(14f) In silico Development of Amorphous Solid Dispersions for Optimal Performance and Stability

The focus of the present work lies on screening formulations
for amorphous solid dispersions (ASDs)  with a computational tool which allows
a comprehensive set of virtual experiments to be performed without API
expenditure and with a fast turnover and consequently to explore the design
space in full prior to manufacturing prototypes in the laboratory.

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,
successful development of amorphous solid dispersions for optimal performance
and stability depends on both the formulation (e.g. drug load, polymer system
and surfactants) and on the manufacturing technology/process conditions. For
example, adequate solvent mixtures used in the process  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]. On the other hand, excessively complex formulations can lead
to undesirable phase separation which can compromise physical stability [5]. However,
optimizing the formulation (e.g. drug load, polymer system and solubilizers)
and the process (e.g. drying kinetics and droplet/particle size) requires
extensive laboratory work, which is often compromised by time and cost
constraints. Therefore the ability to perform virtual experiments is highly
advantageous and cost-effective.  

In this presentation we cover the mathematical modeling of
the various concurrent physical phenomena that a solution of API and polymer
(and sometimes other excipients) undergo prior to forming an amorphous solid
dispersion, such as atomization, co-solvent evaporative dynamics, propensity
for phase separation and shell formation [6,7]. We show a set of case studies
of in silico screening benchmarked against data from solvent casting and
spray drying experiments and also show a case-study where an excessively
complex ASD formulation led to phase separation and  compromised the stability
of the amorphous intermediate.

Figure 1: Sketch of various stages throughout the droplet
drying history and the concomitant propensity for phase separation and
crystalization if the formulation and/or process are not adequately designed.

References

[1] Perrie Y., Rades T. “Pharmaceutics - Drug Delivery and
Targeting”, Pharmaceutical Press, 2010.

[2] Wulsten, E., Kiekens, F, van Dycke, F., Voorspoels, J.
& Lee, G., “Levitated single-droplet drying: Case study with itraconazole
dried in binary organic solvent mixtures”, Int. J. Pharmaceutics, 2009,
378(1-2) pp. 116-121

[3] Janssens, S, Anné, M., Rombaut, P. & Van den
Mooter, G., “Spray drying from complex solvent systems broadens the
applicability of Kollicoat IR as a carrier in the formulation of solid
dispersions”, Eur. J. Pharm. Sci. 2009, 237, pp. 241-248.

[4] Paudel, A. & Van den Mooter, G., “Influence of
Solvent Composition on the Miscibility and Physical

Stability of Naproxen/PVP K 25 Solid Dispersions Prepared by
Cosolvent Spray-Drying”, Pharm. Res. 2012, 29, pp. 251-270.

[5] Janssens, S., Nagels, S., de Armas, H.N., D’Autry, W.,
Van Schepdael, A. & Van den Mooter, G., “Formulation and characterization
of ternary solid dispersions made up of Itraconazole and two excipients, TPGS
1000 and PVPVA 64, that were selected based on a supersaturation screening
study”, Eur. J. Pharm. Biopharm, 69:1, 2008

[6] Duarte, Í., Santos, J. L, Pinto, J. G & Temtem, M.,
“Screening methodologies for the development of spray-dried amorphous solid
dispersions”, Pharm. Res., 2015, 32 pp. 222 – 237, 2015.

[7] Prudic, A., Ji, Y. & Sadowski, G., “Thermodynamic
Phase Behavior of API/Polymer Solid Dispersions”, Mol. Pharmaceutics, 2014,
11(7), pp. 2294-2304