(233ac) Comparing and Contrasting the Solid-State Esterification of APIs with Excipient: Computational and Experimental Assessment

Wood, G., Pfizer
Khinast, J. G., Research Center Pharmaceutical Engineering
Paudel, A., European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM)
Sluggett, G., Pfizer Worldwide R&D
Chemical stability of pharmaceutical products is one of the key quality attributes. There are limited studies that attempt to construct a molecular level definition of a drug product and predict how solid state factors influence the chemical stability of solid pharmaceutical products. In this study, we aim to combine computational and experimental approaches in an effort to better understand drugâ??excipient degradation reactions in the solid state.
For our studies, we chose carvedilol (CAR) and codeine phosphate (COP) in formulation with citric acid (CA) as our model systems. Both CAR and COP possess a secondary alcohol and are known to undergo esterification in presence of CA [1,2]. To identify effects that are purely based on differences in the crystal structure, all calculations and experiments were carried out with two different polymorphic forms of, each, CAR and COP. For the morphologically important crystal faces, Molecular Dynamics (MD) simulations were used to calculate a range of descriptors which we expect to account for relevant structural, energetic and kinetic properties of the API crystal surfaces [3].
For the experimental assessment of the solid state stability, we first recrystallized the different crystal forms of CAR and COP and fractionated different sizes by sieving in order to obtain crystals with defined characteristics such as particle size and surface area. We then produced mixtures of the model APIs with citric acid and stored the samples at accelerated conditions. The accelerated storage conditions were chosen in a way that all crystal forms are stable, i.e. no polymorphic transformation and no loss of crystal water would occur. A different set of degradation experiments was performed where disorder was introduced to our APIâ??excipient systems by ball milling.
By comparing results from our computational and experimental assessments, we gain insights into which material properties crucially determine the stability of pharmaceuticals in formulation with excipients in the solid state.

[1] Larsen, J, Cornett, C, Jaroszewski, JW, Hansen, SH. (2009) Reaction between drug substances and pharmaceutical excipients: formation of citric acid esters and amides of carvedilol in the solid state J. Pharm. Biomed. Anal., vol. 15, pp. 11-17.
[2] Silver, B and Sundholm, EG. (1987) Solid-State Esterification of Codeine Phosphate by the Acid Constituent of Effervescent Tablets J. Pharm Sci., vol. 76, pp. 53â??55.
[3] Brunsteiner, M, Gressl, Khinast, JG Paudel, A 1 C, Davis, AL, Landis, M, Pencheva, K, Scrivens, G, Wood, GPF (2015) Stability by Design (SbD): Utilizing material science principles to predict physical and chemical stability of pharmaceutical solids AIChE 2015.