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
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 !
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