The reversible pressure-induced phase transformation of urea during powder compaction was investigated using a compaction simulator. The reversible change in solid density observed between 600 MPa and 900 MPa is consistent with the known pressure-induced reversible phase transformation between urea forms I and III. These findings establish compaction simulation as a material-sparing method for detecting pressure-induced phase transformations of active pharmaceutical ingredients during tableting, provided that the density change due to the polymorphic form transition is sufficiently large.
Oligonucleotide therapeutics (ONTs) have revolutionized the medical landscape by enabling the precise modulation of genetic pathways. This perspective highlights the major conjugation strategies for ONTs, using antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) as representative modalities. We describe diverse classes of targeting ligands, including small molecules, cell-penetrating peptides (CPPs), antibodies, and aptamers. For example, triantennary N-acetylgalactosamine (GalNAc) conjugation has enabled a number of approved oligonucleotide therapeutics. Meanwhile, other emerging conjugation technologies have expanded oligonucleotide delivery to extrahepatic tissues to address a broader range of diseases. We further summarize the clinical translation of these delivery platforms, highlighting approved therapeutics alongside emerging clinical candidates. Finally, we provide an outlook on challenges and opportunities for the next generation of oligonucleotide therapeutics.
Prefilled syringes (PFSs) with staked-in-needles are widely used for high-concentration biologics but are vulnerable to needle clogging driven by water evaporation of trapped liquid in the needle lumen. This study quantitatively links trapped liquid volume, water vapor egress, and drying dynamics to inform device- and condition-dependent clogging risk. Commercial staked-in-needle PFSs with three rigid needle shield (RNS) elastomer formulations were characterized by X-ray computed tomography (XRCT). Elastomer water vapor permeabilities measured under controlled temperature and humidity were utilized. These data parameterized a steady-state Fickian diffusion model in COMSOL Multiphysics® to compute water vapor concentration fields and water egress rates as functions of temperature, relative humidity, and needle/RNS design. A closed-form expression for egress rate and a Pareto sensitivity analysis were derived. Simulations showed water egress rates ranged from 0 to 0.7 nL/day, increasing with temperature and elastomer permeability and decreasing with ambient humidity, accompanied by minor influence of needle geometry within the tested range of 0.275 and 0.300 mm inner diameter and needle insertion depth shifts (± 1 mm). Estimated evaporation times for 4.5–13.3 nL liquid droplets can span days to months depending on storage conditions. This integrated experimental–computational framework quantitatively relates nanoliter-scale liquid retention to vapor-driven drying in staked-in-needle PFSs and identifies temperature, humidity, and elastomer permeability as key levers to mitigate needle-clogging risk at the device level.
Understanding the precipitation risk of active pharmaceutical ingredients (APIs) in amorphous solid dispersions (ASDs) is still a major challenge in their development. In a previous study (Nakhla et al., Int. J. Pharm. X, 11, 2026, 100475) (Nakhla et al. 2026), we demonstrated the dual functionality of HPMCAS in high drug-load nifedipine (NIF) ASD tablets prepared by hot-melt extrusion, where HPMCAS-H acted both as an effective dry binder and as a precipitation inhibitor. While the experimental data clearly showed prolonged supersaturation and improved tablet performance upon addition of HPMCAS-H, the thermodynamic origin of this precipitation inhibition remained unresolved. The present work directly builds upon these findings and provides a mechanistic interpretation of the observed release behavior using thermodynamic modeling. The dissolution behavior of binary NIF ASDs with either PVP-VA64 (a fully water-soluble polymer) or HPMCAS (a water-dispersible polymer) was analyzed with and without pre-dispersed polymers. Under the conditions investigated, both systems generated initial apparent supersaturation, followed by rapid loss of filter-passing NIF for PVP-VA64-based ASDs. Pre-dispersed PVP-VA64 and HPC-EXF did not prevent this decrease in the present NIF system. In contrast, pre-dispersed HPMCAS-H suppressed or substantially delayed the loss of filter-passing NIF, consistent with its stabilizing effect in ASD tablets. To rationalize these differences, ternary NIF/polymer/water phase diagrams were predicted using PC-SAFT. The calculations support formation of an HPMCAS-H-rich liquid/polymer-rich phase that can accommodate NIF and may manifest experimentally as a colloidal dispersion. Effective stabilization therefore depends on the specific balance of API-polymer and polymer-water interactions captured by the ternary phase diagrams.
