Mol Pharm. 2026 Apr 9. doi: 10.1021/acs.molpharmaceut.5c01779. Online ahead of print.
ABSTRACT
Amorphous drug formulations offer a powerful strategy for enhancing the apparent solubility and bioavailability of poorly water-soluble drugs. However, their inherent physical instability, particularly the tendency to recrystallize during downstream processing, remains a significant hurdle. This study investigates the influence of pharmaceutical compaction parameters ─specifically compression pressure and dwell time─ on the stability and performance of melt-quenched amorphous formulations, using nifedipine (NIF) as a model compound. Compacts, prepared under varying pressures (50-250 MPa) and dwell times (1-60 s), were characterized by DSC, XRD, and ATR-FTIR, supported by multivariate analyses. Isothermal crystallization studies revealed that compression accelerated the amorphous-to-β-NIF transformation, with onset times significantly affected by both pressure and dwell time. A full factorial design confirmed statistically significant main and interaction effects. The subsequent NIF β → α transformation was observed during long-term storage under both low and high humidity, with faster polymorphic conversion under high humidity conditions. Intrinsic dissolution rate (IDR) measurements showed that higher compaction generally reduced dissolution, though under the most extreme compression conditions (i.e., 250 MPa and 60 s), a modest increase in IDR was observed. Porosity measurements revealed a partial correlation between matrix densification and reduced dissolution or recrystallization resistance, though exceptions indicated the involvement of additional structural phenomena. Compared to previous findings on celecoxib, NIF exhibited a more pronounced and consistent sensitivity to both mechanical pressure and dwell time, despite sharing similar glass forming ability (GFA) classification and physicochemical properties. These findings emphasize the compound-specific nature of amorphous drug compression-induced destabilization and highlight the need for tailored assessment strategies during downstream processing of such amorphous drug formulations.
PMID:41955580 | DOI:10.1021/acs.molpharmaceut.5c01779
