miniaturization of drug nanocrystals production · miniaturization of drug nanocrystals production....
TRANSCRIPT
The miniaturization of nanosizing was studied using fenofibrate as a model API.
Suspension volume : 800 µL
Fenofibrate : from 20 mg to 200 mg
Stabilizers
Hydroxypropylmethylcellulose 603 (HPMC), HPMC/API 14,5%
Sodium lauryl sulfate (SDS), SDS/API 20%
Particle size distribution
Malvern Mastersizer 2000, Hydro SM wet dispersion unit
Dispersion in a 0,48% Tween 20 solution saturated with
fenofibrate
MINIATURIZATION OF DRUG NANOCRYSTALS PRODUCTION
Caroline Twarog1, Frantz Deschamps1
E-mail : [email protected] STANIPHARM, 5 rue Jacques Monod, BP 10, 54250 Champigneulles, France
MINIATURIZATION DEVELOPMENT USING FENOFIBRATE
The manufacturing of nanosuspensions starting from drugpowders with various particle size distributions wasassessed.
Similar nanosuspensions were produced starting frommicronized fenofibrate or from a coarse 400-800 µmfenofibrate powder.
NANOSIZING COARSE POWDERS
Nanosizing drug particles is a common approach to tackle the poorsolubility issue of Active Pharmaceutical Ingredients and produce oraldosage forms exhibiting an enhanced bioavailability.
For the 6 marketed drug products containing drug nanoparticles, such asfenofibrate 145 mg tablets, nanosuspensions are produced by “top-down”techniques: wet ball milling or high pressure homogenization.
NANOSIZING OF OTHER APIs
The successful production of 800 µL nanosuspensions starting from 20 mg API coarse powders was demonstrated.
Further work is in progress so as to process API amounts of around 5 mg and produce stable dried formulations using a wider range of stabilizers during the nanosizing step.
For nanosuspensions stabilized with SDS,freeze-dried formulations made it possibleto produce a ~150 nm nanosuspensionafter gentle reconstitution in water.
Conversely, a reconstitution by gentlehomogenization in water led to anincrease of particle size for someformulations stabilized with Poloxamer188.
200 mg 80 mg 50 mg 20 mgdv(0,5)(nm)
162 153 148 154
dv(0,9)(nm)
414 421 372 411
Water Trehalose Sucrose Mannitol
SDSdv(0,5)(nm)
165 168 156 158
P188dv(0,5)(nm)
173 175 207 197
0 days 7 days 14 days
dv(0,5)(nm) 150
155170
161187
dv(0,9)(nm) 402
433650
4791 302
Production of nanosuspensions from 20 mg of drug powder was assessed for other drugs using 3 different stabilizers.
0
5
10
0,01 0,1 1 10 100 1000
Freq
uenc
y (%
)
Size (µm)
APREPITANT
0
5
10
0,01 0,1 1 10 100 1000
Freq
uenc
y(%
)
Size (µm)
ITRACONAZOLE
0
5
10
0,01 0,1 1 10 100 1000Freq
uenc
y (%
)
Size (µm)
NIFEDIPINE
Raw API SDS F68 Tween 80
dv(0,5) nm dv(0,9) nm
Raw API SDS P188 Tween 80 Raw API SDS P188 Tween 80
Aprepitant 30 276 129 127 126 108 436 262 219 246
Itraconazole 13 101 125 140 123 286 651 205 668 200
Nifedipine 207 721 127 131 133 581 454 273 241 286
CONCLUSION
154
412
158
509
152
442
153
424
0
200
400
600
dv(0,5) (nm) dv(0,9) (nm)
Size
(nm
)
5 µm 400<x<800 µm 150<x<400 µm x<150µm
0123456789
10
Freq
uenc
y(%
)
Size (µm)
200 mg
80 mg
50 mg
20 mg
PRODUCTION OF STABLE DRY FORMULATIONS
At early stages of drug development, drug compound availability is limitedand can hinder the assessment of the enabling nanosizing approach forpoorly soluble new chemical entities.
This study aimed at developing a nanosizing device for the production ofdrug nanosuspensions
using mg amounts of drugs
starting from coarse drug powders, without any pre-milling
INTRODUCTION OBJECTIVES
The particle size of fenofibratenanosuspensions increases upon storage at4°C and 25°C for 14 days.
Dry formulations were thus produced byfreeze-drying using 3 differentcryoprotectants at 80 mg/ml: trehalose,sucrose, mannitol.
25°C 4°C