(486e) Developing Predictive Models for Degradation of APIs during Hot Melt Extrusion in Pharmaceutical Processes

Drug product manufacture requires a demonstrated control of all parameters which may impact product quality. While several common methods exist to manufacture a drug product, Hot Melt Extrusion (HME) has gained wide acceptance to produce amorphous solid dispersions with high bioavailability and consistent, sustained release;^[1] however, the high temperatures of the melt during extrusion can lead to decomposition of the Active Pharmaceutical Ingredient (API). Developing a thorough understanding of the fundamental scientific phenomena that govern degradation of an API during the conditions of HME helps to provide a robust control strategy and a well-defined operating space. Stability of the API under the conditions of HME is a function of many variables, including heat transfer, mass transfer, thermodynamics, physical properties of the formulation, impurities in the matrix, and intrinsic reaction kinetics. To fully map out the experimental space to account for all of these factors can lead to significant time and material constraints, especially during early stages of development, wherein multi-kg quantities of API may not yet be readily available. For this reason, demonstration of appropriate scale-down methodologies to evaluate such degradation adds significant value to the drug product development lifecycle.

In this presentation, we will provide a methodology for elucidating the degradation mechanisms and governing factors that control API decomposition to form impurities during HME. Such a methodology begins through generation of 1D models to predict the temperature profile that results from selection of the extruder operating conditions and by heat generation from viscous dissipation.^[2] Further, the important role of screw configuration and operating conditions on the residence time distribution of the melt will be discussed. Selection of an appropriate solvent system can then be used to mimic the solvation environment and impurities of common pharmaceutical excipients to deconvolute the intrinsic reaction kinetics. By combining the residence time distribution and temperature profile with the intrinsic reaction kinetics, we will discuss how we have applied this understanding to model API degradation to de-risk the operating space for manufacture of drug products by HME.

[1]. Repka, M. A., et al., Drug Dev. Ind. Pharm., 33 (2007) 1043-1057.

[2]. Eitzlmayr, A., et al., Int. J. Pharm., 474 (2014) 157-176.