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This work spotlights on the rapid and effective separation method for the no-carrier-added (NCA) 47Sc from natural irradiated Ti target using an anionic exchanger resin; AN-31 impregnated with 4-(2-Pyridylazo) resorcinol (PAR). The newly prepared resin (An-PAR) was characterized by FTIR and SEM. The Influence of pH on the distribution coefficients (Kd) of Sc(III) and Ti(IV) ions was investigated by batch technique and the results revealed that Ti(IV) ions are strongly adsorbed by AN-PAR rather than AN-31, while Sc(III) ions are weakly adsorbed on the both resin materials. The radiochemical separation of 47Sc(III) from irradiated natural Ti target was successfully carried out, where the elution efficiency for 47Sc reached 89 ± 1.5% with high radiochemical, radionuclidic and chemical purities. Our findings thus hold a great promise for the use of 47Sc radioisotope in the preparation of radiopharmaceuticals for theranostics applications.

Brain-targeting delivery of 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is limited by its hydrophilic property and chemical instability. In order to solve this problem, herein, we develop a facile protocol through combining antisolvent precipitation and emulsion-solvent evaporation method to synthesize midazolam (MDZ) coated MMB4 DMS (MMB4@MDZ) nanoparticles. The as-prepared MMB4@MDZ had a MMB4 DMS nanocrystal (MMB4-NC) core and a MDZ shell. The MDZ shell prevented the MMB4-NC core from contacting the aqueous environment, and thus, guaranteed the chemical stability of MMB4 DMS. Most charmingly, the iron mimic cyclic peptide CRTIGPSVC (CRT) was modified on MMB4@MDZ surfaces to produce CRT-MMB4@MDZ which was endowed with ability to absorb transferrin (Tf)-abundant corona. Taking advantages of the Tf-abundant corona, CRT-MMB4@MDZ achieved transferrin receptor (TfR)-mediated brain-targeting delivery. With the fascinating chemical stability and brain-targeting delivery effect, CRT-MMB4@MDZ showed great clinical transform prospect as a brand-new nanomedicine. Of particular importance, this work promised not only a core–shell carrier-free nanomedicine platform for effective delivery of unstable water-soluble drug, but also a protein corona-manipulating strategy for targeting delivery.

Carrier-free nanomedicines without structural modification are attractive for the development of natural small molecules (NSMs) and biomedical applications. Moreover, the combination of NSMs is expected to obtain nanomedicines with high efficacy and low side effects due to their inherent pharmacological activities and health benefits. However, poor water solubility and low bioavailability of NSMs limit their wider biomedical and clinical applications. In this study, we revealed the co-assembly properties of pentacyclic triterpenoids and constructed a series of carrier-free nanodrugs, which are co-assembled nanoparticles (NPs) formed by the combination of two NSMs via a supramolecular assembly strategy. Experimental work and simulation studies were combined to reveal the co-assembly mechanism of non-covalent interactions between NSMs. Not only do co-assembled NPs have rapid cellular uptake ability and passive targeting tumor ability based on the EPR effect, but also their constituent units could arrest the cell cycle at different stages of tumor cells and induce apoptosis, showing synergistic anti-tumor effects (CI < 0.7). Compared with self-assembled NPs and positive control, co-assembled NPs show the strongest therapeutic effect in vivo. Importantly, the co-assembled NPs highlight the unique advantages of NSMs in terms of biosafety and health benefits, and systemic toxicity and histological examination confirm that co-assembled NPs have reliable biosafety, and no side effects and nano toxicity risks were observed.

Carrier-free nanodrugs composed of photosensitizers and chemotherapeutic drugs show great potential in synergistic photothermal-chemotherapy. However, the targeting specificity to tumor cells is still a major obstacle for carrier-free nanodrugs. Meanwhile, almost all exogenous tumor-targeting ligands show no therapeutic effect by themselves. Here, a tumor microenvironment-driven self-targeting supramolecular nanodrug was successfully constructed via an indocyanine green (ICG)-templated small-molecule self-assembly strategy with methotrexate (MTX, folic acid-like antitumor drug) followed by post-insertion of weak acidity-responsive PEG for synergistic photothermal-chemotherapy. Interestingly, the size and morphology could be adjusted by changing the ICG-to-MTX ratio. Notably, the dynamic introduction of PEG not only could temporarily shield self-targeting function in blood to prolong the circulation time, but also could trigger the activation of self-targeting via re-exposing MTX ligands within the tumor microenvironment to enhance cellular uptake. Furthermore, the dePEGylated nanodrug would be disassembled to release MTX on-demand for chemotherapy via both stimuli of stronger lysosomal acidity and an external NIR laser. Moreover, the elimination of tumors could be realized through NIR-II fluorescence/PA imaging-guided synergistic photothermal-chemotherapy. The tumor microenvironment-driven carrier-free nanodrug based on self-targeting activation via ICG-templated assembly might provide a brand-new idea for synergistic photothermal-chemotherapy.

This protocol assesses proinflammatory properties of nucleic acid nanoparticles (NANPs) using a validated preclinical model, peripheral blood mononuclear cells (PBMCs), that is highly predictive of cytokine responses. The experimental procedure details the preparation of pyrogen-free NANPs, isolation of PBMCs from freshly collected human blood, and analysis of characteristic biomarkers (type I and III interferons) produced by PBMCs transfected with NANPs. Although representative NANPs with high and low immunostimulatory potential are used as standards throughout the procedure, this protocol can be adapted to any NANPs or therapeutic nucleic acids, irrespective of whether they are carrier based or carrier free; additional cytokine biomarkers can also be included. We test several commercial platforms and controls broadly accessible to the research community to quantify all biomarkers in either single- or multiplex format. The continuous execution of this protocol takes

Ursolic acid (UA), a natural pentacyclic triterpenoid, possesses widespread biological and pharmacological activities. However, drawbacks such as low bioavailability, poor targeting and rapid metabolism greatly hinder its further clinical application. Recently, with the development of nanotechnology, various UA nanosystems have emerged as promising strategies for effective cancer therapy. This article reviews various types of UA-based nano-delivery systems, primarily with emphasis placed on novel UA-based carrier-free nano-drugs, which are considered to be innovative methods for cancer therapy. Moreover, this review presents carrier-free nano-drugs that co-assembled of UA and photosensitizers that displayed synergistic antitumor performance. Finally, the article also describes the development and challenges of UA nanosystems for future research in this field. Overall, the information presented in this review will provide new insight into the rational utilization of nano-drugs in cancer therapy., Graphical abstract Image, graphical abstract

The development of protein-based therapeutics faces many challenges, for example, carrier-dependence, safety concerns, endocytosis-dependence, and uncertain in vivo therapeutic outcomes. Small molecules are rarely used for intracellular organelle-targeting and disease tissue-specific carrier-independent delivery of therapeutic proteins. Here, we report that rhodamine B, after modification with proteins, is able to guide carrier-free delivery into mitochondria and tissue-dependent distributions of functional proteins through organic cation transporters (OCTs). The enrichment of the modified catalase in the cancer tissue efficiently suppresses xenograft human lung tumor in mice. This carrier-free delivery platform of proteins may emerge as a simple yet powerful approach for cancer treatment.

Enzyme-linked immunosorbent assay (ELISA) is an economic and easy operation technique that has been widely used for the detection of protein in industry. However, the low loading capacity of the enzyme reporter has contributed to the low sensitivity of traditional ELISA, and the cross-linking procedures of the enzyme-labeled antibody in ELISA methods can lead to the inactivation of the enzyme, which will further decrease the sensitivity. To address this issue, herein we fabricated "carrier-free" nanoparticles to obtain a horseradish peroxidase (HRP) labelled reporter with a high HRP loading capacity. A disulphide-containing bis-N-hydroxy succinimide (NHS) crosslinker (NHS-SS-NHS) was used to control the link and release of traceless HRPs, thus without reduction of its enzymatic activity. The HRP nanoparticle (NanoHRP) was successfully applied for dot blotting and ELISA. When carcinoembryonic antigen (CEA) was used as a target, the detection limit of the NanoHRP-based ELISA was 0.005 ng mL-1, which was about 400 times more sensitive than traditional ELISA. A good correlation between the CEA concentrations and the response values measured by NanoHRP ELISA was obtained in the range of 0.005 to 1 ng mL-1. This concept could be exploited to improve ELISA tests, especially those requiring a high accuracy, to facilitate physicians in deciding the appropriate medical treatment.

A new approach for extraction of 99Mo tracer as a lighter homolog of Seaborgium (Sg) by three different the ionic liquids are studied. Aliquat-336 [Aliq-336.Cl-] as anion exchange has been used for the preparation of three ionic liquid, namely: ([Aliq-336]+ [SCN]-), ([Aliq-336]+ [S]- ) and ([Aliq-336]+ [Fe(CN)6]-). Their potential extraction of carrier free 99Mo from HNO3 solutions has been evaluated. The obtained results demonstrated that successful extraction of carrier free 99Mo from HNO3 solutions is achieved. The ([Aliq-336]+ [Fe(CN)6]-) is found to give the highest extraction affinity for 99Mo than the others ionic liquids investigated. The preliminary results could be useful for the upcoming aqueous experiments of Seaborgium.

We aim to investigate the separation of carrier free 99Mo as a homolog of Sg (element-106) from HCl, HNO3, H2SO4 and HF solutions using Bio-resin impregnated by trioctylamine (TOA), (BR-TOA). Distribution coefficient (Kd) of carrier free 99Mo has been investigated under various conditions by batch mode. To get knowledge towards the chemical behavior of Sg(IV) and Sg(VI), set of different chemical system, including mixed reducing agent with an acid solution for possible reduction and/or subsequent separation of 99Mo species was tested. The preliminary results are demonstrated that possible separation of different species of 99Mo as a homolog of Sg using BR-TOA.

Carrier-free nanomedicines mainly composed of drug nanocrystals are considered as promising candidates for next-generation nanodrug formulations. However, such nanomedicines still need to be stabilized by additive surfactants, synthetic polymers, or biologically based macromolecules. Based on the strong intermolecular interactions between indomethacin (IDM, a COX-2 inhibitor) and paclitaxel (PTX, a chemotherapy drug), we herein successfully engineered a novel kind of carrier-free nanomedicines that organized as IDM-induced PTX nanocrystal aggregates via one-pot self-assembly without any nonactive excipients. In the assemblies of IDM and PTX (IDM/PTX assemblies), PTX nanocrystals were casted with amorphous IDM molecules, like a "brick-cement" architecture. In serum, these nanoassemblies could rapidly collapse into a great number of smaller nanoparticles, thus targeting the tumor site through the EPR effect. Under the assistance of IDM on immunotherapy, the IDM/PTX assemblies showed obviously improved synergetic antitumor effects of immunotherapy and chemotherapy. The self-assembly of two synergistic active substances into nanomedicines without any nonactive excipients might open an alternative avenue and give inspiration to fabricate novel carrier-free nanomedicines in many fields.

Enzymes are versatile catalysts for numerous industrial biocatalytic processes. Cross-linked enzyme aggregates (CLEAs) as a carrier free immobilization approach has drawn much attention being simple, cost efficient, capable of preserving high catalytic efficiency and improve enzyme reusability. The aim of this study was to develop a reusable, thermally and operationally stable trypsin CLEAs through co-aggregation with chitosan (CHS). Physicochemical characterization of the prepared CLEAs, including pH and temperature optimum, kinetic parameters, and operational and thermal stability in the absence (CLEA-T), and presence (CLEA-T-CHS) of CHS was carried out. CLEA-T-CHS and CLEA-T were prepared under mild conditions and cross linked using glutaraldehyde with 92% and 31% residual activity, respectively. Immobilized trypsin showed improved pH stability at alkaline pH. At 70EC the immobilized enzyme had 62% residual activity while the free enzyme lost 91% of its initial activity. The kinetic parameters (Km and Vmax) of the immobilized trypsin marginally increased, leading to a decreased catalytic efficiency. Operational and thermal stability were highly improved for CLEA-T-CHS; the half-life (t 1/2) of free trypsin and CLEA-T-CHS were 15 min and 65 min, respectively. Storage stability was highly improved; CLEAT-CHS and the free enzyme had 82% and 21% residual activity, respectively, after storage for 4 weeks. CLEA-TCHS retained 64% residual activity after five consecutive hydrolytic cycles, thus reinforcing its robust potentials. In this study, we successfully prepared a thermally stable and highly active immobilized trypsin through crosslinking in the presence of CHS. Results suggest that CLEA-T-CHS has great potential for industrial applications, including re-use in protein digestion.

A radiotracer technique has been used to achieve the carrier-free separation of 115mIn from its parent 115Cd in hydrochloric acid medium on a chromatographic column packed with TODGA-impregnated silica gel. At 8 M HCl, both cations are bound at the chelating site, which results in maximum adsorption. When the column is treated with 2 M HCl, the daughter complex gets desorbed and is eluted from the column, whereas the parent remains undisturbed. Pure silica gel does not adsorb radioactivity under these conditions. The radiochemical purity of daughter was checked by its half-life (4.49 h).

A new and recyclable protocol was developed for Pd(OAc) 2 -catalyzed the cross-coupling reaction of terminal alkynes with arylboronic acids using environmentally friendly H 2 O/TBAB as reaction medium. A series of cross-coupling products containing internal acetylenic bond can be obtained with good selectivity and yield. The Pd(OAc) 2 /H 2 O/TBAB system was stable in the Sonogashira-type cross-coupling reaction and could be used at least three cycles without considerable decrease in catalytic performance. The results suggest that the unsupported and recyclable systems can be extended to the other realm of C C bond formation in synthetic organic chemistry.

High-performance photothermal theranostics is urgently desired for cancer therapy because of their good controllability and noninvasive features. The relatively low photothermal conversion efficiency is still at the drawbacks because of the absence of efficient extraneous carriers. Herein, a carrier-free nanomedicine is developed to in vivo self-deliver organic photothermal agents for efficient cancer phototheranostics. By a facile self-assembly strategy, the near-infrared (NIR)-absorbing conjugated oligomer IDIC-4F is fabricated into a carrier-free nanoparticle (DCF-P), showing ultrasmall size of nearly 4.0 nm with a nearly 100% of drug loading capacity. Notably, DCF-P achieves a superhigh photothermal conversion efficiency of 80.5% that is far greater than that of IDIC-4F-loaded nanomicelle DCF-M (57.3%). With the guidance of NIR fluorescence and photoacoustic dual-imaging, it is verified that DCF-P could well achieve tumor-preferential accumulation and retention at 4 h postinjection, and meanwhile shows highly efficient in vivo tumor elimination with good biosafety. This study thus contributes a novel concept for designing ultrasmall nanoparticle characteristics of preferential accumulation in tumors, and also provides a strategy for creating high-performance carrier-free nanomedicine via highly ordered molecular stacking.

Bacterial inclusion bodies (IBs) consist of unfolded protein aggregates and represent inactive waste products often accumulating during heterologous overexpression of recombinant genes in Escherichia coli. This general misconception has been challenged in recent years by the discovery that IBs, apart from misfolded polypeptides, can also contain substantial amounts of active and thus correctly or native-like folded protein. The corresponding catalytically-active inclusion bodies (CatIBs) can be regarded as a biologically-active sub-micrometer sized biomaterial or naturally-produced carrier-free protein immobilizate. Fusion of polypeptide (protein) tags can induce CatIB formation paving the way towards the wider application of CatIBs in synthetic chemistry, biocatalysis and biomedicine. In the present review we summarize the history of CatIBs, present the molecular-biological tools that are available to induce CatIB formation, and highlight potential lines of application. In the second part findings regarding the formation, architecture, and structure of (Cat)IBs are summarized. Finally, an overview is presented about the available bioinformatic tools that potentially allow for the prediction of aggregation and thus (Cat)IB formation. This review aims at demonstrating the potential of CatIBs for biotechnology and hopefully contributes to a wider acceptance of this promising, yet not widely utilized, protein preparation.

67 Cu radioisotope is a beta particle-emitting nuclide used in radioimmunotherapy (RIT) as well as for imaging, tracer kinetic studies and dosimetry. 67 Cu can be produced by bombarding nat Zn with deuterons. In this study, the physical yields of 67 Cu via nat Zn(d,x) 67 Cu reaction channel as well as via subreactions of 68 Zn(d,2pn) 67 Cu, 67 Zn(d,2p) 67 Cu, 70 Zn(d,2p3n) 67 Cu, 68 Zn(d,x) 67 Ni(T 1/2 =21 s)→ 67 Cu and 70 Zn(d,x) 67 Ni(T 1/2 =21 s)→ 67 Cu in the nat Zn target have been calculated by using the MCNPX-2.6, TALYS-1.8 and SRIM codes. Also, the total cross sections for production of 67 Cu from nat Zn(d,x) 67 Cu reaction channel in the energy range of 15–45 MeV have been estimated by TALYS code. The best reaction to produce 67 Cu radionuclide in a carrier free form was chosen with deuteron energy around 30 MeV on 70 Zn thick target. Good agreement between the calculated results and the experimental values shows that the employed methods can be used for prediction and production estimation in cyclotron.

Despite the success in developing various pharmaceutical formulations, most of the active pharmaceutical ingredients (APIs)/drugs, according to the Biopharmaceutics Classification System (BCS), often suffer from various intrinsic limitations of solubility and permeability, substantially hindering their bioavailability in vivo. Regardless of the fact that the availability of different particle fabrication approaches (top-down and bottom-up) towards pharmaceutical manufacturing, the supercritical fluid (SCF) technology has emerged as one of the highly effective substitutes due to the environmentally benign nature and processing convenience, as well as the economically promising character of SCFs. The exceptional features of SCFs have endowed the fabrication of various APIs either solely or in combination with the compatible supramolecular species towards achieving improved drug delivery. Operating such APIs in high-pressure conditions often results in arbitrary-sized particulate forms, ranging from micron-sized to sub-micron/nano-sized particles. Comparatively, these SCF-processed particles offer enhanced tailorable physicochemical and morphological properties (size, shape, and surface), as well as improved performance efficacy (bioavailability and therapy) over the unprocessed APIs. Although the “carrier-based” delivery is practical among diverse delivery systems, the direct fabrication of APIs into suitable particulate forms, referred to as “carrier-free” delivery, has increased attention towards improving the bioavailability and conveying a high payload of the APIs. This review gives a comprehensive emphasis on the SCF-assisted fabrication of diverse APIs towards exploring their great potential in drug delivery. Initially, we discuss various challenges of drug delivery and particle fabrication approaches. Further, different supercritical carbon dioxide (SC-CO2)-based fabrication approaches depending on the character of SCFs are explicitly described, highlighting their advantages and suitability in processing diverse APIs. Then, we provide detailed insights on various processing factors affecting the properties and morphology of SCF-processed APIs and their pharmaceutical applications, emphasizing their performance efficacy when administered through multiple routes of administration. Finally, we summarize this compilation with exciting perspectives based on the lessons learned so far and moving forward in terms of challenges and opportunities in the scale-up and clinical translation of these drugs using this innovative technology.

An attempt was made in this work to evaluate a simple flat sheet supported liquid membrane technique for the separation of carrier free 90Y from 90Sr using two diglycolamide carrier ligands, (i) N,N,N′,N′-tetra-n-octyl-diglycolamide (TODGA), and (ii) N,N,N′,N′-tetra-(2-ethylhexyl)-diglycolamide (TEHDGA). Various experimental parameters were optimized to get selective transport of 90Y over 90Sr. At 6 M HNO3 feed acidity, >95% 90Y could be recovered selectively in just 4 h with both the ligands. Under identical experimental conditions, about 0.1% transport of Sr was also recorded which could be completely removed by passing through a Sr selective column to get medical grade 90Y pure product. A mathematical model equation was also derived and experimentally validated for predicting the transport of 90Y through membrane.

A new ion-exchanger having chemical formula [Me2NH2]3[Mo12O40S] and belonging to the class of Keggin type polyoxometalate was synthesized and characterized by single-crystal X-ray structure determination. The crystal of the exchanger is rhombohedral, space group R-3 with cell dimensions, a =16.504(18) A, b =16.504(18)A (1) A, c =25.23(3)A and α=90.00°, β=90.00°, γ=120.00° and Z =6, 3.284gcm-3. The compound behaves as an ion-exchanger and it is significantly stable towards thermal, chemical environments and total radiation dose of 35.0kGy. Radiochemical separation of the short-lived daughter carrier-free 9°Y (T1/2 =64.08h) from its long-lived parent 90Sr (T1/2 =29 a) using this material at pH 6.0 with 1.0% EDTA solution as an eluent.

Budesonide (BUD) is a potent inhaled corticosteroid widely used for treatment of asthma and chronic obstructive pulmonary disease (COPD). The aim of the present study was to develop carrier free inhaled dry powder containing only BUD using supercritical fluid particle design (SCF PD) technique. The powder was perpetrated using the proprietary apparatus of SCF PD-Lab and characterized in terms of crystal behavior, surface property and suitability for pulmonary delivery. SCF PD-BUD powder shown itself large specific area and lower surface energy measured by iGC-SEA, and the aerodynamic performances relative to the milled powder and the marketed Pulmicort® powder was considerably improved, the pulmonary deposition rate increased substantially up to FPF

Objective To investigate influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations. Materials and methods Milled and unmilled IBU samples were characterized thermally and spectroscopically. Physicochemical characterization was performed by quantifying specific surface area, density, and angle of repose. Performance testing was conducted on IBU formulations in combination with a high resistance Monodose RS01 using Next Generation Impactor. Results and discussion There were no detectable differences between IBU samples thermally and spectroscopically. The milled IBU sample exhibited improved powder flow in comparison with the unmilled sample. The milled IBU powders possessed surprisingly high in vitro aerodynamic performance with a fine particle fraction percentage between 67 and 85%, and a minimum respirable fraction percentage of 49%. The capsule fill weights, from 10 to 50 mg, and milling batch sizes did not significantly influence performance. The importance of powder conditioning following milling was illustrated as the storage duration and temperature negatively affected performance. Conclusion In vitro aerodynamic performance of IBU is independent of capsule fill weight and batch size; however, some period of powder conditioning is recommended to reduce variability in formulation performance.

Although the immobilization of enzymes with improved activity and stability has been the subject of growing interest for many years, new opportunities arose by implementing nanomaterials as immobilizing carriers. The nano-carriers not only offer larger surface area and lower mass-transfer limitation but also endow the native enzyme with specific performances due to their various physical or chemical properties. A carrier-free nanobiocatalyst, cross-linked enzyme aggregates (CLEAs), has been developed for applications in industrial bioprocesses. This review illustrates the recent achievements in nanobiocatalysts, including the carrier-bound and carrier-free enzymes. These nanobiocatalysts provide enzymes with broad properties to serve in the fields of biocatalysis, biomedicine and biosensors.

article Copper (Cu) is an essential micronutrient for marine phytoplankton, but can cause toxicity at elevated intracel- lular concentrations. The majority of Cu (N99.9%) in oceanic surface waters is bound to strong organic ligands, presumablyproduced byprokaryotestodetoxifyCu.Althoughlaboratory studieshave demonstratedthatorgan- ically complexed Cu may be bioavailable to marine eukaryotic phytoplankton, the bioavailability of Cu organic complexes to indigenous marine phytoplankton has not been examined in detail. Using the carrier free radioiso- tope 67 CuatanironlimitedstationinthenortheastsubarcticPacificOcean,weperformedsizefractionatedshort

Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders.

Dry powder inhaler (DPI) products have traditionally comprised a simple formulation of micronised drug mixed with a carrier excipient, typically lactose monohydrate. The presence of the carrier is aimed at overcoming issues of poor flowability and dispersibility, associated with the cohesive nature of small, micronised active pharmaceutical ingredient (API) particles. Both the powder blend and the DPI device must be carefully designed so as to ensure detachment of the micronised drug from the carrier excipient on inhalation. Over the last two decades there has been a significant body of research undertaken on the design of carrier-free formulations for DPI products. Many of these formulations are based on sophisticated particle engineering techniques; a common aim in formulation design of carrier-free products being to reduce the intrinsic cohesion of the particles, while maximising dispersion and delivery from the inhaler. In tandem with the development of alternative formulations has been the development of devices designed to ensure the efficient delivery and dispersion of carrier-free powder on inhalation. In this review we examine approaches to both the powder formulation and inhaler design for carrier-free DPI products.

Several diglycolamide-functionalized calix[4]arenes containing four and eight diglycolamide (DGA) moieties were evaluated for their relative extraction efficiencies towards Y(III) and Sr(II). Ligands containing four DGA units with n-propyl, iso-pentyl, and n-octyl groups at the amidic N atom adjacent to the calix[4]arene skeleton showed efficient extraction of Y(III) from 3M HNO3. The extraction of Sr(II) was poor in all cases in the entire acidity range (0.1-6M HNO3) studied. The ligands with a hydrogen atom and an n-propyl group at the concerning amidic N atom showed a very high separation efficiency as reflected in separation factor (S.F.=DY/DSr) values in the range of 10(5)-10(6). A method was developed for the separation of carrier-free (90)Y from a (90)Y-(90)Sr mixture involving consecutive extraction-stripping cycles. The product purity was checked using half-life measurements. Two consecutive cycles of extraction and stripping were found to be sufficient for obtaining pure (90)Y. The results obtained in the present studies were compared with those obtained previously using analogous ligands such as TODGA (N,N,N',N'-tetraoctyl diglycolamide), T2EHDGA (N,N,N',N'-tetra-2-ethylhexyl diglycolamide), and PC-88A (bis(2-ethylhexyl) phosphonic acid).

To employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform.Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler.For the carrier-free formulation considered, turbulence was determined to be the primary deaggregation mechanism. A strong quantitative correlation was established between the mass median diameter (MMD) and newly proposed non-dimensional specific dissipation (NDSD) factor, which accounts for turbulent energy, inverse of the turbulent length scale, and exposure time. A 3D rod array design with unidirectional elements maximized NDSD and produced the best deaggregation with MMD1 μm.The new NDSD parameter can be used to develop highly effective dry powder inhalers like the 3D rod array that can efficiently produce submicrometer aerosols for next-generation respiratory drug delivery applications.

Using the TANDY AMS facility (600 kV) at ETH Zurich the seawater-derived (authigenic) Be-10/Be-9 ratio of marine sediment samples is measured without the addition of Be-9 carrier. This novel method ...

129 I has been successfully applied as tracer in environmental, geological, and oceanographic research. For samples with low stable iodine concentration and ultra low level 129 I, the sample preparation technique to separate iodine prior to AMS measurement has been a bottleneck, limiting the applicability of 129 I. We have reported a carrier-free method, using coprecipitation, to avoid the potential introduction of 129 I through the use of stable iodine carrier iodine. In this work, the detection limit and the analytical uncertainty of this method are investigated and minimum sample amount required to obtain reliable analytical results are estimated. The method is validated with a series of samples in ranges of known iodine concentrations and 129 I/ 127 I ratios. The results confirm our previous conclusion that an AMS target containing 5.0 μg iodine can be used for analyzing samples with 129 I/ 127 I > 10 −12 , and that for samples with 129 I/ 127 I −13 more than 25 μg iodine is necessary.

We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs).Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery was obtained by HPLC and fine particle fraction computed. Air flow patterns were simulated using Computational Fluid Dynamics (CFD).The straight tube did not de-agglomerate emitted powder. However, the USP throat and AG further de-agglomerated powders from the Spinhaler, but not the Turbuhaler and Osmohaler. While budesonide powder deposited similarly in all induction ports, deposition was significantly higher in the AG for both DSCG and mannitol. CFD revealed agglomerates impacting on the USP throat with higher localized velocity compared with the straight tube. CFD further showed a more complex flow pattern with high-velocity air jets in the AG, which explains the higher FPF for DSCG and the lower FPF for mannitol using the AG.The USP throat further de-agglomerated the emitted powder from the DPI when it did not sufficiently disperse the powder. Other tools such as laser diffraction may be used for cross-examining to avoid artifacts in the results.

Labeling of disodium dihydrogen 1-hydroxyethane-1,1-diphosphonate (HEDP) with 188Re was studied. Stannous chloride was used as a reducing agent for the reduction of 188ReO 4 − . The dependence of the yield of 188Re-HEDP complex upon the HEDP concentration, tin(II) content, reaction time, amount of antioxidant, pH, reaction temperature, and presence of carrier was examined. The optimum conditions ensuring high labeling yield of 188Re-HEDP complex (91.0% with carrier-free Re and 96.5% with carrier-added Re) are as follows: 15 mg of HEDP, 2 mg of Sn(II), 4 mg of ascorbic acid, pH 1.2, 100°C, 10 min. The amount of the carrier added is 200 μg of KReO4. The 188Re-HEDP complex prepared at 100°C is more stable than that prepared at 30°C, and the carrier-added 188Re-HEDP complex is more stable than the no-carrier-added complex.

The present article gives a comparative account of the efficiency of carrier-free 90Y separation from 90Sr by solvent extraction, flat sheet-supported liquid membrane (FSSLM) and hollow fiber-supported liquid membrane (HFSLM) methods using bis(2-ethylhexyl) phosphonic acid (PC88A) as the carrier extractant. The major focus of this work has been to develop the HFSLM method for the separation of Y(III) on a relatively large scale. The feed and receiver phase conditions were optimized by carrying out batch solvent-extraction studies. The extraction of Sr(II) by PC88A was negligible in the acidity range of 0.01–3 M HNO3, whereas the extraction of Y(III) was significantly large at lower acidity (≤0.1 M HNO3) with a separation factor (SF = DY/DSr) of 8.5 × 104. HFSLM studies suggested selective and efficient transport of Y(III) into 3 M HNO3 from a feed solution containing a mixture of Y(III) and Sr(II) at 0.1 M HNO3. On the other hand, transport of Sr(II) was negligible in the receiver phase. The purity of the...