Mathematical descriptions of bioactive release invoke Fickian diffusion, Case II swelling, and surface erosion, yet each is usually treated in isolation. This work unifies the three within one analytical skeleton for homogeneously loaded monolithic devices of canonical geometry — slabs, cylinders, and spheres — excluding compressed tablets, osmotic systems, and reservoir devices, grounding their coefficients in polymer–solvent thermodynamics. Eigenfunction series give the diffusion solutions and short-time √t asymptotics; moving-boundary kinematics give polynomial swelling and erosion laws. Coefficients are linked to Hansen–van Krevelen solubility parameters and the Flory–Huggins χ. The mechanisms are coupled as a multiplicative product form and an additive Dirichlet mixture whose weights are fixed a priori by each mechanism’s characteristic rate — the leading Laplacian eigenvalue for diffusion, the front-traversal rate for the moving fronts — termed Thermodynamic Rate Decomposition (TRD). Validation comprises an exponent consistency check and fit-free tests against a propranolol–HPMC cylinder, an etofylline–PEO slab, and the published sphere case. Power-law fitting returns Fickian exponents of 0.50, 0.46, and 0.45 for slab, cylinder, and sphere (consensus 0.50, 0.45, 0.43) and a slab Case II exponent of 1.00. With no parameter fitted to the release curve, predictions reproduce both measured profiles to within about 13 ∈ 1, 2, 3, giving compact, thermodynamically traceable equations that support a priori mechanism assignment and first-pass quantitative analysis within this device class. A unified, geometry-indexed framework expresses diffusion-, swelling-, and erosion-controlled release from slabs, cylinders, and spheres (n = 1, 2, 3) in a single form. Kinetic coefficients are grounded in polymer–solvent thermodynamics: Hansen solubility parameters yield the Flory–Huggins χ through the Hansen-distance regular-solution form, which modulates the diffusivity through the thermodynamic factor Γ = φp(1 − 2χφs) and the Case II front velocity through a (½ − χ)m dependence. The three mechanisms are coupled in two complementary ways that bracket the true response — a multiplicative product form (independence bracket), given in both exact and exponential-surrogate variants, and a rate-weighted additive Dirichlet mixture (rate-proportional bracket) whose weights wi = λi / (λD + λS + λE) are computed from the mechanism characteristic rates rather than fitted.
Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, improved the type 2 diabetes mellitus treatment and obesity by its glucose-lowering and weight loss effects. Although the subcutaneous route provides high bioavailability and stable pharmacokinetics, the development of oral semaglutide makes a significant advancement in peptide therapeutics. However, oral delivery remains limited by an absolute bioavailability of only approximately 0.4–1
Synthetic peptide test products referencing recombinant-origin products present unique regulatory challenges in demonstrating higher-order structural (HOS) comparability beyond primary sequence sameness. Liraglutide, a lipidated glucagon-like peptide-1 (GLP-1) receptor agonist with defined self-association behavior, represents an important model for such assessments. A head-to-head comparability study was performed between a chemically synthesized liraglutide product and its recombinant reference listed drug (RLD). An orthogonal analytical framework integrating spectroscopic, biophysical, nuclear magnetic resonance (NMR)-based, and in vitro functional methods was applied to assess secondary structure, supramolecular assembly, aggregation propensity, molecular conformational fingerprints, and biological activity. The test products and RLD demonstrated highly comparable structural and functional profiles across all evaluated dimensions. Secondary structural characteristics, NMR fingerprints, and spatial conformational features were highly consistent. Solution-state analyses showed comparable diffusion behavior and a dominant low-oligomeric assembly, with apparent aggregation numbers close to the hexamer-to-heptamer range and without evidence of abnormal aggregation or fibrillation. Functional studies further confirmed comparable GLP-1 receptor activity and stability profiles. Orthogonal structural and functional characterization can substantially reduce residual uncertainty for synthetic peptide generics referencing recombinant products and provides a practical framework for comparability assessment of complex peptide drugs.
Direct-to-infant (D2I) transnasal aerosol surfactant therapy (AST) offers a promising non-invasive alternative for treating neonatal respiratory distress syndrome (RDS). However, achieving high lung delivery efficiency with dry powder inhalers (DPIs) requires careful optimization of complex fluid–particle interactions. This study used computational fluid dynamics (CFD) to optimize an Infant Air‑Jet Dry Powder Aerosol Delivery System (iDP‑ADS) and derive transferable design principles. A CFD model of the iDP‑ADS coupled to a 31‑week preterm nose‑throat geometry was validated against in vitro measurements. Sensitivity analyses evaluated modeling assumptions (steady‑state vs. transient, monodisperse vs. polydisperse) and critical design parameters influencing aerosol delivery, such as upstream air volume, interface geometry, temporal aerosol emission profiles, and actuation flow rates. The CFD model demonstrated strong in vitro agreement (2.8
Subcutaneous (SC) administration has emerged as a promising route for delivering large therapeutic proteins, offering advantages such as improved patient convenience and reduced healthcare costs. However, the mechanisms that regulate the uptake of these macromolecules are not yet fully understood. A recent surge in computational and experimental studies has systematically analyzed the transport of large proteins from the SC injection site to the lymphatic system, advancing our understanding of how tissue environments and injection parameters affect lymphatic uptake kinetics. This review summarizes the current literature on factors affecting the lymphatic uptake of subcutaneously administered large therapeutic proteins. First, we outline the transport mechanisms of therapeutic proteins from the local SC injection site to initial lymphatics. Then we analyze the impact of injection site, tissue properties, device selection, and molecular characteristics, on lymphatic uptake kinetics and pharmacokinetics (PK). Finally, we evaluate how recent modeling and experimental advancements have transformed our mechanistic understanding of SC delivery.
Deletion or functional inactivation of tumor suppressor genes is a hallmark of human cancers. Unlike hyperactive oncogenes, which produce proteins that are targetable through pharmacologic inhibition, treatments to restore tumor suppressor protein activity are challenging given the loss-of-function nature of tumor suppressors. Current replacement-based strategies to re-establish tumor suppressor function using viral vectors and non-amplifying RNA therapeutics are fraught with challenges, including transient and/or insufficient expression of the restored tumor suppressor protein. In this Review, we highlight self-amplifying RNA (saRNA) as a next-generation platform for tumor suppressor restoration. saRNA enables intracellular RNA amplification and prolonged protein expression at lower doses while avoiding genomic integration, potentially overcoming key limitations of existing replacement approaches. Furthermore, by integrating genomic recurrence, delivery feasibility, construct constraints, and pathway biology, we describe a translational prioritization framework to identify tumor suppressors best suited for saRNA-based replacement, with particular emphasis on cancers harboring recurrent homozygous deletions. Effective restoration of tumor suppressor protein activity using saRNAs will open new avenues for cancer therapeutics.
This research aimed to develop a next-generation ultra-long-acting insulin analog with dual long-chain fatty acid conjugation, addressing unmet needs of frequent injections and hypoglycemia risk in diabetes therapy. LPJT-026, a dual C20 fatty acid-modified insulin (LysA22 and LysB29), was designed, synthesized and characterized. Head-to-head comparisons with marketed insulin icodec (Awiqli®) were performed via in vitro binding assays (HSA/INSR/IGF-1R) and in vivo PK/PD evaluations in STZ-induced type 1 diabetic (T1D) rats and Beagle dogs. Long-term efficacy (HbA1c reduction) and safety (hypoglycemia-related mortality) were assessed in 8-week repeated-dose studies. LPJT-026 (purity ≥ 98
To investigate the performance of a capsule-based dry powder inhaler (DPI) under two device configurations — free-axis and fixed-axis capsule rotation — across steady-state and transient inhalation profiles. Two new research-based transparent capsule-based DPI were developed—one with a fixed capsule rotational axis and another with a floating capsule configuration. High-speed imaging was used to capture capsule motion, and the effects of flow regimes (laminar, transient, and turbulent), capsule rotation, and breathing profiles on capsule RPM, wall collisions, and powder retention were analyzed. Fixed-axis rotation significantly outperformed free-axis rotation ( 6 × higher RPM and lower powder retention). Higher flow rates and faster-accelerating transient profiles increased RPM and collision frequency, enhancing drug release. Fixing the rotational axis of the capsule had the greatest benefit for the slow inhalation profile. The findings offer key insights for the design of future capsule-based DPIs.
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. 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. 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. 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.
Achieving the Analytical Evaluation Threshold (AET) for leachables is critical in quantification for patient safety evaluation but presents challenges for drug products with large dosing volumes or complex matrices. This paper reviews these challenges, presents industry perspectives, and proposes scientifically justified approaches to ensure patient safety where the AET is not analytically achievable. An industry-wide survey conducted by the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium among 23 member companies identified common hurdles and alternative approaches used in leachables risk assessments. Findings were supplemented with case studies and a review of current analytical and regulatory strategies. The survey identified large dosing volumes (74
Dysphagia in neurological patients complicates oral drug administration. Manual preparation of lozenges/troches lacks precision and scalability. This study investigates the feasibility of implementing a pharmaceutical 3D printer in a hospital pharmacy for the automated production of personalized baclofen troches. Baclofen troches were manufactured in a hospital pharmacy setting, both manually and via pharmaceutical 3D printer. Quality was evaluated using Process Analytical Technologies (PAT). Performance was assessed through European Pharmacopoeia (EP) tests for drug content, mass uniformity, in vitro dissolution, disintegration, and a six-month stability study. Printed troches complied with all EP acceptance criteria for drug content and mass uniformity, whereas manual formulations failed, particularly at the lowest dose. Printed troches demonstrated immediate drug release, consistent quality across batches, and remained stable for six months. 3D printing showed superior precision over traditional manual compounding. This research describes the first successful implementation of an automated blister-filling workflow using a pharmaceutical 3D printer within a hospital pharmacy setting, spanning from manufacturing and dispensing to direct patient administration. The automated approach provides a significant advancement in personalized medicine, ensuring safer, more accurate, and efficient treatment options for patients with specific needs like dysphagia.
To investigate how polysorbate 80 (PS-80) hydrolysis byproducts, especially oleic acid, affect monoclonal antibody (mAb) stability and contribute to protein particle formation. The study evaluated oleic acid-associated protein particle formation using microflow imaging (MFI), Scanning Electron Microscopy-Energy Dispersive X-ray spectroscopy (SEM–EDX), field-flow fractionation (FFF), and Fourier Transform Infrared (FT-IR) particle characterization. The proposed electrostatic interaction mechanism was examined by varying ionic strength with saline and arginine, adjusting pH, and considering mAb isoelectric points. Oleic acid was associated with the formation of proteinaceous particles. The data supported the idea that oleic acid induces mAb aggregation through electrostatic interactions. Oleic acid-induced protein aggregate formation was reversible in the presence of additional salt, suggesting that increased ionic strength disrupts the charged interactions driving aggregation. PS-80 degradation byproducts, particularly oleic acid, can promote reversible mAb aggregation and particle formation through electrostatic interactions. These findings improve understanding of particle formation in protein formulations and may help guide buffer selection, ionic strength, pH optimization, and prediction of stability in intravenous solutions such as saline.
Transdermal drug delivery systems (TDDS) represent a clinically established yet mechanistically complex platform for systemic drug administration, offering advantages such as avoidance of hepatic first-pass metabolism, sustained drug input and improved patient adherence. However, their development and regulatory evaluation remain challenging due to the physiological variability of the skin barrier, site-dependent absorption and formulation–skin interactions. In vitro–in vivo correlation (IVIVC) has therefore emerged as a critical translational framework for linking in vitro permeation characteristics with systemic pharmacokinetic outcomes and thereby supporting formulation optimization, regulatory decision-making and reduction of repetitive clinical studies. This review provides a comprehensive and integrative analysis of IVIVC in TDDS, encompassing experimental methodologies, mechanistic modelling strategies, regulatory perspectives and translational challenges. Emphasis is placed on the limitations of classical empirical correlations when applied to transdermal systems, where lag time, cutaneous depot formation and nonlinear absorption frequently violate traditional IVIVC assumptions. Mechanistic and physiologically based pharmacokinetic (PBPK) approaches are highlighted as more robust alternatives capable of incorporating skin physiology, variability and formulation-specific effects. Evidence from successful and unsuccessful case studies demonstrates that predictive IVIVC is achievable but strongly dependent on methodological standardisation, model validity and physiological representation. Regulatory frameworks currently regard IVIVC primarily as a supportive tool; however, increasing integration with Quality-by-Design (QbD) principles, model-informed drug development (MIDD) and advanced experimental platforms indicates growing acceptance. The review ultimately reframes IVIVC for TDDS as a continuum of translational strategies rather than a binary outcome and identifies key knowledge gaps whose resolution will be essential for advancing predictive, regulatorily trusted IVIVC models for next-generation transdermal therapeutics.
To evaluate how ssDNA cargo size influences the physicochemical characteristics and stability behavior of AAVX vectors under thermal, chemical, and other accelerated stress conditions. AAVX vectors with differing ssDNA cargo length (i.e. 2.8 kb and 4.6 kb) were analyzed under manufacturing-relevant, storage-related, and accelerated stress conditions using complementary analytical methods to assess capsid stability, genome integrity, potency, and capsid chemical modifications. Thermal and chemical denaturation experiments showed similar capsid unfolding across the cargo sizes tested. Under accelerated thermal stress (40°C), the shorter-genome vector showed less ssDNA release and better preservation of capsid and genome titers than the longer-genome vector. Fragmentation of encapsulated ssDNA was also observed for the shorter cargo. Capsid chemical modifications, including asparagine deamidation and aspartic acid isomerization, increased markedly at 40°C. These findings provide a case-study view of how cargo size can affect AAV stability readouts in a condition-dependent behavior and highlight the value of multi-attribute characterization for evaluating AAV vector stability. In addition, our results also suggest that suggest that, under the conditions tested for AAVX, the same capsid may be useful for evaluating vector stability with different genome sizes.
Polymeric carriers for nucleic acid delivery must overcome two sequential intracellular barriers: escape from the endosome and release of the cargo into the cytosol. These steps are typically treated as independent design problems and optimized separately. This review argues that escape and release are coupled through the same electrostatic and pH-dependent interactions, creating a fundamental tradeoff . The cationic charge that enables a polymer to destabilize endosomal membranes also tightens its grip on the nucleic acid payload, so conditions favoring escape simultaneously inhibit release. We trace this tradeoff across the major strategy classes in the polymeric delivery literature, evaluating each by where and when its trigger acts relative to the escape event. We further assess the assay toolkit for measuring escape and release, and the translational variables that shift the balance in vivo. pH-responsive polymers tune the activation zone for membrane destabilization but cannot decouple escape from binding, since both depend on the same protonation events. Charge-shifting polymers address release more directly by programming a loss of cationic character after endosomal entry. Non-pH triggers, including disulfide, thioketal, diselenide, and esterase-responsive chemistries, off er orthogonal release mechanisms but face spatial and temporal alignment constraints. Characteristic failure modes recur: premature release, redundant triggering, and kinetic misalignment. No existing assay measures endosomal disruption and cargo release state simultaneously, and translational variables including protein corona formation, cell-type-dependent endosomal acidifi cation, and PEG shielding shift the balance in ways in vitro screening does not capture. The tradeoff cannot be resolved by chemistry alone, meaning the responsive trigger considered in isolation. Its resolution requires coordination across spatial (architectural domain segregation), temporal (kinetic alignment of escape and release), and formulation-level (N/P ratio, PEG density, formation pH) design axes.
To comprehensively characterize the solution and sublimation thermodynamics of 1:1 multicomponent crystals of the antidepressant drug iproniazid (IPN) with six positional isomers of dihydroxybenzoic acid (DHBA) in acetonitrile, and to establish structure-thermodynamic relationships guiding coformer selection in pharmaceutical development. Temperature-dependent solubilities were measured over 293.15–313.15 K using the shake-flask method. Activity coefficients were derived via the Schrӧder-van Laar equations. Standard formation thermodynamic parameters were calculated from solubility data. Sublimation parameters were indirectly evaluated using a thermodynamic cycle linking dissolution, solvation, and sublimation. Activity coefficients showed positive deviations from ideality for most compounds, while 25DHBA and 35DHBA exhibited negative deviations, indicating favorable solute–solvent interactions. All stable systems formed spontaneously through an enthalpy-driven mechanism. Sublimation enthalpies were highly endothermic (233.2–266.5 kJ·mol−1) and correlated with the calculated total lattice energies, providing a quantitative measure of crystal lattice strength relevant to pharmaceutical processing and storage. Positional isomerism of the DHBA coformer governs the thermodynamic stability of IPN multicomponent crystals through a balance of intra- and intermolecular interactions. The integrated thermodynamic cycle approach offers an experimentally accessible framework for evaluating sublimation parameters, providing practical guidance for coformer selection, solid form screening, and predicting physical stability in pharmaceutical development.
Continuous distillation is widely used in the commodity and petrochemical industry to purify fine chemicals on massive industrial scales; however, this key separation strategy is largely unused within the pharmaceutical industry. This article investigates the development of a pilot-scale continuous distillation system for in-line removal of an excess amine reactant (i.e., tert-butylamine) when incorporated within an advanced manufacturing technology (AMT) for continuous drug substance production. Initial design parameters were simulated in ASPEN + to assess potential process solvents, setpoint parameters, and azeotrope formation. Complementary analytical characterization was performed with high performance liquid chromatography (HPLC) and gas chromatography – flame ionization detection (GC-FID). Early continuous distillation prototypes and key engineering design decisions are highlighted. The final engineered system is comprised of a + 3-foot distillation column fitted with an Allihn condenser, a 250 mL three-necked round bottom flask, and an automated system for reflux ratio (RD) control. The column is readily integrated within an advanced manufacturing system to continuously remove amine reagent during continuous manufacturing of albuterol sulfate at a 3.0 mL/min process basis, corresponding to a theoretical throughput of approximately 1,800 doses per hour based on the demonstrated process flowrate, reaction stoichiometry, and operating conditions. The application of continuous distillation offers a unique strategy for impurity removal during advanced pharmaceutical manufacturing and can be scaled to meet target throughputs. Here we provide general criteria necessary for successful implementation of similar continuous in-line distillation systems.
Amorphous solid dispersions (ASDs) have been shown to be an effective formulation strategy for improving apparent solubility, dissolution rate, and hence oral bioavailability of poorly aqueous soluble drugs. In this perspective, we review recent progress in understanding the role of polymer concentration, particularly the overlap concentration, c*, in governing crystallization of high drug loaded ASDs. The overlap concentration, c*, is a threshold above which adjacent polymer coils start to contact. Recent work has shown that when polymer concentration is below c*, the presence of the continuous polymer-free amorphous drug domain allows crystallization to proceed similarly to neat drug, resulting in limited inhibition. Above c*, formation of a homogeneous polymer rich matrix suppresses crystallization, primarily by delaying the first nucleation event. Representative case studies demonstrate the generality of this framework across diverse drug-polymer systems, although limitations arise for sufficiently high molecular weight polymers. Overall, the c*-guided rheological approach provides a mechanistic basis for rational polymer selection and optimization in high drug loaded, and therefore reduced overall volume, ASD formulations.
Hydration of metastable anhydrates during dissolution can eliminate their supersaturation advantage and compromise formulation performance. This study used nitrofurantoin as a model system to clarify how surfactant molecular structure regulates solution-mediated phase transformation (SMPT) from anhydrate to monohydrate and supersaturation maintenance. Six surfactants, including SDS, DTAB, CTAB, STAB, Tween 20, and Tween 80, were evaluated by dissolution testing, solid-state characterization, crystallization kinetics, and molecular dynamics simulations. Surfactants inhibited SMPT in a structure-dependent manner, following the order Tween 80 > STAB > Tween 20 > CTAB > DTAB > SDS ≈ plain buffer. Longer hydrophobic chains more effectively delayed monohydrate nucleation and reduced crystal growth, whereas differences in head-group characteristics further modulated surface adsorption and inhibition among surfactants with comparable chain lengths. Molecular dynamics simulations suggested that stronger adsorption on monohydrate surfaces was associated with greater blockage of growth sites. This study provides mechanistic insight into surfactant-regulated nitrofurantoin hydration, highlighting hydrophobic chain length and head-group characteristics as key structural factors governing surfactant adsorption and stabilization of the anhydrate during dissolution.
