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Generation of Phenytoin particles and

drug-polymer solid dispersions by
means of compressed gas precipitation
ChE 702-002: Modules in Nanopharmaceuticals, Spring 2007
Micaela Caramellino mc246@njit.edu
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Use of compressed gas precipitation to enhance the
dissolution behavior of a poorly water-soluble drug:
Generation of drug microparticles and drug-polymer
solid dispersions
Dense Gas Antisolvent Precipitation: a comparative
investigation of the GAS and PCA techniques
Papers
F. Fusaro, M. Hanchen, M. Mazzotti, G. Muhrer, B. Subramaniam
Ind. Eng. Chem. Res., 2005
G. Muhrer, U. Meier, F. Fusaro, S. Albano, M. Mazzotti
Int. Journal of Pharmaceutics, 2006
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Outline
Goal: elucidating the potential of gas antisolvent and precipitation
with compressed antisolvent processes to enhance the dissolution
behavior of poorly water-soluble drugs by investigating the
micronization of neat drug substance and the generation of drug-
polymer co-formulations.
Outline:
Description of the processes involved
GAS experiments
PCA experiments
Co-precipitation experiments
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Gas Antisolvent (GAS) precipitation
Technique for precipitating or crystallizating
solutes dissolved in a liquid solvent system by
addition of a supercritical antisolvent
Rapid Expansion of Supercritical solutions (RESS)
Technique for precipitating solutes dissolved in
a supercritical solution by means of a sudden
pressure change
Processes
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RESS
GAS
Processes
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PCA - Precipitation with compressed antisolvent
Processes
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M
0
= amount of starting solution
M
A
= rate of antisolvent addition
Q
A
= M
A
/M
0
Initial phenytoin conc.
Operating conditions:
V = 400ml
T = 30C
n = 400rpm
Precipitation of Phenytoin GAS experiments
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Q
A
= 0.07
Q
A
= 0.2
Q
A
= 0.5
Q
A
= 0.1
- Effect of the specific antisolvent addition rate (Q
A
)
The average crystal size and volume decreases when Q
A
is increased
S
0
(initial
saturation ratio)
was kept constant
Higher value of
nucleation rate
Precipitation of Phenytoin GAS experiments
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- Effect of the solvent
Operating conditions:
V = 400 ml
T = 25C
n = 400 rpm
Q
A
=0.2 min
-1
M
0
=50 g
Acetone G3
75 % vol. ethanol
25% vol. acetone
G11
Ethanol G8
Precipitation of Phenytoin GAS experiments
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Precipitation of Phenytoin PCA experiments
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P=150 bar (P5)
P=95 bar (P3)
P=120 bar (P4)
- Effect of temperature and pressure
The experimental point
approaches the mixture
critical point
CO
2
-acetone system
Precipitation of Phenytoin PCA experiments
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In the supercritical mixture region, due to the vanishing of the
interfacial tension and the fact that solvent and antisolvent become
fully miscible, fluid mixing rather than jet break-up into droplets
becomes the controlling mechanism for particle formation.
Lengsfeld et al., 2000
The distance from the critical region affects the shape of the final
particle different fluid flows regimes appear:
-Droplet formation in the sub or near-critical region two phase
region
-Gas-like jet in the supercritical region
For drug particles
Precipitation of Phenytoin PCA experiments
- Effect of temperature and pressure
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- Effect of the flow rate ratio
The ratio between the solution flow rate
and the CO
2
flow rate controls the
supersaturation level that can be reached
in the injection device
For the experimental conditions of the
runs considered, it is expected particle
formation to be controlled by mixing rater
than by jet break-up into droplets
M
A
to M
SOL
ratio of 60 (P6)
M
A
to M
SOL
ratio of 160
(P7)
Increasing M
A
relative to M
SOL
yields to
a product containing both needles and
crystals
Precipitation of Phenytoin PCA experiments
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- Effect of the initial concentration
Precipitation of Phenytoin PCA experiments
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Needles up to
200 mm
Decrease in the
needles length
Needles
Particles
highly
agglomerated
P9 2%
P10 3%
P8 -3%
P1 - 4%
Precipitation of Phenytoin PCA experiments
- Effect of the initial concentration
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Precipitation of Phenytoin PCA experiments
Particles size
for different
runs
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PCA and GAS used for generating solid dispersions of
poorly water-soluble compounds in water-soluble
polymeric carrier
Compare the in vitro dissolution behavior with
particles obtained with spray-dried technique
Drug-polymer coformulations of phenytoin and PVP
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First experiment:
GAS recrystallization of PVP-K30 from ethanol/acetone mixtures
Initial concentration: 0.5 8% wt.
Operating temperature: 5 - 30C
CO
2
addition rate: 0.5-2 min
-1
Liquid-liquid phase separation
yielding large porous,
interconnected polymer
structures rather than discrete
particles.
Second experiment:
PCA precipitation of pure PVP-K30 microparticles
Ethanol/acetone mixture
(24% wt. ethanol) as organic
solvent phase
Operating pressure below the
critical pressure of the binary
system (80 bar)
Operating temperature: 25C
Better results
Drug-polymer coformulations of phenytoin and PVP
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Possibility of molecularly dispersing phenytoin in a continuous matrix
of polyvinyl-pyrrolidone to form a solid dispersion
Ethanol/Acetone mixture (24% wt. ethanol)
Pressure = 80 bar
Temperature = 25C
PCA co-precipitation experiments
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Taki et al. (2001)
The relative concentration of active agent and polymer was
reported to have a decisive influence on the encapsulation
efficiency
Effect of the relative amount of
phenytoin and PVP-K30
1:4 ratio drug to polymer
Ratios between 1:4 and 1:2 :
The co-precipitate appears as
agglomerates of spherical
primary particles below 500
nm in size no needle like
crystals
PCA co-precipitation experiments
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When the concentration of phenytoin in the
initial solution is small compared to the
concentration of PVP-K30 (ratios of less than
1:2), the product appears as micron size
agglomerates of spherical nanoparticles that
were completely amorphous and showed no
recrystallization tendency after several weeks
of storage.
At higher drug concentrations no true solid
solutions were formed anymore
PCA co-precipitation experiments
Effect of the relative amount of
phenytoin and PVP-K30
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Dissolution performances
PCA co-precipitation
Spray drying
-The drug if first
tabletted (know
and constant area)
- then it is
contacted with the
dissolution medium
The dissolution rate
is proportional to
the particle size
and PSD
PCA co-precipitation experiments
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Dissolution rate = slope of the curve
High pressure hom.
PCA run P3
PCA run C1
Spray drying
Physical mixture
PCA
Spray drying
PCA co-precipitation experiments
Dissolution performances
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The increase in the dissolution rate is
- up to eight-fold when compared to pure drug
particles
- 25% when compared to spray-dried solid
dispersions
The increase is more evident with increasing
the polymer content
PCA co-precipitation experiments
Dissolution performances
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Conclusions
Compressed fluid antisolvent precipitation is
an efficient method for oral bioavailability
enhancement of poorly water-soluble
compounds
A parametric analysis has been successfully
conducted
The study needs to be extended to higher
polymer contents to optimize the dissolution
performance