Determining the Impact of Roller Compaction Processing Conditions on Granulate and API Properties: Impact of Formulation API Load.

Previous work demonstrated that roller compaction of a 40%w/w theophylline-loaded formulation resulted in granulate consisting of un-compacted fractions which were shown to constitute between 34 and 48%v/v of the granulate dependent on processing conditions. The active pharmaceutical ingredient (API) primary particle size within the un-compacted fraction was also shown to have undergone notable size reduction. The aim of the current work was to test the hypothesis that the observations may be more indicative of the relative compactability of the API due to the formulation being above the percolation threshold. This was done by assessing the impact of varied API loads in the formulation on the non-granulated fraction of the final granulate and the extent of attrition of API particles within the non-granulated fraction. The influence of processing conditions for all formulations was also investigated. The results verify that the observations, both of this study and the previous work, are not a consequence of exceeding the percolation threshold. The volume of un-compacted material within the granulate samples was observed to range between 34.7 and 65.5% depending on the API load and roll pressure, whilst the API attrition was equivalent across all conditions.

Maximizing Archimedes spiral packing density area.

In this paper, we experimentally demonstrate a broadband Archimedes spiral delay line with high packing density on a silicon photonic platform. This high density is achieved by optimizing the gap between the adjacent waveguides (down to sub-micron scale) in the spiral configuration. However, care must be taken to avoid evanescent coupling, the presence of which will cause the spiral to behave as a novel type of distributed spiral resonator. To this end, an analytical model of the resonance phenomenon was developed for a simple spiral. Moreover, it is demonstrated that this distributed spiral resonator effect can be minimized by ensuring that adjacent waveguides in the spiral configuration have different propagation constants (ß). Experimental validations were accomplished by fabricating and testing multiple spiral waveguides with varying lengths (i.e., 0.4, 0.8, and 1.4 mm) and separation gaps (i.e., 300 and 150 nm). Finally, a Linear Density Figure of Merit (LDFM) is introduced to evaluate the packing efficiency of various spiral designs in the literature. In this work, the optimum experimental design with mitigated resonance had a length of 1.4mm and occupied an area of 60 × 60µm, corresponding to an LDFM of 388km-1.

Determining the Impact of Roller Compaction Processing Conditions on Granule and API Properties.

The attrition of drug particles during the process of dry granulation, which may (or may not) be incorporated into granules, could be an important factor in determining the subsequent performance of that granulation, including key factors such as sticking to punches and bio-performance of the dosage form. It has previously been demonstrated that such attrition occurs in one common dry granulation process train; however, the fate of these comminuted particles in granules was not determined. An understanding of the phenomena of attrition and incorporation into granule will improve our ability to understand the performance of granulated systems, ultimately leading to an improvement in our ability to optimize and model the process. Unique feeding mechanisms, geometry, and milling systems of roller compaction equipment mean that attrition could be more or less substantial for any given equipment train. In this work, we examined attrition of API particles and their incorporation into granule in an equipment train from Gerteis, a commonly used equipment train for dry granulation. The results demonstrate that comminuted drug particles can exist free in post-milling blends of roller compaction equipment trains. This information can help better understand the performance of the granulations, and be incorporated into mechanistic models to optimize such processes.

Sn6SiO8, a Tin(II) Silicate with a Zinc Blende Related Structure and High Thermal Stability.

The crystal structure of a novel cubic tin(II) silicate, Sn6SiO8 (space group F4̅3m, a = 10.40708(2) Å, and Z = 4), synthesized by microwave-assisted hydrothermal synthesis has been solved by Rietveld refinement of the powder X-ray diffraction (PXRD) data. The structure, analogous to zinc blende, comprises a face-centered-cubic array of [Sn6O8]4- anions, with Si4+ occupying half of the tetrahedral holes. The tin(II) silicate has been further characterized by variable-temperature PXRD, demonstrating stability of the structure and resistance to SnII oxidation up to ∼600 °C, when the compound begins to thermally decompose.

Pd-Catalyzed Aerobic Oxidation Reactions: Strategies To Increase Catalyst Lifetimes.

The palladium complex [(neocuproine)Pd(µ-OAc)]2[OTf]2 (1, neocuproine = 2,9-dimethyl-1,10-phenanthroline) is an effective catalyst precursor for the selective oxidation of primary and secondary alcohols, vicinal diols, polyols, and carbohydrates. Both air and benzoquinone can be used as terminal oxidants, but aerobic oxidations are accompanied by oxidative degradation of the neocuproine ligand, thus necessitating high Pd loadings. Several strategies to improve aerobic catalyst lifetimes were devised, guided by mechanistic studies of catalyst deactivation. These studies implicate a radical autoxidation mechanism initiated by H atom abstraction from the neocuproine ligand. Ligand modifications designed to retard H atom abstractions as well as the addition of sacrificial H atom donors increase catalyst lifetimes and lead to higher turnover numbers (TON) under aerobic conditions. Additional investigations revealed that the addition of benzylic hydroperoxides or styrene leads to significant increases in TON as well. Mechanistic studies suggest that benzylic hydroperoxides function as H atom donors and that styrene is effective at intercepting Pd hydrides. These strategies enabled the selective aerobic oxidation of polyols on preparative scales using as little as 0.25 mol % of Pd, a major improvement over previous work.

Localizing Perturbations of the Racemic Equilibria Involving Dipicolinate-Derived Lanthanide(III) Complexes.

Helical D3 tris(4-amino-2,6-pyridine-dicarboxylate)terbium(III) and europium(III) complexes, which form a racemic equilibrium in aqueous solution, were prepared to study their secondary coordination sphere interactions with chiral amino acids. These interactions were probed using a combination of circularly polarized luminescence (CPL) and 13C NMR spectroscopy. The results indicate that, regardless of the interaction between the chiral molecule and the complex, without an accessible hydrogen-bond donor on the associating molecule, perturbation of the racemic equilibrium cannot occur. A generalized conclusion is established that indicates that the mechanism of chiral recognition by tris(dipicolinate)lanthanide(III) complexes is similar across a variety of analogous ligands.

Catalytic Role of Multinuclear Palladium-Oxygen Intermediates in Aerobic Oxidation Followed by Hydrogen Peroxide Disproportionation.

Aerobic oxidation of alcohols are catalyzed by the Pd-acetate compound [LPd(OAc)]2(OTf)2 (L = neocuproine = 2,9-dimethyl-1,10-phenanthroline) to form ketones and the release of hydrogen peroxide, but the latter rapidly undergoes disproportionation. We employ a series of kinetic and isotope labeling studies made largely possible by electrospray ionization mass spectrometry to determine the role of intermediates in causing this complex chemical transformation. The data suggested that multiple catalytic paths for H2O2 disproportionation occur, which involve formation and consumption of multinuclear Pd species. We find that the trinuclear compound [(LPd)3(µ(3)-O)2](2+), which we have identified in a previous study, is a product of dioxygen activation that is formed during aerobic oxidations of alcohols catalyzed by [LPd(OAc)]2(OTf)2. It is also a product of hydrogen peroxide activation during disproportionation reactions catalyzed by [LPd(OAc)]2(OTf)2. The results suggest that this trinuclear Pd compound is involved in one of the simultaneous mechanisms for the reduction of oxygen and/or the disproportionation of hydrogen peroxide during oxidation catalysis. Electrospray ionization mass spectrometry of hydrogen peroxide disproportionation reactions suggested the presence of other multinuclear Pd-O2 species in solution. Theoretical calculations of these compounds yield some insight into their structure and potential chemistry.

Droplet spray ionization from a glass microscope slide: real-time monitoring of ethylene polymerization.

Ambient ionization mass spectrometry is achieved in a simple manner by loading a sample solution onto a corner of a microscope cover glass positioned in front of the inlet to a mass spectrometer and applying a high voltage to the sample. The resulting stream of charged droplets is stable, has no contamination from the substrate platform, and can be used repeatedly. The utility of droplet spray for in situ analysis and real-time monitoring of chemical reactions was demonstrated by the bis(cyclopentadienyl)zirconium dichloride (zirconocene dichloride)/methylaluminoxane, Cp2ZrCl2/MAO, homogeneously catalyzed polymerization of ethylene in various solutions. Reaction times ranged from seconds to minutes, and catalytically active species and polymeric products of ethylene were acquired and identified by tandem mass spectrometry.

Modes of activation of organometallic iridium complexes for catalytic water and C-H oxidation.

Sodium periodate (NaIO4) is added to Cp*Ir(III) (Cp* = C5Me5(-)) or (cod)Ir(I) (cod = cyclooctadiene) complexes, which are water and C-H oxidation catalyst precursors, and the resulting aqueous reaction is investigated from milliseconds to seconds using desorption electrospray ionization, electrosonic spray ionization, and cryogenic ion vibrational predissociation spectroscopy. Extensive oxidation of the Cp* ligand is observed, likely beginning with electrophilic C-H hydroxylation of a Cp* methyl group followed by nonselective pathways of further oxidative degradation. Evidence is presented that the supporting chelate ligand in Cp*Ir(chelate) precursors influences the course of oxidation and is neither eliminated from the coordination sphere nor oxidatively transformed. Isomeric products of initial Cp* oxidation are identified and structurally characterized by vibrational spectroscopy in conjunction with density functional theory (DFT) modeling. Less extensive but more rapid oxidation of the cod ligand is also observed in the (cod)Ir(I) complexes. The observations are consistent with the proposed role of Cp* and cod as sacrificial placeholder ligands that are oxidatively removed from the precursor complexes under catalytic conditions.

Trinuclear Pd3O2 intermediate in aerobic oxidation catalysis.

The activation of O2 is a key step in selective catalytic aerobic oxidation reactions mediated by transition metals. The bridging trinuclear palladium species, [(LPd(II))3(µ(3)-O)2](2+) (L=2,9-dimethylphenanthroline), was identified during the [LPd(OAc)]2(OTf)2-catalyzed aerobic oxidation of 1,2-propanediol. Independent synthesis, structural characterization, and catalytic studies of the trinuclear compound show that it is a product of oxygen activation by reduced palladium species and is a competent intermediate in the catalytic aerobic oxidation of alcohols. The formation and catalytic activity of the trinuclear Pd3O2 species illuminates a multinuclear pathway for aerobic oxidation reactions catalyzed by Pd complexes.

Predicting tablet properties using In-Line measurements and evolutionary equation Discovery: A high shear wet granulation study.

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study presents an opportunity to predict the properties of the granules and tablets through torque measurement of the granulation bowl and the force exerted on a novel force probe within the powder bed. Inline force measurements are found to be more sensitive than torque measurements to the granulation process. The characteristic force profiles present the overall fingerprint of the high shear wet granulation, in which the evolution of the granule formation can improve our understanding of the granulation process. This provides rich information relating to the properties of the granules, identification of the even distribution of the binder liquid, and potential granulation end point. Data were obtained from an experimental high shear mixer across a range of key process parameters using a face-centred surface response design of experiment (DoE). A closed-form analytical model was developed from the DOE matrix using the discovery of evolutionary equations. The model is able to provide a strong predictive indication of the expected tablet tensile strength based only on the data in-line. The use of a closed form mathematical equation carries notable advantages over other AI methodologies such as artificial neural networks, notably improved interpretability/interrogability, and minimal inference costs, thus allowing the model to be used for real-time decision making and process control. The capability of accurately predicting, in real time, the required compaction force required to achieve the desired tablet tensile strength from upstream data carries the potential to ensure compression machine settings rapidly reach and are maintained at optimal values, thus maximising efficiency and minimising waste.

Chemoselective Pd-catalyzed oxidation of polyols: synthetic scope and mechanistic studies.

The regio- and chemoselective oxidation of unprotected vicinal polyols with [(neocuproine)Pd(OAc)]2(OTf)2 (1) (neocuproine = 2,9-dimethyl-1,10-phenanthroline) occurs readily under mild reaction conditions to generate α-hydroxy ketones. The oxidation of vicinal diols is both faster and more selective than the oxidation of primary and secondary alcohols; vicinal 1,2-diols are oxidized selectively to hydroxy ketones, whereas primary alcohols are oxidized in preference to secondary alcohols. Oxidative lactonization of 1,5-diols yields cyclic lactones. Catalyst loadings as low as 0.12 mol % in oxidation reactions on a 10 g scale can be used. The exquisite selectivity of this catalyst system is evident in the chemoselective and stereospecific oxidation of the polyol (S,S)-1,2,3,4-tetrahydroxybutane [(S,S)-threitol] to (S)-erythrulose. Mechanistic, kinetic, and theoretical studies revealed that the rate laws for the oxidation of primary and secondary alcohols differ from those of diols. Density functional theory calculations support the conclusion that ß-hydride elimination to give hydroxy ketones is product-determining for the oxidation of vicinal diols, whereas for primary and secondary alcohols, pre-equilibria favoring primary alkoxides are product-determining. In situ desorption electrospray ionization mass spectrometry (DESI-MS) revealed several key intermediates in the proposed catalytic cycle.

Reviewing the Impact of Powder Cohesion on Continuous Direct Compression (CDC) Performance.

The pharmaceutical industry is undergoing a paradigm shift towards continuous processing from batch, where continuous direct compression (CDC) is considered to offer the most straightforward implementation amongst powder processes due to the relatively low number of unit operations or handling steps. Due to the nature of continuous processing, the bulk properties of the formulation will require sufficient flowability and tabletability in order to be processed and transported effectively to and from each unit operation. Powder cohesion presents one of the greatest obstacles to the CDC process as it inhibits powder flow. As a result, there have been many studies investigating potential manners in which to overcome the effects of cohesion with, to date, little consideration of how these controls may affect downstream unit operations. The aim of this literature review is to explore and consolidate this literature, considering the impact of powder cohesion and cohesion control measures on the three-unit operations of the CDC process (feeding, mixing, and tabletting). This review will also cover the consequences of implementing such control measures whilst highlighting subject matter which could be of value for future research to better understand how to manage cohesive powders for CDC manufacture.

CRISPR/Cas9 mutagenesis of the Arabidopsis GROWTH-REGULATING FACTOR (GRF) gene family.

Genome editing in plants typically relies on T-DNA plasmids that are mobilized by Agrobacterium-mediated transformation to deliver the CRISPR/Cas machinery. Here, we introduce a series of CRISPR/Cas9 T-DNA vectors for minimal settings, such as teaching labs. Gene-specific targeting sequences can be inserted as annealed short oligonucleotides in a single straightforward cloning step. Fluorescent markers expressed in mature seeds enable reliable selection of transgenic or transgene-free individuals using a combination of inexpensive LED lamps and colored-glass alternative filters. Testing these tools on the Arabidopsis GROWTH-REGULATING FACTOR (GRF) genes, we were able to create a collection of predicted null mutations in all nine family members with little effort. We then explored the effects of simultaneously targeting two, four and eight GRF genes on the rate of induced mutations at each target locus. In our hands, multiplexing was associated with pronounced disparities: while mutation rates at some loci remained consistently high, mutation rates at other loci dropped dramatically with increasing number of single guide RNA species, thereby preventing a systematic mutagenesis of the family.

Structural and photophysical properties of visible- and near-IR-emitting tris lanthanide(III) complexes formed with the enantiomers of N,N'-bis(1-phenylethyl)-2,6-pyridinedicarboxamide.

The enantiomers of N,N'-bis(1-phenylethyl)-2,6-pyridinedicarboxamide (L), namely, (R,R)-1, and (S,S)-1, react with Ln(III) ions to give stable [LnL(3)](3+) complexes in an anhydrous acetonitrile solution and in the solid state, as evidenced by electrospray ionization mass spectrometry, NMR, luminescence titrations, and their X-ray crystal structures, respectively. All [LnL(3)](3+) complexes [Ln(III) = Eu, Gd, Tb, and Yb; L = (R,R)-1 and (S,S)-1] are isostructural and crystallize in the cubic space group I23. Although the small quantum yields of the Ln(III)-centered luminescence clearly point to the poor efficiency of the luminescence sensitization by the ligand and the intersystem crossing and ligand-to-metal energy transfers, the ligand triplet-excited-state energy seems relatively well suited to sensitize many Ln(III) ion's emission for instance, in the visible (Eu and Tb), near-IR (Nd and Yb), or both regions (Pr, Sm, Dy, Er, and Tm).

Speciation, luminescence, and alkaline fluorescence quenching of 4-(2-methylbutyl)aminodipicolinic acid (H2MEBADPA).

4-(2-Methylbutyl)aminodipicolinic acid (H(2)MEBADPA) has been synthesized and fully characterized in terms of aqueous phase protonation constants (pK(a)'s) and photophysical measurements. The pK(a)'s were determined by spectrophotometric titrations, utilizing a fully sealed titration system. Photophysical measurements consisted of room temperature fluorescence and frozen solution phosphorescence as well as quantum yield determinations at various pH, which showed that only fully deprotonated MEBADPA(2-) is appreciably emissive. The fluorescence of MEBADPA(2-) has been determined to be quenched by hydroxide and methoxide anions, most likely through base-catalyzed excited-state tautomerism or proton transfer. This quenching phenomenon has been quantitatively explored through steady-state and time-resolved fluorescence measurements. Utilizing the determined pK(a)s and quenching constants, the fluorescent intensity of MEBADPA(2-) has been successfully modeled as a function of pH.

Isolation of recombinant proteins from culture broth by co-precipitation with an amino acid carrier to form stable dry powders.

Protein-coated microcrystals can be generated by co-precipitation of protein and a water-soluble crystalline carrier by addition to excess water miscible organic solvent. We have investigated this novel process for its utility in the concentration and partial purification of a recombinant protein exported into the culture broth during expression by Pichia pastoris. Co-precipitation with a L-glutamine carrier selectively isolated the protein content of the culture broth, with a minimal number of steps, and simultaneously removed contaminants including a novel yeast metabolite. This pigment co-elutes during aqueous chromatography but its elucidation as a benzoylated glycosamine suggested a simple route of removal by partition during the co-precipitation process. Scale-up of the process was readily achieved through in-line mixing and subsequent reconstitution of the dried protein-coated microcrystals yielded natively folded, bioactive protein. Additional washing of the crystals with saturated L-glutamine facilitated further purification of the recombinant protein immobilized on the L-glutamine carrier. Thus, we present a novel method for the harvesting of recombinant protein from culture broth as a dry powder, which may be of general applicability to bioprocessing.

An investigation into the impact of approaches to learning on final-year student nurses' clinical decision-making.

This research aimed to investigate whether a correlation exists between students' approach to learning and clinical decision-making and to determine whether an educational learning intervention would impact on clinical decision-making outcomes. Tait, Entwistle and McCune's Approaches to Study Skills for Students (ASSIST) and Jenkins' Clinical Decision Making Nursing Scale (CDMNS) was administered to a convenience sample of adult nursing students (n = 78) at a university in central London, UK, at the beginning of the final year of their nursing course and, following the learning intervention, again at the end of the year. Pre-intervention, 38% of participants predisposed to the surface approach to learning; post-intervention, less than 8%. Clinical decision-making scores were statistically significantly higher for students adopting the strategic approach at the pre-intervention point and significantly higher for those adopting the deep approach at the post-intervention point. At both pre- and post- intervention data collection points there was a negative correlation between the surface approach and clinical decision-making scores. Findings indicate a statistically significant relationship exists between participants' approach to learning and their clinical decision-making. Changing from the surface to either the strategic or deep approach to learning is shown to impact positively on clinical decision-making outcomes.

Quantitation of biomolecules conjugated to nanoparticles by enzyme hydrolysis.

A novel method for quantifying biomolecules immobilised onto gold and silver nanoparticles is reported; fluorescent-labelled antibodies and DNA are hydrolysed on the surface of the nanoparticles by the addition of trypsin and DNase I, respectively, resulting in the release of the quantifiable fluorescent label into the bulk solution.

SERRS coded nanoparticles for biomolecular labelling with wavelength-tunable discrimination.

The preparation and use of tri-functional linkers for surface complexation to both gold and silver nanoparticles is reported. These molecules confer excellent stability towards nanoparticles ensuring particle monodispersity in biological buffers, and also incorporate dyes to allow use of the functionalised nanoparticles as SERRS reporters. Biomolecule conjugation and quantitation has been illustrated using Alexafluor 680 labelled streptavidin. Variation of the chromophore has been introduced, which allows for exquisite control of the SERRS by manipulation of laser wavelength. This demonstrates the potential of SERRS functionalised nanoparticles for multiple, simultaneous monitoring of excitation events, an area of research where the capability of molecular fluorophores and quantum dots is limited.