Blair K. Brettmann

Solid-State NMR Characterization of High-Loading Solid Solutions of API and Excipients Formed by Electrospinning

A major focus area in improving pharmaceutical manufacturing is decreasing powder-handling steps such as milling, granulation, and blending. One approach to go directly from active pharmaceutical ingredients (API) and excipients in solution to a formulated drug product is to use electrospinning to make solid formulations of API in a polymer. Because of the rapid evaporation rate in electrospinning, the process usually results in a well-mixed solid dispersion of drugs in the polymer. In this study, solid-state nuclear magnetic resonance is used to examine phase separation in formulations of aliskiren (SPP) and indomethacin (IND) with polyvinylpyrrolidone (PVP) prepared by electrospinning and hot-melt extrusion. It was found that 1:1 SPP-PVP, 1:1 IND-PVP, and 4:1 SPP-PVP formulations prepared by electrospinning are homogeneous solid solutions down to a 2-11 nm length scale, whereas a 4:1 SPP-PVP formulation prepared by hot-melt extrusion exhibits phase separation with domain sizes of 20-100 nm or larger.

Free Surface Electrospinning of Fibers Containing Microparticles

Many materials have been fabricated using electrospinning, including pharmaceutical formulations, superhydrophobic surfaces, catalysis supports, filters, and tissue engineering scaffolds. Often these materials can benefit from microparticles included within the electrospun fibers. In this work, we evaluate a high-throughput free surface electrospinning technique to prepare fibers containing microparticles. We investigate the spinnability of polyvinylpyrrolidone (PVP) solutions containing suspended polystyrene (PS) beads of 1, 3, 5, and 10 μm diameter in order to better understand free surface electrospinning of particle suspensions. PS bead suspensions with both 55 kDa PVP and 1.3 MDa PVP were spinnable at 1:10, 1:5, and 1:2 PS:PVP mass loadings for all particle sizes studied. The final average fiber diameters ranged from 0.47 to 1.2 μm and were independent of the particle size and particle loading, indicating that the fiber diameter can be smaller than the particles entrained and can furthermore be adjusted based on solution properties and electrospinning parameters, as is the case for electrospinning of solutions without particles.

Templated Nucleation of Acetaminophen on Spherical Excipient Agglomerates

We investigated the effect of spherical agglomeration of heterogeneous crystalline substrates on the nucleation of acetaminophen (AAP). Optical and electron microscopy showed that the surface morphologies of single crystal triclinic lactose and D-mannitol differed significantly from their counterparts formed via spherical agglomeration. Spherical agglomerates of lactose were shown to enhance the nucleation rate of acetaminophen (AAP) by a factor of 11 compared to single crystal lactose; however, no such enhancement was observed for D-mannitol. X-ray powder diffraction identified the presence of new crystal faces of lactose present only in the spherical agglomerates However, D-mannitol did not show any significant change in crystal morphology. The new crystal faces of triclinic lactose were analyzed using geometric lattice matching software and molecular dynamics simulations to establish any new and significant epitaxial matches between lactose and AAP. A coincident lattice match and a large favorable energy interaction from hydrogen bonding were observed between the (141¯) and (001) crystal faces of lactose and AAP, respectively. The enhanced nucleation kinetics, X-ray data, and computational studies indicated that the spherical crystallization of lactose exposed the (141¯) face on the surface of the agglomerates, which subsequently enhanced the nucleation rate of AAP through geometric lattice matching and molecular functionality. This study highlights the importance of exploring different heterogeneous substrate morphologies for enhancing nucleation kinetics.

Solid‐state nuclear magnetic resonance study of the physical stability of electrospun drug and polymer solid solutions

A major challenge in utilizing the amorphous form of an active pharmaceutical ingredient (API) in a final oral dosage form is preventing crystallization over time and ensuring stability. One method to improve stability is lowering the mobility of an API by formulating as a solid solution with an excipient. In this work, we use electrospinning to prepare solid solutions of API, aliskiren (SPP) or indomethacin (IND), and a polymer, polyvinylpyrrolidone (PVP). The stability of the solid solutions over 6-month storage in a desiccator at 40 °C was investigated. Using X-ray diffraction and differential scanning calorimetry, it was determined that no crystals were present in the four formulations tested--1:1 SPP-PVP, 4:1 SPP-PVP, 1:1 IND-PVP, and 2:1 IND-PVP at any time. Solid-state nuclear magnetic resonance relaxation time measurements were used to determine whether phase separation of the API and polymer occurred during the study period. It was found that all formulations remained homogeneous down to at least a 2-10 nm length scale, indicating that for these APIs, electrospinning is an acceptable method for forming stable amorphous solid solutions.

Effects of Test Methods on Crevice Corrosion Repassivation Potential Measurements of Alloy 22

Abstract Alloy 22 (UNS N06022) may be used as the waste package outer container material for disposal of high-level waste at the potential repository at Yucca Mountain, Nevada. Crevice corrosion is one of the corrosion processes that may affect the performance of the waste package outer container. The relative susceptibility of Alloy 22 to crevice corrosion is evaluated through the measurement of crevice corrosion repassivation potential (Ercrev) using electrochemical test methods. The main purpose of the work described in this paper is to verify some Ercrev values reported in the literature and investigate the effects of different electrochemical test methods on the measurement of Ercrev. This work also provides risk insights and reduces the measurement uncertainties associated with evaluating the effects of the fabrication process on crevice corrosion susceptibility. In this work, Ercrev was measured in various chloride solutions at 90°C (194°F) using three methods: ASTM G61-86, the potentiodynamic pola...

Multivalent ions induce lateral structural inhomogeneities in polyelectrolyte brushes

Polymer chain bridging by multivalent ions and solvophobic attractions drives structure formation in charged polymer brushes. Subtle details about a polyelectrolyte’s surrounding environment can dictate its structural features and potential applications. Atomic force microscopy (AFM), surface forces apparatus (SFA) measurements, and coarse-grained molecular dynamics simulations are combined to study the structure of planar polyelectrolyte brushes [poly(styrenesulfonate), PSS] in a variety of solvent conditions. More specifically, AFM images provide a first direct visualization of lateral inhomogeneities on the surface of polyelectrolyte brushes collapsed in solutions containing trivalent counterions. These images are interpreted in the context of a coarse-grained molecular model and are corroborated by accompanying interaction force measurements with the SFA. Our findings indicate that lateral inhomogeneities are absent from PSS brush layers collapsed in a poor solvent without multivalent ions. Together, AFM, SFA, and our molecular model present a detailed picture in which solvophobic and multivalent ion–induced effects work in concert to drive strong phase separation, with electrostatic bridging of polyelectrolyte chains playing an essential role in the collapsed structure formation.

Bulk and nanoscale polypeptide based polyelectrolyte complexes.

Polyelectrolyte complexes (PECs) formed using polypeptides have great potential for developing new self-assembled materials, in particular for the development of drug and gene delivery vehicles. This review discusses the latest advancements in PECs formed using polypeptides as the polyanion and/or the polycation in both polyelectrolyte complexes that form bulk materials and block copolymer complexes that form nanoscale assemblies such as PEC micelles and other self-assembled structures. We highlight the importance of secondary structure formation between homogeneous polypeptide complexes, which, unlike PECs formed using other polymers, introduces additional intermolecular interactions in the form of hydrogen bonding, which may influence precipitation over coacervation. However, we still include heterogeneous complexes consisting of polypeptides and other polymers such as nucleic acids, sugars, and other synthetic polyelectrolytes. Special attention is given to complexes formed using nucleic acids as polyanions and polypeptides as polycations and their potential for delivery applications.