Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

A variety of formulation strategies have been developed to mitigate the inadequate aqueous solubility of certain therapeutic agents. Among these, achieving supersaturation in vivo is a promising approach to improve the extent of oral absorption. Because of the thermodynamic instability of supersaturated solutions, inhibitors are needed to kinetically hinder crystallization. In addition to commonly used polymeric additives, bile salts, naturally present in the gastrointestinal tract, have been shown to exhibit crystallization inhibition properties. However, the impact of bile salts on solution thermodynamics is not well understood, although this knowledge is essential in order to explore the mechanism of crystallization inhibition. To better describe solution thermodynamics in the presence of bile salts, a side-by-side diffusion cell was used to evaluate solute flux for solutions of telaprevir in the absence and presence of the six most abundant bile salts in human intestinal fluid at various solute concentrations; flux measurements provide information about the solute thermodynamic activity and hence can provide an improved measurement of supersaturation in complex solutions. Trihydroxy bile salts had minimal impact on solution phase boundaries as well as solute flux, while micellar dihydroxy bile salts solubilized telaprevir leading to reduced solute flux across the membrane. An inconsistency between the concentration-based supersaturation ratio and that based on solute thermodynamic activity (the fundamental driving force for crystallization) was noted, suggesting that the activity-based supersaturation should be determined to better interpret any modification in crystallization kinetics in the presence of these additives. These findings indicate that bile salts are not interchangeable from a thermodynamic perspective and provide a foundation for further studies evaluating the mechanism of crystallization inhibition

PERFORMANCE OBJECTIVES FOR TANK FARM CLOSURE PERFORMANCE ASSESSMENTS

This report documents the performance objectives (metrics, times of analyses, and times of compliance) to be used in performance assessments of Hanford Site tank farm closure

A quasilocal calculation of tidal heating

We present a method for computing the flux of energy through a closed surface containing a gravitating system. This method, which is based on the quasilocal formalism of Brown and York, is illustrated by two applications: a calculation of (i) the energy flux, via gravitational waves, through a surface near infinity and (ii) the tidal heating in the local asymptotic frame of a body interacting with an external tidal field. The second application represents the first use of the quasilocal formalism to study a non-stationary spacetime and shows how such methods can be used to study tidal effects in isolated gravitating systems.Comment: REVTex, 4 pages, 1 typo fixed, standard sign convention adopted for the Newtonian potential, a couple of lines added to the discussion of gauge dependent term

Quasilocal equilibrium condition for black ring

We use the conservation of the renormalized boundary stress-energy tensor to obtain the equilibrium condition for a general (thin or fat) black ring solution. We also investigate the role of the spatial stress in the thermodynamics of deformation within the quasilocal formalism of Brown and York and discuss the relation with other methods. In particular, we discuss the quantum statistical relation for the unbalanced black ring solution.Comment: v2: refs. added, matches the published versio

Many worlds in one

A generic prediction of inflation is that the thermalized region we inhabit is spatially infinite. Thus, it contains an infinite number of regions of the same size as our observable universe, which we shall denote as \O-regions. We argue that the number of possible histories which may take place inside of an \O-region, from the time of recombination up to the present time, is finite. Hence, there are an infinite number of \O-regions with identical histories up to the present, but which need not be identical in the future. Moreover, all histories which are not forbidden by conservation laws will occur in a finite fraction of all \O-regions. The ensemble of \O-regions is reminiscent of the ensemble of universes in the many-world picture of quantum mechanics. An important difference, however, is that other \O-regions are unquestionably real.Comment: 9 pages, 2 figures, comments and references adde

Algebraic approach to quantum black holes: logarithmic corrections to black hole entropy

The algebraic approach to black hole quantization requires the horizon area eigenvalues to be equally spaced. As shown previously, for a neutral non-rotating black hole, such eigenvalues must be $2^{n}$-fold degenerate if one constructs the black hole stationary states by means of a pair of creation operators subject to a specific algebra. We show that the algebra of these two building blocks exhibits $U(2)\equiv U(1)\times SU(2)$ symmetry, where the area operator generates the U(1) symmetry. The three generators of the SU(2) symmetry represent a {\it global} quantum number (hyperspin) of the black hole, and we show that this hyperspin must be zero. As a result, the degeneracy of the $n$-th area eigenvalue is reduced to $2^{n}/n^{3/2}$ for large $n$, and therefore, the logarithmic correction term $-3/2\log A$ should be added to the Bekenstein-Hawking entropy. We also provide a heuristic approach explaining this result, and an evidence for the existence of {\it two} building blocks.Comment: 15 pages, Revtex, to appear in Phys. Rev.