Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing

Abstract

Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.

Recent Advances in Amorphous Solid Dispersions: Preformulation, Formulation Strategies, Technological Advancements and Characterization

“…Consequently, the existing technologies prevailed to spray-dryers and hot melt extruders, making them viable for ASD commercial manufacturing [ 10 ]. Additionally, the developments in the manufacturing arena helped to identify the impact of process variables over critical quality attributes (CQA’s) of ASDs and also led to the development of novel manufacturing processes like Kinetisol ® dispersing (KSD) [ 29 ], selective laser sintering (SLS) [ 30 ] and fused deposition modeling (FDM) 3D printing [ 31 ], electronanospinning, and others [ 32 ]. It is worth mentioning the recent advancements in preformulation space, which aimed to understand the interactions between the formulation components at a molecular level [ 33 ]; this was possible through analytical techniques and molecular simulation predictions using in-silico tools [ 34 ].…”

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

“…Considering the nominal amount of degradants allowed in a dosage form, formulation scientists have encountered difficulty in manufacturing ASDs using high-energy and thermal processes, particularly when the drug is heat- and shear-labile or when the drug undergoes excipient-induced degradation in these circumstances ( Dong and Choi, 2008 ; Hengsawas Surasarang et al, 2017 ; Monschke et al, 2020 ; Tan et al, 2020 ). In certain situations, especially for heat- and shear-labile compounds, eliminating trace crystallinity requires a higher energy input ( Thompson and Williams, 2021 ), but crystallinity is eliminated at the expense of increasing degradant levels.…”

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

“…The ASD is generated in shorter processing times and lower processing temperatures, offering a key advantage over conventional HME. Recent advancements in the addition of thermally conductive excipients have further increased the applicability of the KinetiSol ® process [ 125 ].…”