binary mixtures depends not only on the process parameters, but also on the mass, heat and ... Schematic representation
T2212 EVAPORATION OF BINARY MIXTURES AND SHELL FORMATION IN SPRAY DRIED DROPLETS Pedro C. Valente1, Íris Duarte1, Tiago Porfírio1, Xu Liu2, Feng Zhang2, Márcio Temtem2,* 1
Hovione PharmaScience S.A., Sete Casas, 2674-506 Loures, Portugal; *
[email protected] or +351 219 847 569
2
University of Texas at Austin, Austin, TX 78712, United States of America
PURPOSE
RESULTS AND DISCUSSION Combination of the co-solvent evaporation and the phase separation models: Model predictions of the film drying history. The co-
To fully explore the potential of spray dried ASDs from co-solvent drugDROPLET DRYING HISTORY
polymer solutions, a fundamental understanding of the solvent
solvents and solids fraction as well as the onset of supersaturation/precipitation are obtained for various film heights as well as the time lag between (super)saturation and the drying end point. This time lag relates to the crystallization tendency when no polymer is present.
chemistry, droplet composition throughout drying and its impact on the drug-polymer interaction, stability and phase behavior are required.
Internal mixing (varying droplet composition)
These mechanisms are, in turn, strongly influenced by the process
Drying gas
conditions, such as thermodynamic layout, atomizing characteristics and
Drug + polymer
Drug + polymer
h=0 h ~ H/2 h~H
h=0 h ~ H/2 h~H
spray drier geometry. The focus of the present work lies on the the onset of supersaturation/precipitation and phase separation during
Spray drying chamber
(Droplet diameter) 2
binary mixtures depends not only on the process parameters, but also on the mass, heat and momentum transfer within the droplet since the different evaporation rates lead to a relative diffusion between the two solvents. Due to the droplet’s spherical symmetry the 1D diffusion problem is solved. The importance of the relative diffusion between the
EtOH DCM
DCM
100:0
60
(poster M1259): The wetting contact angle is a good surrogate of the Time
fraction of polymer/drug at the surface. Lower contact angles generally
Figure 2A. Temporal decrease of droplet size due to co-solvent evaporation for the limiting cases of (left) zero diffusivity and (right) infinite diffusivity.
50:50
Figure 5. Time to reach saturation at the top and bottom of the film together with the drying end point (t_drying) for various solvent fractions. The difference corresponds to supersaturation “exposure time”, Δt.
correspond to a larger fraction of polymer at the surface which correlates well with the lower time of exposure to a supersaturated state during drying.
Drug + Polymer
58 56 54 52 50
The co-solvent evaporation model is also implemented on the previously
48
developed platform for phase separation prediction of drug-polymerZero diffusion
solvent systems to systems with binary solvent blends in an effort to generalize a screening methodology for ASDs (Figure 3). The TKE model
Figure 6: Model prediction of exposure time of the film surface to a supersaturated state against contact angle data obtained experimentally.
microstructure evolution.
DCM
obtained from feed solutions with a mixture of DCM:EtOH (varying
0,4 0,5 Δtsurface
0,6
0,7
0,8
and phase separation. Both effects have a strong impact on the ASD stability and crystallization risk as shown experimentally (see poster M1259). Solvents
ratios). The drying temperature is set to 41ºC and the initial film height to
Higher crystallization risk
Drug solubility
50µm.
Drug becomes supersaturated
Polymer gel point
OUTPUTS
Crystalline risk is proportional to the time between supersaturation
ϕdrug or polymer
hfilm
Drug
Droplet drying history
Polymer
and polymer gelification
Phenomenon occuring first? Solvents
Lower crystallization risk
Polymer gel point
Lfilm
Lfilm
NO PHASE SEPARATION ✔
PHASE SEPARATION ✖
ASD stability is proportional Polymer gelification
Drug solubility
Drug REFERENCES: [1] Law, C.K., Prog. Energy Combust. Sci., Vol. 8, pp. 171-201; [2] Duarte I. et al. Pharm Res, 32(1), 2015, pp. 222-237.
0,3
polymer gelification or the opposite occurs. The 1D model further allows taking into account heterogeneity in the solvents composition
Figure 2B. Co-solvent composition during the droplet drying for the two limiting cases of zero and infinite co-solvent diffusivity.
Figure 3. Two limiting results given by the TKE model (2D simulations).
0,2
Predicting the droplet drying history allows a preliminar estimate on whether the drug becomes supersaturated in advance of the
EtOH
INPUTS
0,1
CONCLUSIONS
Solubility curve
theories (i.e., Cahn-Hilliard and Allen-Cahn) to describe drug-polymer
0
Infinite diffusion
is a system of partial differential equations based on diffuse interface
Hovione 2015 – Copyright
Δtbase
90:10 70:30 DCM:EtOH (% v/v)
EtOH
Comparison with the experimental data of contact angles of Xiu et al.
Time
2. Phase separation model - TKE model based on Flory-Huggins [2]:
The model system consists of 50:50 %w/w Itraconazole:PVP/VA 64
Δtsurf
0
Figure 4. Heterogeneity within film height predicted by 1D model for (left) 90:10 % v/v DCM:EtOH and (right) 50:50 % v/v DCM:EtOH.
(Droplet diameter) 2
Unlike the single component counterpart modelling the evaporation of
Case Study
t_drying
0,6
Solubility curve
Solubility curve
1. Co-solvent evaporation model:
cases of infinitely slow or infinitely fast relative diffusion [1].
t_satura5on (h=0)
0,2
Figure 1. Schematic representation of the droplet drying history
solvents is demonstrated in Figure 2 by considering the two limiting
0,8
t_satura5on (h=H)
0,4
Contact angle (0.8s)
phase separation applied to film casting.
1
Solid particles
the droplet drying history. These dynamics are investigated numerically with (1) a model of co-solvent evaporation coupled to (2) a model for
1,2 6me (s)
Shell formation
evaporative dynamics of binary solvent droplets and how they impact
1,4
to the polymer/drug distribution within particle.
Polymer
