Adding a New Dimension to the Amorphous Solid Dispersion Phase Diagram: Studying Dissolution Kinetics of Crystalline Drugs in a Polymer Matrix Using Temperature Dependent XRPD and DSC

Hot-melt-extrusion (HME) is an enabling technology used for poorly soluble active pharmaceutical ingredients (APIs) to increase the bioavailability by embedding the drug in a water soluble and often amorphous carrier such as a polymer. Knowledge of the most critical factors impacting the dissolution rate of crystalline API in the polymer during manufacturing will provide useful insight for process improvement. In this study, crystal-line APIs (Acetaminophen, APAP and Indomethacin, IMC) were analyzed in a polymeric matrix (Copovidone, PVP-VA64) via X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) to follow the dissolution process under various conditions in a down-scaled static laboratory system. The combination of in-situ XRPD measurements and a kinetic model based on DSC data proved to be a suitable tool to investigate the dissolution process and can be applied to various APIs and polymers to avoid residual crystallinity and thermal degradation. Thus, the temperature-composition phase diagram in a thermodynamic equilibrium is augmented by the kinetic component as new dimension. The obtained findings set the foundation for investi-gating the dissolution kinetics and enable the transition from a static to a dynamic system.(c) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

Hot-melt-extrusion (HME) is a technology used to improve the bioavailability of poorly soluble pharmaceutical ingredients by embedding them in a polymer carrier. In this study, the dissolution process of crystalline drug compounds in a polymer matrix was investigated using X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC), and a new temperature-composition phase diagram model was proposed.