(766f) Modeling Spray Dried Dispersion: From Droplet to Particle | AIChE

(766f) Modeling Spray Dried Dispersion: From Droplet to Particle


Curtis-Fisk, J. - Presenter, The Dow Chemical Co
Mecca, J., The Dow Chemical Company
Khot, S., The Dow Chemical Co.
Porter, W. III, The Dow Chemical Co.

Modeling Spray Dried Dispersion: From Droplet to Particle

Jaime L. Curtis-Fisk1, Priti
Jain2, Jodi Mecca1,Bart Rijksen, 3
Shrikant Khot1,  William W. Porter III1
1The Dow Chemical Company, Midland, MI USA

Chemical International Private Limited, Mumbai, India

3 Dow
Benelux BV, Terneuzen, Netherlands


Poorly soluble APIs are often formulated as a solid
amorphous dispersion in combination with an excipient polymer to enhance their
solubility. A common route to producing the dispersion is through spray drying.
This process involves spraying a solution of polymer, active pharmaceutical
ingredient (API) and solvent into a heated drying gas where the liquid spray
droplets dry into solid particles of the amorphous dispersion.  Hydroxypropyl
methylcellulose acetate succinate (HPMCAS), such as AFFINISOL™ HPMCAS, is one
polymer shown to significantly enhance API solubility when in an amorphous
dispersions.  The purpose of this work is to develop a droplet drying model
connecting the fundamental properties of HPMCAS polymer solutions to the spray
drying particle formation kinetics and the resulting particles’ morphology and
compositional uniformity. With this modeling capability, it may be possible to
predict and gain insight into the observed properties of amorphous spray dried


and Methods:

A particle formation model was developed considering
the balance between solvent evaporation and solute diffusion to predict
particle morphology and composition. The model, as illustrated in Figure 1, considers
the diffusion of API and excipient towards the core of the droplet and surface
recession of the solvent as the two main counteracting mechanisms in the drying
of droplets. Methods for predicting particle formation are known, but do not
fully address the complexities of producing spray dried dispersions from a
solution containing API and polymer.[i]
This model framework builds upon these references and addresses the
non-ideality of the liquid phase due to the use of polymeric excipients,
including the interaction between solutes and the change in evaporation rate
due to non-ideal vapour liquid equilibrium. This added complexity will provide
a more accurate route to predicting the impact of formulation and spray drying
conditions on particle morphology.


To provide inputs to the model, fundamental
properties including viscosity and diffusivity of HPMCAS-API solutions were
characterized in a wide range of solvents and solvent blends.  Additionally
methods to characterize HPMCAS-API interactions were used to understand potential
effects on mass transport within the solution droplet. 




Figure 1. The model framework combines process conditions, solution
properties, and evaporation rate in an Athena framework to generate predictions
of particle morphological properties


This particle formation model was shown to compare well
against experimental results in the literature. Figure 2 illustrates a
comparison of the model predictions of spray dried trehalose against results
from Vehring et al.[ii] The samples
evaluated cover a low Peclet number range of 0.44 to 1, with an initial droplet
diameter of 20 µm resulting in a dry particle diameter of 1.7 to 1.8 µm. The model accurately predicts
the measured dry particle density, which is near the density of amorphous
trehalose indicating solid particles.



Figure 2. Comparison of experimental results from Vehring
et al and model predictions of trehalose particles formed through spray drying.


It was also found to predict well the experimental results
from Vehring et al.ii for
spray drying of glycoprotein solution as shown in Figure 3.  As the Peclet number
increases, the particle diameter increases while the density decreases. Both
the experimental and modeled particle densities (0.1 to 0.5 g/cc) are
significantly lower than the density of solid glycoprotein. This indicates
hollow particles with void space, a result confirmed through microscopy of the
generated particles.

Figure 3. Comparison
of experimental results from Vehring et al and model predictions of glycoprotein
particles formed through spray drying.

To apply the droplet drying model to spray drying API-HPMCAS
dispersions, fundamental solution properties were characterized.  The
viscosities of such solutions were found to vary strongly based on the specific
HPMCAS polymer and spray drying solvent.  As shown in Figure 4, at similar concentrations
a wide range of viscosities were observed indicating very different polymer
configurations in solution. Similar measurements were conducted to quantify the
diffusivity of polymer and API solutes in solution and the surface tension of
these solutions.  Having quantified these properties, predictions around the
droplet drying process and resulting particle properties will be shared.  It
will be shown that depending on the solvents selected for spray drying,
diffusion controlled or surface recession controlled drying kinetics can occur
resulting in very different particle morphologies and compositional uniformity.

Figure 4: Viscosity of Polymer/Solvent Solutions that
serve as inputs for particle formation modeling


Experimental analysis of formulation solution properties and
polymer chemistry provide a solid framework for building modeling capabilities
to predict the formation of solid particles from liquid droplets in the spray
dried dispersion process. The two examples presented highlight the dramatically
different potential outcomes from a spray drying process, from solid particles
of high density to low density hollow particles. The ability to predict the
nature of the particles formed based on formulation and process properties
provides the formulator with a valuable tool to optimize this process to hone
in on a targeted outcome prior to conducting time consuming experiments. Particle
morphology can play a critical role in downstream processing and ultimately the
application performance. Combining polymer chemistry and formulation expertise
with modeling capabilities provides formulators with a streamlined route to
product development.






[i] Chen, Xiao Dong; Sidhu, Harvinder;
Nelson, Mark; “Theoretical probing of the phenomenon of the formation of the
outermost surface layer of a multi-component particle, and the surface chemical
composition after the rapid removal of water in spray drying,” Chem. Eng. Sci.
66 (2011) 6375-6384.

[ii] Vehring, Reinhard; Foss, Wiillard R.;
Lechuga-Ballesteros, David; “Particle formation in spray drying,” Aerosol
Science 38 (2007) 728-746.