427772 Stability By Design (SbD): Utilizing Material Science Principles to Predict Physical and Chemical Stability of Pharmaceutical Solids

Friday, November 13, 2015: 8:30 AM
Ballroom D (Salt Palace Convention Center)
Michael Brunsteiner1, Corinna Gressl1, Johannes G. Khinast2, Amrit Paudel3, Adrian L. Davis4, Margaret Landis5, Klimentina Pencheva4, Garry Scrivens4 and Geoff Wood6, (1)RCPE, Graz, Austria, (2)Research Center Pharmaceutical Engineering (RCPE), Graz, Austria, (3)Advanced Products and Delivery, RCPE, Graz, Austria, (4)Pfizer Worldwide R&D, Sandwich, Kent UK, Kent, England, (5)Pfizer Worldwide R&D, Groton, CT, Groton, CT, (6)Pfizer

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.


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.


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