Avermectin在不同溶剂中溶解度的测定与关联

本文用动态法测定avermectin在甲醇、乙醇、正丙醇、正丁醇和正戊醇中的溶解度曲线，并分别用理想溶液模型、Apelblat溶解度模型和多项式经验方程对实验测定溶解度数据进行关联。结果显示理想溶液模型的误差较大，多项式经验方程的误差最小。实验得到的溶解度曲线及关联结果对avermectin结晶工艺的研究具有较大的指导意义。     

截短侧耳素C-14侧链的修饰及其抗菌活性研究进展#br#

抗生素的广泛使用和滥用导致耐药性细菌日益增加。为了应对这种局面,研究人员加大了对抗耐药性细菌抗生素的研发力度。基于此,20世纪50年代,从高等真菌中分离的具有良好抗菌活性的先导化合物截短侧耳素得到了越来越多的关注和研究。构效关系研究表明,截短侧耳素的三环母核结构的改造对抗菌活性的提高作用不大,而对C-14侧链的修饰则可以增加截短侧耳素的抗菌活性和改善其药动学性质。本文就近10年来国内外对截短侧耳素C-14侧链的修饰、抗菌活性和构效关系研究进行综述,并总结了目前研究中存在的问题。     

人用截短侧耳素类抗生素的研究现状与发展趋势

为了应对日益严重的细菌耐药性问题,人们不断研发具有新型作用机制的抗菌药物,其中截短侧耳素及其衍生物作为重要的一类兽用抗生素,具有独特的作用机制,其特点不易产生交叉耐药性.已经上市的泰妙菌素、沃尼妙林均具有抗菌谱广及较强的抗菌活性,而2007年4月批准的瑞他莫林是近二十年来首个新的局部应用的抗菌药物,被认为是第一个人用截短侧耳素衍生物,标志着截短侧耳素类从兽用跨越到人用领域.本文就截短侧耳素的作用机制、耐药机制、人用截短侧耳素的临床研究现状以及新型截短侧耳素衍生物研发等方面的最新进展做简要概述.     

截短侧耳素类抗生素及其耐药研究进展

截短侧耳素(Pleuromutilins)是从担子菌纲侧耳属Pleurotus mutilus和Pleurotus passeckerianus中分离得到的二萜类抗生素，对革兰阳性菌和支原体具有良好的抗菌活性。截短侧耳素类药物用途广泛，泰妙菌素(Tiamulin)和沃尼妙林(Valnemulin)作为兽用药用于防治由病原微生物引起的猪痢疾、支原体肺炎等疾病；人用批准的瑞他莫林(Retapamulin)和来法莫林(Lefamulin)主要用于治疗球菌感染和获得性细菌性肺炎。近年来，截短侧耳素类药物耐药监测表明，在病原微生物的rplC、rplD、23sRNA、Cfr和vga基因中报道了多种新的突变位点，导致侧耳素类药物敏感性降低。本文对已上市的截短侧耳素类药物进行回顾，并对近十年该类药物的耐药机制研究进行综述，以期为新型截短侧耳素类药物的创制提供参考。     

盐酸强力霉素在几种溶剂体系中的溶解度测定

利用盐酸强力霉素在不同比例的乙醇—水溶剂中的溶解过程所出现pH值的改变,测定它在该溶液中的溶解度。把此数据与观察法、差重法所测得的数据相比较基本吻合,而以pH值法求得的较为准确。 盐酸强力霉素在乙醇—水溶剂中的溶解平衡为一级弱酸电离平衡。其溶解度随溶液中水组分的增加而增大,并随温度的升高而增大;在乙醇—盐酸溶液中用差重法测得的溶解度规律是随盐酸含量的增加,溶解度减小,温度升高溶解度增大;在盐酸—乙醇—水溶剂中,溶解度规律是随盐酸的含量增加,溶解度减小。     

截短侧耳素及其衍生物的研究进展

截短侧耳素是重要的二萜类兽用抗生素.发现至今,针对其衍生物进行了深入研究,发现了抗菌活性更强、应用范围更广的泰妙菌素、沃尼妙林、retapamulin和一系列水溶性衍生物等.其中retapamulin是2007年4月FDA批准的近二十年来第一个新的局部应用的抗菌药物,同时作为第一个人用截短侧耳素衍生物,标志着此类抗生素实现了从兽用到人用的飞跃.本文就截短侧耳素的作用机制、生物合成及其衍生物应用等方面的最新进展做简要概述.     

提高难溶性药物溶解度的研究

目的提供解决药物难溶解问题的方法。方法对目前提高药物溶解度方法进行分析归纳。结果加入增溶剂、加入助溶剂、使用复合溶剂、调节溶液pH值等都可以增加难溶性药物的溶解度。结论每种方法都各有长处,应综合利弊进行合理选择。     

杨梅素-咖啡因共晶在不同有机溶剂中的形成热力学特征

目的考察了杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的形成热力学特征。方法通过测定杨梅素、咖啡因、杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的溶解度,探讨杨梅素-咖啡因共晶的溶液络合模型,计算相关热力学参数,并绘制3种溶剂的共晶三元相图。结果杨梅素-咖啡因共晶在3种溶剂中均符合1∶1溶液络合模型;共晶形成反应为热力学自发反应(ΔG°<0),随着温度升高,溶度积(Ksp)逐渐增大,络合常数(K11)逐渐减小,反应自发程度减弱,低温有利于共晶的形成;共晶的溶解为吸热过程(Δ_(sol)H_m>0),升高温度有利于共晶的溶解。杨梅素-咖啡因-溶剂(甲醇、乙醇和丙酮)三元体系的三相图为对称相图,共晶形成区域在乙醇和丙酮中较甲醇中大,共晶更易形成。结论利用热力学研究方法为选择共晶制备用溶剂及优化共晶制备条件奠定了理论和应用基础。     

Lefamulin：一种新型人用截短侧耳素类抗菌药物的临床药学研究

摘要：Lefamulin是全球首个静脉和口服剂型的人用截短侧耳素类抗菌药物,具有独特的作用机制,与其他临床用抗菌 药物不易产生交叉耐药性。对社区获得性肺炎、皮肤软组织感染以及性传播疾病的常见病原体有良好的抗菌活性。本文就 lefamulin的作用机制、耐药机制、抗菌活性以及临床使用等方面进行综述。     

治疗人革兰阳性球菌皮肤感染的截短侧耳素类抗生素Retapamulin

Retapamulin(SB-275833)是开发为人类局部用药的首个截短侧耳素类抗生素,对葡萄球菌和β-溶血性链球菌有抗菌活性,对金葡菌和酿脓链球菌的MIC90分别为0.12和≤0.03μg/mL.未发现其对耐苯唑西林、红霉素或莫匹罗星的病原菌亚型有交叉耐药性.     

3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸4-硝基苄酯在不同溶剂中溶解度测定与关联

采用平衡法测定了283.15~353.15K范围内美罗培南中间体(3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸 4-硝基苄酯)在乙酸乙酯、乙酸甲酯、正丙醇和丙酮溶液中的溶解度，并用Apelblat模型、经验多项式模型、λ-h模型对实验数据进行关联。结果证明：3-酮-2硫杂-5-氮杂双环[2.2.1]庚烷-5-酸4-硝基苄酯溶解度随着温度的升高而增加。Apelblat模型平均相对误差小于8%，经验模型平均相对误差小于10%，λ-h方程拟合平均相对误差小于2%，效果最佳。应用单晶衍射仪首次确定了晶体属正交晶系，空间群P21，晶胞参数a=7.1630nm、b=9.1713nm、c=20.998nm、α=90°、β=90°和γ=90°。     

Measurement and correlation of solubility data for albendazole in ten pure solvents and two binary solvent systems from 278.15 K to 323.15 K

The equilibrium solubility of albendazole (ABZ) in ten single solvents and two binary solvent mixtures of different ratio was measured by a typical static method combined with ultraviolet (UV) spectrophotometry within the temperature range from 278.15 K to 323.15 K. Meanwhile, the modified Apelblat model, Van't Hoff equation and λh equation were used to correlate the solubility data of ABZ in pure solvent, the modified Apelblat model, λh equation, Sun model, GSM equation and NRTL model were used to correlate the solubility data of ABZ in binary mixed solvent, the 100RD, 100ARD, 103RMSD and 103ORMSD values of the above models were calculated respectively. The results show that the experimental data of six models have a good correlation with the calculated data. Especially, the Van't Hoff equation in pure solvent has the best fitting effect, and the GSM equation in binary mixed solvent has the best fitting effect. Additionally, the Van't Hoff equation was used to calculate and evaluate the thermodynamic properties of the ABZ dissolution process, including enthalpy (ΔdisH), entropy (ΔdisS) and Gibbs free energy (ΔdisG).     

Solution thermodynamics and solubility prediction of glibenclamide in Transcutol + water co-solvent mixtures at 298.15–333.15 K

Solution thermodynamics and solubility of glibenclamide (GBN) in binary co-solvent mixtures of Transcutol + water at temperature range of 298.15–333.15 K were investigated in present study. The modified Apelblat model was used to predict the solubility of GBN in co-solvent mixtures at various temperatures. The highest and lowest solubility of GBN were observed in pure Transcutol and pure water, respectively. Moreover, all co-solvent mixtures had highest solubility at 333.15 K. The experimental solubility data of GBN was correlated well with the modified Apelblat model at each temperature studied with relative absolute deviation in the range of 0.008–5.903 %. The correlation coefficients in co-solvent mixtures were observed in the range of 0.995–0.999 which indicated good fitting of experimental data with calculated one. The enthalpies and entropies for GBN dissolution were observed in the range of 2.012–38.215 kJ mol^?1 and 6.748–114.709 J mol^?1 K^?1, respectively indicating its dissolution is endothermic and an entropy-driven process. These results indicated that Transcutol can be used as a co-solvent in preformulation studies and formulation development of GBN.     

Thermodynamics-based mathematical model for solubility prediction of glibenclamide in ethanol–water mixtures

Abstract

Temperature-dependent solubility data of glibenclamide (GBN) in various ethanol–water mixtures is not reported in literature so far. Therefore, the aim of this study was to determine the mole fraction solubility of GBN in various ethanol–water mixtures at the temperature range of 293.15 to 318.15?K. The solubility of GBN was determined by reported shake flask method and the experimental data was fitted in thermodynamics-based modified Apelblat model. The solubility of GBN was found to be increased with increase in temperature and mass fraction of ethanol in ethanol–water mixtures. The experimental data of GBN was well correlated with the modified Apelblat model at each temperature range with correlation coefficient of 0.9940–1.0000. The relative absolute deviation (AD) was found to be less than 0.1% except in pure ethanol and water. The positive values of enthalpies and entropies for GBN dissolution indicated that its dissolution is endothermic and an entropy-driven process.     

General treatment of pH-solubility profiles of weak acids and bases and the effects of different acids on the solubility of a weak base

The pH-solubility profile of a weak acid or base is shown to be a function of its pKsp, pKa, and uncharged species solubility. Equations are presented that can be used to calculate the solubility as a function of pH. These equations can also be used when there is added salt present. Experimental data was obtained in three cosolvent systems consisting of methanol-water and ethanol-water. Also, the effect of different acids on the solubility of a weak base is reported. A pronounced effect on the solubility by the addition of salt is explained in terms of the Ksp.     

Excess free energy approach to the estimation of solubility in mixed solvent systems I: Theory

An approach is developed by which the solubility of an organic compound in mixed solvents may be estimated. In this approach, an expression for the excess Gibbs free energy of mixing for multicomponent solvent systems was used to obtain parameters characteristic of the interaction between the solvents. A fairly simple equation which predicts the solubility of a solute in a binary solvent system over the entire solvent composition range was then derived. The equation may be partitioned into terms that contain (a) pure solvent solubilities, (b) solvent-solvent interaction contributions, and (c) contributions from the solute-mixed solvent interactions. The required data are the molar volume of the solute, the pure solvent solubilities, and, theoretically, one experimentally determined solubility in a solvent mixture. The equation can be easily extended for systems with three or more solvents.     

Solubility Prediction of Satranidazole in Propylene Glycol-Water Mixtures Using Extended Hildebrand Solubility Approach

Extended Hildebrand solubility approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various propylene glycol-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility equation employs term interaction energy (W) to replace the geometric mean (δ₁δ₂), where δ₁ and δ₂ are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in δ₁ of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in propylene glycol-water mixtures. The expression yields an error in mole fraction solubility of ~3.74%, a value approximating that of the experimentally determined solubility. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.     

RP-HPLC法测定陆英颗粒与陆英糖浆中乌索酸与齐墩果酸含量

目的测定陆英颗粒和陆英糖浆中乌索酸与齐墩果酸的含量。方法用RP HPLC法。色谱柱为Kromasil C18柱(250 mm×4.6 mm,5μm),流动相为甲醇水(体积比为87∶13),检测波长为210 nm,流速为1.0 mL.min-1,柱温为35℃,进样量为20μL。结果在该色谱条件下,乌索酸质量浓度在5.4~86.4 mg.L-1内,质量浓度与峰面积具有良好的线性关系,回归方程为A=9.58×103ρ-2.769×104,r=0.999 0;齐墩果酸质量浓度在5.2~83.2 mg.L-1内,质量浓度与峰面积具有良好的线性关系,回归方程为A=7.604×103ρ-2.253×104,r=0.999 0。陆英颗粒中乌索酸与齐墩果酸加样回收率分别为101.0%(RSD=1.9%)、99.6%(RSD=1.3%);陆英糖浆剂中乌索酸与齐墩果酸加样回收率分别为99.9%(RSD=1.4%)、100.3%(RSD=1.1%)。结论该法为陆英颗粒及陆英糖浆的质量控制提供了依据。     

A Study on Improvement of Solubility of Rofecoxib and its effect on Permeation of Drug from Topical Formulations

Rofecoxib, a practically insoluble cox-2 selective nonsteroidal antiinflammatory agent was subjected to improvement in solubility by preparing its binary mixtures with β cyclodextrin using various methods such as physical mixing, co-grinding, kneading with aqueous methanol and co-evaporation from methanol-water mixture. Characterization of the resulting binary mixtures by differential scanning calorimetry and X-ray diffraction studies indicated partial amorphization of the drug in its binary mixtures. In vitro dissolution studies exhibited remarkable increase in rate and extent of dissolution of the drug from its complexes with β -cyclodextrin. Pure rofecoxib as well as its co-ground binary mixture were formulated as aqueous gels for topical application. In vitro skin permeation of rofecoxib from formulation containing rofecoxib-cyclodextrin complex was significantly higher (p<0.05) at 1, 2, 12, 18 and 24 hr as compared to formulation containing pure rofecoxib. This could be attributed to better solubility of binary mixture in the aqueous gel vehicle leading to greater concentration gradient between the vehicle and skin and hence higher flux of the drug.