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Short-chain Alcohols (short-chain + alcohol)
Selected AbstractsDrug substances presented as sulfonic acid salts: overview of utility, safety and regulationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009David P. Elder Abstract Objectives Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. Key findings The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. Summary An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions. [source] Toxicity of short-chain alcohols to the nematode Caenorhabditis elegans: A comparison of endpointsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2005Grace Thompson Abstract The toxicities of 4 short-chain alcohols,namely methanol, ethanol, iso -propanol and iso -butanol,were compared in the nematode Caenorhabditis elegans using several different ecotoxicological endpoints. Range-finding tests were conducted using transgenic PC161 worms carrying a double reporter construct (GFP plus lacZ) linked to the stress-inducible hsp16-1 promoter. These tests showed little response from the GFP reporter, but gave good dose,response curves for the lacZ reporter,showing clear induction at 0.5% v/v ethanol in an overnight assay, but only at 4% in a shorter 6-h assay. Comparison of the short-term dose,response curves shows a confusing pattern of differences between the four alcohols tested, although dose-dependence is evident across at least part of the concentration range. Feeding inhibition assays are somewhat inconclusive with regard to alcohol type, although iso -butanol and iso -propanol appear more toxic than ethanol, while methanol is least toxic. To resolve some of the remaining ambiguities, we also used a fecundity assay to show that iso -propanol is more toxic than ethanol, and a lethality assay to show that iso -butanol is more toxic than iso -propanol. Most of the endpoints studied are consistent with the following order of toxicity: iso -butanol > iso -propanol > ethanol , methanol. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:87,95, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20060 [source] Microemulsion polymerization of styrene stabilized by sodium dodecyl sulfate and short-chain alcoholsJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 19 2001Chorng-Shyan Chern Abstract Styrene microemulsion polymerizations with different short-chain alcohols [n -CiH2i+1OH (CiOH), where i = 4, 5, or 6] as the cosurfactant were investigated. Sodium dodecyl sulfate and sodium persulfate (SPS) were used as the surfactant and initiator, respectively. The desorption of free radicals out of latex particles played an important role in the polymerization kinetics. An Arrhenius expression for the radical desorption rate coefficient was obtained from the polymerizations at temperatures of 50,70 °C. The polymerization kinetics were not very sensitive to the alkyl chain length of alcohols compared with the temperature effect. The maximal polymerization rate in decreasing order was C6OH > C4OH > C5OH. This was related to the differences in the water solubility of CiOH and the structure of the oil,water interface. The feasibility of using a water-insoluble dye to study the particle nucleation mechanisms was also evaluated. The parameters chosen for the study of the particle nucleation mechanisms include the cosurfactant type (CiOH), the SPS concentration, and the initiator type (oil-soluble 2,2,-azobisisobutyronitrile versus water-soluble SPS). © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3199,3210, 2001 [source] Octanol Modulation of Neuronal Nicotinic Acetylcholine Receptor Single ChannelsALCOHOLISM, Issue 11 2004Yi Zuo Background: We have previously shown that alcohols exert a dual action on neuronal nicotinic acetylcholine receptors (AChRs), with short-chain alcohols potentiating and long-chain alcohols inhibiting acetylcholine (ACh)-induced whole-cell currents. At the single-channel level, ethanol increased the channel open probability and prolonged the channel open time and burst duration. In this study, we examined the detailed mechanism of the inhibitory action of the long-chain alcohol n -octanol on the neuronal nicotinic AChR. Methods: Single-channel currents induced by application of 30 nm ACh were recorded with the patch-clamp technique from human embryonic kidney cells stably expressing the human ,4,2 AChR. Results: Several single-channel parameters were markedly changed by octanol. At least two conductance-state currents were induced by low concentrations of ACh, and octanol increased the proportion of the low-conductance-state current relative to the high-conductance-state current without changing the current amplitude. Major analyses of temporal properties of single-channel currents were performed on the high-conductance-state currents. Octanol decreased the burst duration and duration of openings within burst and prolonged the mean closed time. All of these changes contributed to the decrease in the open probability in a concentration-dependent manner. Conclusions: Several aspects of octanol action on neuronal AChRs at the single-channel level are compatible with an atypical open channel block model reported with muscle nicotinic AChRs. The potentiating action of short-chain alcohols and the inhibitory action of long-chain alcohols on the neuronal nicotinic AChR are mediated through different mechanisms. [source] Acetylcholine and Alcohol Sensitivity of Neuronal Nicotinic Acetylcholine Receptors: Mutations in Transmembrane DomainsALCOHOLISM, Issue 12 2002Cecilia M. Borghese Background The effect of n-alcohols on glycine and ,-aminobutyric acid type A receptors depends on two specific amino acids (AAs) located in the transmembrane domains (TM) 2 and 3. Our aim was to assess whether the corresponding AAs in the neuronal nicotinic acetylcholine receptor (nAChR) also formed a binding pocket for alcohols. Methods We made single AA substitutions in the homologous sites in rat neuronal nAChR ,2 and ,4 (,L261 and ,L283) and expressed them in Xenopus laevis oocytes in combination with ,4 wild type. The effect of different n-alcohols was studied in ,4(L261A),4 and ,4(L283A),4 nAChRs. The effect of ethanol, propanol, and octanol on acetylcholine (ACh) responses was studied in ,2(L261X),4 and ,2(L283X),4 nAChRs. Results Most of the mutations in the ,2 subunit, in either the 261 or the 283 position, induced changes in ACh sensitivity and increased alcohol action, but none was able to reduce ethanol potentiation. In ,4(L283A),4, enhancement of potentiation by short-chain alcohols was observed, as well as a change from inhibition to potentiation for long-chain alcohols. The exposure of the AAs was assessed through the action of a charged thiol-specific reagent on ,2(L261C),4 and ,2(L283C),4, and these experiments suggest that the AA in TM2 is located in a water-accessible position, whereas the AA in TM3 is inaccessible. However, a noncharged thiol-specific reagent did not affect either ACh responses or ethanol effect on ,2(L261C),4. Conclusions The AAs located at positions 261 and 283 of the ,2 and ,4 nAChR subunits do not seem to form a binding pocket for alcohols. Additional studies are required to determine whether alcohols act on a site near these AAs or on sites unrelated to the TM2-TM3 site found in glycine and ,-aminobutyric acid type A receptors. [source] |