Loss of tensile strength in roller compacted granules compared to the pregranulation blend is a critical concern when selecting the roller compaction process for drug product manufacturing. While this loss in compactibility is attributed to granule size enlargement and granule hardening by earlier studies, the phenomenon of unified compaction curve (UCC) model to explain this decrease in compactibility has long been overlooked despite of its mechanistic interpretation. The present study offers a profound improvement of the UCC model structure where a proper workflow in predicting granule tabletability was first established from the compaction characteristics of the pregranulation blend only. Following this workflow, the original model though revealed varying extent of overestimation for realistic multicomponent formulations. This shortcoming was addressed by introducing the modified UCC model where different tabletability slopes for pregranulation blend and granules were critically considered that consistently performed better than the UCC model. A correction factor was finally introduced to directly predict granule tabletability of virtual formulations from the compression characteristics of the pregranulation blend. The study demonstrates an integrated digital design-based predictive platform to screen virtual formulations through a minimum 25-fold reduction in batch size compared to typical conventional operations.
Onychomycosis is difficult to treat topically because the keratinized nail plate restricts drug diffusion and solution-based products are readily removed by washing. This study evaluated a fast-drying, polymer-based film-forming nail platform designed to create a wash-resistant surface reservoir and enhance transungual delivery. Terbinafine, efinaconazole, and amorolfine were formulated in the same platform and compared with marketed products (Terclara®, Jublia®, and Loceryl®) using bovine hoof keratin membranes and distal human nail clippings in Franz diffusion cells. In this bovine hoof model, cumulative permeation at 72 h was 9.5-fold higher for terbinafine versus Terclara® and 25.5-fold higher for efinaconazole versus Jublia®; although the amorolfine permeation difference was not significant, receptor solutions from all three platform formulations produced significantly larger zones of inhibition against Trichophyton rubrum and Trichophyton mentagrophytes than their comparators, indicating that permeated drug remained biologically active. In a 28-day once-daily distal human nail model, the optimized terbinafine formulation (HLK-5003) maintained cumulative permeation and antifungal activity whereas the solution comparator showed minimal delivery and no detectable inhibition; advantages for the efinaconazole and amorolfine formulations were not established. These in vitro findings indicate that rapid film formation and wash-resistant reservoir behavior can improve sustained transungual delivery in a formulation- and API-dependent manner.
Peptide therapeutics are prone to aggregation, denaturation, and interfacial adsorption, which can compromise product quality, reduce potency, increase immunogenicity, and shorten shelf life. Although surfactants are widely used to stabilize protein biologics, their use in commercial parenteral peptide formulations appears to be more selective. Specifically, the literature does not provide a clear rationale for using surfactants in this context, and their effects on peptides remain poorly understood. Here, we investigate the effects of three common surfactants, polysorbate 80 (PS80), polysorbate 20 (PS20), and poloxamer 188 (PX188), on the conformational stability, oligomerization, and aggregation of liraglutide as the primary model peptide, followed by exploratory evaluation of semaglutide and glucagon, under agitation stress. For liraglutide, which forms dynamic oligomers that are not intrinsically stable under agitation stress, SEC and CD reveal extensive aggregation and structural rearrangement in the presence of both PS80 and PX188, with PS80 driving more rapid aggregation. NMR shows strong, specific interactions between liraglutide and PS80 but not PX188, suggesting different mechanisms: PS80 perturbs the native oligomer via peptide-surfactant interactions, whereas PX188 likely promotes aggregation through interfacial stress. Consistent with this, PS20, with its shorter, less hydrophobic chain, caused less disruption than PS80, underscoring the importance of surfactant-peptide interaction strength. In contrast, semaglutide, which forms more stable oligomers, showed only limited changes in aggregation behavior in the presence of surfactants. For glucagon, which has a strong intrinsic tendency to fibrillate, surfactants modestly changed aggregation rates but did not prevent fibril formation. It is worth noting that, unlike therapeutic monoclonal antibodies, which primarily adopt monomeric structures stabilized by extensive intramolecular and interdomain interactions, peptides drugs are more flexible and therefore more susceptible to perturbation by surfactants. Overall, surfactant effects on peptide stability are highly molecule-dependent and reflect a balance among peptide-peptide and peptide-surfactant interactions, surfactant-mediated interfacial stress, and the intrinsic stability of peptide oligomers.
Determining the particle size distribution (PSD) of the active pharmaceutical ingredient (API) in nasal spray suspensions is a challenging task that usually requires the use of morphologically-directed Raman spectroscopy (MDRS). A dissolution-based modeling strategy was established to characterize the entire PSD of starting API in mometasone furoate nasal sprays using dissolution data of finished formulations, whereas MDRS measures API PSD in the final products. A dissolution-PSD model was built in-house to derive the API PSD from the dissolution data of target products, with model parameters estimated using test products with known raw API PSD and dissolution profiles. To obtain representative dissolution data that could better reflect the intrinsic API PSD characteristics of the formulation, different sample pretreatment procedures and dissolution approaches were investigated. The results suggested that the dissolution profile acquired by the paddle method following combined enzymatic hydrolysis and ultrasonication pretreatment was preferable for characterizing the starting API particle size features. Model predictions demonstrated that the commercial Nasonex® displayed a bimodal volume-weighted PSD and a relatively high Dv90 of 15.8 μm, which differed from previous reports. A modified MDRS was applied for cross-checking, and the modeled Dv90 was in agreement with the measured results. Cross-validation for the model using five test batches yielded prediction errors mostly <10%, indicating acceptable performance. For nasal suspension products that typically present complex PSD features, the present method may provide a feasible auxiliary tool for guiding formulation screening and optimizing manufacturing parameters in the preliminary development stage.
N-nitrosamine contamination originating from polymer-based packaging materials is an emerging concern, yet amine precursors in these materials or their contribution to nitrosamine formation are not well characterized. In this study, an SPE-LC-MS/MS method was developed to quantify amines in polymer raw materials used for large volume parenteral (LVP) packaging. Amines were detected in these polymer materials with a linear correlation between amine and nitrosamine levels, indicating that amine precursor content in the packaging itself may play an important role for nitrosamine formation. Since such precursors can migrate or react during LVP’s shelf life, predictive stability studies were conducted on LVP stored in stability chambers. The results indicated that N-Nitrosodimethylamine levels were markedly higher in stability chamber compared to warehouse storage. These findings indicated that it might be beneficial to control nitrosamine precursors in polymer and conventional stability studies may not fully represent real-world nitrosamine risks.
