Nano-mixing of Dipyridamole Drug andNano-mixing of Dipyridamole Drug and Excipient Nanoparticles by Sonication in

Liquid CO2q 2

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)(. CCDAR tDi l ti

Decreasing particle size

Increasing surface area (by

)( bs CCh

n RateDissolutio −×=

A – Surface area

D Diff i ffi i tsolid 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*ElanTechnologies

http://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

Method for deagglomeration and mixing

Mechanism: Mixing by cavitation in liquid CO2

7

Materials

Dipyridamole (Used as an anti-thrombosis agent)

D 25 75Dosage = 25-75 mgAqueous Solubility = 0.012 mg/mlDose/Solubility = 5000 > 250 mlMP 163 °CMP= 163 °ClogP =1.5pKa =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

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) – 10-15 gm/ming

Ultrasound Amplitude – 25-40 %

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

Continued….

Production of dipyridamole nanoflakes

10 µm 2 µm

Drug from supplier (Sigma-Aldrich) Dipyridamole flakes produced by SAS-EM

35

40

45 Drug  from SAS‐EM method

10

15

20

25

30

35

Leng

th (µ

m)

100

5

10

0 5 10 15 20

Width (µm)

Apparatus for nanomixing

Sonication in Liquid CO2

Pressure = 1100 psig

T t 5 10 °CTemperature = 5-10 °C

11

Deagglomerationgg

Deagglomeration and Mixing by SonicationAgglomerated Dipyridamole flakes

Deagglomeration and mixing of dipyridamole with lactose

Sonication

Drug Particles

Sonication

Lactose2 µm

12

Drug homogeneity

5

g g y

S l i ht 104 Silica

Sample weight = 10 mg

n=10

)( −∑ CCn

i

2

3

RSD

%

1

)(1 1

−=

∑=

n

CC

CRSD i

i

1

00 1 2 3 4 5 6

Drug content (wt%)

Low RSD is indicator of better mixing quality! 13

Drug Dissolutiong

100

120

80

100

d (%

)

40

60

Dis

solv

e

20

40

Dru

g D

Nanomixed -drug nanoflakes/lactose (5 wt%)

Physical Mixture - drug nanoflakes/lactose (5 wt% drug)

Drug Nanoflakes

00 15 30 45 60 75 90

Drug Nanoflakes

Supplier Drug

14Higher dissolution rate for nanomixed mixture!Time (minutes)

Deagglomeration and mixing by sonicationgg g ySilica Nanomixed-silica/drug nanoflakes

SonicationDrug Particles

Dipyridamole flakes

2 µm 15

Handling Propertiesg p

Component or Mixture AeratedDensity

Tapped Density

C.I. (%) HausnerRatioDensity

(mg/ml)Density (mg/ml)

Ratio

Silica (Hydrophobic) 37.13 45.97 19.2 1.23Dipyridamole ( SAS-EM) 36.4 55.7 52.9 1.53Sonication-Dipyridamole

(SAS-EM) and silica 150.3 167 10.0 1.11

Flow Character C.I. (%) Hausner RatioExcellent < 10 1.00-1.11

Good 11-15 1.12-1.18

Compressibility Index (%)

Fair 16-20 1.19-1.25Passable 21-25 1.26-1.34

Poor 36-31 1.35-1.45Very poor 32-37 1.46-1.59

Very Very poor >38 >1.60

Hausner Ratio

Better handling properties ! 16

Conclusions

Effective deagglomeration and mixing of drug nanoparticles with excipients

Potential use of this method in deagglomeration and mixing for low drug strength dosage (RSD of 3.8 % for 0.14 wt% g g g (drug)

Nanomixed drug-lactose mixture shows higher dissolutionNanomixed drug lactose mixture shows higher dissolution rate than agglomerated drug nanoflakes

Drug silica mixture has better flowability as compared to pureDrug-silica mixture has better flowability as compared to pure drug nanoflakes

P f i i t ti l b t fl kPresence of excipient particles between nanoflakes can improve physical stability or shelf life 17

Acknowledgementg

The National Science FoundationNIRT grant DMI-0506722

Technical discussion on sonication with Prof. Rajesh N Dave (NJIT Newark)N. Dave (NJIT, Newark)

Thank you !

18