截短侧耳素在醇——水复合溶剂体系溶解度的测定与关联
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摘要
截短侧耳素是一种三环二萜类抗生素,因其抗菌机制独特,与一般抗菌药物不发生交叉耐药,而日益受到重视。本研究测定了截短侧耳素在不同甲醇(或乙醇)-水复合溶剂(醇含量0～50%)中在273.15～333.15K溶解度,并采用多项式经验方程和Apelblat方程进行关联。结果表明,随着温度的提高,随溶剂中甲醇或乙醇含量的增加,截短侧耳素的溶解度显著同步增加。多项式经验方程和Apelblat方程都能很好拟合截短侧耳素溶解度数据,回归系数都在0.993以上。热力学分析表明,截短侧耳素在甲醇(或乙醇)-水复合溶剂中的溶解过程焓变都是正值,且随着溶剂中醇含量的增加而增加,是一吸热过程。溶解过程的熵变在纯水中是负值,随着溶剂中醇含量的增加,熵变也随之增加并且成为溶解度大幅提升的主要驱动力。本论文的研究结果可为截短侧耳素的提取工艺优化及制剂工艺开发提供重要的科学依据。
Pleuromutilin attracts more and more research interest because of its unique antibacterial mechanism and no cross-resistance to common antibiotics, especially when antibiotic resistance becomes more often nowadays. In this paper, the solubility of pleuromutilin in the binary solvents of ethanol-water and methanol-water was investigated in the temperature range of 273.15～333.15 K and the alcohol content of 0～50%(V/V) by the static equilibrium method, and correlated with polynomial empirical equation and Apelblat equation. The results showed that the solubility of pleuromutilin in the binary system of ethanol-water and methanol-water increase sharply with an augment in alcohol concentration and temperature in the range investigated. In addition, solubility data were well fitted by polynomial empirical equation and Apelblat equation with a minimum R2=0.993. The analysis of thermodynamics showed that the molar enthalpy was positive, which implied that the solution process is endothermal. The molar entropy increased from negative to positive, and became the main driving force of solubility increase. The results will extend the database of experimental solubility of pleuromutilin and provide theoretical support for the optimization of pleuromutilin purification and formulation technology.
Pleuromutilin attracts more and more research interest because of its unique antibacterial mechanism and no cross-resistance to common antibiotics, especially when antibiotic resistance becomes more often nowadays. In this paper, the solubility of pleuromutilin in the binary solvents of ethanol-water and methanol-water was investigated in the temperature range of 273.15～333.15 K and the alcohol content of 0～50%(V/V) by the static equilibrium method, and correlated with polynomial empirical equation and Apelblat equation. The results showed that the solubility of pleuromutilin in the binary system of ethanol-water and methanol-water increase sharply with an augment in alcohol concentration and temperature in the range investigated. In addition, solubility data were well fitted by polynomial empirical equation and Apelblat equation with a minimum R2=0.993. The analysis of thermodynamics showed that the molar enthalpy was positive, which implied that the solution process is endothermal. The molar entropy increased from negative to positive, and became the main driving force of solubility increase. The results will extend the database of experimental solubility of pleuromutilin and provide theoretical support for the optimization of pleuromutilin purification and formulation technology.
引文
[1]黄贺贤,曾振灵,黄显会.截短侧耳素类抗生素-泰妙菌素的研究进展[J].中国兽药杂志,2010,44(6):42-45.
[2]Fazakerley N J,Procter J D,Synthesis and synthetic chemistry of pleuromutilin[J].Tetrahedron,2014,39(70):6911-6930.
[3]Brown P,Dawson J M,Chapter Three-a perspective on the next generation of antibacterial agents derived by manipulation of natural products[J].Prog Med Chem,2015,54:135-184.
[4]Gao M L,Zeng J,Fang X,et al.Design,synthesis and antibacterial evaluation of novel pleuromutilin derivatives possessing piperazine linker[J].Eur J Med Chem,2017,127:286-295.
[5]孙影,周紫薇,李思谦,等.人用截短侧耳素类抗生素的研究现状与发展趋势[J].国外医药抗生素分册,2017,38(3):99-108.
[6]王茜.截短侧耳素类抗生素的专利分析[J].生物技术世界,2015,(4):159.
[7]陈剑慧,韩勤更,冒永松.截短侧耳素的发酵方法:CN,200810022973[P],2008-07-04.
[8]Novak R,Shlaes D M.The pleuromutilin antibiotics:A new class for human use[J].Curr Opin Invest Dr,2010,2(11):182-191.
[9]Sun S,Ai L,Zhang H,Weng C,et al.Enhanced production of pleuromutilin by pleurotus mutilus and study on its molecular structure[J].Food Chem,2017,230:350-353.
[10]张翔,黄宇琪,邹祥,等.截短侧耳素溶剂提取工艺的优化[J].食品与发酵工业,2010,36(5):151-155.
[11]韦玮,金日显,陈燕军,等.二萜类化合物的提取与纯化工艺研究进展[J].中国实验方剂学杂志,2007,13(12):66-70.
[12]许红霞,姜林锟,王利生.伊维菌素在醇及醇-水混合溶剂中溶解度的测定与关联[J].南京理工大学学报:自然科学版,2014,38(1):173-180.
[13]Apelblat A,Manzurola E.Solubilities of o-acetylsalicylic,4-aminosalicylic,3,5-dinitrosalicylic,and p-toluic acid,and magnesium-dl-aspartate in water from T=(278 to 348)K[J].J Chem Thermodyn,1999,31(1):85-91.
[14]Apelblat A,Manzurola E.Solubilities of l-aspartic,dlaspartic,dl-glutamic,p-hydroxybenzoic,o-anisic,p-anisic,and itaconic acids in water from T=278K to T=345K[J].JChem Thermodyn,1997,(29):1527-1533.
[15]Hu Y H,Chen X,Yang W G.et al.Measurement and correlation of the solubility of urea l-tartaric acid in aqueous ethanol solution[J].Thermochim Acta,2009,484(1-2):38-40.
[16]Fan J P,Xie Y L,Tian Z Y,et al.Solubilities of evodiamine in twelve organic solvents from T=(283.2 to 323.2)K[J].JChem Therm,2013,58:288-291.
[17]Wang P,Wang J,Gong J,et al.Determination of the solubility,dissolution enthalpy and entropy of deflazacort in different solvents[J].Fluid Phase Equilibr,2011,306(2):171-174.
[2]Fazakerley N J,Procter J D,Synthesis and synthetic chemistry of pleuromutilin[J].Tetrahedron,2014,39(70):6911-6930.
[3]Brown P,Dawson J M,Chapter Three-a perspective on the next generation of antibacterial agents derived by manipulation of natural products[J].Prog Med Chem,2015,54:135-184.
[4]Gao M L,Zeng J,Fang X,et al.Design,synthesis and antibacterial evaluation of novel pleuromutilin derivatives possessing piperazine linker[J].Eur J Med Chem,2017,127:286-295.
[5]孙影,周紫薇,李思谦,等.人用截短侧耳素类抗生素的研究现状与发展趋势[J].国外医药抗生素分册,2017,38(3):99-108.
[6]王茜.截短侧耳素类抗生素的专利分析[J].生物技术世界,2015,(4):159.
[7]陈剑慧,韩勤更,冒永松.截短侧耳素的发酵方法:CN,200810022973[P],2008-07-04.
[8]Novak R,Shlaes D M.The pleuromutilin antibiotics:A new class for human use[J].Curr Opin Invest Dr,2010,2(11):182-191.
[9]Sun S,Ai L,Zhang H,Weng C,et al.Enhanced production of pleuromutilin by pleurotus mutilus and study on its molecular structure[J].Food Chem,2017,230:350-353.
[10]张翔,黄宇琪,邹祥,等.截短侧耳素溶剂提取工艺的优化[J].食品与发酵工业,2010,36(5):151-155.
[11]韦玮,金日显,陈燕军,等.二萜类化合物的提取与纯化工艺研究进展[J].中国实验方剂学杂志,2007,13(12):66-70.
[12]许红霞,姜林锟,王利生.伊维菌素在醇及醇-水混合溶剂中溶解度的测定与关联[J].南京理工大学学报:自然科学版,2014,38(1):173-180.
[13]Apelblat A,Manzurola E.Solubilities of o-acetylsalicylic,4-aminosalicylic,3,5-dinitrosalicylic,and p-toluic acid,and magnesium-dl-aspartate in water from T=(278 to 348)K[J].J Chem Thermodyn,1999,31(1):85-91.
[14]Apelblat A,Manzurola E.Solubilities of l-aspartic,dlaspartic,dl-glutamic,p-hydroxybenzoic,o-anisic,p-anisic,and itaconic acids in water from T=278K to T=345K[J].JChem Thermodyn,1997,(29):1527-1533.
[15]Hu Y H,Chen X,Yang W G.et al.Measurement and correlation of the solubility of urea l-tartaric acid in aqueous ethanol solution[J].Thermochim Acta,2009,484(1-2):38-40.
[16]Fan J P,Xie Y L,Tian Z Y,et al.Solubilities of evodiamine in twelve organic solvents from T=(283.2 to 323.2)K[J].JChem Therm,2013,58:288-291.
[17]Wang P,Wang J,Gong J,et al.Determination of the solubility,dissolution enthalpy and entropy of deflazacort in different solvents[J].Fluid Phase Equilibr,2011,306(2):171-174.