Understanding the material deformation behavior in tablet dies is crucial for pharmaceutical development, as it directly influences manufacturability and final tablet properties. Heckel analysis provides a theoretical framework for assessing material deformation during compaction, but its direct correlation with real-world tableting behavior remains an area of interest. This study introduces a framework for characterizing the deformation mechanisms of pharmaceutical powders. It addresses limitations in conventional methods that rely solely on yield pressure (Py) and strain rate sensitivity (SRS), which fail to fully differentiate elastic and plastic deformation. The heuristic framework for comparative deformation mapping enables differentiation of excipients across the brittle-plastic-elastic space using two parameters from a compaction simulator: Py (from Heckel analysis) and pressure drop (ΔP, from an in-die stress relaxation test). ΔP is treated as a descriptor of time-dependent (viscoplastic and viscoelastic) deformation rather than as a direct measure of elasticity, and its use as an empirical surrogate for elastic character was benchmarked against independent force-displacement elastic energy. Applied to ten common pharmaceutical excipients, the framework differentiated materials that Py and SRS alone did not resolve (SRS was determined for the four reference materials). Across the ten materials, ΔP tracked elastic energy mainly between excipient classes, whereas within the six lactose grades the relationship was reversed, indicating that ΔP differences within a class reflect time-dependent deformation. The framework is therefore proposed as a comparative, material-sparing screening tool for early-stage excipient selection, not as a predictor of tableting performance or scale-up behavior.

Dry eye disease (DED) is a multifactorial inflammatory eye disease caused mainly by immune dysregulation through JAK/STAT, which leads to a turbulent tear film, damage to the corneal epithelia, and poor visualization. Topical therapies of the conventional type show less ocular bioavailability with quick precorneal excretion. This research was done to design and test a new NanoMiLens system loaded with Tofacitinib Citrate (TFC), which is a selective JAK inhibitor, in order to have a controlled and prolonged contact lens delivery manageable with DED. TFC Polymeric Nano-Micelles (PoT-PNMs) were prepared using a thin-film hydration method employing Poloxamer 407 as the amphiphilic polymer and Tween 80 as the stabilizing surfactant in acetone, then rehydrated with simulated tear fluid. PBD ANOVA confirmed polymer concentration and surfactant concentration as dominant factors for EE%. CCD quadratic modelling yielded R[2] = 0.9904 for EE%, 0.9789 for CDR%, and 0.9408 for particle size, with model validation errors < 1%. The optimized PoT-PNMs (200 mg Poloxamer 407, 0.30 mL Tween 80) achieved particle size 92 ± 2.6 nm, PDI 0.246, EE% 90.60 ± 0.44%, and CDR% 93.10 ± 1.2% over 12 h. FTIR, DSC, and XRD confirmed drug amorphization and drug-excipient compatibility. The optimized PoT-PNMs were loaded into freeze-thaw-crosslinked PVA/pHEMA hydrogel contact lenses via soak-loading. The optimized PoT-PNMs -loaded contact lens (NMCL12) showed % transmittance 96.11 ± 0.22%, swelling index 96.48 ± 0.24%, drug content 90.60 ± 0.44%, in-vitro CDR% 96.50 ± 0.30% over 12 h, and mechanical strength 142 ± 6 folds. This system is an effective, scalable method of topical immunomodulatory treatment of inflammatory dry eye disease.

This study aimed to develop rifaximin (RFX) loaded chitosan (CS)-tripolyphosphate (TPP) nanoparticles for potential colonic delivery as a drug delivery system for the management of irritable bowel syndrome (IBS). Nanoparticles were prepared using the ionotropic gelation method and optimized by varying stirring speed, TPP concentration, and polymer-to-drug ratio. The optimized formulation (F41) exhibited a particle size of 262.4 ± 24.3 nm, a polydispersity index (PDI) of 0.389 ± 0.033, a zeta potential of + 9.91 ± 0.94 mV, and an encapsulation efficiency (EE%) of 94.75 ± 0.04%. In vitro release studies demonstrated nearly complete drug release within 36 h, which was faster compared to other formulations (52-64 h). Scanning electron microscopy (SEM) confirmed spherical morphology, while differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR) analyses indicated successful drug encapsulation without chemical interaction. In vivo evaluation using a chronic restraint stress (CRS) induced IBS model showed that F41 significantly improved physiological parameters, including reduced fecal water content (20.655 ± 23.494%), increased body weight gain (22.716 ± 3.903%), and a decreased disease activity index (p < 0.05). These findings indicate that, the optimized nanoparticle system demonstrated favorable physicochemical properties, sustained drug release, and improved therapeutic outcomes. Owing to the cationic nature of CS, the system may also provide enhanced interaction with colonic mucus, potentially contributing to prolonged local residence. These findings suggest that the developed formulation represents promising approach for potential colonic delivery of RFX in IBS management; however, further studies are required to directly evaluate its mucoadhesive properties and underlying mechanisms.

Conventional preservative efficacy tests for ophthalmic formulations rely on discrete colony counts and therefore provide limited insight into the dynamic processes of microbial inactivation and recovery. Such endpoint-based evaluations can obscure formulation-dependent differences in antimicrobial performance and hinder rational optimization of preservative systems. In this study, we developed a quantitative framework that integrates a high-throughput WST-8-based colorimetric microplate assay with nonlinear mixed-effects (NLME) modeling to characterize bacterial killing and regrowth dynamics in borate-buffered systems. Escherichia coli responses were analyzed across 43 formulations using L27 orthogonal and Box-Behnken experimental designs. Bacterial inactivation was described by first-order kinetics, while post-exposure regrowth was modeled using a damage-dependent suppression term. The resulting hierarchical NLME model adequately described bacterial growth trajectories across all formulations, as confirmed by goodness-of-fit diagnostics, visual predictive checks, and bootstrap analyses. Multivariate covariate analysis suggested that borax and pH-related physicochemical conditions contributed to variability in bacterial inactivation rate constants, indicating that antimicrobial activity in borate systems is influenced by buffer composition and the associated physicochemical environment rather than by total borate concentration alone. By coupling structured experimental design with hierarchical population modeling, the proposed framework enables dynamic and mechanism-informed evaluation of preservative efficacy. This approach extends conventional endpoint-based testing and provides a quantitative platform for data-driven optimization and risk assessment of ophthalmic formulations.

Mucopenetrating systems are drug delivery platforms designed to overcome the intestinal mucus barrier, facilitating access to epithelium and enhancing the bioavailability of lipophilic compounds. Copaiba oil (CO) is a compound displaying broad therapeutic potential but low aqueous solubility, which limits its bioavailability. This study aimed to assess how two CO-loaded delivery systems, an emulsion (EM) and a self-emulsifying system (SE), interact with the intestinal mucus layer and how effectively they permeate it. Thus, interactions with mucin and porcine intestinal mucosa were evaluated via oscillatory rheometry, by determining rheological synergism, and the in vitro and ex vivo mucoadhesion assays. The retention of the emulsion systems on the intestinal mucosa was also assessed, along with mucopermeation, using Transwell inserts coated with porcine intestinal mucus and mucin solution. Rheological analysis demonstrated a significant interaction between SE and mucin, evidenced by positive rheological synergism, whereas EM showed limited interaction. In mucoadhesion studies, EM behavior was primarily associated with its higher consistency, while SE exhibited more specific interactions with mucin. Ex vivo retention studies demonstrated greater retention of EM on the intestinal mucosa. In contrast, SE showed superior permeation through the mucus layer in mucopermeation assays, a behavior attributed to the presence of PEG 400. Overall, SE exhibited a more favorable balance between mucoadhesion and mucus penetration than EM. The SE demonstrated enhanced mucopermeation while maintaining adequate interaction with intestinal mucus, suggesting its potential as a promising oral delivery platform for improving the intestinal transport and bioavailability of copaiba oil.

A stability-assessment framework integrating Zeneth in silico degradation prediction, AIBN-mediated radical autoxidation, and ASAPprime® accelerated kinetic modeling was developed for olaparib drug substance and a prototype immediate-release tablet. Zeneth predicted benzylic oxidation as the dominant degradation pathway (pathway score 912). Under AIBN stress, Impurity 6 formed at 2.15%, with radical-initiator dependence confirmed by an AIBN-free control (< 0.1% total impurity); aqueous hydrogen peroxide (1.0%) provided degradant mass for LC-MS/MS characterization. Impurity 6 was confirmed as the benzylic ketone (C24H21FN4O4) against an authenticated reference standard (Schymanski Level 1; mass error + 0.7 ppm); the reprocessed HRMS/MS fragmentation ladder was fully reconciled with this assignment, and Impurity 6 was chromatographically resolved from its isomeric Impurity 4 (relative retention times 1.45 versus 1.02). Isoconversion ASAPprime® studies (drug substance: 50-80 °C/11-75% RH; formulation: 40-70°C/11-75% RH) were validated against 12-month real-time data. The drug substance followed first-order kinetics (Ea = 91.2 ± 6.7 kJ·mol[-][1]) with negligible humidity sensitivity (B = 0.004 ± 0.003; p > 0.05), yielding a model-derived 95% confidence shelf-life estimate of 3.4 years (MAPD = 5.3%; Q[2] = 0.96). The formulation showed accelerated kinetics (Ea = 85.4 ± 5.9 kJ·mol[-][1]; B = 0.014 ± 0.005; p < 0.05) and a shelf-life estimate of 2.6 years (MAPD = 5.2%; Q[2] = 0.93). These projections require confirmation by longer-term real-time data. The workflow provides a development stage stability risk assessment tool; Impurity 6 was structurally confirmed at Level 1 against an authenticated reference standard, and the formulation was single batch and unoptimized.

Amorphous nanosuspensions can generate supersaturated drug concentrations far above crystalline solubility, but their performance depends on stabilizing both the metastable amorphous phase and the high interfacial energy of nanosized particles against recrystallization and Ostwald ripening. ATZ was selected as a model weakly basic drug because its poor dissolution and rapid desupersaturation at intestinal pH provide a rational formulation space for probing the biopharmaceutical relevance of amorphous nanosuspensions. The present study addressed these limitations through the development of ATZ amorphous nanosuspension using acid-base neutralization method. Polymer-surfactant screening was performed through desupersaturation assay and drug-rich droplet size analysis which identified HPMCAS-MG and Soluplus as optimal precipitation inhibitors. Box-Behnken design optimization yielded nanosuspension with a mean particle size of 146.7 ± 5.56 nm and polydispersity index of 0.261 ± 0.05, and a zeta potential of - 4.54 ± 0.78 mV. Solid-state and spectroscopic analyses confirmed successful amorphization of ATZ and the presence of hydrogen-bonding and hydrophobic interactions in ATZ-ANS. Further, non-sink in vitro dissolution testing revealed that ATZ-ANS effectively sustained supersaturation with limited precipitation. The formulation retained its nanoscale characteristics and did not show evidence of recrystallization during six months of accelerated stability testing at 40 °C/75% relative humidity (RH). The in vivo pharmacokinetic evaluation in Sprague Dawley rats demonstrated that ATZ-ANS achieved 16.59-fold higher Cmax (ng/mL) and 6.31-fold higher AUC0-t (ng-h/mL) than crystalline ATZ, and a 2.08-fold and 3.22-fold increase over the marketed formulation (Reyataz®), respectively. Our findings highlighted amorphous nanosuspension as a pragmatic approach for difficult to deliver drugs.

Peptide-based therapies have transformed the management of chronic illnesses such as diabetes, cancer, and cardiovascular problems, owing to their remarkable specificity, effectiveness, and low toxicity. Nonetheless, their therapeutic efficacy is frequently impeded by obstacles such as inadequate bioavailability, fast enzymatic breakdown, and restricted systemic stability. Conventional delivery strategies, such as oral and intravenous injection, have considerable constraints in efficiently transporting peptides to target locations. Transdermal drug delivery systems, especially microneedles (MNs) and bioinspired microneedles (BMNs), have garnered considerable interest as a less invasive and effective option to surmount these obstacles. MNs form microchannels in the epidermis and dermis, facilitating the direct administration of peptides into systemic circulation, hence dramatically improving peptide delivery across the skin. Recent improvements in BMNs technology have enhanced peptide delivery through better mechanical strength, skin contact, and controlled release. This paper mainly focuses on the importance of peptide drugs, the obstacles related to their administration, and the potential of BMNs for effective transdermal delivery. We emphasize current advancements in BMNs that improve peptide stability, permeability, and therapeutic effectiveness, facilitating their practical use in the treatment of chronic and acute disorders.

Oral delivery of poorly water-soluble drugs such as praziquantel (PZQ) is frequently limited by poor absorption and low bioavailability. Lipid-based carriers represent a promising strategy, as their matrices enhance solubility by incorporating hydrophobic molecules within a lipophilic environment. In this study, PZQ-loaded beeswax (BW) oleogels were formulated using palm oil (PO) or cottonseed oil (CSO) as lipid carriers, followed by physicochemical characterisation and in vitro studies. We hypothesised that differences in oil composition would influence the structure and physicochemical properties of BW oleogels, affecting drug release, in vitro digestion behaviour, and intestinal permeation. BW oleogels exhibited gelation at a critical concentration of 5% (w/w), resulting in a high oil-binding capacity of at least 98%. Microscopy and X-ray diffraction indicated concentration-dependent development of a dense, needle-like semi-crystalline network, while rheological analysis confirmed stable gel behaviour (G' > G″). For the first time, we demonstrate the application of a modified everted gut sac model, adapted to quantitatively investigate the intestinal interaction and permeation behaviour of PZQ-loaded oleogels. Simulated in vitro digestion revealed negligible release under salivary conditions and limited gastric release (< 16%), followed by a bioaccessible fraction of 52-57%. The BW oleogels exhibited reduced intestinal permeation relative to the free drug, indicating drug entrapment within the oleogel, while oleogel-intestinal tissue interaction remained below 7.8%. These findings highlight the potential of BW oleogels as oral carriers for hydrophobic compounds such as PZQ and suggest their applicability as modified-release delivery systems.

Compressibility is a critical material attribute in tablet manufacturing, as it governs powder densification, inter-particulate bonding, and the mechanical integrity of solid oral dosage forms. Intrinsic solid-state properties such as polymorphism, crystal structure, molecular packing, slip planes, and hardness influence the primary mechanism for deformation and ultimately determine whether materials undergo plastic deformation, elastic deformation, or brittle fracture during compaction. These effects are controlled by the properties of the particles and surface properties. Factors such as particle size and shape, surface free energy, particle aggregation, density, and flow affect the development of the contact area and the transmission of stress within the tablet. Environmental conditions and processing parameters also alter these fundamental responses, thereby affecting densification efficiency, tensile strength, and defect formation. Compressibility, compactibility, and tabletability are determined by these interrelated factors, which ultimately influence manufacturability and product robustness. This review emphasizes the importance of a holistic understanding of the mechanisms governing API compressibility by integrating solid-state properties, compaction behavior, and empirical modeling techniques. It highlights how these interconnected factors influence powder desnsification, mechanical strength, and tablet performance, providing a scientific framework for the rational design and optimization of pharmaceutical formulations. Furthermore, the concept discussed in this review may facilitate the application of Quality by Design(QbD) principles and support the development of robust manufacturing strategies for solid oral dosage forms.

Artificial intelligence (AI) and machine learning (ML) are increasingly explored to improve predictive modelling and optimization in pharmaceutical formulation development. This study compared predictive performance of conventional statistical approaches and AI/ML-based models using an experimentally generated dataset from PLGA-mPEG-based Intelligent Nano Depot (iNDEP), smart depot forming long-acting injectable system for sustained co-delivery of Memantine hydrochloride (MH) and Galantamine hydrobromide (GH). Central Composite Design (CCD) dataset of 17 experimental formulations were employed to develop predictive models. The % cumulative drug release (CDR), implant formation time and particle size were measured to determine effects of PLGA-mPEG, Span 80 and Tween 80. Design of Experiments (DoE), SPSS-based Multiple Linear Regression (MLR), Artificial Neural Networks (ANN) and ML workflows in Orange Data Mining and KNIME Analytics Platform were used to produce predictive models. Root mean squared error (RMSE), mean squared error (MSE), and coefficient of determination (R[2]) were used to evaluate model performance. Models developed using DoE were good fit with R[2] values ranging from 0.9882 to 0.9916. The MLR models predicted perfectly (R[2] = 0.866-0.951) for the %CDR responses using SPSS. ANN models successfully captured nonlinear relationships between formulation and response. Analysis of ML workflows indicated varying performance of algorithms depending on response; there was no one model that performed good across all responses. Traditional statistical and AI-based predictive methods complement each other. The integration of DoE with AI- and ML-based modelling offers a comprehensive tool for enhancing prediction accuracy and guiding formulation and optimization of pharmaceutical products.

Erlotinib hydrochloride (ERL), an oral tyrosine kinase inhibitor used in non-small cell lung cancer, is a classic example of drug polymorphism. However, the influence of crystallisation methods, PLGA, and thermal ageing on its polymorphic behaviour remains unexplored. This study investigated ERL polymorphism in binary mixtures prepared by blending, co-grinding, and solvent evaporation. PXRD revealed that blending and co-grinding retained ERL polymorphic form A, whereas solvent evaporation yielded form B in all binary mixtures. Thermal ageing has a significant effect on ERL crystallinity. DSC melting endotherms for form A are at 213.75 and 233.26°C, whereas form B shows a single melting endotherm at 231.96°C. MDSC efficiently captured the melt-mediated recrystallisation of form A. Further, ATR-FTIR with chemometric analysis differentiated the polymorphs into form A (anti) and form B (syn) conformations based on spectral regions at 3270 cm[-][1] (non-classical H-bonding) and 2540 cm[-][1] (N[+]-H···Cl[-] interactions). SEM revealed plate-like and needle-like morphologies for forms A and B, respectively. Conversely, saturation solubility results reported higher solubility for the solvent-evaporated drug, due to its crystal morphology. Drug content by RP-HPLC (98-102% w/w) confirmed that the observed changes were solely physical transitions. Overall, this study provides insights into the development of ERL-loaded PLGA microspheres.

The management of Alzheimer's disease requires continuous therapeutic intervention due to its progressive nature. Currently, the FDA has approved acetylcholinesterase inhibitors, NMDA receptor antagonists, and disease-modifying monoclonal antibodies for the treatment of Alzheimer's disease. This study aimed to develop a long-acting injectable formulation for symptomatic therapy. An in-situ gel formulation, DM00PG-M13, comprising Lipoid, PLGA (50:50), and sesame oil, was developed and loaded with memantine and donepezil for combination therapy. The optimized gel formulation demonstrated good uniformity with a pH of 7.80 ± 0.015. Rheological and syringeability studies showed a consistent viscosity in the range of 0.20-0.22 Pa·s and an injection force of 9.97 ± 0.29 N using a 22-G needle. In vitro drug release studies performed in phosphate-buffered saline (pH 7.4) demonstrated sustained drug release over one month, with cumulative releases of 82.58% for donepezil and 87.61% for memantine after 30 days. Furthermore, the release kinetics were best described by the Peppas-Sahlin model for donepezil and the Weibull-lag model for memantine. Ex vivo studies evaluating the optimized formulation injected into pig muscle tissue showed release profiles comparable to the in vitro release pattern, with approximately 20% release of donepezil and 26% release of memantine over 7 days, indicating sustained release behavior. Cytotoxicity studies using NIH/3T3 fibroblast cells confirmed the formulation's safety profile. Overall, these results suggest that the drug-loaded DM00PG-M13 formulation can be administered intramuscularly as a depot system for sustained drug release, potentially improving patient compliance.

High-melting-point active pharmaceutical ingredients (APIs) frequently undergo amorphization during hot-melt extrusion (HME) through progressive dissolution and incorporation in a softened polymer rather than by direct melting. The kinetics of this process are strongly influenced by particle size, yet rapid experimental methods for evaluating particle dissolution behaviour in the softened polymer prior to extrusion remain limited. In this work, a quantitative hot-stage microscopy (HSM)-based workflow combined with image analysis was developed to evaluate particle-size-dependent dissolution of a model high-melting-point API into softened Kollidon[®] VA 64 under predefined thermal conditions. The dissolved fraction of individual particle-size classes was quantified throughout the experiment to determine the particle-size range associated with complete and incomplete dissolution. Complete dissolution was consistently observed for particles smaller than approximately 15-20 μm, whereas particles exceeding approximately 40 μm exhibited a markedly increased probability of retaining residual drug particle under the applied conditions. Between these limits, the dissolved fraction decreased progressively with increasing particle size. Because the methodology evaluates particle dissolution under static thermal conditions, the identified particle-size limits should be regarded as conservative, formulation-specific estimates rather than universal HME processing limits. The proposed workflow transforms HSM from a primarily qualitative visualization technique into a quantitative preformulation screening tool that enables rapid evaluation of particle-size-related processing risks while requiring only minimal quantities of material.

5-Aminosalicylic acid (5-ASA) is a cornerstone therapy for ulcerative colitis (UC), but its clinical performance is highly variable due to pH-dependent solubility, formulation design, and intestinal metabolism. Significant intersubject variability (ISV), particularly for modified-release drug products such as Lialda (> 75% variability in Cmax and > 50% in AUC) and Pentasa (> 30 to < 50% for Cmax and > 30% for AUC), limits predictable therapeutic outcomes and necessitates a better understanding using biopredictive tools. An empirical, semi-mechanistic, and mechanistic physiologically based pharmacokinetic (PBPK) model was developed using intravenous (IV) and oral data. In vitro dissolution profiles generated under different pH, molarity, and hydrodynamic conditions were fitted and integrated into the PBPK framework to establish biorelevant dissolution methods and predict the in vivo performance of Lialda 1200 mg and Pentasa 4000 mg. Nonlinearity was observed, with 2.7-7.8-fold increases in AUC due to N-acetyltransferase-1 (NAT1) saturation. Optimal predictivity was achieved at pH 7.0 (5 mM) for Lialda (%PE: 4.7% Cmax, 1.2% AUC) and pH 7.5 (25 mM) for Pentasa (%PE: 4.9% Cmax, 4.6% AUC). Variability was driven by NAT1 saturation, pH-dependent solubility/permeability, and formulation effects. PBPK simulations enabled the identification of formulation-specific biorelevant dissolution conditions. The model successfully described pharmacokinetic variability, including intra- and inter-subject differences.