Chemical and analytical characterization of related organic impurities in drugs

A system is proposed for the classification of related organic impurities in drugs and drug products including among others (separated and non-separated) intermediates, various kinds of by-products, among them products of different side reactions, epimeric/diastereomeric, enantiomeric impurities, impurities in natural products, and finally degradation products. Examples are taken mainly from the author's own experience and from among the named impurities in the European Pharmacopoeia with focus on impurities in hydrocortisone, prednisolone, enalapril maleate, lisinopril, ethynodiol diacetate, pipecuronium bromide, cimetidine, and ethynylsteroids. The methodological aspects of impurity profiling from the detection to the identification/structure elucidation and quantitative determination of impurities are briefly summarized.This paper is Part 23 in the series "Estimation of impurity profiles of drugs and related materials". For Part 22 see ref. [1].     

Synthesis, characterization and thermal properties of new aromatic quaternary ammonium bromides: precursors for ionic liquids and complexation studies

Series of new aromatic R₂R′₂N⁺Br⁻ (R=benzyl, 4-methylbenzyl, 2-phenylethyl, 3-phenylpropyl; R′=ethyl, methyl, isopropyl) or RR′₂NH⁺Br⁻-type (R=benzyl, R′=isopropyl) quaternary ammonium bromides were prepared by using novel synthetic route in which a formamide (N,N-diethylformamide, N,N-dimethylformamide, N,N-diisopropylformamide) is treated with aralkyl halide in presence of a weak base. The compounds were characterized by ¹H-NMR and ¹³C-NMR spectroscopy and mass spectrometry. Structures of the crystalline compounds were determined by X-ray single crystal diffraction, and in addition the powder diffraction method was used to study the structural similarities between the single crystal and microcrystalline bulk material. Three of the compounds crystallized in monoclinic, two in orthorhombic and one in triclinic crystal system, showing ion pairs, which are interconnected by weak hydrogen bonds and weak π-π interactions between the phenyl rings. Three of the compounds appeared as viscous oil or waxes. Finally, TG/DTA and DSC methods were used to analyze thermal properties of the prepared compounds. The lowest melting points were obtained for diethyldi-(2-phenylethyl)ammonium bromide (122.2 °C) and for diethyldi-(3-phenylpropyl)-ammonium bromide (109.1 °C). In general, decomposition of the compounds started at 170-190 °C without identifiable cleavages, thus liquid ranges of 30-70 °C were observed for some of the compounds.     

Li2Br(NH2): Das erste ternäre Alkalimetallamidhalogenid

Li₂Br(NH₂): The First Ternary Alkali Metal Amide Halide The pseudobinary system LiNH₂/LiBr was investigated by X-ray methods. The crystal structure of the compound Li₂Br(NH₂) was solved by single crystal data: Li₂Br(NH₂): Pnma, Z = 8, a = 12.484(2) Å, b = 7.959(1) Å, c = 6.385(1) Å, Z(F_o) with (F_o)² ≧ 3σ(F_o)² = 348, Z (parameter) = 51, R/R_w = 0.019/0.021 Li₂Br(NH₂) crystallizes in a new type of structure. To one another isolated chains of [Li₂Li_4/2(NH₂)₂²⁺] show the motif of closest rod packing. They are connected via bromide ions in a distorted cubic primitive arrangement.     

甲基化的β-环糊精与十六烷基三甲基溴化胺的相互作用

环糊精与表面活性剂的相互作用已有许多研究,但多局限于β－环糊精（β－CD）,而修饰的β－环糊精与表面活性剂的相互作用研究较少[1－3]．分子内扭转电荷转移（TICT）激发态对介质极性高度敏感性,已成功地用于探针环糊精与表面活性剂的相互作用[4]．研究表明,β－CD能够诱     

Indium Mediated Conjugate Addition of Allyl Bromide to Nitroalkenes in DMF—H2O Media

Allylindium bromide prepared by metallic indium and allyl bromide was added to nitroalkenes to give conjugate addition compounds in moderate to good yields in an aqueous media.     

Die Gadoliniumcarbidhalogenide Gd4C2X3 (X = Cl,Br)

The Gadolinium Carbide Halides, Gd₄C₂X₃ (X = Cl, Br) The compounds Gd₄C₂X₃ (X = Cl, Br) and Tb₄C₂Br₃ have been prepared by reaction of the metals (RE), REX₃, and C in sealed Ta capsules at 1 100° and 1 300°C, respectively. Monophasic samples of Gd₄C₂Br₃ and Tb₄C₂Br₃ were obtained by reacting stoichiometric mixtures of the starting materials for five days. The needle shaped crystals are bronze-coloured and sensitive to air and moisture. Gd₄C₂X₃ crystallizes in the space group Pnma (No. 62) with lattice constants a = 1 059.6(4), b = 368.4(1), c = 1 962.7(8) pm (Gd₄C₂Cl₃), a = 1 084.4(1), b = 373.0(1), c = 2 036.1(1) pm (Gd₄C₂Br₃). According to Guinier photographs, Tb₄C₂Br₃ is isotypic (a = 1 074.3(2), b = 370.6(1), c = 2 019.4(1) pm). In the crystal structure C is octahedrally coordinated by Gd. The Gd₆ octahedra are linked via common edges to form corrugated layers. The X-anions coordinate all free edges and corners of these layers and connect them via Xⁱ? Xⁱ contacts parallel [001]. Gd₄C₂Br₃ shows metallic conductivity. The magnetic susceptibility follows at high temperatures a Curie Weiss law with an effective moment of 7.95 μ_B. At temperatures below 50 K antiferromagnetic order is observed.     

Asymmetric Reduction Using Lithium Aluminum Hydride Modified with Chiral Ligands Prepared from (1R)-(-)-β-Pinene

The reduction of prochiral ketones using chiral reducing reagents, prepared from lithium aluminum hydride and (-)-(1R, 2S, 3S, 5R)-10-anilinopinanediol (5) and (-)-(1R, 2S, 3S, 5R)-10-N-methylanilinopinanediol (6), affords chiral secondary alcohols in useful chemical yields (70 ～ 93%) but in low optical purity (8 ～ 33% ee). Modifiers 5 and 6 are synthesized from (lR)-(-)-β-pinene in three steps.     

Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl₃-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl₃ was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC₅₀ values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.     

The investigation of the (p,ρ,T) and (ps,ρs,Ts) properties of {(1−x)CH3OH + xLiBr} for the application in absorption refrigeration machines and heat pumps

The (p,ρ,T) and (p_s,ρ_s,T_s) properties of {(1−x)CH₃OH + xLiBr} over a wide range of state parameters are reported for the first time. The experiments were carried out in a constant volume piezometer over a temperature range from 298.15 K to 398.15 K, at 0.08421, 0.13617, 0.19692, 0.23133 and 0.26891 mole fractions and from atmospheric pressure up to 60 MPa. The experimental uncertainties are ΔT=±3 mK for temperature, Δp=±5·10⁻² MPa for high pressure and Δp=±5·10⁻⁴ MPa for atmospheric pressure, Δρ=±3·10⁻² kg · m⁻³ for density. An equation of state was derived for correlation of the experimental data of the solutions.     

维生素K1合成的改进

维生素K1分子侧链上有一双键，因而存在几何异构体．天然维生素K1是2，3一反式构型，合成品为顺式和反式异构体的混合物，而顺式异构体几乎没有生理活性．故此，八十年代以后，各国药典均对维生素K；顺式异构体规定了限量，中国药典（1995版）规定顺式异构体的含量不得超过ZI．0％［’］．目前国内流行的制备方法是以甲素配为起始原料，须经还原、乙酸化、水解、缩合、再水解和氧化五步反应制得［’］，步骤长、收率低、对环境污染大．而用异植物酶合成引人侧链时，制备的维生素K；顺式异构体含量较高，达不到药典要求．为满足新版药典的…