Solid-State Physical Form Detection and Quantitation of Pharmaceuticals in Formulations

The majority of pharmaceutical dosage forms are marketed as solids, and the active pharmaceutical ingredient (API) can exist in various physical forms. These physical forms can be either crystalline or amorphous, and will have different physical properties. The physical form of the API is selected to provide the appropriate solubility, stability, and bioavailability for the formulation. However, processing steps involved in the production of the formulation can induce changes in the physical form of the API and thus impact the performance of the formulation. Therefore, it is critical to characterize the physical form of the API in the formulation, and to monitor it for any changes in the physical form during storage. Multiple solid-state characterization techniques are typically employed in order to identify and quantitate physical forms of APIs. However, most of these techniques suffer from significant issues related to the interference of excipient signals with API signals when analyzing formulations. Additionally, in order to perform quantitative measurements pure standards are needed and calibration curves must be generated for most of these characterization techniques. This dissertation demonstrates the superior ability of solid-state nuclear magnetic resonance (SSNMR) spectroscopy to both detect and quantitate physical forms of APIs within formulations, relative to other solid-state characterization techniques. Specifically, SSNMR has been used to understand the dehydration of levofloxacin hemihydrate, including the discovery of a previously unreported anhydrous polymorph. Three formulations for pulmonary delivery have been characterized by both differential scanning calorimetry (DSC) and SSNMR. DSC could not clearly identify the physical form of the APIs in the formulations, but SSNMR was able to unambiguously determine the physical forms of the APIs in all cases. The work presented in the dissertation also demonstrates that SSNMR can be used to quantitate the relative amounts of physical forms of APIs within formulations without pure standards or calibration curves. Finally, the relative ability of SSNMR and other solid-state characterization techniques were compared and clearly illustrate that SSNMR is considerably more powerful in the relative quantitation of API physical form in both pure materials and formulations

Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution

PURPOSE. Nanoparticle technology represents an attractive approach for formulating poorly water soluble pulmonary medicines. Unfortunately, nanoparticle suspensions used in nebulizers or metered dose inhalers often suffer from physical instability in the form of uncontrolled agglomeration or Ostwald ripening. In addition, processing such suspensions into dry powders can yield broad particle size distributions. To address these encumbrances, a controlled nanoparticle flocculation process has been developed. METHOD. Nanosuspensions of the poorly water soluble drug budesonide were prepared by dissolving the drug in organic solvent containing surfactants followed by rapid solvent extraction in water. Different surfactants were employed to control the size and surface charge of the precipitated nanoparticles. Nanosuspensions were flocculated using leucine and lyophilized. RESULTS. Selected budesonide nanoparticle suspensions exhibited an average particle size ranging from ~160–230 nm, high yield and high drug content. Flocculated nanosuspensions produced micron-sized agglomerates. Freeze-drying the nanoparticle agglomerates yielded dry powders with desirable aerodynamic properties for inhalation therapy. In addition, the dissolution rates of dried nanoparticle agglomerate formulations were significantly faster than that of stock budesonide. CONCLUSION. The results of this study suggest that nanoparticle agglomerates possess the microstructure desired for lung deposition and the nanostructure to facilitate rapid dissolution of poorly water soluble drugs

In-vivo heterogeneous functional and residual strains in human aortic valve leaflets

Residual and physiological functional strains in soft tissues are known to play an important role in modulating organ stress distributions. Yet, no known comprehensive information on residual strains exist, or non-invasive techniques to quantify in-vivo deformations for the aortic valve (AV) leaflets. Herein we present a completely non-invasive approach for determining heterogeneous strains – both functional and residual – in semilunar valves and apply it to normal human AV leaflets. Transesophageal 3D echocardiographic (3DE) images of the AV were acquired from open-heart transplant patients, with each AV leaflet excised after heart explant and then imaged in a flattened configuration ex-vivo. Using an established spline parameterization of both 3DE segmentations and digitized ex-vivo images (Aggarwal et al., 2014), surface strains were calculated for deformation between the ex-vivo and three in-vivo configurations: fully open, just-coapted, and fully-loaded. Results indicated that leaflet area increased by an average of 20% from the ex-vivo to in-vivo open states, with a highly heterogeneous strain field. The increase in area from open to just-coapted state was the highest at an average of 25%, while that from just-coapted to fully-loaded remained almost unaltered. Going from the ex-vivo to in-vivo mid-systole configurations, the leaflet area near the basal attachment shrank slightly, whereas the free edge expanded by ~10%. This was accompanied by a 10° −20° shear along the circumferential-radial direction. Moreover, the principal stretches aligned approximately with the circumferential and radial directions for all cases, with the highest stretch being along the radial direction. Collectively, these results indicated that even though the AV did not support any measurable pressure gradient in the just-coapted state, the leaflets were significantly pre-strained with respect to the excised state. Furthermore, the collagen fibers of the leaflet were almost fully recruited in the just-coapted state, making the leaflet very stiff with marginal deformation under full pressure. Lastly, the deformation was always higher in the radial direction and lower along the circumferential one, the latter direction made stiffer by the preferential alignment of collagen fibers. These results provide significant insight into the distribution of residual strains and the in-vivo strains encountered during valve opening and closing in AV leaflets, and will form an important component of the tool that can evaluate valve׳s functional properties in a non-invasive manner

Coronary revascularization after intravenous tissue plasminogen activator for unstable angina pectoris: Results of a randomized, double-blind, placebo-controlled trial

To determine the role of intravenous tissue plasminogen activator (t-PA) in unstable angina, it was compared with placebo in a randomized, double-blind trial. Forty patients with angina at rest and provocable ischemia (pacing induced) had baseline coronary angiography, study drug infusion and then repeat angiography at 20 +/- 9 hours. All patients received diltiazem, nitrates, [beta] blockers, aspirin and intravenous heparin. During study drug infusion (150 mg over 8 hours), refractory ischemia necessitating emergency bypass surgery (CABG) or coronary angioplasty (PTCA) occurred in 4 of 20 t-PA patients compared with 1 of 20 placebo patients (p = 0.21). Before discharge, revascularization for persistent, provocable ischemia and a residual stenosis >= 60% was as follows: t-PA patients, 8 PTCA and 7 CABG; placebo patients, 11 PTCA and 8 CABG (p = 0.39). Quantitative angiographic percent diameter stenosis of the culprit artery at baseline and follow-up was: t-PA 71 +/- 17 and 63 +/- 22; placebo 70 +/- 19 and 67 +/- 22 (difference not significant). However, 3 t-PA patients compared with no placebo patients demonstrated an insignificant (< 60% diameter) residual stenosis and averted PTCA (p = 0.14). There were no complications of PTCA in the 8 t-PA patients; in contrast, 3 of 11 placebo patients had abrupt closure, necessitating emergency CABG in 2 (p = 0.23). Thus, intravenous t-PA in unstable angina can eliminate the need for PTCA in a few patients, does not appear to decrease the overall or emergency rate of revascularization procedures and may facilitate the safety of PTCA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27162/1/0000157.pd

Recovery of Metastable Dense Bi Synthesized by Shock Compression

X-ray free electron laser (XFEL) sources have revolutionized our capability to study ultrafast material behavior. Using an XFEL, we revisit the structural dynamics of shock compressed bismuth, resolving the transition sequence on shock release in unprecedented details. Unlike previous studies that found the phase-transition sequence on shock release to largely adhere to the equilibrium phase diagram (i.e., Bi-V → Bi-III → Bi-II → Bi-I), our results clearly reveal previously unseen, non-equilibrium behavior at these conditions. On pressure release from the Bi-V phase at 5 GPa, the Bi-III phase is not formed but rather a new metastable form of Bi. This new phase transforms into the Bi-II phase which in turn transforms into a phase of Bi which is not observed on compression. We determine this phase to be isostructural with β-Sn and recover it to ambient pressure where it exists for 20 ns before transforming back to the Bi-I phase. The structural relationship between the tetragonal β-Sn phase and the Bi-II phase (from which it forms) is discussed. Our results show the effect that rapid compression rates can have on the phase selection in a transforming material and show great promise for recovering high-pressure polymorphs with novel material properties in the future

Endoplasmic Reticulum Stress signalling - from basic mechanisms to clinical applications

The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes

Allocation mechanisms, incentives, and endemic institutional externalities

Whether an economic agent’s decision creates an externality often depends on the institutional context in which the decision was made. Indeed, in orthodox economics, a technological or exogenous externality occurs just in case one agent’s economic welfare or production possibilities are directly affected by the market decisions of other agents. A pecuniary externality occurs just in case one consumer’s economic welfare or producer’s profit is affected indirectly by price changes caused by changes in other agents’ decisions. Similarly, an institutional or endogenous externality may arise whenever allocations are determined by a mechanism that is not strategy proof for some agent. Then even a resource balance constraint creates an institutional externality except in special cases such as when no individual agent’s action can affect market clearing prices — i.e., there are no pecuniary externalities

Femtosecond diffraction studies of solid and liquid phase changes in shock-compressed bismuth

Bismuth has long been a prototypical system for investigating phase transformations and melting at high pressure. Despite decades of experimental study, however, the lattice-level response of Bi to rapid (shock) compression and the relationship between structures occurring dynamically and those observed during slow (static) compression, are still not clearly understood. We have determined the structural response of shock-compressed Bi to 68 GPa using femtosecond X-ray diffraction, thereby revealing the phase transition sequence and equation-of-state in unprecedented detail for the first time. We show that shocked-Bi exhibits a marked departure from equilibrium behavior - the incommensurate Bi-III phase is not observed, but rather a new metastable phase, and the Bi-V phase is formed at significantly lower pressures compared to static compression studies. We also directly measure structural changes in a shocked liquid for the first time. These observations reveal new behaviour in the solid and liquid phases of a shocked material and give important insights into the validity of comparing static and dynamic datasets

Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat

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