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Micronization by air jet milling is often used to produce drug substance particles of acceptable respirable size for use in dry powder inhaler formulations. The energy from this process often induces surface disordered sites on the micronized particles with potential consequences for the long-term stability of the drug substance. In this study, two lots of the same drug substance were qualitatively determined to have different extents of disordered surface using dynamic vapor sorption and scanning electron microscopy. These differences led to observable divergences in particle size and morphology between lots of drug substances on long-term and accelerated stability. The studies investigate the contribution of temperature and humidity, morphology prior to milling, and stability behavior post-micronization. The results highlight the importance of controlling the crystallization solvents upstream of micronization and their contribution to a material's susceptibility to milling-induced disorder on long-term physical stability. Furthermore, this work proposes an accelerated technique useful in predicting stability behavior of micronized drug substances in days rather than months, especially in cases where small differences cannot be detected by standard solid-state techniques.

SummaryBackgroundIn the era of improving overall survival rates of malignant diseases, the impact of a previous malignancy (PM) on treatment and outcome of lung cancer (LC) remains unclear.MethodsWe reviewed all LC patients from our institution that were treated from 2004 to 2006 for the occurrence of LC with PM excluding patients with multiple primary LC.ResultsA total of 444 and 2698 LC patients with and without a history of a PM were identified (prevalence of 14.1%). PM were most often located in breast (15.5%), prostate (14.9%), bladder (9.0%) and kidney (8.8%). Compared to never smokers, patients with nicotine consumption had more often a cancer history of prostate, gastrointestinal, and the head-neck region. The median interval until diagnosis of LC was 72.2 months (range 0–537 months) with most LC diagnosed 5 years after PM diagnosis. With a similar distribution of histology, stage and localization compared to controls, NSCLC patients with PM and stage IV disease showed a favorable overall survival (p

The major product in the intramolecular Pauson-Khand reaction of 3,4-disubstituted 1,6-heptenynes to form bicyclo[3.3.0]octenones is highly dependent on the relative configurations of the two stereocenters of the substrate. For example, cycloaddition of the “syn,syn” stereoisomer of 3,5-dimethyl-4-propargyl-1,6-heptadiene gives predominantly an enone containing both substituents in more hindered endo orientations; the “syn,anti” stereoisomer, upon reaction across the “syn” linkage similarly gives mostly endo product, but upon reaction across the “anti” portion of the molecule affords almost exclusively an enone in which the C6 methyl group possesses exo stereochemistry. Parallel results obtain from enynes built upon cyclohexane frameworks. Calculated energies of pre-cycloaddition enynes, metallacycles presumed to be the penultimate intermediates in the cyclization mechanism, and the final products are examined in order to develop a reasonable predictive model.

The optically active, facial complex Cr(CO)3(PP′P″) (1) with the tridentade ligand PP′P″ = (R)-(+)-1,2,4-tris (diphenylphosphino)butane has been synthesized and characterized. The complex Cr(CO)3(PP′)P″ (PP′ = (R)-(+)-prophos, P″ = PMe2Ph) forms two pairs of diastereomers, facial (3, 4) and meridional (5, 6), respectively, that can be separated by preparative column chromatography. Surprisingly, the CD spectra of Cr(CO)3(PP′P″) (1) and the facial diastereomer of Cr(CO)3(PP′P″ (3), which have the same configuration at the Cr atom, are dissimilar. The meridional configuration of the two isomers 5 and 6 of Cr(CO)3 (PP′)PMe2Ph is supported by the 31P and 1H NMR spectra of the optically inactive complex Cr(CO)3(PP′)P″ (PP′ = 1-[di (4-methoxyphenyl)phosphinol-2-(diphenylphosphino)ethane P″ = PMePh2) which forms the meridional isomers 9 and 10.