(758a) Stability By Design (SbD): Utilizing Material Science Principles to Predict Physical and Chemical Stability of Pharmaceutical Solids

Stability by Design (SbD):
Utilizing material science principles to predict physical and chemical
stability of pharmaceutical solids

M. Brunsteiner ¹, C. Gressl¹, J.G.
Khinast¹, A. Paudel¹

Adrian L. Davis ², Meg Landis ³,
Klimentina Pencheva ², Garry Scrivens ², Geoffrey P.F.
Wood ³

¹Research
Center Pharmaceutical Engineering, Graz, Austria

² Pfizer Worldwide
R&D, Sandwich, Kent UK

³Pfizer
Worldwide R&D, Groton, CT, USA

Ensuring, both,
physical and chemical long-term stability of the drug product is one of the key
requirements in successful drug formulation development. While significant
knowledge exists on solution-state stability of pharmaceuticals, the predictive
knowledge of solid-state physical and chemical stability in solid oral dosage
forms is limited. Here we present two examples of our research towards
achieving stability by design (SbD) for solid oral
dosage forms through the use of in-silico
methods to accelerate and streamline formulation development.

As a model for
chemical drug degradation we consider Carvedilol (CAR), a compound used in the
treatment of congestive heart failure. The compounds secondary alcohol has been
shown to undergo esterification when formulated with citric acid (CA)as an excipient.(1) The free base form of CAR can
crystallize in at least two different polymorphic forms. Based on structural
and energetic results from Molecular Dynamics (MD) simulations of the crystal
surfaces of two different CAR polymorphs in contact with vacuum or citric acid,
we calculated a range of descriptors, including surface energies and exposed
reactive surface areas. A thorough analysis of these descriptors and their
relative magnitudes for different crystal surfaces of the CAR polymorphs allows
us to investigate the relative importance of degradation of molecules on
crystal surfaces versus degradation of molecules that are highly mobile due to
surface defects and partial amorphization. Accordingly, two different
crystalline forms (included in MD simulation) and an amorphous form of CAR were
generated of two different size ranges. Following the comprehensive solid-state
and particulate characterization, CAR-CA blends prepared using different
solid-states and sizes of CAR were subjected to accelerated condition of
50°C. The comparison of the experimental data on kinetics and extent of
CAR-CA interaction products formation with the descriptors derived from MD
simulations will provide the predictability of chemical stability by the
computed descriptors.

As models for
physical drug stability, we consider a series of API-polymer combinations that
have been used to produce amorphous solid dispersions (ASD), (2) a commonly
used strategy in the formulation of poorly soluble drugs. We performed
extensive MD simulations of ASDs at various drug loads and calculated
descriptors such as relative hydrogen boding propensities, free volumes, API
mobilities, and API-polymer intermolecular interactions. A comparison of the
obtained results with existing literature data for the relative stabilities of
the different ASDs shows that both kinetic and energetic factors can play a
role in determining the stability of ASDs. We suggest criteria that can be
determined in-silico and used to
estimate the relevance of these factors for a given API-polymer combination.

References

1.   Larsen, J., Cornett,
C., Jaroszewski, J. W., and Hansen, S. H. (2009)
Reaction Between Drug Substances and Pharmaceutical Excipients: Formation of
Citric Acid Esters and Amides of Carvedilol in the Solid State., Journal of
Pharmaceutical and Biomedical Analysis 49, 11–17.

2.   Eerdenbrugh,
B. V., and Taylor, L. (2010) Small Scale Screening to Determine the Ability of
Different Polymers to Inhibit Drug Crystallization upon Rapid Solvent
Evaporation, Molecular Pharmaceutics 7, 1328–1337.