A novel honeycomb-like 3D-printed device for rotating-disk sorptive extraction of organochlorine and organophosphorus pesticides from environmental water samples.

In this study, 3D-printing based on fused-deposition modeling (FDM) was employed as simple and cost-effective strategy to fabricate a novel format of rotating-disk sorptive devices. As proof-of-concept, twenty organochlorine and organophosphorus pesticides were determined in water samples through rotating-disk sorptive extraction (RDSE) using honeycomb-like 3D-printed disks followed by gas chromatography coupled to mass spectrometry (GC-MS). The devices that exhibited the best performance were comprised of polyamide + 15 % carbon fiber (PA + 15 % C) with the morphology being evaluated through X-ray microtomography. The optimized extraction conditions consisted of 120 min of extraction using 20 mL of sample at stirring speed of 1100 rpm. Additionally, liquid desorption using 800 µL of acetonitrile for 25 min at stirring speed of 1100 rpm provided the best response. Importantly, the methodology also exhibited high throughput since an extraction/desorption platform that permitted up to fifteen simultaneous extractions was employed. The method was validated, providing coefficients of determination higher than 0.9706 for all analytes; limits of detection (LODs) and limits of quantification (LOQs) ranged from 0.15 to 3.03 µg L-1 and from 0.5 to 10.0 µg L-1, respectively. Intraday precision ranged from 4.01 to 18.73 %, and interday precision varied from 4.83 to 20.00 %. Accuracy was examined through relative recoveries and ranged from 73.29 to 121.51 %. This method was successfully applied to analyze nine groundwater samples from monitoring wells of gas stations in São Paulo. Moreover, the greenness was assessed through AGREEprep metrics, and an overall score of 0.69 was obtained indicating that the method proposed can be considered sustainable.

Ivermectin-Loaded Mesoporous Silica and Polymeric Nanocapsules: Impact on Drug Loading, In Vitro Solubility Enhancement, and Release Performance.

Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM's high partition coefficient value (log P) on its drug release performance, it is relevant to explore whether IVM nanoencapsulation in organic or inorganic nanoparticles would afford comparable enhanced aqueous solubility. To date, the use of inorganic nanoparticles remains an unexplored approach for delivering IVM. Therefore, here we loaded IVM in mesoporous silica particles (IVM-MCM), as inorganic nanomaterial, and in well-known poly(ε-caprolactone) nanocapsules (IVM-NC). IVM-MCM had a well-organized hexagonal mesoporous structure, reduced surface area, and high drug loading of 10% w/w. IVM-NC had a nanometric mean size (196 nm), high encapsulation efficiency (100%), physicochemical stability as an aqueous dispersion, and drug loading of 0.1% w/w. Despite differing characteristics, both nanoencapsulated forms enhance IVM's aqueous intrinsic solubility compared to a crystalline IVM: after 72 h, IVM-MCM and IVM-NC achieve 72% and 78% releases through a dialysis bag, whereas crystalline IVM dispersion achieves only 40% drug diffusion. These results show distinct controlled release profiles, where IVM-NC provides a deeper sustained controlled release over the whole experiment compared to the inorganic nanomaterial (IVM-MCM). Discussing differences, including drug loading and release kinetics, is crucial for optimizing IVM's therapeutic performance. The study design, combined with administration route plans and safety considerations for humans and animals, may expedite the rational optimization of IVM nanoformulations for swift clinical translation.

Magnetic Mesoporous Silica for Targeted Drug Delivery of Chloroquine: Synthesis, Characterization, and In Vitro Evaluation.

Malaria is a dangerous tropical disease, with high morbidity in developing countries. The responsible parasite has developed resistance to the existing drugs; therefore, new drug delivery systems are being studied to increase efficacy by targeting hemozoin, a parasite paramagnetic metabolite. Herein, magnetic mesoporous silica (magMCM) was synthesized using iron oxide particles dispersed in the silica structure for magnetically driven behavior. The X-ray diffractogram (XRD) and Mössbauer spectra show patterns corresponding to magnetite and maghemite. Furthermore, Mössbauer spectroscopy revealed superparamagnetic behavior, attributed to single magnetic domains in particles smaller than 10 nm. Even in the presence of iron oxide particles, the hexagonal structure of MCM is clearly identified in XRD (low-angle region) and the channels are visible in TEM images. The drug chloroquine (CQ) was encapsulated by incipient wetness impregnation (magMCM-CQ). The N2 adsorption-desorption isotherms show that CQ molecules were encapsulated in the pores, without completely filling the mesopores. BET surface area values were 630 m2 g-1 (magMCM) and 467 m2 g-1 (magMCM-CQ). Encapsulated CQ exhibited rapid delivery (99% in 3 h) in buffer medium and improved solubility compared to the non-encapsulated drug, attributed to CQ encapsulation in amorphous form. The biocompatibility assessment of magMCM, magMCM-CQ, and CQ against MRC5 non-tumoral lung fibroblasts using the MTT assay after 24 h revealed no toxicity associated with magMCM. On the other hand, the non-encapsulated CQ and magMCM-CQ exhibited comparable dose-response activity, indicating a similar cytotoxic effect.

3D printed matrix solid forms: Can the drug solubility and dose customisation affect their controlled release behaviour?

The use of 3D printing in pharmaceutics has grown over the last years, along with the number of studies on the impact of the composition of these formulations on their pharmaceutical and biopharmaceutical properties. Recently, we reported the combined effect of the infill percentage and the presence of a pore former on the drug release behaviour of 3D printed matrix solid forms prepared by fused deposition modelling. However, there are some open questions about the effect of the drug solubility and the size of these dosage forms on their controlled release properties. Therefore, we produced poly(Ɛ-caprolactone) filaments containing different soluble forms of dexamethasone (free acid, DEX; acetate ester, DEX-A; and phosphate salt, DEX-P), which showed suitable mechanical properties and printability. 3D printed solid forms were produced in two different sizes. The formulations composed of DEX-P released about 50% of drug after 10 h, while those containing DEX or DEX-A released about 9%. The drug release profiles from the 3D printed forms containing the same drug form but with different sizes were almost completely overlapped. Therefore, these 3D printed matrix solid forms can have their drug content customised by adjusting their size, without changing their controlled release behaviour.

A critical review of traditional and advanced characterisation tools to drive formulators towards the rational development of 3D printed oral dosage forms.

The high degree of precision and control of 3D printing has given formulators the autonomy to engineer sophisticated and personalised medicines, starting a revolution in pharmaceutics. In addition, dosage forms with tailored drug release profile can be produced by changing some parameters of the 3D printing processes. Therefore, 3D printed medicines must be characterised in an orthogonal approach, to establish their physicochemical and biopharmaceutical features, and consequently to understand how these characteristics can be customised by changing the formulation and process parameters to ensure medicines' safety and efficacy. Given the recent regulation and commercialisation of 3D printed medicines, several methods and techniques have been transposed from official compendia; however, formulators must still make a critical assessment of their practical implications. A comprehensive review of the findings obtained by the characterisation of 3D printed oral dosage forms using traditional and advanced techniques is therefore presented here, to drive formulators towards a rational pharmaceutical development pathway. The characterisation methods have been classified in terms of their physicochemical or biopharmaceutical character. Interestingly, beyond the rise of modern characterisation techniques, the reassessment of data obtained by traditional methods has provided knowledge and a solid foundation to support the evolution of 3D printing techniques in pharmaceutics.

Drug-loaded mesoporous silica on carboxymethyl cellulose hydrogel: Development of innovative 3D printed hydrophilic films.

3D printing has been explored as an emerging technology for the development of versatile and printable materials for drug delivery. However, the alliance of 3D printing and nanomaterials has, to date, been little explored in pharmaceutics. Herein, a mesoporous silica with nanostructured pores, SBA-15, was used as a drug carrier for triamcinolone acetonide, a hydrophobic drug, with the aim of incorporating the drug formulation in a hydrophilic printable ink. The adsorption of the drug in the SBA-15 pores was confirmed by the decrease in its surface area and pore volume, along with an increase in the apparent aqueous solubility of triamcinolone acetonide, as shown by in vitro release studies. Thereafter, a hydrophilic ink composed of carboxymethyl cellulose containing drug-loaded SBA-15 was formulated and 3D printed as hydrophilic polymeric film using the semisolid extrusion technique (SSE). The 3D printed films showed complete drug release after 12 h, and the presence of the triamcinolone acetonide-loaded SBA-15 improved their in vitro mucoadhesion, suggesting their promising application in oral mucosa treatments. Besides representing an innovative platform to develop water-based mucoadhesive formulations containing a hydrophobic drug, this is the first report proposing the development of SSE 3D printed nanomedicines containing drug-loaded mesoporous silica.

Bioadhesive 3D-Printed Skin Drug Delivery Polymeric Films: From the Drug Loading in Mesoporous Silica to the Manufacturing Process.

The alliance between 3D printing and nanomaterials brings versatile properties to pharmaceuticals, but few studies have explored this approach in the development of skin delivery formulations. In this study, clobetasol propionate (CP) was loaded (about 25% w/w) in mesoporous silica nanomaterial (MSN) to formulate novel bioadhesive and hydrophilic skin delivery films composed of pectin (5% w/v) and carboxymethylcellulose (5% w/v) by 3D printing. As a hydrophobic model drug, CP was encapsulated in MSN at a 3:1 (w/w) ratio, resulting in a decrease of CP crystallinity and an increase of its dissolution efficiency after 72 h (65.70 ± 6.52%) as compared to CP dispersion (40.79 ± 4.75%), explained by its partial change to an amorphous form. The CP-loaded MSN was incorporated in an innovative hydrophilic 3D-printable ink composed of carboxymethylcellulose and pectin (1:1, w/w), which showed high tensile strength (3.613 ± 0.38 N, a homogenous drug dose (0.48 ± 0.032 mg/g per film) and complete CP release after 10 h. Moreover, the presence of pectin in the ink increased the skin adhesion of the films (work of adhesion of 782 ± 105 mN·mm). Therefore, the alliance between MSN and the novel printable ink composed of carboxymethylcellulose and pectin represents a new platform for the production of 3D-printed bioadhesive films, opening a new era in the development of skin delivery systems.

Multiple variable effects in the customisation of fused deposition modelling 3D-printed medicines: A design of experiments (DoE) approach.

Fused deposition modelling (FDM) is the most explored three-dimensional (3D) printing technique in pharmaceutics. However, there is still a lack of knowledge about the factors influencing the properties of the printed forms. Here, the main and combined effects of the presence of a pore former (mannitol, 0% or 10%), the infill percentage (50% or 100%) and the drug percentage (5% or 10%) on the pharmaceutical properties of 3D-printed forms were evaluated by a design of experiments (DoE) approach. Poly(Ɛ-caprolactone) filaments were produced by hot-melt extrusion and dexamethasone was used as a hydrophobic model drug. The 23 factorial design afforded eight formulations printed at 105 °C. The drug content ranged from 9.87 to 25.59 mg/unit, depending on the drug and infill percentages. The drug release profiles followed the Higuchi model. The infill percentage modulated the drug release rate, whereas the pore former had a combined effect on this parameter, depending on the drug and infill percentage levels. According to the DoE data, besides the changes in the infill percentage, the addition of a pore former can also tailor the drug release rate from 3D-printed solid forms. These findings may assist the development of personalised tumour implants by 3D printing.

Designing a Support for Lipase Immobilization Based On Magnetic, Hydrophobic, and Mesoporous Silica.

A mesoporous, magnetic, and hydrophobic material was designed step by step to act as a support for lipase immobilization. Its pore size (8.0 nm) is compatible with the size of lipase from Thermomyces lanuginosus (TLL), and its hydrophobic surface (contact angle of a water drop = 125°) was planned to interact with lipase on its interfacially activated form (open conformation). The presence of magnetite particles provides magnetic retrieval of the material and enables recyclability of the biocatalysts. Regarding immobilization parameters, the hydrophobic support was tested in comparison to the unmodified hydrophilic support in phosphate buffer solution (50 mmol L-1, pH 7.5) at 25 °C. Hydrophobicity was found to be critical for the amount of immobilized TLL (immobilization yield of 97% versus 36% for the hydrophilic support), whereas the hydrophilic support favors the native conformational state and substrate access to the enzyme's catalytic site (specific activity of 5.7 versus 4.7 U g-1 for the hydrophobic support, even when it has higher TLL content). Therefore, the hydrophobic support immobilizes higher amounts of TLL and the hydrophilic support keeps the enzyme hyperactivated. Last, due to the stronger interactions of TLL with hydrophobic surfaces, the hydrophobic support offers better preservation of enzyme activity in repeated cycles (76% of activity retained after three cycles versus 50% for the hydrophilic support).