Search Results (229)

Additive manufacturing, also known as 3D printing (3DP), is intended to enable personalised medicine by producing drug products on demand at the Point of Care (PoC), with dose, drug-release profile, and geometry tailored to the individual patient. Despite its promise, widespread adoption is limited by the absence of ready-to-use quality control (QC) methods for printlets at the PoC. Process Analytical Technology (PAT) tools, particularly vibrational spectroscopic methods like Near-Infrared and Raman spectroscopy, can offer real-time monitoring to ensure the safety and consistency of printed dosage forms. Integrating these tools within a Quality-by-Design (QbD) framework can enhance process understanding, control variability, and minimise risk. Regulatory implementation and technological innovation remain essential for the broader clinical implementation of 3DP in pharmaceutical manufacturing. This review presents an overview of currently existing studies on PAT tools explored for non-destructive quality control across 3DP techniques, examines the correlation between Critical Process Parameters (CPPs), Critical Material Attributes (CMAs), and the Critical Quality Attributes (CQAs) of 3D-printed dosage forms within a QbD context, and outlines the current regulatory landscape alongside key limitations and future directions for the broader integration of 3DP into pharmaceutical development and manufacturing. Current evidence shows that PAT application remains uneven across printing technologies and is predominantly directed at final product quality control, rather than the real-time process monitoring required for a fully closed-loop QbD framework. Existing spectroscopic models are largely restricted to single formulations, printers, and APIs, and the absence of standardised validation reporting and transferability assessments represents a key barrier to routine implementation. Full article

Background/Objectives: Diclofenac (DCF) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation management; however, their clinical significance is limited by poor aqueous solubility, short biological half-life, and dose-dependent gastrointestinal, renal, and cardiovascular adverse effects. Nanocarrier-based delivery systems have been extensively explored because they can enhance the apparent solubility of poorly water-soluble NSAIDs, provide controlled and sustained drug release, prolong systemic circulation, and improve drug localization at the site of action. By reducing peak plasma concentrations and off-target exposure, these systems may decrease dose-dependent gastrointestinal and systemic adverse effects while maintaining therapeutic efficacy. Most studies focus on optimizing formulation composition, while the manufacturing process is often treated as a secondary parameter. The research critically evaluates conventional and emerging fabrication methods for NSAID nanocarriers, using DCF as the principal reference compound, with emphasis on their impact on physicochemical characteristics, reproducibility, scalability, and translational potential. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science (2015–2026, with emphasis on 2022–2026) for DCF and NSAID-loaded submicron delivery systems reporting quantitative formulation data and clearly defined fabrication methods, resulting in a narrative review of approximately 375–395 eligible studies, comprising 75 DCF-specific studies and approximately 300–320 studies involving other NSAIDs that were included as representative surrogate systems when DCF-specific evidence was unavailable for particular fabrication approaches. The review followed Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. Studies were analyzed using a standardized seven-parameter framework including encapsulation efficiency, release profile, particle size control, polydispersity, scalability, reproducibility, and process complexity. Results: Batch-based techniques, such as thin-film hydration for chitosan-coated liposomal systems, consistently provide high encapsulation efficiency, sustained drug release, and good biocompatibility. However, these methods are often associated with batch-to-batch variability, operator dependence, and limited scalability. In contrast, continuous manufacturing approaches, including microfluidic mixing, nanostructured lipid carriers, and Quality-by-Design (QbD)–guided processes, demonstrate improved control over particle size distribution and polydispersity, enhanced reproducibility, and better scalability potential. Conclusions: Manufacturing methodology is an important determinant of DCF and NSAID nanocarrier performance alongside formulation composition. Continuous manufacturing approaches offer promising improvements in reproducibility, process control, and scalability, but current evidence remains uneven across different nanocarrier classes. Further standardized comparative studies are needed to support their broader translation into clinical applications. Full article

Background: Conventional ophthalmic eye drops have low bioavailability (<5%) and poor patient adherence, driving the development of sustained-release ophthalmic drug delivery systems. The lacrimal drainage system represents a unique anatomical site for minimally invasive depot formulations. Objective: To summarize and critically appraise punctal and intracanalicular drug delivery systems, occlusive devices, and in situ-forming hydrogels with respect to composition, release mechanisms, clinical efficacy, safety, and critical quality attributes (CQAs). Methods: A narrative literature review was conducted using PubMed, Scopus, Web of Science, Google Scholar, ClinicalTrials.gov, and patent/regulatory sources, including FDA materials and Google Patents, covering 2001–2026. Anatomical features, materials, active pharmaceutical ingredients, release profiles, and adverse events were analyzed. Results: Seventy-one sources were included. Occlusive plugs without an active pharmaceutical ingredient demonstrate premature expulsion in up to 57.4% of cases and bacterial colonization in 44%. Drug delivery systems provide release from 7 days (PEGDA hydrogels) to 3 months (Eximore, Ocular Therapeutix™). DEXTENZA^® (dexamethasone) is FDA-approved for postoperative inflammation, whereas pivotal trials of travoprost (OTX-TP) and latanoprost systems (L-PPDS, EXP-LP) did not demonstrate superiority over placebo or eye drops. In situ systems eliminate size-fitting requirements but face challenges related to gelation control and biodegradation. Conclusions: We propose the following candidate CQAs: retention (>80% over 4 weeks), swelling degree (30–60%), controlled burst release (<40% within 24 h), and mechanical compatibility. The proposed QTPP matrices for punctal, intracanalicular, and in situ systems may guide the development of ophthalmic drug delivery platforms. Full article

Background/Objectives: Tirzepatide is a dual GIP and GLP-1 receptor agonist indicated for the treatment of type 2 diabetes and obesity. Oral delivery of tirzepatide is limited by poor gastrointestinal permeability, pH-dependent solubility, and manufacturing challenges associated with high-dose absorption enhancers. Methods: This study developed an immediate-release oral tirzepatide tablet using a Quality by Design (QbD) approach. Sodium caprate (C10) was selected as the absorption enhancer based on acid-neutralizing capacity, Caco-2 permeability enhancement, and preliminary rat pharmacokinetic screening. Quality target product profile, critical quality attributes, preliminary hazard analysis, and failure mode and effects analysis identified binder/disintegrant ratios as critical material attributes and hammer milling conditions as critical process parameters. Face-centered central composite designs and multiple-response optimization (MRO) were applied to optimize dissolution, flowability, and tablet mechanical integrity. Results: The optimized binder/disintegrant composition produced benchmark-comparable dissolution profiles against oral semaglutide tablets in pH 1.2, 4.0, and 6.8 media, with f₂ values exceeding 50 for both C10 300 mg and 500 mg formulations. The optimized process yielded tablets with low friability (0.58%) and acceptable flowability (Carr’s index, 24). In beagle dogs, the C10 300 mg formulation achieved higher systemic exposure than the C10 500 mg formulation, with a C_max of 46.49 ± 23.79 ng/mL and AUC_last of 1261.03 ± 690.44 h·ng/mL. Conclusions: These results support C10-mediated oral tirzepatide delivery and QbD-based optimization for oral peptide tablets. Full article

Background/Objectives: Direct compression of cohesive powders is often challenged by poor flow, blend heterogeneity, and variable tablet quality. This study investigated how mixing time, fill level, and rotational speed affect the blending behavior and tablet properties of a sodium naproxen–calcium carbonate formulation and aimed to define a robust operating space for process optimization. Methods: Powder blends were prepared in a V-type mixer according to a central composite design and analyzed using response surface methodology. The effects of the three process parameters were evaluated through powder flow descriptors (angle of repose, angle of fall, and angle of difference) and tablet quality attributes, including thickness, mass, active pharmaceutical ingredient (API) content, and abrasiveness. Statistical significance was assessed by ANOVA, and a design space was established using predefined acceptance criteria. Results: Mixing time significantly affected the angle of difference, indicating changes in blend cohesiveness and flow uniformity, whereas fill level significantly influenced API content. Tablet thickness and mass remained relatively stable across the tested conditions. Abrasiveness showed the greatest numerical variability and tended to increase at high fill levels combined with short mixing times. Response surface analysis identified two acceptable operational regions that satisfied the quality criteria for blend homogeneity, API content, and abrasiveness. Conclusions: The studied process variables exerted selective, property-specific effects rather than uniform changes across all quality attributes. The results support QbD-based process design for cohesive direct-compression systems and show that robust tablet manufacture can be achieved within more than one operating window. Full article

Recently, the Quality by Design (QbD) principle has been implemented in the pharmaceutical industry to enhance product and process understanding through a science- and risk-based approach. This study aimed to apply QbD principles to the formulation development of felodipine push–pull osmotic pump (PPOP) capsules. The quality target product profile (QTPP) and critical quality attributes (CQAs) were established. A Box–Behnken experimental design was employed to optimize the formulation variables, including the amounts of Polyox WSR N80, Polyox WSR Coagulant, and sodium chloride, selected based on the initial risk assessment. Four responses were monitored: lag time, release rate and R² based on zero-order release kinetics, and drug release at 24 h. Results indicated that the optimal formulation consisted of 125 mg Polyox WSR N80, 26 mg Polyox WSR Coagulant, and 30 mg sodium chloride. This formulation met the predefined criteria for lag time (≤6 h) and release kinetics (R² ≥ 0.95), while drug release at 24 h remained below the target value (≥80%). Because most fitted response surface models were not statistically significant, the generated regression equations and response surfaces were interpreted qualitatively to identify formulation trends rather than as predictive models. Experimental verification showed reasonable consistency in overall response trends, although substantial deviations between predicted and observed values were observed for some responses, particularly drug release at 24 h. Therefore, the present work should be considered a formulation-development and QbD feasibility study rather than a definitive optimization study. These findings demonstrate that the QbD-based approach enabled systematic, multivariate optimization and design space establishment, providing a more structured framework for formulation refinement compared with prior exploratory development and supporting controlled drug release characteristics of felodipine PPOP capsules. Full article

Even though the functional food market has rapidly increased in recent years, the links between bioactive-rich formulations and consumers’ health benefit are not fully established, mainly because of insufficient consideration of food matrix effects. This review provides a comprehensive and integrated evaluation of how food matrix properties (structural and physicochemical) affect the bioaccessibility of plant bioactive compounds. Unlike many reviews that focus on a single nutrient approach, we highlight quantitative evidence of how bioaccessibility can be affected by matrix properties, illustrating the interactions between main food components (lipids, proteins, dietary fiber and minerals). This review integrates fragmented information among different areas of food and nutrition sciences, i.e., food structure, gastrointestinal science, mineral chemistry, protein chemistry, providing a holistic framework for Quality by Design (QbD) functional food development. Synergisms and antagonistic behaviors, threshold effects, and concentration-dependent behaviors are analyzed comparatively for the most common plant-derived bioactives, such as polyphenols, carotenoids, curcuminoids and minerals (iron, zinc and calcium). We propose a matrix-informed optimization as a prerequisite for credible health claims and sustainable plant-based nutrition strategies. This can ultimately serve as a foundation for next-generation functional food development based on bioaccessibility, supporting the central argument that functional food development should move from composition-based fortification to bioaccessibility-based matrix engineering. Full article

Phase-inversion in situ implants (PIISIs) represent a versatile polymer platform in which the rational choice of matrix former and solvent system directly governs the macroscopic properties of the resulting depot. This study applied a Quality by Design (QbD) approach to rationalize a bleached shellac–based PIISI, with particular focus on the physicochemical interactions between the polymer and the injection vehicle. Bleached shellac—a natural, low-cost, biodegradable oligomeric resin bearing –COOH, –OH, and ester functional groups—was selected as the matrix former and screened in seven neat solvents and five 1:1 binary combinations at 25% (m/m). Twelve formulations were evaluated against a predefined set of critical quality attributes, including injectability, phase-inversion kinetics, solvent diffusion volume, and implant structure (n = 5 per formulation; mean ± standard deviation (SD); one-way analysis of variance (ANOVA) with Tukey’s post hoc test, p < 0.05). Three lead solvent systems—propylene glycol/N-methylpyrrolidone (PG+NMP), PG/dimethyl sulfoxide (PG+DMSO), and DMSO/benzyl alcohol (DMSO+BA)—were identified as those providing an optimal balance between hydrogen-bond donor/acceptor solvation and controlled solvent extraction. In the second stage, shellac concentration (20–35%) was optimized, with 30% shellac in PG+NMP yielding the fastest phase inversion (~50 s), a structurally uniform matrix, and the lowest swelling (22%). A working mechanistic framework consistent with all observed critical quality attribute (CQA) trends in which solvent hydrogen-bond donor/acceptor balance and water miscibility govern implant architecture is proposed, and it is intended as a hypothesis-generating basis for the rational design of PIISI formulations; direct validation by spectroscopic, thermal-analytical, and biological methods is identified as the next step. The developed formulations are presented as a preliminary physicochemical platform; biological validation (in vitro cytocompatibility and inflammatory response assessment) is required before the system can be considered a validated formulation for dental drug delivery. Full article

Trimethyl chitosan (TMC)-coated alginate/dextran sulfate (ADS) nanoparticles were developed as mucoadhesive nanocarriers for oral insulin delivery using a Quality-by-Design strategy. In a first screening step, a two-level factorial design was applied to evaluate the influence of ADS concentration, TMC concentration, insulin concentration, and poloxamer^® concentration on particle size and encapsulation efficiency. The screening design identified the ADS-TMC pair as the main formulation parameter for particle size, while TMC and poloxamer^® were the most influential factors for encapsulation efficiency. In a second step, formulation optimization was performed using a three-factor, three-level Box–Behnken design in which ADS concentration, TMC concentration, and the degree of quaternization (DQ) of TMC were investigated as critical material attributes. Particle size, zeta potential, and in vitro mucoadhesion were selected as critical quality attributes. Across the Box–Behnken design, the experimental formulations showed particle sizes ranging from 316 to 1340 nm, zeta potentials between +17 and +39 mV, and mucin-binding values from 7 to 87%. Numerical optimization by Design-Expert^® desirability analysis identified an optimal formulation composed of 0.096% (w/v) ADS and 0.700% (w/v) TMC with 60% DQ. The model predicted a particle size of 316.24 nm, a zeta potential of +38.43 mV, and an in vitro mucoadhesion of 87.14%. Experimental confirmation yielded values of 330.79 nm, +37.09 mV, and 84.61%, respectively, with prediction errors below 5% for all responses. In simulated gastric medium, partial insulin leakage was observed during the first 120 min, whereas cumulative insulin release reached 54% after 5 h in simulated intestinal medium. These results demonstrate the usefulness of a QbD framework combined with desirability-based optimization for defining robust formulation conditions for mucoadhesive TMC-coated ADS nanoparticles intended for oral insulin delivery. Full article

Historically, pharmaceutical formulation development relied heavily on trial-and-error experimentation, which was useful for empirical progress but often provided limited mechanistic understanding and insufficient efficiency for increasingly complex drug products. The introduction of Design of Experiments (DoE) and Quality by Design (QbD) established a more systematic framework for studying formulation variables, manufacturing parameters, and Critical Quality Attributes (CQAs). Approaches such as factorial designs, response-surface methodology, and mixture designs have therefore become central to modern pharmaceutical development because they improve experimental efficiency and support the definition of design space. However, as formulations become more nonlinear, high-dimensional, and multi-objective, these classical approaches may no longer be sufficient on their own. This review examines the evolution of experimental design in pharmaceutical research, from one-factor-at-a-time experimentation to structured DoE/QbD strategies, and then to emerging intelligent optimization methods. Its central objective is to clarify when conventional DoE/QbD remains appropriate and when it should be complemented by machine learning, Bayesian optimization, digital twins, and closed-loop experimental systems. The review first summarizes the foundations and strengths of classical experimental design; then, it discusses its practical limitations in complex formulation settings, and finally evaluates how data-driven and hybrid approaches can extend pharmaceutical development. Evidence from tablets, capsules, nanocarriers, transdermal patches, and biotherapeutic systems suggests that intelligent optimization can improve predictive performance and experimental efficiency when used alongside, rather than instead of, established pharmaceutical development principles. Full article

Background: Fused deposition modeling (FDM) is one of the most well-known and often published methods for 3D-printed drug delivery systems. In early scientific reports, the active pharmaceutical ingredients were added by soaking, but later, a new milestone was established, after researchers started to manufacture their own filaments by hot-melt extrusion (HME). The number of publications covering this method has multiplied in the last decade, a wide range of natural and synthetic polymers have been tested with versatile active pharmaceutical ingredient components, and various printing parameters and their effects have been investigated. Objectives: In this review, we aim to synthesize how the available quality by design approaches and the scientific results established so far can facilitate the creation of a guideline for appropriate quality production of HME-FDM 3D-printed pharmaceuticals. Methods: Based on PRISMA 2020 guidelines, a systematic search of relevant publications from 2015 to 2025 was carried out using the PubMed database. Twenty-six articles were included, based on number of monitored parameters and methodological description. Reporting of important quality processes and material parameters was assessed. Results: HME, the FDM, and analytical testing experiences were compared and collected into three tables from the selected publications. In two different sections, the pharmacopeial dosage-form tests and the involvement of process analytical technologies (PAT) were also analyzed. We found that reporting of influential parameters is heterogenous, and lack of robust reporting schemes limits the development of QbD approaches. Conclusions: Regarding the data, trends were synthetized, and a guideline was created which is limited by inconsistent parameter reporting. Full article

Quality by design (QbD) is a systematic approach focused on achieving consistent, predictable quality based on predefined objectives. Unlike traditional methods, QbD prioritizes risk assessment and management, which significantly enhances the robustness of the analytical method. In this study, we initiated factor screening using a three-factor, two-level design to evaluate three independent variables: flow rate, pH, and mobile phase composition. To further investigate the interaction of these variables, we employed Central Composite Design (CCD). This allows us to apply response surface methodology to the Critical Analytical Attributes (CAAs), specifically retention time, peak area, and symmetry factor, by conforming to the method’s robustness. The combination of pregabalin and duloxetine hydrochloride (HCl) dosage form was determined using a straightforward, exact, specific, and accurate reverse-phase HPLC approach. The results showed retention times of 3.265 min and 4.318 min for duloxetine HCl and pregabalin, respectively. Pregabalin demonstrated linearity from 100 to 200 μg/mL (R² = 0.998), whilst duloxetine HCl demonstrated linearity between 20 and 120 μg/mL (R² = 0.997). Lower LOD values of 0.925 µg/mL and 0.853 μg/mL and LOQ values of 2.809 μg/mL and 2.587 μg/mL of pregabalin and duloxetine HCl, respectively, suggest good sensitivity for the technique. The drug content of the commercial formulation may thus be determined using the recommended method. This technique can be used for standard quality control studies to simultaneously estimate pregabalin and duloxetine HCl. The novelty of the present studies lies in the development of a robust RP-HPLC method for simultaneous estimation of pregabalin and duloxetine HCl using a systematic AQbD approach, enhancing robustness, reproducibility, and reliability, making it highly suitable for routine quality control and regulatory applications. Full article

Background/Objectives: A robust and scalable manufacturing framework for lipid-based nanocarriers remains a critical challenge, particularly for labile phytochemicals such as curcuminoids in turmeric. This study presents an integrated Quality by Design (QbD)-driven and Outcome-Based Design (ObD) strategy to establish a scalable, resource-efficient manufacturing process for curcuminoids-loaded nanostructured lipid carriers (NLCs). Methods: To overcome the limitations of conventional multivariate design of experiments (DOE), which require extensive experimental runs, a risk-based, knowledge-driven single-factor screening approach was employed. Guided by risk assessment tools, including Ishikawa diagrams and failure mode considerations, 12 representative processing conditions were selected to define the design space. Critical quality attributes (CQAs), namely, particle size, polydispersity index (PDI), and zeta potential, were predefined to establish a robust control strategy. A two-step homogenization process—high-shear homogenization (HSH) for pre-emulsification followed by high-pressure homogenization (HPH) for nanoscale refinement—was systematically optimized. Results: Multivariate data analysis using principal component analysis (PCA) and hierarchical cluster analysis (HCA) identified key critical process parameters (CPPs), particularly HSH speed, processing time, and HPH cycles, as dominant factors influencing nanoparticle characteristics. The optimized 1-h process enabled successful scale-up of NLCs from 100 g to 5000 g, demonstrating the capability to generate nanosized particles within 100–500 nm. The combined HSH–HPH approach produced smaller, more uniform nanoparticles with high encapsulation efficiency and physical stability, outperforming HSH alone. Conclusions: Overall, this study establishes a practical and industrially viable framework that integrates QbD principles with data-driven optimization tools, for enabling reliable translation from laboratories to semi-industrial production. Full article

Microalgae and cyanobacteria have emerged as platforms for producing recombinant biologics, vaccine antigens, and bioactive compounds of pharmaceutical interest. However, their translation beyond proof-of-concept remains limited by light-field heterogeneity, gas–liquid mass-transfer constraints, product instability, and matrix complexity, all of which affect recovery, selectivity, and batch comparability. This review synthesizes and organizes published evidence using a process-engineering framework organized around product class, product localization, upstream–downstream coupling, and photobioreactor scale-up. It further considers the role of Quality by Design (QbD), model-informed development, techno-economic assessment (TEA), and life cycle assessment (LCA) in route selection and quality-oriented process development. Across the reported routes, the dominant burden shifts from disruption and clarification in intracellular products to extracellular stability and time-to-capture in secreted products, whereas biomass-based formulations are governed by potency and stabilization consistency, and analog-rich metabolites by profile control and selective fractionation. Current limitations include the scarcity of models that incorporate quality attributes as explicit outputs, the incomplete representation of regulated manufacturing burdens in TEA and LCA, and the lack of minimal, reproducible analytical panels adapted to product class and matrix. By framing these organisms as pharmaceutical process platforms rather than as hosts assessed only by titer, this review provides an engineering basis for scale-up, route prioritization, and controllable manufacturing. Full article

Background: This study aimed to investigate, from a scientific and formulation perspective, an oral semaglutide tablet incorporating sodium caprate (C10) as an intestinal absorption enhancer and to optimize its formulation performance using a Quality by Design (QbD)-based approach. Semaglutide—a peptide-based therapeutic—provides effective glycemic control and weight reduction; however, its extremely low oral bioavailability has limited administration to subcutaneous injection. Although various attempts have been made to improve peptide absorption, achieving consistent delivery through oral routes remains a significant challenge due to enzymatic degradation and poor membrane permeability. Methods: To overcome these limitations, an absorption enhancer (sodium caprate) was incorporated to enhance oral absorption, and a Quality by Design (QbD)-based approach was applied to systematically guide formulation development. Following the definition of the Quality Target Product Profile and critical quality attributes, risk assessments (Preliminary Hazard Analysis and Failure Mode and Effects Analysis) were conducted to identify key formulation factors. A design of experiments approach was then employed to determine the optimal tablet composition. Results: Consequently, the resulting formulation met all predefined quality criteria, including hardness, disintegration, friability, and content uniformity. In addition, the in vitro dissolution profile demonstrated a release pattern comparable to that of the reference product, with similarity factor values of 74.4, 74.7, and 71.3 at pH 1.2, 4.0, and 6.8, respectively. Conclusions: These findings indicate that the formulation can achieve consistent and reproducible quality performance as an oral semaglutide dosage form. The QbD-based formulation design strategy presented in this study provides a robust and broadly applicable approach for developing oral delivery systems for peptide drugs, including semaglutide, and ultimately provides useful formulation insight for future peptide-based oral delivery research. Full article