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Incorporation of water-soluble API in lipid-based
microspheres obtained by prilling:
from the process to the controlled release mechanisms
Lipid Based Drug Delivery Graduate Student Award
Perrine Pivette1, Vincent Faivre1, Georges Daste2, Michel Ollivon1, and Sylviane Lesieur1
1 Université Paris-Sud XI, UMR CNRS 8612, 5 rue J.B. Clément, 92290 Châtenay Malabry, France ;
2 Sanofi-Aventis, 20 avenue Raymond Aron, 92165 Antony, France
ABSTRACT
•
•
•
Purpose: The aim of this work is to prepare and characterize lipid microspheres loaded with
water-soluble API of industrial interest in order to control its release kinetics. The purpose
here focuses on the correlation between the process and the release properties.
Methods: Sustained release microspheres for oral route were obtained by melting excipients
and API. By extrusion through vibrating nozzles, molten solutions were dispersed into
calibrated droplets which solidify during their fall in a temperature-regulated air column.
Microspheres were essentially characterized using XRD, DSC and SEM.
Results: Model equations were established to predict the solidification time required to
crystallize the molten mixture as a function of its thermal characteristics and optimize prilling
operating parameters. It results from these calculations that droplet cooling rates are very fast,
in the range of thousands of K/min.
Taking advantage of the process and this rapid cooling rate, it is possible to generate perfectly
spherical microspheres in which the crystalline domains are very thin and drug finely
dispersed. In such kind of inert lipid-based microspheres, and considering the important
water-solubility of the API, the release kinetics is governed i) by the water diffusion through
the drug-filled channels and ii) by the API molecular diffusion in the pores created after drug
dissolution.
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ABSTRACT
•
•
•
In practice, microspheres were prepared, characterized and dissolution analysis attested a
prolonged release dissolution profile. Shape studies have shown that the matrix remains
globally intact during dissolution.
To get further insight onto the drug release mechanisms, XRD and HPLC analysis were made
simultaneously to quantify the solubilized-drug fraction within the particles and the effective
released fraction respectively. The XRD analysis also confirmed the stability of the lipid
matrix structure at a supramolecular level, allowing the use of model equations based on
dissolution-diffusion mechanisms to fit the kinetics data.
Conclusion: In agreement with the theoretical prediction, we prepared by prilling process
lipid microspheres able to control the release of a water-soluble drug. Monitoring the
crystallized-API disappearance within the matrix complements classical dissolution methods
which measure the drug fraction released in the dissolution media.
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INTRODUCTION
• Microspheres, as a delivery system for oral route, present
some interest compared to monolithic delivery system:
• Easier administration
• Distribution over a large area :
 better reproducibility of the stomach filling
 lower risk of physical injury of the gastro-intestinal tract.
• Lipid formulation
• Enhancement of hydrophobic drug bioavailability
• Control release rate
• Taste masking
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Prilling head
INTRODUCTION
Liquid phase
Heater
 Heating
 Extrusion of the liquid through calibrated
nozzles and break up of the liquid jet with a
vibrating technology
 Solidification of the liquid droplets during
falling in cool air (10-20°C)
Prilling has the advantage to produce solid microparticles,
very reproducible in size and shape but implies very fast
cooling rates which could lead to supercooling
phenomenon or crystallization into unstable forms, due to
polymorphic behaviour of the materials.
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Cooling tower
• Prilling
Solid phase
Microspheres 300-400 µm
INTRODUCTION
• It is well known that lipid components exhibit complex
physical state behaviour depending on thermal treatments
and/or the temperature of storage, mainly due to their
polymorphic properties.
• Therefore, the knowledge of thermotropic and structural
characteristics of the lipids appears a necessary prerequisite for
our research work to control lipid-based formulation and its
stability with time as a function of the preparation process.
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OBJECTIVES
• To evaluate theoretically and experimentally the solidification
behavior of two lipid excipients: Compritol® and paraffin,
during the production of microspheres through prilling process
[1].
• To characterize prilled microspheres loaded with an highly
water-soluble drug.
• To better understand dissolution kinetics using X-Ray based
methods.
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MATERIALS
• Compritol® (glyceryl behenate): mixture of mono-, di-, triglyceride of behenic acid
→ melting point 69-74°C
• Paraffin wax: aliphatic chains (mean C27)
→ melting point 52-54°C
We studied the solid state of both binders separately and in a
50/50 (w/w) binary mixture.
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METHODS
– The thermal behaviour of Compritol and paraffin (transition temperatures and
enthalpy variation) were studied by differential scanning calorimetry
(DSC): DSC 7 Perkin-Elmer, heating/cooling from 10 to 90°C at 5°C/min.
– Structural characterization was performed by Small and Wide Angle X-ray
Diffraction (SAXS-WAXS XRD) measurements: SAXS beamline of the
Elettra synchrotron (Trieste, Italy) and Lab instrument (UMR 8612).
– Microcalix, a device developed in our laboratory which coupled X-ray
diffraction and calorimetric study was also used [2]. Thanks to this device,
we finely correlated thermal and structural behaviours of the lipid binders.
– SEM (Scanning Electron Microscopy)
– X-Ray Microtomography Elettra synchrotron (Trieste, Italy)
– Complementary studies: HPLC, infrared, polarized light microscopy,
particle size analysis
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RESULTS
• A first part of our work was to established model equations to predict the
solidification time required to actually crystallize the lipid as a function of its
thermal characteristics and then optimize operating temperatures within the
prilling tower. Indeed, the main issue of prilling process is to obtain solid
microspheres at the end of the process.
Time to obtain solid microspheres =
Time to reach crystallization temperature tr
Volumic mass of molten
lipid (kg/m3)
Specific heat capacity
Droplet
(kJ/kg.K)
diameter (m)
tr  
 mC p d d
Heat transfer
coefficient (W/m2K)
6h
 T T 
ln c a 
 Ti  Ta 
Crystallization time tc
+
Latent heat of
crystallization (kJ/kg)
Tc Crystallization T°C
Ta Air cooling T°C
Ti Initial heating T°C
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tc 
Characteristic
length (m)
 H  m Lc
h(Tc  Ta )
RESULTS
Thanks to data provide by DSC and data provide in the literature, we were able to
calculate solidification time for Compritol, Paraffin and a 50/50 (w/w) binary
mixture of both.
Numerical application
(heating T° 95°C, air T° 10°C)
DSC 5°C/min
Compritol
ΔHmelt/crys
tr
tc
0.2s
0.5s
0.5s
0.7s
0.4s
1s
129 J/g
CP
CP + PF
PF
Heat flow (endo up)
Tonset 72°C
Compritol + Paraffin
50/50 w/w
ΔHmelt/crys
107 J/g
Tonset 67°C
Paraffin
ΔHmelt/crys
138 J/g
Tonset 54°C
20
30
40
50
60
70
80
90
Fall time available in prilling tower
Total solidification
time
0.9
0.9s
1.5s
1.5 - 1.6s
Time necessary to obtain solid microspheres
compared to the fall duration of the particles
in the device shows that solid microspheres
can be yielded in the experimental conditions
used even if paraffin alone behaves closely to
the limits of the process.
Temperature (°C)
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RESULTS
• Morphological study by SEM:
In practice, microspheres were produced with the setting temperatures presented
before and a morphological study by SEM was performed to evaluate the proper
conduct of the process.
No traces of impaction are
visible on the microgranule
surfaces, confirming their
solidification before final
contact with the prilling
device walls.
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RESULTS
• Then, we studied the incidence of the fast cooling rate on the structure.
To do so, we compared the XRD pattern of bulk samples, slowly cooled at
5°C/min, with XRD pattern of microspheres obtained by prilling.
61.6Å
Intensity (a.u.)
Bragg reflections occur almost at
the same positions in either bulk
matrix or microspheres. However,
the
diffraction
peaks
from
microspheres appear broader and
less intense.
The very fast cooling added to the
dispersed liquid state likely disturbs
crystal growth within droplets so
that
long-range
packing
of
molecules is less ordered.
X-Ray diffraction
bulk
spheres
Compritol
X7
Sub-α
Sub-α
62.4Å
62.3Å
63.2Å
Compritol
+ Paraffin
37.7Å
37.9Å
37.3Å
Paraffin
Orth..
Orth.
37.3Å
0.04 0.08 0.12 0.16 0.20 0.24
SAXS
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0.30
0.40
q Å-1
1.40
1.50
1.60
WAXS
1.70
RESULTS
•
Drug loaded microspheres: highly water-soluble drug + binary
mixture of Compritol/Paraffin
– Dissolution tests were performed according to the pharmacopeia
standards by measuring released fraction in the dissolution media with
time.
– To go further into the understanding of the release mechanism, we also
checked the structural state of microspheres during the dissolution test
by analyzing microspheres with XRD at each control point.
HPLC (dissolution medium)
Drug release measurement
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XRD (microspheres)
Remaining crystalline drug and
lipid structure characterization
RESULTS
• The dissolution profile shows a sustained release of the drug.
• XRD during dissolution media incubation: intensity and surface area decrease of
drug diffraction peaks with time informs about drug solubilization.
SEM
X-Ray Diffraction
Lipid matrix
intensity (a.u.)
API
t0
t + 8h
Solubilized or released fraction
1
Before dissolution
Solubilized fraction
0.8
0.6
Released fraction
0.4
After dissolution t+24h
0.2
0
0.20
0.30
0.40
0.50
1.0
-1
q (A )
1.2
1.4
1.6
1.8
0
50
100
150
200
Time (min.)
The structural (XRD) and morphological (SEM) stability of the lipid matrix during
dissolution confirms a mechanism of diffusion from a non degradable system (no
erosion or swelling).
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Virtual slices
RESULTS
• X-Ray Microtomography: To confirm diffusion mechanism, we
compared totally loaded and partially emptied microspheres.
A time 0, we observe completely filled microspheres while we observe a corona of
channels on partially loaded particles.
In these inert lipid-based microspheres, loaded with water-soluble drug finely
dispersed, release kinetics is governed by: i) diffusion of the dissolution medium
through the drug-filled pathways, ii) solubilized drug diffusion through micronic
liquid filled channels created by its progressive dissolution.
Corona
thickness
Crystalline
drug
Drug loaded microspheres Partially emptied microspheres
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Water diffusion
Drug release
Resolution 3.4 µm
CONCLUSION
• The studied lipid excipients, Compritol® and paraffin, were shown suitable
for production of crystalline microspheres by prilling, in agreement with
the theoretical prediction.
• The fast cooling kinetics imposed by prilling induces slightly disordered
organization but does not lead to polymorphism troubles.
• It is possible to load this lipid microspheres with a water-soluble drug.
• Monitoring API solubilisation within the crystalline matrix complements
classical dissolution methods measuring the drug fraction released in the
dissolution media.
• Drug release is governed by both water diffusion into microspheres and
drug diffusion through the channels created by its solubilization.
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ACKNOWLEDGMENTS
• UMR 8612 CNRS: V. Faivre, S. Lesieur, M.Ollivon;
And all the team «physico-chimie des systèmes polyphasés».
• Sanofi-Aventis: G. Daste and all the «prilling» team.
• MEB: N. Tsapis, CECM Vitry sur Seine, France.
• X-Ray Diffraction: H. Amenitsch, ELETTRA synchrotron, Trieste, Italy.
• X-Ray Microtomography: L. Mancini, ELETTRA synchrotron, Trieste,
Italy.
• Dissolution: C. Guetin, (HPLC), A. Chaar (Master 1)
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REFERENCES
• [1] P. Pivette, V. Faivre, G. Daste, M. Ollivon, S. Lesieur; Rapid cooling of
lipid in a prilling tower Theoretical considerations and consequences on the
structure of the microspheres, J. Therm. Anal. Cal.. (2009), 98:47-55.
• [2] M. Ollivon, G. Keller, C. Bourgaux, D. Kalnin, P. Villeneuve, P.
Lesieur; DSC and high resolution X-ray diffraction coupling, J. Therm.
Anal. Cal. (2006), 85: 219–224.
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BIOS/CONTACT INFO
Perrine PIVETTE is a PhD student in Physical-Chemistry and Pharmaceutical
Technology from University Paris-Sud 11 (France), Laboratory UMR CNRS 8612
(Physical-chemistry, Pharmaceutical technology, Biopharmaceutics).
She received her PharmD. degree in 2006 from University of Angers (France). In the
same year she received her Master’s degree in Pharmaceutical Technology and
Biopharmaceutics (Conception and development of dispersed systems and solid
formulations) from University Paris-Sud 11 (France).
She joined the UMR CNRS 8612 (Paris University) for her PhD program under
supervision of Dr Vincent FAIVRE, Dr Sylviane LESIEUR, Dr Michel OLLIVON in
a collaboration with Sanofi-Aventis company. Her doctoral research is focused on the
study of constituents and process parameters influence on the drug release kinetics
from lipid microspheres obtained by a prilling process.
Address: UMR CNRS 8612, Universite Paris-Sud 11; 92296 Chatenay Malabry; France
Phone: +33630207663
Mail: perrine.pivette@u-psud.fr (University) / perrine.pivette@free.fr (Personal)
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