Integrating AFM adhesion profiling with supercritical antisolvent fluidized-bed CO₂ processing to optimise drug loading

Improving drug loading and dissolution of poorly water-soluble active pharmaceutical ingredients (APIs) remains a major challenge in formulation development. Here, we integrate atomic force microscopy (AFM) adhesion-force profiling with supercritical antisolvent fluidized-bed (SAS-FB) technology to establish a predictive framework for drug–carrier selection. Enzalutamide (ENZ), a highly crystalline and poorly soluble biopharmaceutics classification system (BCS) Class II compound, was used as a stringent model drug. Single-particle force spectroscopy measurements quantified nanoscale interaction forces between SAS-processed ENZ microcrystals and seven carrier materials. Among these, lactose T70 exhibited the highest adhesion force, which strongly correlated with its superior encapsulation efficiency (EE = 92.7 %) under identical SAS-FB processing conditions. Statistical analysis revealed a robust linear relationship between mean adhesion force and EE (R² = 0.94453), identifying adhesion force as a quantitative predictor of drug deposition efficiency. This predictive capability was further validated using three additional model compounds (naringenin, dihydromyricetin, and luteolin). Comprehensive physicochemical characterization (SEM, PSD, EDS, DSC, XRD, FT-IR, and ¹H NMR) confirmed effective deposition of ENZ onto lactose T70, particle-size reduction, preserved chemical integrity, and SAS-induced polymorphic transformation. The optimized ENZ@SAS-FB(T70) formulation achieved a 5.5-fold increase in dissolution compared with unprocessed ENZ, attributed to uniform coating, enhanced wetting, and improved dispersion of micronized drug on the carrier surface. Collectively, this study establishes AFM-guided carrier screening as a mechanistic and efficient strategy for optimizing SAS-FB formulations. By linking nanoscale adhesion forces to macroscopic encapsulation outcomes, this framework offers a generalizable approach for accelerating the development of high-performance formulations for poorly soluble APIs.