Solvent-mediated polymorphic transformations (SMPTs) employing nonconventional solvents (polymer melts) is an underexplored research topic that limits the application of polymer-based formulation processes. Acetaminophen (ACM), a widely studied active pharmaceutical ingredient (API), is known to present SMPTs spontaneously (<30 s) in conventional solvents such as ethanol. In situ Raman spectroscopy was employed to monitor the induction time for the SMPT of ACM II to I in polyethylene glycol (PEG) melts of different molecular weights (Mw, 4000, 10 000, 20 000, 35 000 g/mol). The results presented here demonstrate that the induction time for the SMPT of ACM II to I in PEG melts is driven by its diffusivity through the polymer melts. Compared to conventional solvents (i.e., ethanol) the mass transfer (diffusion coefficient, D) in melts is significantly hindered (Dethanol = 4.84 × 10-9 m2/s > DPEGs = 5.32 × 10-11-8.36 × 10-14 m2/s). Ultimately, the study proves that the induction time for the SMPT can be tuned by understanding the dispersant's physicochemical properties (i.e., η) and, thus, the D of the solute in the dispersant. This allows one to kinetically access and stabilize metastable forms or delay their transformations under given process conditions.
Keywords: active pharmaceutical ingredients; crystalline solid dispersion; diffusivity; melt; polymorphism; solvent-mediated polymorphic transformation.