Hot-Stage Microscopy as a Quantitative Preformulation Tool for Assessing API Particle Dissolution in Molten Polymer...

High-melting-point active pharmaceutical ingredients (APIs) frequently undergo amorphization during hot-melt extrusion (HME) through progressive dissolution and incorporation in a softened polymer rather than by direct melting. The kinetics of this process are strongly influenced by particle size, yet rapid experimental methods for evaluating particle dissolution behaviour in the softened polymer prior to extrusion remain limited. In this work, a quantitative hot-stage microscopy (HSM)-based workflow combined with image analysis was developed to evaluate particle-size-dependent dissolution of a model high-melting-point API into softened Kollidon^® VA 64 under predefined thermal conditions. The dissolved fraction of individual particle-size classes was quantified throughout the experiment to determine the particle-size range associated with complete and incomplete dissolution. Complete dissolution was consistently observed for particles smaller than approximately 15-20 μm, whereas particles exceeding approximately 40 μm exhibited a markedly increased probability of retaining residual drug particle under the applied conditions. Between these limits, the dissolved fraction decreased progressively with increasing particle size. Because the methodology evaluates particle dissolution under static thermal conditions, the identified particle-size limits should be regarded as conservative, formulation-specific estimates rather than universal HME processing limits. The proposed workflow transforms HSM from a primarily qualitative visualization technique into a quantitative preformulation screening tool that enables rapid evaluation of particle-size-related processing risks while requiring only minimal quantities of material.