(384e) Evaporation of Binary Mixtures and Shell Formation in Spray Dried Droplets

Evaporation of binary
mixtures and shell formation in spray dried droplets

P.C. Valente¹,
Í. Duarte¹, T. Porfirio¹, X. Liu²,
F. Zhang²
& M.N. Temtem¹  

¹ R&D
Drug Product Development, Hovione Farmaciência
S.A, Sete Casas, 2674-506 Loures, Portugal;

² College of Pharmacy, University of Texas at
Austin, U.S.A;

Amorphous solid
dispersions (ASDs) of poorly water soluble active pharmaceutical ingredients
(APIs) in hydrophilic polymeric matrices are a commonly used strategy to
increase the solubility and dissolution rate of oral-dosage forms [1]. However,
since the polymer is hydrophilic and the API is poorly water soluble, it is often
difficult to find a common solvent for both and a mixture of co-solvents is used
instead. Solvent mixtures also offer the possibility of influencing particle
morphology and drying rate [2] and have been reported to offer advantages in
the solid state drug-polymer miscibility and on the stability of the ASDs [3,4].

To fully explore the
potential of spray dried ASDs from co-solvent drug-polymer solutions, a fundamental
understanding on the solvent chemistry, droplet composition history throughout
drying and its impact on the drug-polymer interaction, stability and phase behavior
are required. These mechanisms are, in turn, strongly influenced by the process
conditions, such as thermodynamic layout, atomizing characteristics and spray
drier geometry.

The focus of the present
work lies on the evaporative dynamics of binary solvent droplets and how they
are influenced by process conditions. Unlike the single component counterpart, modelling
the evaporation of binary mixtures depends not only on the process parameters,
but also on the mass (and momentum) transfer within the droplet [5]. For example,
if one considers solely the molecular diffusion for solvent mixtures with
starkly different vaporization enthalpies, the evaporation rate of each solvent
will be proportional to their initial mass fraction and, counter-intuitively,
will be independent of the vaporization enthalpies [6].  However, whenever there is a non-negligible
relative velocity between the droplet and the surrounding drying gas, the
internal circulation within the droplet can lead to a steep increase in the
effective mass diffusion rate. The
evaporation rate of each solvent will also strongly depend on their
vaporization enthalpy (see Figure 1). This leads to the more intuitive case
where the more volatile solvent tends to evaporate first.

We show that these two
limits lead to dramatically different drying kinetics and can strongly affect
the onset of drug/polymer precipitation and shell formation. After shell
formation the drying kinetics tend to be strongly modified, highlighting the
importance in predicting the onset of shell formation to bound the
applicability of the drying models. These two limiting cases of infinitely slow
or infinitely fast droplet component diffusion may be used to formulate scalar
(0D) evaporation models [5,6]. In practical spray
drying situations, both limits can be attained depending on the binary mass
diffusion coefficients, atomization characteristics, temperature profile or
drying gas flow velocity, to name a few parameters.  These evaporation models are particularly
useful when coupled to a numerical solver to predict stability and phase
separation of amorphous solid dispersions [7,8] or a numerical solver of the Navier-Stokes equations, commonly denoted as computer fluid
dynamics (CFD) [9,10].

We extend the
previously developed platform for phase separation prediction of
drug-polymer-solvent systems to systems with binary solvent blends in an effort
to generalize a screening methodology for ASDs and compare the data against
experimental results.

Figure 1:
Sketch of various stages throughout the droplet drying history: a) droplet with internal circulation caused by the relative
velocity between the droplet and the surrounding gas, b) shell formation and c)
the final particle.

References

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378(1-2) pp. 116-121

[3] Janssens,
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[5] Sirignano,
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[8] Prudic,
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[9] Sazhin,
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[10] Maqua, C., Castanet, G. & Lemoine,
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