Clinical applications and perspectives of circulating tumor DNA in gastric cancer.

Gastric cancer remains a leading cause of cancer-related death worldwide, largely due to inadequate screening methods, late diagnosis, and limited treatment options. Liquid biopsy has emerged as a promising non-invasive approach for cancer screening and prognosis by detecting circulating tumor components like circulating tumor DNA (ctDNA) in the blood. Numerous gastric cancer-specific ctDNA biomarkers have now been identified. CtDNA analysis provides insight into genetic and epigenetic alterations in tumors, holding promise for predicting treatment response and prognosis in gastric cancer patients. This review summarizes current research on ctDNA biology and detection technologies, while highlighting clinical applications of ctDNA for gastric cancer diagnosis, prognosis, and guiding treatment decisions. Current challenges and future perspectives for ctDNA analysis are also discussed.

Dual Functionality of Poloxamer 188 in Freeze-Dried Protein Formulations: A Stabilizer in Frozen Solutions and a Bulking Agent in Lyophiles.

Poloxamer 188 (P188) was hypothesized to be a dual functional excipient, (i) a stabilizer in frozen solution to prevent ice-surface-induced protein destabilization and (ii) a bulking agent to provide elegant lyophiles. Based on X-ray diffractometry and differential scanning calorimetry, sucrose, in a concentration-dependent manner, inhibited P188 crystallization during freeze-drying, while trehalose had no such effect. The recovery of lactate dehydrogenase (LDH), the model protein, was evaluated after reconstitution. While low LDH recovery (∼60%) was observed in the lyophiles prepared with P188, the addition of sugar improved the activity recovery to >85%. The secondary structure of LDH in the freeze-dried samples was assessed using infrared spectroscopy, and only moderate structural changes were observed in the lyophiles formulated with P188 and sugar. Thus, P188 can be a promising dual functional excipient in freeze-dried protein formulations. However, P188 alone does not function as a lyoprotectant and needs to be used in combination with a sugar.

Interlayer Potassium Single-Atom-Coordinated g-C3N4 for Significantly Boosted Visible Light Photocatalytic H2 Production.

In recent years, graphitic carbon nitride (g-C3N4) has attracted considerable attention because it includes earth-abundant carbon and nitrogen elements and exhibits good chemical and thermal stability owing to the strong covalent interaction in its conjugated layer structure. However, bulk g-C3N4 has some disadvantages of low specific surface area, poor light absorption, rapid recombination of photogenerated charge carriers, and insufficient active sites, which hinder its practical applications. In this study, we design and synthesize potassium single-atom (K SAs)-doped g-C3N4 porous nanosheets (CM-KX, where X represents the mass of KHP added) via supramolecular self-assembling and chemical cross-linking copolymerization strategies. The results show that the utilization of supramolecules as precursors can produce g-C3N4 nanosheets with reduced thickness, increased surface area, and abundant mesopores. In addition, the intercalation of K atoms within the g-C3N4 nitrogen pots through the formation of K-N bonds results in the reduction of the band gap and expansion of the visible-light absorption range. The optimized K-doped CM-K12 nanosheets achieve a specific surface area of 127 m2 g-1, which is 11.4 times larger than that of the pristine g-C3N4 nanosheets. Furthermore, the optimal CM-K12 sample exhibits the maximum H2 production rate of 127.78 µmol h-1 under visible light (λ ≥ 420 nm), which is nearly 23 times higher than that of bare g-C3N4. This significant improvement of photocatalytic activity is attributed to the synergistic effects of the mesoporous structure and K SAs doping, which effectively increase the specific surface area, improve the visible-light absorption capacity, and facilitate the separation and transfer of photogenerated electron-hole pairs. Besides, the optimal sample shows good chemical stability for 20 h in the recycling experiments. Density functional theory calculations confirm that the introduction of K SAs significantly boosts the adsorption energy for water and decreases the activation energy barrier for the reduction of water to hydrogen.

Polymeric Unimolecular CO Dehydrogenase Mimic with both Inner and Outer Spheres for Enhanced Photocatalytic CO2 Reduction in Aqueous Solution.

Inspired by carbon monoxide dehydrogenase (CODH), mimicking its inner and outer spheres is a promising strategy in CO2 reduction catalyst design. However, artificial CODH-like catalysts are generally limited to the inner sphere effect and only applicable in organic solvents or for electrocatalysis. Herein, an aqueous CODH mimic with both inner and outer spheres for photocatalysis is reported. In this polymeric unimolecular catalyst, the inner sphere is composed of cobalt porphyrin with four appended amido groups and the outer sphere consists of four poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) arms. Upon visible light irradiation (λ >420 nm), the as-prepared catalyst exhibits a turnover number (TONCO ) of 1731.2 in the reduction of CO2 into CO, which is comparable to most reported molecular catalysts in aqueous solution. The mechanism studies indicate that, in this water-dispersible and structurally well-defined CODH mimic, the cobalt porphyrin core serves as the catalysis center and the amido groups function as hydrogen-bonding pillars helping to stabilize the CO2 adduct intermediate, whereas the PDMAEMA shell renders both water solubility and a CO2 reservoir through reversibly capturing of CO2 . The present work has clarified the significance of coordination sphere effects for improving the aqueous photocatalytic CO2 reduction performance of CODH mimics.

Role of Poloxamer 188 in Preventing Ice-Surface-Induced Protein Destabilization during Freeze-Thawing.

The phase behavior of poloxamer 188 (P188) in aqueous solutions, characterized by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry, revealed solute crystallization during both freezing and thawing. Sucrose and trehalose inhibited P188 crystallization during freeze-thawing (FT). While trehalose inhibited P188 crystallization only during cooling, sucrose completely suppressed P188 crystallization during both cooling and heating. Lactate dehydrogenase (LDH) served as a model protein to evaluate the stabilizing effect of P188. The ability of P188, over a concentration range of 0.003-0.800% w/v, to prevent LDH (10 µg/mL) destabilization was evaluated. After five FT cycles, the aggregation behavior (by dynamic light scattering) and activity recovery were evaluated. While LDH alone was sensitive to interfacial stress, P188 at concentrations of ≥0.100% w/v stabilized the protein. However, as the surfactant concentration decreased, protein aggregation after FT increased. The addition of sugar (1.0% w/v; sucrose or trehalose) improved the stabilizing function of P188 at lower concentrations (≤0.010% w/v), possibly due to the inhibition of surfactant crystallization. Based on a comparison with the stabilization effect of polysorbate (both 20 and 80), it was evident that P188 could be a promising alternative surfactant in frozen protein formulations. However, when the surfactant concentration is low, the potential for P188 crystallization and the consequent compromise in its functionality warrant careful consideration.

Solid-State NMR Spectroscopy to Probe State and Phase Transitions in Frozen Solutions.

Freezing is commonly encountered during the processing and storage of biomacromolecule products. Therefore, understanding the phase and state transitions in pharmaceutical frozen solutions is crucial for the rational development of biopharmaceuticals. Solid-state nuclear magnetic resonance spectroscopy (ssNMR) was used to analyze solutions containing sodium phosphate buffer, histidine, and trehalose. Upon freezing, crystallization of disodium phosphate hydrogen dodecahydrate (Na2HPO4·12H2O, DPDH) and histidine was identified using 31P and 13C ssNMR, respectively, and confirmed by synchrotron X-ray diffractometry (SXRD). Using histidine as a molecular probe and based on the chemical shifts of atoms of interest, the pH of the freeze concentrate was measured. The unfrozen water content in freeze concentrates was quantified by 1H single pulse experiments. 13C-insensitive nuclei enhancement by polarization transfer (INEPT) and cross-polarization (CP) experiments were used as orthogonal tools to characterize the solutes in a "mobile" and a more "solid-like" state in the freeze-concentrated solutions, respectively. The above analyses were applied to a commercial monoclonal antibody (mAb) formulation of dupilumab. This work further establishes ssNMR spectroscopy as a highly capable biophysical tool to investigate the attributes of biopharmaceuticals and thereby provide insights into process optimization and formulation development.

Effects of Additives on the Physical Stability and Dissolution of Polymeric Amorphous Solid Dispersions: a Review.

Polymeric amorphous solid dispersion (ASD) is a popular approach for enhancing the solubility of poorly water-soluble drugs. However, achieving both physical stability and dissolution performance in an ASD prepared with a single polymer can be challenging. Therefore, a secondary excipient can be added. In this paper, we review three classes of additives that can be added internally to ASDs: (i) a second polymer, to form a ternary drug-polymer-polymer ASD, (ii) counterions, to facilitate in situ salt formation, and (iii) surfactants. In an ASD prepared with a combination of polymers, each polymer exerts a unique function, such as a stabilizer in the solid state and a crystallization inhibitor during dissolution. In situ salt formation in ASD usually leads to substantial increases in the glass transition temperature, contributing to improved physical stability. Surfactants can enhance the wettability of ASD particles, thereby promoting rapid drug release. However, their potential adverse effects on physical stability and dissolution, resulting from enhanced molecular mobility and competitive molecular interaction with the polymer, respectively, warrant careful consideration. Finally, we discuss the impact of magnesium stearate and inorganic salts, excipients added externally upon downstream processing, on the solid-state stability as well as the dissolution of ASD tablets.

Polydopamine-Induced Multilevel Engineering of Regenerated Silk Fibroin Fiber for Photothermal Conversion.

Solid photothermal materials with favorable biocompatibility and modifiable mechanical properties demonstrate obvious superiority and growing demand. In this work, polydopamine (PDA) induced functionalization of regenerated silk fibroin (RSF) fibers has satisfactory photothermal conversion ability and flexibility. Based on multilevel engineering, RSF solution containing PDA nanoparticles is wet spun to PDA-incorporating RSF (PDA@RSF) fibers, and then the fibers are coated with PDA via oxidative self-polymerization of dopamine to form PDA@RSF-PDA (PRP) fibers. During the wet spinning process, PDA is to adjust the mechanical properties of RSF by affecting its hierarchical structure. Meanwhile, coated PDA gives the PRP fibers extensive absorption of near-infrared light and sunlight, which is further fabricated into PRP fibrous membranes. The temperature of PRP fibrous membranes can be adjusted and increases to about 50 °C within 360 s under 808 nm laser irradiation with a power density of 0.6 W cm-2 , and PRP fibrous membranes exhibit effective photothermal cytotoxicity both in vitro and in vivo. Under the simulated sunlight, the temperature of PRP fiber increases to more than 200 °C from room temperature and the material can generate 4.5 V voltage when assembled with a differential thermal battery, which means that the material also has the potential for flexible wearable electronic devices.

Design of Ternary Amorphous Solid Dispersions for Enhanced Dissolution of Drug Combinations.

Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.

Antidepressant effects of cherry leaf decoction on a chronic unpredictable mild stress rat model based on the Glu/GABA-Gln metabolic loop.

Cherry leaves (Prunus pseudocerasus Lindl. [Rosaceae]), a traditional Chinese herbal medicine, can regulate the factors closely related to depression including inflammatory cytokines, oxidative stress and blood glucose level. However, the antidepressant effects of cherry leaves and underlying neuromodulatory mechanisms remain relatively have not been elucidated explicitly. The present study investigated the antidepressant effects of cherry leaf decoction (CLD). The underlying neuromodulatory mechanism was explored by examining the glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) metabolic loop. The chronic unpredictable mild stress (CUMS) rodent model was used in this study. The main flavonoids components of CLD were identified using high-performance liquid chromatography (HPLC). The antidepressant effects of CLD were assessed throughout behavioural tests including the bodyweight, sucrose preference test (SPT), forced swimming test (FPT) and tail suspension test (TST). Moreover, The baseline levels of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. The expression of proteins integrally involved in the Glu/GABA-Gln metabolic loop were observed and quantified by Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. This study found that CLD ameliorated depressive-like behaviours induced by CUMS. The increase of serum ACTH and CORT baseline levels induced by CUMS was also reversed after CLD intervention. Furthermore, CUMS reduced the expression of GAD65, GAD67, GLT-1, GS and GABAA and increased NMDAR1 levels in the rat hippocampus, which was normalized by CLD treatment. The findings demonstrated that CLD could ameliorate the depression-like behaviours induced by CUMS, potentially through the inhibition of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and the regulation of Glu/GABA-Gln metabolic loop.

The protective mechanism of resveratrol against hepatic injury induced by iron overload in mice.

Excessive iron deposition can produce toxicity. Liver, as the main storage site of iron, is more vulnerable to excessive iron than other organs. Many studies have found that Resveratrol (RES) can effectively eliminate oxygen free radicals and resist lipid peroxide damage. However, studies investigating the mechanism of how RES prevents liver injury induced by iron overload are few. This study aims to observe the protective effect of RES on liver injury induced by iron overload in mice. Mice, except for the control group, received an intraperitoneal injection of iron dextran (50 mg/kg) every morning. The L-RES and H-RES groups received intragastric administration of low- and high-concentration RES solutions (20 or 50 mg/kg). The deferoxamine (DFO) group was intraperitoneally injected with DFO (50 mg/kg), while the control and iron overload groups were intraperitoneally injected with the same amount of normal saline every afternoon. Two weeks after continuous administration, iron-overloaded mice treated with high and low doses of RES significantly improved liver injury (GOT and GPT) and decreased LDH activity and MDA content and increased SOD and GSH activities (P < 0.01). Morphological tests showed that RES treatment can reduce liver iron deposition and improve liver pathological changes in iron-overloaded mice. Furthermore, RES treatment caused a significant decrease in Ft expression (P < 0.01). In conclusion, RES can alleviate liver injury in iron-overloaded mice. The mechanism may be related to improve the antioxidant capacity and reduce excess iron in the liver.

Effects of surface diffusion in electrocatalytic CO2 reduction on Cu revealed by kinetic Monte Carlo simulations.

Kinetic Monte Carlo (KMC) methods are frequently used for mechanistic studies of thermally driven heterogeneous catalysis systems but are underused for electrocatalysis. Here, we develop a lattice KMC approach for electrocatalytic CO2 reduction. The work is motivated by a prior experimental report that performed electroreduction of a mixed feed of 12CO2 and 13CO on Cu; differences in the 13C content of C2 products ethylene and ethanol (Δ13C) were interpreted as evidence of site selectivity. The lattice KMC model considers the effect of surface diffusion on this system. In the limit of infinitely fast diffusion (mean-field approximation), the key intermediates 12CO* and 13CO* would be well mixed on the surface and no evidence of site selectivity could have been observed. Using a simple two-site model and adapting a previously reported microkinetic model, we assess the effects of diffusion on the relative isotope fractions in the products using the estimated surface diffusion rate of CO* from literature reports. We find that the size of the active sites and the total surface adsorbate coverage can have a large influence on the values of Δ13C that can be observed. Δ13C is less sensitive to the CO* diffusion rate as long as it is within the estimated range. We further offer possible methods to estimate surface distribution of intermediates and to predict intrinsic selectivity of active sites based on experimental observations. This work illustrates the importance of considering surface diffusion in the study of electrochemical CO2 reduction to multi-carbon products. Our approach is entirely based on a freely available open-source code, so will be readily adaptable to other electrocatalytic systems.

Influence of Crocetin, a Natural Carotenoid Dicarboxylic Acid in Saffron, on L-Type Ca2+ Current, Intracellular Ca2+ Handling and Contraction of Isolated Rat Cardiomyocytes.

Crocetin is a major bioactive ingredient in saffron (Crocus sativus L.) and has favorable cardiovascular effects. Here, the effects of crocetin on L-type Ca2+ current (ICa-L), contractility, and the Ca2+ transients of rat cardiomyocytes, were investigated via patch-clamp technique and the Ion Optix system. A 600 µg/mL dose of crocetin decreased ICa-L 31.50 ± 2.53% in normal myocytes and 35.56 ± 2.42% in ischemic myocytes, respectively. The current voltage nexus of the calcium current, the reversal of the calcium current, and the activation/deactivation of the calcium current was not changed. At 600 µg/mL, crocetin abated cell shortening by 28.6 ± 2.31%, with a decrease in the time to 50% of the peak and a decrease in the time to 50% of the baseline. At 600 µg/mL, crocetin abated the crest value of the ephemeral Ca2+ by 31.87 ± 2.57%. The time to half maximal of Ca2+ peak and the time constant of decay of Ca2+ transient were both reduced. Our results suggest that crocetin inhibits L-type Ca2+ channels, causing decreased intracellular Ca2+ concentration and contractility in adult rat ventricular myocytes. These findings reveal crocetin's potential use as a calcium channel antagonist for the treatment of cardiovascular disease.

Large-Area 3D Hierarchical Superstructures Assembled from Colloidal Nanoparticles.

Assembling nanosized building blocks into macroscopic 3D complex structures is challenging. Here, nanosized metal and semiconductor building blocks with a variety of sizes and shapes (spheres, stars, and rods) are successfully assembled into a broad range of hierarchical (nanometer to micrometer) assemblies of functional materials in centimeter size using butterfly wings as templates. This is achieved by the introduction of steric hindrance to the assembly process, which compensates for attraction from the environmentally sensitive hydrogen bonds and prevents the aggregation of nanosized building blocks. Of these materials, Au nanostar assemblies show a superior enhancement in surface-enhanced Raman scattering (SERS) performance (rhodamine 6G, 1506 cm-1 ) under 532, 633, and 780 nm excitation-this is 3.1-4.4, 3.6-3.9, and 2.9-47.3 folds surpassing Au nanosphere assemblies and commercial SERS substrates (Q-SERS), respectively. This method provides a versatile route for the assembly of various nanosized building blocks into different 3D superstructures and for the construction of hybrid nanomaterials and nanocomposites.

Fluorine-Free Synthesis of High-Purity Ti3 C2 Tx (T=OH, O) via Alkali Treatment.

MXenes, 2D compounds generated from layered bulk materials, have attracted significant attention in energy-related fields. However, most syntheses involve HF, which is highly corrosive and harmful to lithium-ion battery and supercapacitor performance. Here an alkali-assisted hydrothermal method is used to prepare a MXene Ti3 C2 Tx (T=OH, O). This route is inspired from a Bayer process used in bauxite refining. The process is free of fluorine and yields multilayer Ti3 C2 Tx with ca. 92 wt % in purity (using 27.5 m NaOH, 270 °C). Without the F terminations, the resulting Ti3 C2 Tx film electrode (ca. 52 µm in thickness, ca. 1.63 g cm-3 in density) is 314 F g-1 via gravimetric capacitance at 2 mV s-1 in 1 m H2 SO4 . This surpasses (by ca. 214 %) that of the multilayer Ti3 C2 Tx prepared via HF treatments. This fluorine-free method also provides an alkali-etching strategy for exploring new MXenes for which the interlayer amphoteric/acidic atoms from the pristine MAX phase must be removed.

Effect of surfactants on lactate dehydrogenase aqueous solutions: A comparative study of poloxamer 188, polysorbate 20 and 80.

The effect of three commonly used surfactants, poloxamer 188 (P188), polysorbate 20 and 80 (PS20 and PS80), on the stability of a model protein, lactate dehydrogenase (LDH), was compared in aqueous solutions. In the absence of a surfactant, protein solution revealed a gradual decrease in surface tension as a function of time. The addition of surfactant resulted in a rapid decrease in the surface tension. This suggested that the surface behavior was dictated by the surfactant. PS20 and PS80 were more effective than P188 in preventing LDH adsorption on the solution surface. The advantage of polysorbates over P188 was also evident from the higher LDH tetramer recovery after shaking (room temperature, 30 h), especially when the surfactants were used at concentrations ≤ 0.01% w/v. However, PS20 and PS80 accelerated protein unfolding during quiescent storage at 40 °C. Based on circular dichroism results, polysorbates perturbed the tertiary structure of LDH but not the secondary structure, while P188 did not impact the protein structure and stability. Polysorbates were more effective in stabilizing LDH against mechanical stress (shaking), but their adverse effects on protein conformational stability need to be carefully evaluated.

Probing Chemical Equilibrium in Frozen Sodium Phosphate Buffer Solution by 31P Solid-State NMR.

Phosphate buffers are crucial for cryopreservative stability in pharmaceuticals, food processing, biomedical sciences, and biology. However, their freeze concentrates lack quantitative characterization, especially regarding the physicochemical properties of phosphate salt species in equilibrium at subzero temperatures. This study employs 31P solid-state NMR (ssNMR) to analyze frozen sodium phosphate (NaP) solutions, providing insights into phase composition, ionic strength, and pH. For the first time, we have directly quantified phosphate species in frozen NaP buffer, including crystallized disodium phosphate dodecahydrate (Na2HPO4·12H2O) content and the concentrations of H2PO4- and HPO42- in the freeze concentrate. This enabled the calculation of the pH as well as the ionic strength in the freeze concentrate. Trehalose effectively mitigated pH shifts in buffer solutions by preventing the selective crystallization of salt, a spectroscopic phenomenon not previously observed experimentally.

Stabilization effects of saccharides in protein formulations: A review of sucrose, trehalose, cyclodextrins and dextrans.

Saccharides are a popular group of stabilizers in liquid, frozen and freeze dried protein formulations. The current work reviewed the stabilization mechanisms of three groups of saccharides: (i) Disaccharides, specifically sucrose and trehalose; (ii) cyclodextrins (CDs), a class of cyclic oligosaccharides; and (iii) dextrans, a class of polysaccharides. Compared to sucrose, trehalose exhibits a more pronounced preferential exclusion effect in liquid protein formulations, due to its stronger interaction with water molecules. However, trehalose obtains higher phase separation and crystallization propensity in frozen solutions, resulting in the loss of its stabilization function. In lyophilized formulations, sucrose has a higher crystallization propensity. Besides, its glass matrix is less homogeneous than that of trehalose, thus undermining its lyoprotectant function. Nevertheless, the hygroscopic nature of trehalose may result in high water absorption upon storage. Among all the CDs, the ß form is believed to have stronger interactions with proteins than the α- and γ-CDs. However, the stabilization effect, brought about by CD-protein interactions, is case-by-case - in some examples, such interactions can promote protein destabilization. The stabilization effect of hydroxypropyl-ß-cyclodextrin (HPßCD) has been extensively studied. Due to its amphiphilic nature, it can act as a surface-active agent in preventing interfacial stresses. Besides, it is a dual functional excipient in freeze dried formulations, acting as an amorphous bulking agent and lyoprotectant. Finally, dextrans, when combined with sucrose or trehalose, can be used to produce stable freeze dried protein formulations. A strong stabilization effect can be realized by low molecular weight dextrans. However, the terminal glucose in dextrans yields protein glycation, which warrants extra caution during formulation development.

Development of multiple structured extended release tablets via hot melt extrusion and dual-nozzle fused deposition modeling 3D printing.

The study aims to fabricate extended release (ER) tablets using a dual-nozzle fused deposition modeling (FDM) three-dimensional (3D) printing technology based on hot melt extrusion (HME), using caffeine as the model compound. Three different ER tablets were developed, which obtained "delayed-release", "rapid-sustained release", and "release-lag-release" properties. Each type of tablet was printed with two different formulations. A novel printing method was employed in this study, which is to push the HME filament from behind with polylactic acid (PLA) to prevent sample damage by gears during the printing process. Powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) results showed that caffeine was predominately amorphous in the final tablets. The dissolution of 3D printed tablets was assessed using a USP-II dissolution apparatus. ER tablets containing PVA dissolved faster than those developed with Kollicoat IR. Overall, this study revealed that ER tablets were successfully manufactured through HME paired with dual-nozzle FDM 3D printing and demonstrated the power of 3D printing in developing multi-layer tablets with complex structures.

Hydrolysis of Cellulose Acetate Phthalate and Hydroxypropyl Methylcellulose Phthalate in Amorphous Solid Dispersions.

The preparation of amorphous solid dispersions (ASDs) represents a promising strategy for addressing the solubility limitations of poorly soluble drugs, facilitating enhanced oral absorption. Acidic polymers such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HPMCP) have emerged as effective carriers for ASDs. Although the hydrolytic degradation of these polymers has been documented, its impact on the stability of ASDs has not been systematically investigated. This research aimed to explore the potential hydrolysis of CAP and HPMCP and how it influences the stability of ASDs containing ketoconazole (KTZ), at drug loadings of 10 % and 50 %. Our study utilized thermal analysis, infrared spectroscopy, and evaluations of physical and chemical stability. The results revealed that although KTZ remained physically stable in all ASDs over 60 days under various stability conditions, the emergence of crystalline phthalic acid (PA), a byproduct of polymer hydrolysis, was observed at elevated temperatures and relative humidity levels. The acidic microenvironment fostered by the release of PA further catalyzed drug chemical degradation. This study underscores the susceptibility of CAP and HPMCP to hydrolytic degradation, highlighting the inherent risk of PA-induced drug degradation, particularly for acid-labile compounds. These insights into the understanding of polymer hydrolysis in ASDs pave the way for the development of targeted approaches to safeguard drug stability and optimize pharmaceutical formulations for enhanced bioavailability, efficacy, and safety.