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Pharmaceutical cocrystals comprise one active pharmaceutical ingredient (API) and at least one small molecule excipient coformer. While solvent evaporation and mechanochemistry are the preferred methods for their synthesis, some cocrystals are known to form spontaneously at ambient conditions when powders of input materials are mixed—a process not yet fully understood. Aqueous humidity is also known to accelerate spontaneous cocrystal formation. We report here the extent of spontaneous cocrystallization for 14 cocrystal systems, at four levels of humidity. The binary cocrystals in our study consist of a model API (caffeine, theophylline, nicotinamide) and a small chain diacid coformer (oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, glutaric acid). The spontaneous cocrystal formation was monitored ex situ by powder X-ray diffraction over several weeks. Our results show cocrystal formation in all 14 systems to varying extent and are consistent with literature reports that higher humidity correlates with more rapid cocrystal formation. We find that cocrystals containing smaller coformers often form faster. Based on our findings, we identify several cocrystals as candidates for future study. 

Abstract The influenza B M2 protein forms a water-filled tetrameric channel to conduct protons across the lipid membrane. To understand how channel water mediates proton transport, we have investigated the water orientation and dynamics using solid-state NMR spectroscopy and molecular dynamics (MD) simulations. 13 C-detected water 1 H NMR relaxation times indicate that water has faster rotational motion in the low-pH open channel than in the high-pH closed channel. Despite this faster dynamics, the open-channel water shows higher orientational order, as manifested by larger motionally-averaged 1 H chemical shift anisotropies. MD simulations indicate that this order is induced by the cationic proton-selective histidine at low pH. Furthermore, the water network has fewer hydrogen-bonding bottlenecks in the open state than in the closed state. Thus, faster dynamics and higher orientational order of water molecules in the open channel establish the water network structure that is necessary for proton hopping.