D-Homotyrosine hydrobromide salt

Differentiated tissue is particularly vulnerable to alterations in protein and organelle homeostasis. The essential protein VCP, mutated in hereditary inclusion body myopathy, amyotrophic lateral sclerosis and frontotemporal dementia, is critical for efficient clearance of misfolded proteins and damaged organelles in dividing cells, but its role in terminally differentiated tissue affected by disease mutations is less clear. To understand the relevance of VCP in differentiated tissue, we inactivated it in skeletal muscle of adult mice. Surprisingly, knockout muscle demonstrated a necrotic myopathy with increased macroautophagic/autophagic proteins and damaged lysosomes. This was not solely due to a defect in autophagic degradation because age-matched mice with muscle inactivation of the autophagy essential protein, ATG5, did not demonstrate a myopathy. Notably, myofiber necrosis was preceded by upregulation of LGALS3/Galectin-3, a marker of damaged lysosomes, and TFEB activation, suggesting early defects in the lysosomal system. Consistent with that, myofiber necrosis was recapitulated by chemical induction of lysosomal membrane permeabilization (LMP) in skeletal muscle. Moreover, TFEB was activated after LMP in cells, but activation and nuclear localization of TFEB persisted upon VCP inactivation or disease mutant expression. Our data identifies VCP as central mediator of both lysosomal clearance and biogenesis in skeletal muscle.

Despite the high profile of amphetamine, there have been relatively few structural studies of its salt forms. The lack of any halide salt forms is surprising as the typical synthetic route for amphetamine initially produces the chloride salt. (S)-Amphetamine hydrochloride [systematic name: (2S)-1-phenylpropan-2-aminium chloride], C9H14N(+)·Cl(-), has a Z' = 6 structure with six independent cation-anion pairs. That these are indeed crystallographically independent is supported by different packing orientations of the cations and by the observation of a wide range of cation conformations generated by rotation about the phenyl-CH2 bond. The supramolecular contacts about the anions also differ, such that both a wide variation in the geometry of the three N-H...Cl hydrogen bonds formed by each chloride anion and differences in C-H...Cl contacts are apparent. (S)-Amphetamine hydrobromide [systematic name: (2S)-1-phenylpropan-2-aminium bromide], C9H14N(+)·Br(-), is broadly similar to the hydrochloride in terms of cation conformation, the existence of three N-H...X hydrogen-bond contacts per anion and the overall two-dimensional hydrogen-bonded sheet motif. However, only the chloride structure features organic bilayers and Z' > 1.

Bromine K-edge X-ray absorption near-edge structure (XANES) spectroscopy analyses were used to evaluate the crystals of the active pharmaceutical ingredients, eletriptan hydrobromide, dextromethorphan hydrobromide and scopolamine hydrobromide salts and the solid dispersion of eletriptan hydrobromide. The crystals and the solid dispersion of the active pharmaceutical ingredient (API) salts could be discriminated based on the shape of the XANES spectra. The differences in the shape of XANES spectra was ascribable to the differences in the interatomic interactions of the bromine ions based on the crystal structures. Ratio of the eletriptan hydrobromide α-form crystal in mixed powders of α-form and monohydrate crystals could be quantified by the linear-combination fitting using their XANES spectra. These results indicated that the XANES spectroscopy are a potent method for evaluating the APIs of pharmaceutical formulations even at the higher energy region around the bromine K-edge of 13470 eV.