Search Results (161)

Background: Precision medicine refers to the formulation of personalized drug regimens according to the individual characteristics of patients to achieve optimal efficacy and minimize adverse reactions. Additive manufacturing (AM), also known as three-dimensional (3D) printing, has emerged as an optimal solution for precision drug delivery, enabling customizable and the fabrication of multifunctional structures with precise control over morphology and release behavior in pharmaceutics. However, the influence of 3D printing parameters on the printed tablets, especially regarding in vitro and in vivo performance, remains poorly understood, limiting the optimization of manufacturing processes for controlled-release profiles. Objective: To establish the fabrication process of 3D-printed controlled-release tablets via comprehensively understanding the printing parameters using fused deposition modeling (FDM) combined with hot-melt extrusion (HME) technologies. HPMC-AS/HPC-EF was used as the drug delivery matrix and carbamazepine (CBZ) was used as a model drug to investigate the in vitro drug delivery performance of the printed tablets. Methodology: Thermogravimetric analysis (TGA) was employed to assess the thermal compatibility of CBZ with HPMC-AS/HPC-EF excipients up to 230 °C, surpassing typical processing temperatures (160–200 °C). The formation of stable amorphous solid dispersions (ASDs) was validated using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (PLM), and powder X-ray diffraction (PXRD). A 15-group full factorial design was then used to evaluate the effects of the fan speed (20–100%), platform temperature (40–80 °C), and printing speed (20–100 mm/s) on the tablet properties. Response surface modeling (RSM) with inverse square-root transformation was applied to analyze the dissolution kinetics, specifically t_50% (time for 50% drug release) and Q_4h (drug released at 4 h). Results: TGA confirmed the thermal compatibility of CBZ with HPMC-AS/HPC-EF, enabling stable ASD formation validated by DSC, PLM, and PXRD. The full factorial design revealed that printing speed was the dominant parameter governing dissolution behavior, with high speeds accelerating release and low speeds prolonging release through porosity-modulated diffusion control. RSM quadratic models showed optimal fits for t_50% (R² = 0.9936) and Q_4h (R² = 0.9019), highlighting the predictability of release kinetics via process parameter tuning. This work demonstrates the adaptability of polymer composite AM for tailoring drug release profiles, balancing mechanical integrity, release kinetics, and manufacturing scalability to advance multifunctional 3D-printed drug delivery devices in pharmaceutics. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, temperature control, and integration into continuous manufacturing. This study investigates vertical HME as an innovative approach in order to optimize drug polymer interactions and generate stable amorphous dispersions with controlled release behavior. Methods: Extrusion trials were conducted using a vertical hot-melt extruder developed by Rondol Industrie (Nancy, France). Acetylsalicylic acid (ASA) supplied by Seqens (Écully, France) was used as a model API and processed with Soluplus^® and Kollidon^® 12 PF (BASF, Ludwigshafen, Germany). Various process parameters (temperature, screw speed, screw profile) were explored. The extrudates were characterized by powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) to evaluate crystallinity and microstructure. In vitro dissolution tests were performed under sink conditions using USP Apparatus II to assess drug release profiles. Results: Vertical HME enabled the formation of homogeneous amorphous solid dispersions. PXRD confirmed the absence of residual crystallinity, and SAXS revealed nanostructural changes in the polymer matrix influenced by drug loading and thermal input. In vitro dissolution demonstrated enhanced drug release rates compared to crystalline ASA, with good reproducibility. Conclusions: Vertical HME provides a compact, cleanable, and modular platform that supports the development of stable amorphous dispersions with controlled release. It represents a robust and versatile solution for pharmaceutical innovation, with strong potential for cost-efficient continuous manufacturing and industrial-scale adoption. Full article

The burgeoning crisis of plastic waste accumulation necessitates innovative approaches towards sustainable packaging solutions. Polylactic acid (PLA), a leading biopolymer, emerges as a promising candidate in this realm, especially for environmentally friendly packaging. PLA is renowned for its compostable properties, offering a strategic avenue to mitigate plastic waste. However, its dependency on specific industrial composting conditions, characterized by elevated temperatures, humidity, and thermophilic microbes, limits its utility for household composting. This study aims to bridge the research gap in PLA’s recyclability and explore its feasibility in mechanical recycling processes. The research focuses on assessing the mechanical characteristics of PLA and PLA-based composites post-recycling. Specifically, we examined the effects of two extrusion methods—conical and parallel—on PLA and its composites containing 20 wt.% basalt fibers (BF). The recycling process encompassed repeated cycles of hot melt extrusion (HME), followed by mechanical grinding to produce granules. These granules were then subjected to injection moulding (IM) after 1, 3 and 5 recycling cycles. The tensile properties of the resulting IM-produced bars provided insights into the material’s durability and stability. The findings reveal that both PLA and PLA/BF composites retain their mechanical integrity through up to 5 cycles of mechanical recycling. This resilience underscores PLA’s potential for integration into existing recycling streams, addressing the dual challenges of environmental sustainability and waste management. The study contributes to the broader understanding of PLA’s lifecycle and opens new possibilities for its application in eco-friendly packaging, beyond the limits of composting. The implications of these findings extend towards enhancing the circularity of biopolymers and reducing the environmental footprint of plastic packaging. Full article

Thermokinetic characterization of amorphous carbamazepine was performed utilizing non-isothermal differential scanning calorimetry (DSC) and thermogravimetry (TGA). Structural relaxation of the amorphous matrix was described in terms of the Tool–Narayanaswamy–Moynihan model with the following parameters: Δh* ≈ 200–300 kJ·mol⁻¹, β = 0.57, x = 0.44. The crystallization of the amorphous phase was modeled using complex Šesták–Berggren kinetics, which incorporates temperature-dependent activation energy and degree of autocatalysis. The activation energy of the crystal growth was determined to be >320 kJ·mol⁻¹ at the glass transition temperature (T_g). Owing to such a high value, the amorphous carbamazepine is stable at T_g, allowing for extensive processing of the amorphous phase (e.g., self-healing of the quench-induced mechanical defects or internal stress). A discussion was conducted regarding the converse relation between the activation energies of relaxation and crystal growth, which is possibly responsible for the absence of sub-T_g crystal growth modes. The high-temperature thermal decomposition of carbamazepine proceeds via multistep kinetics, identically in both an inert and an oxidizing atmosphere. A complex reaction mechanism, consisting of a series of consecutive and competing reactions, was proposed to explain the second decomposition step, which exhibited a temporary mass increase. Whereas a negligible degree of carbamazepine degradation was predicted for the temperature characteristic of the pharmaceutical hot-melt extrusion (~150 °C), the degradation risk during the pharmaceutical 3D printing was calculated to be considerably higher (1–2% mass loss at temperatures 190–200 °C). Full article

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles. Full article

The immiscibility of thermoplastic starch (TPS) and polybutylene succinate (PBS) complicates the thermal processing of these materials. This study provides the first comparative assessment of two compatibilizers with differing reaction mechanisms, Joncryl^® ADR 4468 and epoxidized linseed oil (ELO), for the optimization of biobased TPS/PBS blends. A total of 13 batches, varying in compatibilizer and blend composition, were processed via hot melt extrusion and injection molding to produce pellets. Blends were analyzed using tensile and impact testing, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), rheology, and scanning electron microscopy (SEM). The findings suggest that both compatibilizers can improve the compatibility of these blends, as evidenced by higher glass transition temperatures (T_g) compared to the reference batch (100-0-N/A). Joncryl^® ADR 4468 batches exhibit superior tensile strength and Young’s moduli, while ELO batches demonstrate greater elongation at break. The enhanced processability observed in Joncryl^® ADR 4468 is attributed to the increased polymer chain entanglement and molecular weight, whereas ELO facilitates greater chain mobility due to its plasticizing effect. These differences arise from the distinct mechanisms of action: Joncryl^® ADR 4468 promotes chain extension and crosslinking, whereas ELO mainly enhances flexibility through plasticization. Overall, this study provides a comparative assessment of these compatibilizers in TPS/PBS blends, laying the groundwork for future investigations into optimizing compatibilizer concentration and blend composition. Full article

As the severe environmental impacts of plastic pollution demand determined action, the European Union (EU) has included recycling at the core of its policies. Consequently, evolving jurisdiction now aims to achieve a recycling rate of 65% for non-PET plastic bottles by 2040. However, the widespread use of post-consumer high-density polyethylene (rPE-HD) recyclates in household chemical containers is still limited by PP contamination, poor mechanical properties, and low environmental stress cracking resistance (ESCR). Although previous studies have explored the improvement of regranulate properties through additives, few have examined whether reducing the variety of extrusion blow-moulded PE-HD packaging could offer similar benefits. Therefore, two sorted fractions of rPE-HD hollow bodies were processed into regranulates under industrial conditions, including hot washing, extrusion, and deodorisation. Subsequently, both materials underwent comprehensive characterisation regarding their composition and performance. The opaque material, which was sourced from milk bottles in the UK, exhibited greater homogeneity with minor impurities, leading to improved ductility and melt strain hardening at moderate strain rates compared to the mixed material stream, which contained approximately 2.5% PP contamination. However, both rPE-HD recyclates exhibited similar short-term creep behaviour, relatively low strain hardening moduli, and were almost devoid of inorganic particles. Considering the sum of the investigated properties, melt blending with suitable virgin material is likely one of the most effective options to maximise regranulate utilisation in hollow bodies, followed by recycling-oriented packaging design (e.g., for efficient sorting), and the employment of advanced sorting technology. Full article

Background/Objectives: Triamcinolone acetonide (TA), a poorly water-soluble corticosteroid, presents formulation challenges due to limited membrane permeability. This study aimed to identify suitable drug–polymer–plasticizer systems for TA using combined theoretical and experimental methods. Methods: Using Hansen solubility parameters, seven hot-melt extrusion (HME)-grade polymers and four plasticizers were initially screened for miscibility with TA. Based on Δδt values, four polymers—Eudragit^® L100 (EUD), Parteck^® MXP (PVA), Plasdone^® S-630 (PVPVA), and Aquasolve™ AS-MG (HPMCAS)—along with triethyl citrate (TEC), were selected for experimental evaluation. Differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy assessed thermal behavior, miscibility, and chemical compatibility. Results: Amorphous TA content was highest with EUD (81.1%), followed by PVA (67.5%), PVPVA (45.6%), and HPMCAS (8.5%). Thermal incompatibility and TEC evaporation were observed in PVA, PVPVA, and HPMCAS systems. FTIR suggested TEC should be avoided in melt-based formulations with PVA and PVPVA due to PVA degradation and partial TA oxidation. No significant interactions were detected in HPMCAS samples heated to 220 °C, aligning with theoretical predictions. In contrast, the EUD–TEC system showed limited chemical reactivity and maintained TA’s structural integrity. Infrared bands at 1758 and 1802 cm⁻¹ indicated minor anhydride formation above 160 °C with partial TEC evaporation. Conclusions: EUD/TEC were identified as a promising combination for the HME processing of TA. This work supports the rational formulation of stable amorphous systems for thermolabile drugs with poor solubility. Full article

Objectives: Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk management, and limited process analytical technology (PAT) integration hinder its industrial application. This study aimed to develop a proof-of-concept HME platform for CCs, assess process risks, and evaluate PAT-enabled monitoring to facilitate robust production. Methods: Using carbamazepine (CBZ) and nicotinamide (NIC) as model compounds, an HME platform compatible with PAT tools was established. A systematic risk assessment identified five key risk domains: materials, machinery, measurement, methods, and other factors. A Box–Behnken design of experiments (DoE) evaluated the impact of screw speed, temperature, and mixing sections on CC quality. Near-infrared (NIR) spectroscopy monitored CBZ-NIC co-crystal formation in real time during HME process. Results: DoE revealed temperature and number of mixing sections significantly influenced particle size (D₅₀: 2.0–4.0 μm), while screw speed affected efficiency. NIR spectroscopy detected a unique CC absorption peak at 5008.3 cm⁻¹, enabling real-time structural monitoring with high accuracy (R² = 0.9999). Risk assessment highlighted material attributes, process parameters, and equipment design as critical factors affecting CC formation. All experimental batches yielded ≥ 94% pure CCs with no residual starting materials, demonstrating process reproducibility and robustness. Conclusions: Overall, this work successfully established a continuous hot-melt extrusion (HME) process for manufacturing CBZ-NIC co-crystals, offering critical insights into material, equipment, and process parameters while implementing robust in-line NIR monitoring for real-time quality control. Additionally, this work provides interpretable insights and serves as a basis for future machine learning (ML)-driven studies. Full article

Zinc (Zn), copper (Cu), iron (Fe), manganese (Mn), as well as selenium (Se) are vital trace minerals supplemented for pigs and broilers that support their biological activities. In animals, trace minerals demonstrate a variety of effects that promote growth and improve health, depending on the form of supplementation (such as inorganic, organic, or nano forms) and the supplementation levels. Inorganic minerals with low bioavailability are excreted into the environment through feces, causing pollution. In contrast, organic minerals, which have higher bioavailability, can reduce mineral excretion into the environment. However, their high cost and the complexity of chelate analysis limit the complete replacement of inorganic minerals. Nano minerals, with their high biological surface area, exhibit enhanced bioavailability. Nonetheless, their effects are inconsistent, and their optimal usage levels have not been clearly established. Hot Melt Extrusion (HME) technology serves as an innovative mineral processing technology tailored to pigs and broilers. Minerals processed through HME achieve nanoscale size, providing a larger surface area and improved bioavailability. Additionally, heat and pressure reduce toxicity, allowing for a lower usage level of minerals compared to inorganic, organic, or nano minerals, while offering various advantages. This review aims to explore forms and inclusion levels of trace minerals in pigs and broilers, as well as to discuss HME-minerals generated through HME technology. Full article

Background/Objectives: The oral delivery of large-molecule drugs remains challenging due to poor solubility, perdemeability, and stability in the gastrointestinal tract, resulting in low bioavailability. In this study, hot melt extrusion (HME) was investigated as a solvent-free manufacturing technique for mucoadhesive bilayer films to improve drug absorption. Methods: Polyvinyl alcohol (PVA) and polyethylene oxide (PEO) were evaluated as mucoadhesive film-forming polymers, in conjunction with Eudragit^® RS as a water-insoluble backing layer. Paracetamol and lactase were utilized as small and large molecule APIs, respectively. The resulting films were assembled into bilayer film samples and examined for mechanical properties, mucoadhesion, and dissolution behavior. A novel dissolution model was developed to evaluate unidirectional drug transport. Results: The results showed that bilayer films could be successfully fabricated using HME, with different mechanical properties depending on the polymer and drug content. Tests with the newly developed dissolution model showed a unidirectional drug release. The model also confirmed the need for biorelevant dissolution test systems because of a better differentiation between polymers compared to standard test methods such as the paddle-over-disk method. Furthermore, the investigation revealed that the activity of enzymes was retained after extrusion, thus indicating the feasibility of processing biologics. Conclusions: This study highlights the potential of HME to produce bilayer films as an innovative drug delivery platform offering improved bioavailability for both small and large molecules. Full article

Background: This study demonstrates the application of the sequential design of experiments (DoE) approach within the quality by design (QbD) framework to optimize extrusion processes through screening, optimization, and robustness testing. Methods: An in-line UV–Vis process analytical technology (PAT) system was successfully employed to monitor critical quality attributes (CQAs) of piroxicam amorphous solid dispersion (ASD) extrusion products, specifically lightness (L*). Results: L* measurement proved highly effective for ensuring the quality and uniformity of ASDs, offering real-time insights into their physical appearance and process stability. Small variations in L* acted as early indicators of processing issues, such as phase separation or bubble formation, enabling timely intervention. This straightforward and rapid technique supports real-time process monitoring and control, allowing automated adjustments to maintain product consistency and quality. By adopting this strategy, manufacturers can minimize variability, reduce waste, and ensure adherence to quality target product profiles (QTPPs). Conclusions: Overall, this study highlights the value of in-line UV–Vis spectroscopy as a PAT tool in hot melt extrusion, enhancing CQA assessment and advancing the efficiency and reliability of ASD manufacturing. Full article

Background: Curcumin and hesperetin are plant polyphenols known for their poor solubility. To address this limitation, we prepared amorphous PVP K30–phosphatidylcholine dispersions via hot-melt extrusion. Methods: This study aimed to evaluate the effects of the amounts of active ingredients and phosphatidylcholine, as well as the process temperature, on the performance of the dispersions. A Box–Behnken design was employed to assess these factors. Solid-state characterization and biopharmaceutical studies were then conducted. X-ray powder diffraction (XRPD) was used to confirm the amorphous nature of the dispersions, while differential scanning calorimetry (DSC) provided insight into the miscibility of the systems. Fourier-transform infrared spectroscopy (FTIR) was employed to assess the intermolecular interactions. The apparent solubility and dissolution profiles of the systems were studied in phosphate buffer at pH 6.8. In vitro permeability across the gastrointestinal tract and blood–brain barrier was evaluated using the parallel artificial membrane permeability assay. Results: The quantities of polyphenols and phospholipids were identified as significant factors influencing the biopharmaceutical performance of the systems. Solid-state analysis confirmed the formation of amorphous dispersions and the development of interactions among components. Notably, a significant improvement in solubility was observed, with formulations exhibiting distinct release patterns for the active compounds. Furthermore, the in vitro permeability through the gastrointestinal tract and blood–brain barrier was enhanced. Conclusions: The findings suggest that amorphous PVP K30–phosphatidylcholine dispersions have the potential to improve the biopharmaceutical properties of curcumin and hesperetin. Full article

In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that “one size fits all” is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives. Full article