(252f) Mechanistic Approach to Predict Amorphous Solid Dispersion Thermal Degradation in Spray Drying Processes

Mechanistic approach to predict ASD thermal degradation in
spray drying processes

G. Poeiras^1,3, T. Porfírio^1,2*,
C. Sá Couto¹, J. Pereira¹, R. Silva¹, I.
Duarte¹, M. D. Afonso³, J. Vicente¹

¹Hovione Farmaciência SA, Sete Casas, 2674-506 Loures,
Portugal; *tporfirio@hovione.com

²LAETA, IDMEC, Mechanical Engineering Department, Instituto Superior
Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal

³CeFEMA, Chemical Engineering Department, Instituto Superior Técnico,
Universidade de Lisboa, Av. Rovisco
Pais 1, 1049-001 Lisbon, Portugal

The number of drugs with solubility limitations is
increasing, being the limited aqueous solubility a major challenge in the
development of oral-dosage forms, as it may affect oral bioavailability.
Several solubilization strategies have been developed, being the amorphous
solid dispersions (ASD) one of the most common. Spray drying (SD) process is
one of the most widely used technologies for ASD production allowing the
control of the product attributes, viz. particle size, density and physical
state. SD is a solvent based process that often includes a secondary drying
(post-drying stage) to reduce residual solvent content to values below ICH
guidelines (International Conference on Harmonization of technical requirements
for registration of pharmaceuticals for human use). A key processing phenomena in
both equipment is the particles deposition on the walls and the subsequent build-up
that affects process operation, safety and may impact the product quality through
the deposited particles degradation, Figure 1 [1]. For
that reason, it is crucial to assess the product chemical and physical quality,
which have to be guaranteed throughout the process.

The degradation is intrinsically dependent on the process
conditions in which the product is exposed, such as temperature and saturation.
Computational Fluid Dynamics (CFD) may be used to model the temperature profile
throughout the chamber and provide an estimation
of the product exposure during a manufacturing batch [2]. Moreover,
CFD simulations forecast possible zones of wall accumulation. The output of
such analysis supports the assessment of the accumulated product quality. Subsequently,
the goal is to build a general model capable of predicting the ASD chemical
degradation kinetics for any combination of temperature and relative
saturation.

Figure 1 – Process exemplification
including product accumulation.

As for the physical stability, the thermodynamic properties
and molecular mobility inherent to the amorphous state are responsible for the formation
of crystalline material over time, compromising the bioavailability and
performance of the solid dosage form. Molecular mobility is more or less
pronounced according to the process conditions that the product is subjected to,
namely temperature, humidity and saturation. The experimental determination of
these molecular motions is related to the study of structural relaxation
processes, physical aging or annealing, which consist in the continuous
evolution of the amorphous product towards a more stable equilibrium state at a
given temperature. Structural relaxation can be predicted from the sample thermal
history and its degree of non-equilibrium [3].

In sum, this work developed a mechanistic approach to
predict ASD stability based on (Figure 2):

·        
CFD
to model and predict temperature and saturation profiles inside the spray
drying chamber and/or post drying equipment;

·        
Estimation
of the degree of chemical degradation using a kinetic model;

·        
Physical
stability using structural relaxation studies.

A case study comprising the spray drying
and/or post-drying steps using a model drug to form an ASD will be presented
following the proposed approach. In this case study, the operating conditions
ranges, namely temperature and relative saturation, were defined based on the
results provided by the CFD modelling and also aiming to stress the ASD
chemically and physically.

Figure 2 – Proposed approach for ASD
thermal degradation study.

References

[1] S.
Keshani, W. R. W. Daud, M. M. Nourouzi, F. Namvar, and M. Ghasemi, “Spray
drying: An overview on wall deposition, process and modeling”, Journal of Food Engineering,
pp. 152–162, 2015.

[2] L.
Huang and A. S. Mujumdar, “Simulation of an Industrial Spray Dryer and
Prediction of Off-Design Performance”, Drying Technology, vol. 25, pp. 703–714,
2007.

[3] R.
Hilfiker, Polymorphism in the Pharmaceutical Industry, pp. 260-281, 2006.