(336d) Advances in Dissolution Modeling for Oral Dosage Forms with Amorphous Solid Dispersions

We
present further developments in a mathematical model of disintegration and
dissolution of amorphous solid dispersion-based oral dosage forms. 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]. The dissolution kinetics of ASD-based dosage forms is substantially
different from crystalline based dosage forms due to API supersaturation
capability, the gelling and swelling of the polymer matrices during dissolution
and the nucleation, precipitation and micellization kinetics.

The
proposed models allows the streamlining of oral dosage formulation and process
development in achieving an optimal tradeoff between mechanical strength,
disintegration time and dissolution profile. This is achieved by an early
assessment of dissolution profile with a first principles mathematical model
which takes into account intrinsic material properties of the formulation such
as drug diffusivity in the polymer matrix [2], the polymer swelling/erosion
rate [3] and whether the API is crystalline or is in an amorphous solid
dispersion. The disintegration dynamics are handled with a Population Balance
Equation [4] and are coupled to the dissolution model. Whenever direct
assessment of intrinsic material properties are not possible, these parameters
are obtained via curve-fitting the model to a reference experimental
dissolution data using a particle swarm optimization algorithm.

We
present a case-study on the application of the methodology to the downstream
formulation and process development of an amorphous solid dispersion which
illustrates the advantages of guiding the development with a computational tool
in terms of process and drug performance.

Figure 1: Dissolution profile of a tablet
formulated from an amorphous solid dispersion intermediate obtained both
experimentally and from the presented mathematical model.

Figure 2: Snapshot of the predicted drug and
polymer distribution during dissolution as a function of the radial position
within a dissolving particle showing the polymer-rich/drug-poor particle
surface caused by the flux of drug dissolved. The abscissae is normalized by
the instantaneous radius of the particle which evolves over time as the polymer
swells and erodes

References

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

[2]
Wang, Y., Abrahamsson, B., Lindfors, L. & Brasseur, J.G. “Comparison and
Analysis of Theoretical Models for Diffusion-Controlled Dissolution”, Mol.
Pharmaceutics, 9, 1052-1066, 2012.

[3]
Siepmann, J., Kranz, H., Peppas, N. A., & Bodmeier, R. “Calculation of the
required size and shape of hydroxypropyl methylcellulose matrices to achieve
desired drug release profiles”, Int. J. of Pharm., 201(2), 151–164, 2000.

[4]
Wilson, D., Wren, S. & Reynolds G., “Linking Dissolution to Disintegration
in Immediate Release

Tablets
Using Image Analysis and a Population Balance Modelling Approach”, Pharm. Res.,
29:198-208, 2012.