Multi-layer Raman chemical mapping to investigate the effect of API particle size and blending shear rate on API domain sizes in pharmaceutical tablets.

While macromixing (gross uniformity) has received a lot of attention in pharmaceutical powder blending, micromixing (particularly, particle-level aggregation) has been significantly less studied. This study investigated the impact of active pharmaceutical ingredient (API) particle size (D50: 11, 28, and 70 µm) and blending shear rate (low and high) that was caused by tumbling blending (specifically, a V-blender) on micro-mixing. The effect on micro-mixing (API domain sizes) was assessed in direct compression tablets using high-resolution Raman chemical mapping. Analyses of multiple layers within tablets enabled a more reliable understanding of the variability in API domain sizes with respect to the independent variables. The relationship between API domain sizes and the manufactured tablets' content uniformity (CU) was also investigated using near-infrared transmission spectroscopy. Generally, at low shear, as the API particle size decreased, the frequency and size of API agglomerates increased, resulting in poor CU. However, in all cases, API domain sizes drastically reduced at high shear, resulting in an acceptable CU. The results of this work clearly demonstrated the utility of a multi-layer, multi-tablet, and high-resolution Raman chemical mapping as an off-line process analytical technology (PAT) system, to enable quality-by-design driven formulation and process development.

Performance assessment of linear iterative optimization technology (IOT) for Raman chemical mapping of pharmaceutical tablets.

Raman chemical mapping is an inherently slow analysis tool. Accurate and robust multivariate analysis algorithms, which require least amount of time and effort in method development are desirable. Calibration-free regression and resolution approaches such as classical least squares (CLS) and multivariate curve resolution using alternating least squares (MCR-ALS), respectively, help in reducing the resources required for method development. However, conventional CLS does not consider appropriate constraints, which may result in negative and/or greater than 100 % Raman concentration scores, while MCR-ALS may not always be as accurate as regression-based algorithms. Linear iterative optimization technology (IOT) is another calibration-free algorithm, which with appropriate constraints has previously shown promise in online and offline pharmaceutical mixture composition determination. This paper aims to evaluate the performance of the linear IOT algorithm for Raman chemical mapping of the active pharmaceutical ingredient (API), diluent, and lubricant in pharmaceutical tablets. Two pre-processing strategies were applied to the raw Raman mapping spectra. The results were compared with CLS (current reference method) and MCR-ALS. Special emphasis was given to mapping at low Raman exposure times to enable feasible total acquisition times (< 5 h). The quality of IOT/CLS/MCR-ALS estimated Raman concentration predictions were assessed by calculating a correlation factor between the spectrum corresponding to the maximum predicted concentration (or resolved spectra) of a component for IOT/CLS (or MCR-ALS) and the pure powder component spectrum. The Raman chemical maps were visualized, and the average Raman concentrations scores were compared. The results demonstrated the utility of IOT in Raman chemical mapping of pharmaceutical tablets. The diluent (lactose) and API (semi-fine APAP) used in this study were reliably estimated by IOT at relatively short Raman exposure times. On the other hand, as expected, the lubricant (magnesium stearate) could not be detected in any of the cases investigated here, irrespective of the algorithm used. Overall, for the API and diluent used in this formulation as well as the chemical mapping conditions, linear IOT seemed to better estimate the pure spectrum intensities and the average Raman scores (closer to CLS) in comparison to MCR-ALS. Moreover, application of appropriate constraints in linear IOT avoided the presence of negative and/or greater than 100 % Raman concentration scores, as observed in CLS-based Raman chemical maps.

Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy.

In-line measurements of low dose blends in the feed frame of a tablet press were performed for API concentration levels as low as 0.10% w/w. The proposed methodology utilizes the advanced sampling capabilities of a Spatially Resolved Near-Infrared (SR-NIR) probe to develop Partial Least-Squares calibration models. The fast acquisition speed of multipoint spectra allowed the evaluation of different numbers of co-adds and feed frame paddle speeds to establish the optimum conditions of data collection to predict low potency blends. The interaction of the feed frame paddles with the SR-NIR probe was captured with high resolution and allowed the implementation of a spectral data selection criterion to remove the effect of the paddles from the calibration and testing process. The method demonstrated accuracy and robustness when predicting drug concentrations across different feed frame paddle speeds.

Adsorption of carbon dioxide on Al/Fe oxyhydroxide.

The structure and reactivity of 0-70mol% Al/Fe iron oxyhydroxides (ferrihydrite in the absence and presence of Al) toward gaseous CO2 were investigated with X-ray photoelectron spectroscopy (XPS), atomic absorption (AA), scanning transmission electron microscopy with electron dispersive X-ray spectroscopy (STEM/EDS), X-ray diffraction (XRD), and attenuated total reflectance Fourier transform Infrared spectroscopy (ATR-FTIR) combined with density functional theory (DFT) calculations. Results showed that Al/Fe oxyhydroxide particles containing more than 20 mol% Al consisted at least in part of Fe-oxyhydroxide with incorporated Al and a discrete AlOOH phase. Results from ATR-FTIR experiments and DFT calculations suggested that the bicarbonate complex formed by passing CO2 over the particles was accommodated on at least three distinct binding sites. At the lowest Al concentrations bicarbonate was bound to individual sites with primarily Fe or Al character. At the highest concentrations of Al (>20 mol%) bicarbonate bound to discrete AlOOH phases became apparent. Results also suggested that the amount of CO2 adsorption for a given particle mass increased as the Al concentration was increased from 0 to 30%. This increase was likely due in large part to differences in the morphology of the particle aggregates that formed in the dry state, which would be expected to affect the amount of surface that was available to adsorb CO2.

Neutron pair distribution function study of two-line ferrihydrite.

Pair distribution function (PDF) analysis of neutron total scattering data from deuterated two-line ferrihydrite is consistent with the Keggin-related structural model for ferrihydrite published by Michel et al. (2007). Other models proposed in the literature, such as that of Drits et al. (1993), lead to inferior fits. Bond valence sums indicate that O(1) is bonded to a hydrogen atom, but the quality of the data is such that the exact position of the hydrogen could not be elucidated with confidence.

Photodissolution of ferrihydrite in the presence of oxalic acid: an in situ ATR-FTIR/DFT study.

The photodissolution of the iron oxyhydroxide, ferrihydrite, in the presence of oxalic acid was investigated with vibrational spectroscopy, density functional theory (DFT) calculations, and batch geochemical techniques that determined the composition of the solution phase during the dissolution process. Specifically, in situ attenuated total reflection Fourier transform infrared spectroscopy (ATR- FTIR) was used to determine the structure of the adsorbed layer during the dissolution process at a solution pH of 4.5. DFT based computations were used to interpret the vibrational data associated with the surface monolayer in order to help determine the structure of the adsorbed complexes. Results showed that at pH 4.5, oxalate adsorbed on ferrihydrite adopted a mononuclear bidentate (MNBD) binding geometry. Photodissolution at pH 4.5 exhibited an induction period where the rate of Fe(II) release was limited by a low concentration of adsorbed oxalate due to the site-blocking of carbonate that was intrinsic to the surface of the ferrihydrite starting material. Oxalate displaced this initial carbonate over time, and the dissolution rate showed a corresponding increase. Irradiation of oxalate/ferrihydrite at pH 4.5 also ultimately led to the appearance of carbonate reaction product (distinct from carbonate intrinsic to the starting material) on the surface.

Reactivity of ferritin and the structure of ferritin-derived ferrihydrite.

BACKGROUND: In nature or in the laboratory, the roughly spherical interior of the ferritin protein is well suited for the formation and storage of a variety of nanosized metal oxy-hydroxide compounds which hold promise for a range of applications. However, the linkages between ferritin reactivity and the structure and physicochemical properties of the nanoparticle core, either native or reconstituted, remain only partly understood. SCOPE OF REVIEW: Here we review studies, including those from our laboratory, which have investigated the structure of ferritin-derived ferrihydrite and reactivity of ferritin, both native and reconstituted. Selected proposed structure models for ferrihydrite are discussed along with the structural and genetic relationships that exist among several different forms of ferrihydrite. With regard to reactivity, the review will emphasize studies that have investigated the (photo)reactivity of ferritin and ferritin-derived materials with environmentally relevant gaseous and aqueous species. MAJOR CONCLUSIONS: The inorganic core formed from apoferritin reconstituted with varied amounts of Fe has the same structural topology as the inorganically derived ferrihydrite that is an important component of many environmental and soil systems. Reactivity of ferritin toward aqueous species resulting from the photoexcitation of the inorganic core of the protein shows promise for driving redox reactions relevant to environmental chemistry. GENERAL SIGNIFICANCE: Ferritin-derived ferrihydrite is effectively maintained in a relatively unaggregated state, which improves reactivity and opens the possibility of future applications in environmental remediation. Advances in our understanding of the structure, composition, and disorder in synthetic, inorganically derived ferrihydrite are shedding new light on the reactivity and stability of ferrihydrite derived artificially from ferritin.

Investigation of surface structures by powder diffraction: a differential pair distribution function study on arsenate sorption on ferrihydrite.

Differential pair distribution function (d-PDF) analysis of high energy powder X-ray diffraction data was carried out on 2-line ferrihydrite nanoparticles with arsenate oxyanions adsorbed on the surface to investigate the binding mechanism. In this analysis, a PDF of ferrihydrite is subtracted from a PDF of ferrihydrite with arsenate sorbed on the surface, leaving only correlations from within the surface layer and between the surface and the particle. As-O and As-Fe correlations were observed at 1.68 and 3.29 A, respectively, in good agreement with previously published EXAFS data, confirming a bidentate binuclear binding mechanism. Further peaks are observed in the d-PDF which are not present in EXAFS, corresponding to correlations between As and O in the particle and As-2nd Fe.

Reductive dissolution of ferrihydrite by ascorbic acid and the inhibiting effect of phospholipid.

The interaction of ascorbic acid with ferrihydrite nanoparticles with and without adsorbed phospholipid has been investigated with atomic force microscopy (AFM), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), density functional theory (DFT) cluster calculations, and batch geochemical methods. Both batch geochemical rate measurements and in situ AFM showed that ferrihydrite particles dissolved in the presence of ascorbic acid over a period of hours. The area-normalized dissolution rate derived from AFM measurements of isolated ferrihydrite particles was relatively constant over the period of dissolution and was faster than the dissolution rate derived from batch reaction methods. Results from ATR-FTIR interpreted in view of theoretical calculations suggested that exposure of ferrihydrite to ascorbic acid led to an adsorbed monodentate ascorbate surface complex. Ferrihydrite dissolution was suppressed if particles were exposed to an organic lipid prior to or during exposure to ascorbic acid. AFM analysis of the lipid layer showed that its thickness was close to 7 nm, the expected value for lipid assembled into a bilayer structure.

Ferrihydrite reactivity toward carbon dioxide.

The reaction of ferrihydrite with gaseous CO(2) was investigated with attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and density functional theory (DFT) calculations. ATR-FTIR results show that CO(2) reacts with ferrihydrite resulting in surface adsorbed carbonate species. The carbonate species experimentally observed in view of theoretical calculations are shown to be in large part monodentate binuclear complexes. These carbonate complexes exist as both inner-sphere and outer-sphere hydrogen-bonded complexes. Under "dry" conditions CO(2) reacts with free OH sites on the ferrihydrite surface resulting in a metastable bent CO(2) (bicarbonate-like) complex. Removal of the gaseous reactant leads to the loss of this metastable surface complex. The reaction of CO(2) with hydrated ferrihydrite results in only carbonate formation (no bicarbonate). In this circumstance, experiments and theoretical calculations suggest that hydrogen bound water on surface OH sites prevents the formation of the metastable bicarbonate species. Ferrihydrite that was allowed to react with atmospheric levels of CO(2) and water vapor resulted in the formation of surface carbonate coordinated as both inner and outer-sphere complexes.

Abiotic ammonium formation in the presence of Ni-Fe metals and alloys and its implications for the Hadean nitrogen cycle.

Experiments with dinitrogen-, nitrite-, nitrate-containing solutions were conducted without headspace in Ti reactors (200 degrees C), borosilicate septum bottles (70 degrees C) and HDPE tubes (22 degrees C) in the presence of Fe and Ni metal, awaruite (Ni80Fe20) and tetrataenite (Ni50Fe50). In general, metals used in this investigation were more reactive than alloys toward all investigated nitrogen species. Nitrite and nitrate were converted to ammonium more rapidly than dinitrogen, and the reduction process had a strong temperature dependence. We concluded from our experimental observations that Hadean submarine hydrothermal systems could have supplied significant quantities of ammonium for reactions that are generally associated with prebiotic synthesis, especially in localized environments. Several natural meteorites (octahedrites) were found to contain up to 22 ppm Ntot. While the oxidation state of N in the octahedrites was not determined, XPS analysis of metals and alloys used in the study shows that N is likely present as nitride (N3-). This observation may have implications toward the Hadean environment, since, terrestrial (e.g., oceanic) ammonium production may have been supplemented by reduced nitrogen delivered by metal-rich meteorites. This notion is based on the fact that nitrogen dissolves into metallic melts.

Humidity-induced restructuring of the calcite surface and the effect of divalent heavy metals.

The composition and topography of calcite 10114 cleavage surfaces, with and without exposure to divalent metals, have been investigated as a function of relative humidity. Atomic force microscopy (AFM) was used to understand topographical changes on the calcite surface due to the presence of divalent metal and exposure to different humid environments. Ion scattering spectroscopy (ISS) was used to determine the composition of the near and outermost surface of the calcite after exposure to Cd and Pb and before exposure to the varying humidity conditions. In general, the extent of topographical changes observed on the calcite surface increased with the humidity level, though the initial step density of the cleaved calcite surface affects the extent of surface restructuring. Pretreatment of the calcite surface with aqueous divalent Pb prior to humidity exposure did not appear to alter the humidity-induced structural changes that occurred on the calcite surface. In contrast, calcite pretreated with divalent Cd showed little topographical change following exposure to high humidity. The results suggest that while Pb forms surface precipitates on the calcite surface, Cd exhibits a stronger interaction with the step edges of the calcite surface, which inhibits the ability of the calcite surface to restructure when exposed to a high relative humidity environment.

Characterization and surface reactivity of ferrihydrite nanoparticles assembled in ferritin.

Ferrihydrite nanoparticles with nominal sizes of 3 and 6 nm were assembled within ferritin, an iron storage protein. The crystallinity and structure of the nanoparticles (after removal of the protein shell) were evaluated by high-resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM), and scanning tunneling microscopy (STM). HRTEM showed that amorphous and crystalline nanoparticles were copresent, and the degree of crystallinity improved with increasing size of the particles. The dominant phase of the crystalline nanoparticles was ferrihydrite. Morphology and electronic structure of the nanoparticles were characterized by AFM and STM. Scanning tunneling spectroscopy (STS) measurements suggested that the band gap associated with the 6 nm particles was larger than the band gap associated with the 3 nm particles. Interaction of SO2(g) with the nanoparticles was investigated by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, and results were interpreted with the aid of molecular orbital/density functional theory (MO/DFT) frequency calculations. Reaction of SO2(g) with the nanoparticles resulted primarily in SO(3)2- surface species. The concentration of SO3(2-) appeared to be dependent on the ferrihydrite particle size (or differences in structural properties).

Pretreatment of amphiphilic comb polymer surfaces dramatically affects protein adsorption.

New applications in regenerative biotechnology require the ability to understand and control protein-surface interactions on micrometer and submicrometer length scales. Evidence presented here shows that micropatterned amphiphilic comb polymer films exhibit a pretreatment-dependent behavior with respect to protein adsorption for the proteins fibronectin, laminin, and for serum. A micropatterned surface, consisting of protein-reactive regions, separated by comb polymer, was created and tested for protein adsorption using the surface-sensitive imaging tool TOF-SIMS. Immersion of micropatterned surfaces in solutions of fibronectin or laminin resulted in uniform protein coverage on both the comb polymer and protein-reactive regions. However, preimmersion of similarly patterned surfaces in water for 2 h prior to protein incubation was found to dramatically improve the protein-resistant properties of the comb polymer regions. These results are consistent with poly(ethylene glycol) (PEG) side chain reorientation and/or hydration and poly(methyl methacrylate) (PMMA) backbone segregation away from the interface region.

Divalent Cd and Pb uptake on calcite {1014} cleavage faces: an XPS and AFM study.

The interaction of divalent Cd and Pb with the {101 4} cleavage faces of calcite has been investigated with X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Analysis of the {101 4} cleavage planes of calcite was carried out with X-ray photoelectron spectroscopy (XPS) after exposure to divalent metal-bearing solutions in the 0.1-100 microM concentration range for times ranging from 1 to 24 h. The uptake of Cd2+ by calcite was determined to be greater than that of Pb2+ under similar experimental conditions (1 microM, pH 8.2, 24 h exposure time). In both cases, the majority of the divalent metal was postulated to exist in a surface precipitate. AFM results showed that the exposure of calcite to a 1 microM Pb2+ solution resulted in ellipsoidal surface growths that were attributed to the nucleation of a PbCO3 bulk phase. In the Cd circumstance, AFM showed comparatively flat growth features forming on the calcite surface even at concentrations down to 0.1 microM, where the solution would be expected to be undersaturated with respect to Cd bulk phases. These features were attributed to a (Ca,Cd)CO3 solid solution. The individual exposure of these Cd/CaCO3 and Pb/CaCO3 samples to water pre-equilibrated with calcite (metal free) for 1 h led to the removal of no more than 20% of the divalent metal, suggesting that if there was an adsorbed Pb or Cd complex initially on the calcite surface, it was an minority species compared to the precipitate phase. Exposure of calcite to 100 microM Cd and Pb resulted in the accumulation of precipitate on the calcite surface presumably due to the divalent metal initial solution concentrations exceeding the solubility products of CdCO3 and PbCO3, respectively.