468611 Solid-State Reactivity of Drugs with Potential Reactive Excipient Impurities: In silico and Experimental Studies
One issue that is commonly encountered in the development of solid state drug formulations is the degradation of the active pharmaceutical ingredient (API) through a reaction with small molecule impurities present in excipients [1,2]. Here, we present first results of our attempts to use a combination of computational chemistry and experiments to investigate the impact of the solid state, its structure and dynamics, on chemical degradation in such systems.
We studied this type of reaction using a set of small molecular weight drugs that can potentially react with formaldehyde, a commonly observed impurity in polymeric excipients. Comparing the reactivities of these compounds with formaldehyde in solution to the corresponding reactivities of solid state (crystalline powder) samples, we found that the correlation of relative reactivities of different compounds in solution versus the solid state is limited. We performed an analysis of the solid state samples based on the structures of crystal bulk and surfaces using molecular modelling and Molecular Dynamics (MD) simulations, and defined a number of descriptors that can be calculated from first principles. These descriptors were used to explain the different reactivities observed for the studied drug compounds concentrating on the effects of limited accessibility of reactive sites in the crystalline state and relative lattice and surface stabilities and the related degree of disorder. Our results provide insights into the impact of solid state on relative reactivities and pave the way for the development of theoretical methods that can be used to optimize formulations towards improved stability.
 Hotha, KK, Roychowdhury, S, Subramanian, V. (2016) “Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways.” American Journal of Analytical Chemistry, 7, 107-140.
 Wu, Y, Levons, J, Narang, AS, Raghavan, K, Rao, VM. (2011) “Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility.” AAPS PharmSciTech. 12, 4, 1248-1263.
See more of this Group/Topical: Pharmaceutical Discovery, Development and Manufacturing Forum