Wenlei Jiang

Background: Postprandial gastric conditions such as changed motility and increased viscosity of gastric content can interact with an ingested dosage form, such as a tablet. This can affect the mechanisms of disintegration and dissolution and result in the altered performance of the tablet. Hereby, the individual characteristics of the tablet play a crucial role, since they determine the interaction potential with hydrodynamic and physico-chemical properties of the gastric environment. Excipient properties such as solubility, swellability, or gelling tendency can have an influence. Further, tablet characteristics such as porosity or pore size can affect its breakdown by regulating water uptake or determining its physical stability. Methods: Four midodrine hydrochloride generic products with known in vivo bioequivalence, but different formulations, were used as references to improve the simulated fed-state disintegration and dissolution testing methods involving highly viscous media. The tablet samples were evaluated towards the aforementioned characteristics, estimating which parameters of the testing method influence their dissolution performance under highly viscous conditions. Hereby, different hydrodynamic and mechanical stresses were simulated by a previously presented computed numerical controlled apparatus, as well as a novel flow-through cell for viscous media. By a mechanistic biopharmaceutics modeling approach, the convoluted dissolution data were compared to in vivo plasma profiles. Results: A sequential motion method yielded similar dissolution profiles as assessed by the similarity factor (f2). Convoluted plasma profiles showed good approximation with the in vivo profiles. Conclusions: The sequential dissolution method was established as a biopredictive tool for simulating the fed state by incorporating physiologically increased postprandial chyme viscosity and hydrodynamic stress.

Purpose Long-acting injectables (LAIs) offer substantial clinical and economic advantages, including improved patient adherence, enhanced safety and efficacy, and reduced overall healthcare costs. Despite these benefits, the availability of generic LAIs remains limited, largely due to the complexity of formulation development and regulatory assessment. This study aimed to characterize the landscape of LAI product availability, regulatory frameworks, and approval standards in the United States and Europe, and to identify opportunities to support generic LAI development. Methods A comparative analysis was conducted of LAI product approvals through December 2025, along with regulatory guidance documents issued by the U.S. Food and Drug Administration (FDA) through February 2026, the European Medicines Agency (EMA) through December 2025, and European national agencies through July 2023. Results The FDA approved 64 distinct new LAIs via the 505(b)(1) and 505(b)(2) pathways and 13 generic LAIs via the 505(j) pathway. In contrast, new and generic LAIs covering 26 and 15 active pharmaceutical ingredients (API), respectively, were approved by the EMA and European national agencies. The FDA issued 48 product-specific guidances (PSGs) for LAIs, whereas the EMA published five PSGs in addition to general modified-release guidance documents. Both agencies issued PSGs for five shared LAI products: exenatide, lanreotide, octreotide, and paliperidone palmitate (1-month and 3-month formulations). Comparative review of these PSGs revealed both alignment and differences in bioequivalence recommendations. Global collaborative efforts to promote generic LAI development were highlighted. Conclusions These findings provide a foundation for harmonizing generic LAI approval standards, which may improve resource allocation, promote generic competition, and enhance patient access to LAI therapies. Graphical Abstract

Pegylated liposomal doxorubicin (DOX) was recognized for its efficient drug delivery, reduced toxicity, and prolonged circulation. Ammonium sulfate ((NH₄)₂SO₄) plays a critical role in DOX loading and retention within liposomes, and intraliposomal (NH₄)₂SO₄ concentrations above 200 mM are essential for stable DOX sulfate nanocrystal generation and liposomal stability. Currently available methods, such as ion chromatography, for the selective quantitation of liposomal encapsulated ions require time-consuming separation steps. In this study, a capillary electrophoresis-based separation method coupled with capacitively coupled contactless conductivity detection (CE-C⁴D) was developed and validated for the direct quantitation of total (internal + external) and external ionic excipients in DOX liposomal formulations. Cation and anion analyses, conducted under positive and negative polarities, respectively, demonstrated distinct migration orders (NH₄ ⁺, K⁺, Na⁺, Li⁺ for cations; Cl^–, SO₄ ^2–, F^– for anions) with excellent baseline separation and peak resolution. The method demonstrates linearity with correlation coefficients consistently above 0.999 and low limits of quantitation (below 8.22 μM) for all analyzed ions. The optimized CE-C⁴D method allowed accurate quantitation of total and external ion concentrations including NH₄ ⁺, K⁺, Na⁺, Cl^–, and SO₄ ^2– ions in liposomal DOX formulations. All tested liposomal DOX formulations contained an excess of 200 mM (NH₄)₂SO₄ within liposomes. This method provides an alternative for accurate quantitation of ion species present in liposomal formulations, supporting both brand and generic liposome formulation development and regulatory assessment.

In disintegration and dissolution (D&D) testing, high media viscosity, resembling ingested food, is rarely considered for simulated fed state inves

Purpose U.S. Food and Drug Administration (FDA) recommends reference scaled limits and variability comparison for bioequivalence (BE) demonstration of narrow therapeutic (NTI) drugs while most other regulatory agencies apply direct tightening of BE limits. This study evaluates strengths and limitations of different BE criteria using abbreviated new drug application (ANDA) data received by FDA to support harmonization of NTI drug BE criteria. Methods We analyzed four-way fully-replicated crossover BE study data in NTI ANDAs, applying BE criteria from different agencies and alternative criteria (e.g., Paixão’s criteria, modified Paixão’s and FDA criteria) to compare passing rates. Results Current EMA and FDA criteria seem stringent with NTI drugs having moderate and low within-subject variability (e.g., S_WR), respectively. Capping BE limits at 90.00–111.11% when σ_WR ≤ 0.10 in alternative FDA criteria improved passing rates and better aligns with NTI quality standards. An additional point estimate constraint of 90.00–111.11% enforced geometric mean ratio closer to 1 but reduced passing rates when S_WR was moderate to high. FDA’s regulatory constant resulted in slightly less stringent scaled BE limits than Paixão’s, but may better align with observed S_WR ranges for NTI drugs. Alpha adjustment reduced Type I error but slightly decreased study passing rates. Conclusion Alternative FDA criteria with capping at 90.00–111.11% when σ_WR ≤ 0.10 and applying alpha adjustment provides reasonably stringent standards for BE demonstration of NTI drugs. This in-depth analysis of ANDA BE data will help ICH M13C Expert Working Group make informed decisions about harmonization options for BE demonstration of NTI drugs. Graphical Abstract

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug it contains. The extent of this retardation depends on tablet formulation factors, such as the solubility of its excipients. Objectives: This research aimed to study the effect of filler solubility on the disintegration and dissolution of tablets under different testing conditions. Methods: Tablet formulations containing acetaminophen (as a model compound), mixtures of different ratios of fillers, and other excipients were directly compressed using uniform manufacturing parameters. These formulations were investigated under fasted- and fed-state conditions to determine the influence of viscosity on their disintegration, inspired by the liquid penetration ratio (LPR) theoretical framework. Disintegration and dissolution tests were performed using both compendial and novel testing apparatuses. Results: The soluble fillers in the tablets affected their disintegration and dissolution in the simulated fed-state medium, while fasted-state conditions affected the tablets only marginally. The testing devices showed partially contrasting results, which appeared to be due to the hydrodynamics of the testing media used. The novel CNC (computed numerical control) apparatus offered 3D motion and effectively exposed the tablets to the viscous testing media, unlike the compendial paddle apparatus. Conclusions: This study explored the impact of filler solubility on the disintegration and dissolution of tablets. As the LPR framework revealed, fillers with a higher solubility have positive effects on the disintegration and dissolution of tablets in viscous conditions. Additionally, the proportion of soluble filler used is also inversely correlated with the disintegration time. Further investigation of the formulation parameters, as well as the testing conditions, would provide additional insights into the effects of food on these tablets.

The food-induced viscosity of the media can alter tablet disintegration and eventually the release of the drug. The extent of this retardation depends on tablet formulation factors such as the solubility of excipients. Objectives: This research aimed to study the effect of filler solubility on the disintegration and dissolution performances of tablets in different testing conditions. Methods: Tablet formulations containing acetaminophen as a model compound, mixtures of different ratios of fillers, and other excipients were directly compressed using uniform manufacturing parameters. The formulations were investigated under simulated viscosity of fasted and fed state conditions inspired by a Liquid Penetration Ratio (LPR) theoretical framework. The disintegration and dissolution tests were performed in both compendial and novel testing apparatuses. Results: Soluble fillers in the tablets affected the disintegration and dissolution in simulated fed state media but only marginally under fasted conditions. The testing devices showed partially contrasting results based on the hydrodynamics of the testing media. The novel CNC (computed numerical control) apparatus offered 3D-motion and effectively exposed tablets to the viscous testing media, in contrast to the compendial paddle apparatus. Conclusions: This study explored the impact of filler solubility on tablet disintegration and dissolution performances. As envisaged by the LPR framework, higher filler solubility has positive effects on tablet disintegration and dissolution performance in viscous conditions. Additionally, soluble filler proportion is also inversely correlated with disintegration time. Further investigation of the formulation parameters as well as the testing conditions would provide additional insights into the food effects on the tablets.

Since 2012, the U.S. Food and Drug Administration (FDA) has developed classification criteria of narrow therapeutic index (NTI) drug products and tightened bioequivalence (BE) standards for these products by recommending a fully replicated, two-sequence, two-treatment, four-period crossover study design where BE is based on passing both scaled average BE criterion and within-subject variability comparison criterion, as well as the average BE criterion of 80.00%-125.00%. Currently, the BE study design and criteria for NTI drugs are somewhat different across regulatory agencies. The objective of this study is to survey pharmacokinetic BE data of abbreviated new drug applications (ANDAs) of NTI drugs submitted to the FDA with initial submission dates between January 1, 2013 and October 1, 2022 to identify the impact of FDA’s current BE approach on generic NTI approval. Thirty-three NTI drug products from 100 ANDAs were identified with 93 ANDAs included in analysis. Eighty-seven ANDAs had four-way crossover studies, with 69 and 106 fed and fasting BE studies, respectively. For all NTI drugs, the range of average S_WR for C_max, AUC_t, and AUC_inf was between 0.05 and 0.27. Of the 20 studies that failed BE, 90%, 5%, and 5% failed reference scaled criteria only, variability comparison criteria only, and both, respectively. Further communication of this work with global regulatory agencies and the scientific community will help better understand current FDA NTI BE criteria and review experiences. These efforts will support the development of harmonized BE criteria for NTI drugs, in turn improving patient access to generic NTI drugs. Graphical Abstract