Drug development researchShivani Tyagi, Jayendra Kumar
The goal of the work was to formulate, optimize, and evaluate liquid-Self-nanoemulsifying drug delivery system (L-SNEDDS) co-loaded with Selegiline (SEL), a monoamine oxidase type B (MAO-B) inhibitor, and Biochanin A (BCA), a potent adjunctive neuroprotective agent found in Trifolium pratense, to enhance oral delivery and accelerate anti-Parkinsonian efficacy for the management of Parkinson's disease (PD). Propylene glycol was chosen as co-surfactant, Tween 80 as surfactant, and peppermint oil as oil phase after excipients screening, as this combination exhibited the broadest emulsification region in pseudo-ternary phase diagram. A systematic Quality-by-Design (QbD) approach was adopted, and formulation variables were optimized using Design-Expert software to obtain an optimized L-SNEDDS formulation with desirable physicochemical attributes. Dilution of the optimized SNEDDS led to the spontaneous formation of a stable aqueous nanoemulsion exhibiting a droplet size of 110.9 nm, polydispersity index (PDI) 0.265, transmittance of 98.86 ± 0.37%, zeta potential of -16.3 mV, viscosity of 6.35 ± 2.51 cP, self-emulsification time of 27.35 s, and conductivity of 196.23 ± 0.324 μS cm-1. In vivo studies showed that SEL-BCA-loaded SNEDDS exhibited better oral bioavailability than pure SEL-BCA suspension. Notably, SNEDDS achieved higher brain Cmax values for SEL (5.6 ± 0.41 μg mL-1) and BCA (13.84 ± 1.14 μg mL-1), as well as elevated plasma concentrations of SEL (6.51 ± 0.43 μg mL-1) and BCA (762.65 ± 16.82 μg mL-1). Collectively, the results underscore the potential of the SEL-BCA SNEDDS as a combinational delivery platform that could improve the effectiveness of combination therapy for the management of PD.
Drug deliveryGabriela Koutná, Jan Kotouček, Jan Macků, Kateřina Kubová, Martina Urbanová, Larisa Janisová, Ivana Šeděnková, Jan Muselík, Jakub Vysloužil, Josef Mašek, Elišk…
Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120 min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5 mg/kg) in piglets demonstrated a delayed peak plasma concentration (Cmax 11.67 ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.
ChemMedChemMaría Laura Lavaggi, María Fernanda García, Mauricio Cabrera, Marcos Couto, Hugo Cerecetto
This review summarizes the evolution of our research on anticancer agents, from early efforts on hypoxia-selective cytotoxins to more recent developments in chemoprevention, molecular targeting, and radiopharmacy. Initial studies focused on the design of N-oxide-containing heterocycles as bioreductive-prodrugs activated under tumor hypoxia. While early triazine N-oxides and furoxans showed limited selectivity, these studies underscored the importance of redox-properties in biological activities. This led to the identification of phenazine 5,10-dioxides as a more suitable pharmacophore, affording compounds with improved potency- and hypoxia-selectivity, supported by mechanistic-, physicochemical-, and in vivo studies. Parallel efforts explored metal-based complexes and formulation strategies enhancing bioavailability and therapeutic performance. Alongside these efforts, cancer chemopreventive-agents were investigated, particularly chalcone-derived scaffolds and related hybrids capable of modulating phase I/II enzymes through Nrf2 activation. Additionally, attention has shifted toward targeted- and diagnostic-approaches, including radiopharmaceuticals for hypoxia-imaging and the use of biomolecular recognition systems, such as aptamers, polypeptides, and antibodies, to selectively address tumor-associated biomarkers. These strategies include aptamer-based biotherapeutics for drug delivery and imaging, as well as approaches combining tyrosine kinase receptor targeting with BNCT. Furthermore, bioorthogonal-methodologies have been explored enabling selective in situ activation and targeting. Together, these studies illustrate a multidisciplinary approach integrating chemistry, biology, and pharmacology toward more selective anticancer strategies.
ChemMedChemMaria-Eleni Kouridaki, Mercè Pallàs, Carmen Escolano
The imidazoline receptor (IR) system, comprising the I1R, I2R, and I3R subtypes, consists of binding sites involved in cardiovascular, metabolic, and neurological disorders. This review updates the 2004 compilation by Dardonville and Rozas on IR ligands, emphasizing promising ligands, subtype selectivity, and pharmacological profiling. Representative ligands for each subtype are analyzed to highlight key pharmacological aspects, including affinity, selectivity, and functional activity, integrating findings from preclinical and clinical studies. Critical molecular targets such as Nischarin/IRAS for I1R and MAO-B-associated sites for I2R are discussed in the context of ligand design and CNS penetration. I1R-selective ligands, exemplified by rilmenidine, show improved selectivity over α2-adrenoceptors and exhibit antihypertensive, metabolic, and neuroprotective effects. I2R ligands display neuroprotective, anti-inflammatory, and analgesic activities, with CR4056 progressing to Phase II trials. PET imaging with [11C]BU99008 has validated I2R upregulation as a biomarker for neurodegeneration. Overall, the IR system presents therapeutic opportunities: I1R for cardiovascular and metabolic disorders, I2R for pain and neurodegeneration, and I3R for diabetes. Continued ligand optimization and receptor characterization are essential for clinical translation.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VMuzaffaruddin Ahmed Madny, Khushwant S Yadav
Parkinson's disease is a distinctly age-associated neurodegenerative disorder in which oral levodopa remains the therapeutic foundation, particularly in older adults. Yet with advancing age, the reliability of oral therapy progressively declines not simply due to inadequate dosing, but because ageing reshapes the gastrointestinal environment on which drug absorption depends. This review integrates evidence spanning neuromuscular decline, epithelial barrier fragility, altered luminal chemistry, immune dysregulation, microbiome remodelling, and enteric neurodegeneration to explain how the ageing gut generates exposure instability. Delayed gastric emptying, inconsistent proximal intestinal delivery, microbial drug metabolism, and real-world administration constraints collectively amplify pharmacokinetic variability, producing erratic onset, fluctuating plasma profiles, and reduced therapeutic predictability. Using levodopa as a clinically established model system, we extend these insights to the broader challenge of ensuring reliable performance of oral therapies in ageing populations. We argue that therapeutic success in older adults depends less on maximizing mean bioavailability and more on stabilising exposure under heterogeneous physiological and practical conditions. Accordingly, the review integrates ageing-associated gastrointestinal decline, altered luminal and epithelial determinants of drug absorption, pharmacokinetic instability, and formulation design responses into a unified translational framework for ageing-aware oral therapy. By reframing levodopa failure as a consequence of ageing-driven gut-drug instability, this review proposes an ageing-aware formulation framework and identifies exposure-stability endpoints to guide the development and evaluation of physiologically resilient oral therapies for older adults.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VJuan Ma
The growing demand for subcutaneous (SC) self-administration of biotherapeutics, driven by the rising prevalence of chronic diseases and healthcare cost-containment pressures, has accelerated the development of high-concentration formulations (HCFs). However, protein concentrations exceeding 100 mg/mL introduce significant challenges, including solubility limitations, high viscosity, aggregation propensity, injectability constraints, and manufacturing complexities. This review systematically examines the primary obstacles in HCF development and highlights recent advances in formulation and process technologies. Key strategies include: (i) excipient-based viscosity reducers; (ii) hyaluronidase-enabled large-volume SC delivery; (iii) lyophilization for decoupling manufacturing from final concentration; (iv) spray drying platforms including SnapShot™ and XeriJect®; (v) electrostatic spray drying (Elektroject™ Hypercon™); (vi) Microglassification™ dehydration technology; and (vii) protein crystallization (Crystalomics®). Collectively, these innovations are reshaping the landscape of high-concentration biologic drug products, enabling the transition from intravenous to subcutaneous administration for a broader range of therapeutics. This review serves as a strategic guide for formulation scientists and drug developers engaged in next-generation subcutaneous biologics.
Targeted drug delivery systems play a crucial role in improving the effectiveness and precision of cancer treatments. Liposomes have been widely investigated as drug carriers due to their versatility. Traditional methods for functionalizing liposomes involve covalent bonding of targeting ligands, which, while effective, can be complex and may affect the activity of the ligands. In contrast, non-covalent peptide insertion offers a simpler, more adaptable approach for incorporating targeting peptides into liposomal membranes using mechanisms such as hydrophobic interactions and electrostatic forces. This review examines non-covalent peptide-liposome interactions as the primary focus. We analyze mechanisms, incorporation techniques, and therapeutic applications with emphasis on formulation-relevant criteria including stability, manufacturability, and clinical translation. Critical evaluation of comparative advantages and limitations of each strategy provides decision frameworks for formulation scientists. We also address manufacturing challenges, quality control strategies, and regulatory considerations that influence clinical translation.
AAPS PharmSciTechChrystalla Protopapa, Laura Andrade Junqueira, Siva Satyanarayana Kolipaka, Sophia Economidou, Dimitris Pappas, Dennis Douroumis, Marilena Vlachou
3D printing has emerged as a novel technology for producing personalized dosage forms tailored to patients' therapeutic needs. Hot-melt extrusion (HME) is commonly used to produce filaments for most extrusion-based 3D printers. This study aimed to investigate the effect of three different ethylcellulose (EC) grades (7N, 10N, and 20N) on the physicochemical properties, matrix restructuring, and sustained-release behavior of bupropion hydrochloride (BUP·HCl)-loaded tablets. The extrudates were fabricated using HME, pelletized, and used as feedstock for screw-based 3D printing, thereby overcoming the limitations of filament-based systems. The formulations were evaluated for drug release, hardness, swelling, and porosity before and after dissolution using micro-computed tomography (microCT). The influence of tablet geometry on drug release was also investigated. Morphology, crystallinity, and thermal properties were characterized using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). All formulations exhibited sustained BUP·HCl release, with drug release decreasing as EC viscosity grade increased. Tablets prepared with higher-viscosity EC showed greater hardness, reduced swelling, and lower post-dissolution porosity. MicroCT analysis revealed raster-related internal pores in all tablets before dissolution. However, initial porosity did not correlate with release behavior; tablets containing EC 20N exhibited the highest initial porosity but the lowest post-dissolution porosity and slowest drug release, whereas EC 7N tablets showed the opposite trend. Larger, thinner tablets released drug faster due to higher surface-area-to-volume ratio. The findings demonstrate that EC molecular weight plays a critical role in governing hydration-driven matrix restructuring and controlling sustained-release behavior of the 3D-printed tablets.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VYuta Shiga, Naoto Sakurai, Luca Chiari
Understanding long-term physical changes in lyophilized matrices is essential for rational formulation design and stability assessment. In this study, positron annihilation lifetime spectroscopy (PALS) was applied to monitor time-dependent structural evolution in simple lyophilized carbohydrate-polymer matrices stored for up to 21 months under low and elevated humidity conditions. Formulations containing saccharides, polyols and starch were selected as model amorphous systems to investigate molecular mobility and phase evolution in the absence of active pharmaceutical ingredients. The free volume and ortho-positronium (o-Ps) intensity were determined as complementary indicators of free volume within the amorphous phase and relative amorphous fraction, respectively. Over prolonged storage, composition- and humidity-dependent changes in these parameters were observed. Under elevated humidity, selected formulations exhibited reductions in o-Ps intensity consistent with partial recrystallization, while variations in free volume reflected concurrent structural relaxation within the remaining amorphous phase. Solid-state 1H NMR and X-ray diffraction provided complementary support for these evolution trends. The results demonstrate that PALS sensitively detects physical aging and structural changes in lyophilized matrices by probing free-volume evolution during storage. These findings support the utility of PALS as a non-destructive analytical tool for monitoring long-term physical stability of amorphous lyophilized matrices under defined environmental conditions.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VEun-Soo Jung, Hui-Yeon Jang, Su-Jin Jung, Byoung-Hag Kim, Yoo-Jung Kim, Jeong-Han Moon, Soo-Wan Chae, Seung-Ok Lee
BACKGROUND: Glutathione is a tripeptide involved in antioxidant defense; however, its systemic availability following oral administration remains controversial, and pharmacokinetic differences between formulations in humans are not well characterized. OBJECTIVE: This study compared the pharmacokinetics and short-term supplementation effects of an orally dissolving film (ODF) and a conventional tablet formulation of glutathione in healthy adults. METHODS: In Study I, a randomized open-label crossover trial evaluated single-dose (300 mg) pharmacokinetics following administration of ODF or tablets. In Study II, participants consumed ODF (100 mg/day) or tablets (100 mg/day) for 4 weeks. RESULTS: Plasma glutathione concentrations were higher in the ODF group, with significant differences at 4 and 6 h. The ODF formulation showed a longer Tmax and tended toward higher Cmax and systemic exposure (iAUC0-6h). During 4-week supplementation, both formulations increased circulating glutathione levels, with no significant changes in oxidative stress-related biomarkers. No adverse events were reported. CONCLUSIONS: The ODF formulation exhibited a distinct pharmacokinetic profile and showed a trend toward greater systemic glutathione exposure compared with the tablet formulation. These findings suggest that formulation characteristics may contribute to differences in the bioavailability and pharmacokinetic behavior of orally administered glutathione. CLINICAL TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0011710.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VMaria Antonia S de Albuquerque, Douglas F de Albuquerque
Mathematical models for drug release from polymeric nanocapsules have traditionally relied on Noyes-Whitney-based first-order kinetics, which implicitly predict faster release for drugs exhibiting higher solubility in the oily core. This prediction is inconsistent with numerous experimental observations in which more lipophilic compounds are released more slowly. To address this apparent paradox, a partition-controlled kinetic framework is derived in which the effective release rate scales inversely with oily-core solubility. The resulting model, [Formula: see text] introduces a dimensionless correction factor α and a reference solubility S0, yielding a dimensionally consistent formulation while preserving the mechanistic inverse-solubility dependence predicted by partition equilibrium arguments. A re-analysis of the previously published nanocapsule model reveals a dimensional inconsistency and a tabulation error affecting the reported kinetic parameters. After correction, the published adapalene data are found to be consistent with the proposed inverse-solubility scaling. The model is further evaluated using four release datasets (adapalene in two oily cores, capsaicin, and dihydrocapsaicin), yielding R2 values between 0.925 and 0.969 with Cmax fixed at the final experimental value. These results support partition-controlled release as a physically plausible and dimensionally consistent framework for describing drug release from polymeric nanocapsules.
International journal of molecular sciencesXiaomeng Liu, Huanxiang Liu
Artificial intelligence-driven molecular generation has become an increasingly used computational approach for proposing candidate chemical structures in early-stage drug discovery, yet the practical value of the molecules produced is often difficult to judge. Many studies still rely mainly on model-level metrics such as validity, uniqueness, novelty, and diversity. These metrics describe whether a generator produces parsable, non-redundant structures that extend beyond a reference set, but they do not show whether the molecules are chemically credible, biologically relevant, or experimentally actionable. AI-generated molecules are best treated as testable hypotheses requiring staged, complementary evidence rather than judgments based on generic generative statistics. We discuss the interpretive limits of common metrics, examine complementary levels of evaluation including medicinal chemistry feasibility, target relevance and prediction reliability, structure-based plausibility, and translational readiness, and identify recurring failure modes such as false novelty, reward exploitation, predictor bias, docking overinterpretation, and selective reporting. We propose a six-stage, failure-aware evaluation framework spanning molecular correctness, medicinal chemistry feasibility, novelty and diversity in context, target relevance and prediction reliability, structure-based plausibility, and translational readiness. This framework does not replace experimental validation; instead, it helps align computational claims with the strength of supporting evidence and promotes more transparent and reproducible evaluation of AI-generated molecules in drug discovery.
Acta pharmaceutica (Zagreb, Croatia)Ivana Mitrevska, Dino Karpicarov, Ana Mihailovska, Dejan Mirakovski, Olivera Paneva, Gjorgji Petrushevski
The aim of this study was to evaluate scanning electron microscopy (SEM) combined with energy-dispersive X-ray spectroscopy (EDS) as complementary analytical tools for supporting continuous improvement in pharmaceutical granule manufacturing. Pilot-scale cefixime granules for oral suspension were prepared as defined process scenarios, including placebo, reference, intermediate, stress-exposed, and optimised batches. SEM was used to compare granule morphology, surface integrity, and agglomeration behaviour, whereas EDS provided qualitative and semi-quantitative information on localised elemental composition, with emphasis on sulfur as an API-related marker and oxygen-to--sulfur trends as surface-sensitive indicators of process- or stress-related variability. Intermediate and stress-exposed batches showed increased surface roughness, microstructural deterioration, and higher oxygen-to-sulfur ratios, whereas reference and optimised batches showed more uniform morphology and comparable elemental profiles. The findings indicate that SEM/EDS can provide useful material-level insight into process-related variability and may support root--cause investigation and process refinement. Overall, SEM/EDS is proposed as a complementary, localised, and semi-quantitative approach for supporting continuous improvement in pharmaceutical granule manufacturing.
Drug deliveryJoanna Sobocińska, Chun Yuen Jerry Wong, Emre Gezer, Hui Xin Ong, Youssef Daali, Véronique Serre-Beinier, Daniela Traini, Muriel Cuendet
Resveratrol is a polyphenolic compound with therapeutic potential for pulmonary diseases, yet its use is limited mostly due to low oral bioavailability. Inhalable powder formulations are a promising strategy to help overcome those challenges. Here, we report the development and physicochemical characterization of a spray-dried resveratrol formulation suitable for pulmonary delivery. The pharmacokinetic profile and in vivo toxicity were then assessed. Particle size, interparticle cohesion, morphology, uptake, and stability of the formulation were evaluated. Intratracheal administration was then performed in A/J mice and pulmonary distribution was compared to a micronized resveratrol formulation. Lung and plasma concentrations were quantified by LC-MS/MS at 5-70 min postadministration, followed by long-term toxicity evaluation. The spray-drying process produced resveratrol with improved lung exposure while preserving properties essential for pulmonary delivery. In vivo, the spray-dried formulation achieved improved pulmonary and lower systemic distribution compared to the micronized form, increasing the lung to plasma AUC ratio from 77 to 282. Moreover, a greater number of mice had detectable concentrations of resveratrol in the lungs following spray-dried administration (62.5% vs 37.5% for micronized). The long-term intratracheal administration of spray-dried resveratrol (1 mg, 3× per week for 12 weeks) was well tolerated, with no clinical, biochemical, or histopathological signs of toxicity. Altogether, the spray-dried formulation of resveratrol could be efficiently delivered to the lungs and displayed an excellent safety profile, supporting its future investigation in respiratory disease models.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VTiandian Wang, Anuj A Biswas, Feng Zhang, Rongjin Sun, Ming Hu
With annual overdose deaths in the United States over 1 million, medication-assisted treatment with buprenorphine (BUP) remains the first-line, gold-standard therapy for opioid use disorder (OUD). Because OUD is a chronic, relapsing condition that requires long-term pharmacotherapy, long acting injectables (LAI) and implantable formulations offer important advantages over daily formulations for maintenance treatment. By comparing transmucosal BUP and LAI formulations' systemic exposure profiles and μ-opioid receptor (MOR) occupancy, converging data demonstrate that higher and more sustained BUP exposure with low variability is required to fully suppress withdrawal, cravings, and illicit opioid use. These findings indicated that currently marketed formulations may not adequately address the clinical challenges associated in the fentanyl/polysubstance era. Accordingly, this rationale-based review proposes a mechanistic framework supporting the development of next-generation BUP-PLGA solid biodegradable implants to maintain a conservative therapeutic benchmark (e.g. Css ≥ 5 ng/mL) for extended durations (e.g. 3-6 months) with low variability (e.g. no large burst release, major lag phase or phase inversion). However, progress in implant development has been hindered by limited mechanistic understanding of drug release. In PLGA-BUP systems, poor IVIVC is largely driven by the low and pH-dependent solubility of BUP, which can make dissolution rate-limiting in vivo and interact with the evolving PLGA acidic microenvironment (acidification, porosity formation, and autocatalytic degradation). Future research should be prioritized to determine directly whether polymer erosion coincides with drug release in PLGA depots, or whether residual, poorly soluble BUP persists locally and releases under dissolution-limited kinetics. Clarifying these mechanisms is not only essential to fulfill the regulatory and translational expectations of the FDA and NIDA, but also to deepen mechanistic understanding and accelerate the rational development of LAI formulations for poorly soluble drug.
Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agentsWei Zhao, Beibei Bie, Juning Wang, Xueying Liu, Huanle Fang, Rui Niu
Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure-activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody-drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence.
Molecular pharmaceuticsCarolina Alva, Michael Hink, Aygün Doğan, Jesús Alberto Afonso Urich, Josip Matić, Fabian Specht, Tanja Freichel, Sebastian Reyer, Thomas Rillmann, Susanna Abr…
The bioavailability of highly lipophilic, poorly soluble drugs can be improved effectively, when formulated in lipid-based systems. Solid lipids generally offer greater physical robustness than liquid lipids but slower release. Hot-melt extrusion (HME) and additive manufacturing (AM) enable personalized release by tailoring composition and geometry. However, the limited availability of suitable solid lipid-based materials, particularly for processing thermolabile and lipophilic drugs, restricts their application. Polyglycerol esters of fatty acids (PGFAs) represent a promising class of lipids due to their stable α-form, tunable hydrophilicity, and printability. Nevertheless, the interplay between lipid processing, solid state, and rheological behavior remains insufficiently understood for HME and AM. In this study, felodipine (Biopharmaceutics Classification System (BCS) class II drug) was incorporated into a PGFA matrix to obtain a fully dissolved system at the minimum processing temperature. Drug loading induced melting point depression, delayed crystallization, and introduced disorder in crystal packing, thereby weakening the crystal network and enhancing filament flexibility, enabling printability. Printable filaments were achieved at 95 °C, while an undetectable crystalline drug was observed at 120 °C. This work demonstrates that drug-lipid interactions can be employed to enhance processability: while low-temperature processing of PGFA was feasible, drug modifications into the lipid solid state impacted the rheological and mechanical properties essential for additive manufacturing. Beyond this specific system, this study provides a rational proof of concept for processing solid and liquid lipids via continuous melt-based technologies.
Journal of medicinal chemistryDominga Evangelista, Elliot Nelson, Ben Tehan, Greta Bagnolini, Marinella Roberti, Giovanni Bottegoni
Drug-induced liver injury (DILI) is a leading cause of drug failure and post-market withdrawals. Traditional preclinical methods fail to detect up to 40-45% of clinical hepatotoxicity cases. Computational approaches, particularly those based on machine learning and deep learning (DL), are emerging as promising tools to support medicinal chemistry and early drug discovery, though their predictive capabilities remain under active investigation. In this perspective, we review the development of DILI annotation data sets, tracing their growth from small collections to large, comprehensive resources. We also outline the evolution of computational methods, from simple descriptor-based models to advanced DL and ensemble approaches that incorporate interpretable features. Finally, we highlight recent efforts to integrate standardized causality frameworks, pharmacogenomics, and mechanistic models, aiming to connect computational advances with clinical relevance. This perspective provides valuable insight for researchers and promotes the development of more robust and consensual DILI prediction strategies.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VHai Van Ngo, Stijn Daems, Matthias Govaerts, Clara Aguilar-Pérez, Guy Van den Mooter
Fixed-dose combinations (FDCs) offer significant advantages in the treatment of multidrug-resistant tuberculosis (MDR-TB), including reduced pill burden, increased treatment adherence, minimization of resistance development, and decreased relapse rates. A critical prerequisite for developing FDCs in single-unit formulations is ensuring physicochemical compatibility between the combined drugs, particularly for ionizable compounds. Bedaquiline (BDQ) and clofazimine (CFZ) are weakly basic drugs and promising candidates for next-generation antituberculosis FDCs. BDQ fumarate (BDQF) is widely used in the commercial product due to its improved solubility and oral bioavailability. This study provides a comparative evaluation of binary systems containing BDQ or BDQF with CFZ at different molar ratios, including 1:1, 1:2, and 2:1. Through physicochemical characterization using Fourier transform - InfraRed (FTIR) spectroscopy, X-ray powder diffraction (XRPD), apparent solubility and dissolution studies, we demonstrate that BDQF undergoes counterion transfer with CFZ, leading to the formation of new salts of either CFZ or BDQ. These new salts significantly enhance the dissolution behavior of CFZ in the BDQF-CFZ binary systems, which cannot be seen in the BDQ-CFZ systems. On the other hand, the dissolution rate of BDQF was also decreased in specific drug ratios. More specifically, we found that the ratio of 2:1 can synergistically enhance the solubility of CFZ, maintain the equibilirum solubility and provide adequate dissolution of BDQF. The findings provide mechanistic insights of selecting suitable drug forms in optimizing FDC performance and designing optimal formulations for MDR-TB therapy.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VFabrício Costa Fanhani, Laiene Antunes Alves, Marcel Henrique Marcondes Sari, Antônio Eduardo Matoso Mendes, Roberto Pontarolo, Luana Mota Ferreira
BACKGROUND: Extemporaneous liquid antihypertensive formulations are widely used in pediatrics but frequently lack detailed reporting of excipient safety data, particularly regarding age-specific physiological vulnerability and cumulative exposure. METHODS: A scoping review was conducted in accordance with PRISMA-ScR guidelines to map excipients used in pediatric extemporaneous antihypertensive liquid formulations. A regulatory-oriented assessment was applied, emphasizing age-appropriate safety considerations and exposure-based risk principles, including theoretical daily intake expressed as mg/kg/day. RESULTS: Forty-two studies were included. Reporting of excipient concentrations, age targets, and safety justifications was heterogeneous and often incomplete. Vehicles, co-solvents, preservatives, buffers, antioxidants, surfactants, and flavoring agents were identified, with selection typically driven by a focus on physicochemical stability rather than patient-centered criteria, such as age-appropriate excipient safety, dose flexibility, and acceptable volumes. Exposure-based considerations were addressed by a limited number of studies (n = 5). Exposure calculations based on typical pediatric dosing showed that concentrations considered acceptable in adult formulations may translate into clinically relevant toxicity risks in neonates and infants. Based on observed patterns, a conceptual risk stratification framework was developed to categorize excipients according to age-dependent toxicity, cumulative dose burden, and functional tolerability. CONCLUSIONS: The available literature on compounding antihypertensive formulations mainly emphasizes physicochemical performance, with less attention given to exposure-related safety parameters in pediatric patients. Integrating total daily excipient exposure metrics and structured justification for excipient selection may improve alignment with regulatory expectations and support safer, patient-centered compounding practices in pediatric clinical care.