-27 µm

10

20

30

40

Dru

g D

isso

3-108 µm

10-38 µm

*De Villiers, M. M., 1996.. Int. J. Pharm. 136, 175-179.

5

00 10 20 30 40

Time (minutes)

Available mixers

Currently available mixers are not effective in deagglomeration of particles smaller than 10 micronof 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

Materials

Itraconazole (Used as a antifungal agent)Dosage = 200-400 mgg gAqueous Solubility = 0.004-0.012 mg/mlDose/Solubility = 16500 > 250 mlMP= 166.2 °ClogP =6.939pKa =3.7

Fumed Silica (FDA approved Used as a glidant)Fumed Silica (FDA approved, Used as a glidant)

Surface area = 200 +15 m2/gTapped Density = 40 g/lAgglomerate size = 30-44 µmAggregate size = 200-300 nmPrimary particle size = 9-30 nm

* Wishart, et al.,2006 Nucleic Acids Res. 1(34),D668-D672.

* Cabot Corp. 2007. Available via www.cabot-corp.com. Accessed on June 20, 2007.

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, BocaRaton.

*Gupta, R. B. and Kompella, U. B., 2006. Nanoparticletechnology for drug delivery. Taylor and FrancisGroup., New York.

Dipyridamole Nano-flakes by bottom-up approach

Supercritical antisolvent-enhanced mass transfer (SAS-EM)

Drug Solution Flow rate 1 ml/minDrug Solution Flow rate – 1 ml/min

Drug concentration – 5 mg/ml in DCM

Antisolvent Flow rate (CO2) – 10 gm/ming

Ultrasound Amplitude – 25 %

9P. Chattopadhyay, R. B. Gupta. Int J Pharm. 228 (2001) 19-31.

Continued….

Production of itraconazole nanoflakes

Micronized itraconazole from Itraconazole flakes produced by SAS-EM methodsupplier (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

Method for deagglomeration and mixing

Rapid Depressurization of Supercritical Suspension (RDSS)

A

B

BeginningMixture

*Yang et al., 2003. Adv. Powder Tech. 14, 471-93.

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

Deagglomeration and mixing by RDSSgg g yAgglomerated Itraconazole flakes Deagglomeration and mixing of

itraconazole with silica

RDSS

Silica

Continued…

Physical mixing

Drug Particles Silica

Handling Propertiesg

Angle of ReposeMeasured by flowing 25 ml powderthrough firmly fixed funnel (8 mmdiameter) from height of 5 cm on flatsurface

Compressibility Index (%)

surface

Hausner Ratio

Handling Propertiesg p

Component or Mixture Angle of Repose (°)

AeratedDensity (mg/ml)

Tapped Density (mg/ml)

C.I. (%) HausnerRatio

(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 1.52Itraconazole ( SAS-EM) 46.3 + 0.3 36.4 55.7 52.9 1.53

Physical Mixture –Itraconazole(SAS-EM) and

silica41.7 + 2.6 39.8 49.8 25.0 1.25

RDSS-Itraconazole (SAS-EM) and silica 34.7 + 1.7 105.4 120.5 14.3 1.14and silica

Flow Character Angle of Repose (°)

C.I. (%) Hausner Ratio

Excellent 25-30 < 10 1.00-1.11Good 31 35 11 15 1 12 1 18Good 31-35 11-15 1.12-1.18Fair 36-40 16-20 1.19-1.25

Passable 41-45 21-25 1.26-1.34Poor 46-55 36-31 1.35-1.45

Very poor 56-65 32-37 1.46-1.59Very Very poor >66 >38 >1.60Very Very poor 66 38 1.60

Better handling properties !

Continued…

Physical Stability (by keeping samples at 90°C for 25 days)

Aggregates/Agglomerates of Itraconazole nanoflakes after

storage

RDSS mixture of Itraconazole/silica after storage

g

Drug Dissolution

Silica Titania100

120Particle size:~submicron-14 μm flakes with 150 nm thickness,

Aspect ratio: 1-4

80

100

d

p

40

60

Dis

solv

ed

Particle size:~3-60 μm flakes, Aspect ratio: 8-10

20

40

% D

rug

D

Itraconazole nanoflakes

RDSS mixture (itraconazole nanoflakes/silica nanoparticles)

RDSS mixture after storage (itraconazole nanoflakes/silica nanoparticles)

Itraconazole nanoflakes after storage

00 20 40 60 80 100

Time (minutes)

Itraconazole nanoflakes after storage

Micronized itraconazole from supplier

Time (minutes)

Improvement in shelf-life !

Conclusions

Pure itraconazole flakes have poor flowability and reduced dissolution rate upon storage

Drug nanoflakes and silica nanoparticles deagglomerateDrug 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

Acknowledgementg

The National Science FoundationNIRT grant DMI-0506722

Experimental assistance from Andrew Scott (a NSF REU student)REU student)Technical discussion on RDSS with Prof. Rajesh N. Dave (NJIT, Newark)

Thank you !