Development and Evaluation of Gilteritinib Nanosuspension by High-speed Homogenization: A Quality by Design (QbD) Approach

Abstract

Gilteritinib fumarate is a BCS class II drug taken orally. It is a second-generation FLT3 (FMS-like tyrosine kinase 3) inhibitor. It is used for people with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML). Even though Gilteritinib is very important for patients it has a problem that many modern kinase inhibitors have. Gilteritinib does not dissolve well in water and this changes depending on the pH. This makes it hard for the drug to dissolve and can contribute to variable oral absorption. Nanosuspension technology helps by breaking drug particles down to a small size, much smaller than a micron. These tiny particles are kept stable in a water-based liquid. This is a way to make Gilteritinib dissolve faster and more effectively without needing a lot of extra ingredients like lipids or large amounts of surfactants. High-speed homogenization is a "top-down" way to shrink particle size using mechanical force. This method is cheap, economical and does not use organic solvents. When combined with Quality by Design (QbD) framework the work becomes more organized. This framework includes checking risks finding material traits (CMAs) and important process steps (CPPs) using Design of Experiments (DoE) and setting a design space around critical quality attributes (CQAs). This makes the whole process easy to repeat and meets rules. This review looks at why to use these methods, how to use the QbD approach and how to test a Gilteritinib nanosuspension made through high-speed homogenization. Comparative literature on analogous small-molecule kinase inhibitors like gefitinib and ibrutinib were evaluated to inform formulation design, alongside an analysis of critical process parameters, testing protocols, and prospective formulation hurdles specific to gilteritinib.