摘要
天然产物有效成分是制药的重要原料,黄酮类活性成分更是天然药物研究的
热点。文献报道的黄酮类化合物晶体的结构、溶解度、光谱特性等物化参数往往
存在显著差异,已制约药物开发利用。葛根素就是一例。汇集国内外报道的葛根
素物性数据,颇为分散,已影响到葛根素原料药标准的完善。
本文运用显微观察、红外、热重、差热、X射线粉末衍射等现代分析手段,
确认了葛根素的三种晶体与一种非晶态的存在,其熔点变化范围为182~211℃;
8℃下在水中溶解度随晶型的增大而下降,范围在3.29~3.66mg/ml;与用普通溶
剂结晶相比,发现采用超临界CO_2结晶所得葛根素的溶剂残留最少、与中国药
典中的标准红外光谱最为接近、品质更优。
基于氢键结合与介电常数理论分析,实验考察葛根素在不同溶剂系统中溶解
度的变化,结果表明:葛根素溶解度和溶剂的介电常数有关,其介电需量DR大
致在35左右;通过介电需量选择70%异丙醇作为制剂溶剂,其粘度和溶解度优
于现用的50%丙二醇。
With the research and development of natural products, their active compounds, especially flavonoids had been the focus of drug raw material R&D. But it was reported that structure, solubility and spectrum of crystal flavonoids were different, which had baffled the application of drug, such as puerarin. Determination data of puerarin in recent years showed in disorder, so it had great effect on drug quality standard.
With the help of modern instruments, there were three crystalline forms and one non-crystalline form from magnified pictures, infrared spectrum, DSC, TGA and X-ray powder diffraction; The melting point of puerarin ranged from 182 to 211 ℃; The solubility descended while size of crystal increased, which ranged from 3.29mg/ml to 3.66mg/ml in 8℃; Compared with normal solvents, crystal from super critical fluid extraction had the fewest residue solvents; best quality and shape; and only SCFE crystal IR spectrum was the most similar with the standard IR spectrum in Chinese Pharmacopoeia than other crystals.
From the theory of hydrogen bond and dielectric constant, the solubility of puerarin in different solvents and mixed solvents had been explained. Final results showed the solubility of puerarin was related with dielectric requirement which was 35. Because of low viscidity and high solubility, 70% isopropanol and water had been selected as the solvent of puerarin injection rather than 50% 1,2-propandiol and water.
引文
[1]姚新生,天然药物化学[M],人民卫生出版社,1988年5月第一版
[2]J.B.哈本等,黄酮类化合物[M],科学出版社,1983,4
[3]徐坚,平其能,刘国杰.甲氧氯普胺多晶型特性研究[J].中国药科大学学报,1996,27(12):722
[4]李振华,平其能,朱颖,头孢呋辛酯的多晶型研究[J].中国药科大学学报,1997,28(1):23
[5]尹华,杨腊虎,俞如英.西咪替丁的晶型研究[J].药物分析杂志,2001,21(1):39
[6]李小鹰,王培仁,邵道华.葛根对急性梗塞患者梗塞范围的影响[J].中华心血管杂志,1985,13(3):175-178
[7]安伟建,等.不同产地葛根总黄酮含量的比较(简报)[J].中国中药杂志,1999,24(6):339
[8]刘新,等.愈风宁心片体外溶出度比较[J].中国中药杂志,2001,26(2):132-133
[9]赵晓莉,等.HPLC法测定葛恨素葡萄糖注射液中葛根素及3’-甲氧基葛根素含量[J].中国中药杂志,2000,25(7):413-415
[10]颐龚平,等.野葛组织内抗氧化物质初步分析[J].中国野生植物资源,1999,19(3):33—34
[11]徐进,等.葛根在化妆品中的应用初探[J].中国野生植物资源,1999,19(3):11—13
[12]方起程,林茂,孙庆民.葛根黄酮的研究[J].中华医学杂志,1974,54:271—274
[13]Takao M, Yoshihiro N, Toshio A, Studies on the constituents of Japanese and Chinese crud drugs. Ⅳ. on the constituents of Pueraria root[J], Chem. Pharm. Bull, 1960, 8: 688
[14]王成,刘玉玲,谷士杰.葛根素的溶解性及其络合助溶的研究.中国药学杂志[J],1993,28(5):294-296
[15]牛犇,胡先望等.甘草素与异甘草素分离研究[J].化学世界,1996,(10):539
[16]彭军鹏,姚新生等.甾体皂甙化学研究方法的进展[J],中草药,1992,23(8):437
[17]JuYong, etal. J Agric Food Chem[J], 1998, 46(9): 3785
[18]李文魁,张如意等.朝鲜淫羊藿中一种黄酮醇甙的化学结构[J].高等学校化学学报,1995,16(10):1575
[19]渠桂荣,王素贤等.裂叶苣荬菜黄酮成分的研究[J].中草药,1995,26(5):233
[20]渠桂荣,刘建等.裂叶苣荬菜的黄酮甙成分研究[J].中国中药杂志,1996,20(5):292
[21]崔承彬,等,文冠木中五种黄酮类成分的NMR研究[J].沈阳药学院学报,1991,8(1):36
[22]Kitanaka S, et al. Chem. Pharm. Bull[J]., 1992, 40(1):249
[23]游松,崔承彬等.银杏叶中金松双黄酮的核磁共振谱分析[J].沈阳药学院学报,1991,8(2):124
[24]易以军,曹正中等.茯苓化学成分研究(Ⅳ)[J].药学学报,1998,33(11),873
[25]曹正中,等.膜荚黄芪中新异黄酮苷的结构鉴定[J].药学学报,1999,34(5):392
[26]刘延泽,王荩卿等.天葵化学成分的研究Ⅰ.天葵苷的结构[J].中草药,1999,30(1):5
[27]柴田承二,和汉药成分研究(第一报)葛根成分化学的研究[J],药学杂志 79:757,1959
[28]郭建平,孙其荣,周全,等.葛根黄酮EC、PEG载药系统的研究[J].中国药学杂志,1988,33(10):598~6010.
[29]严汉英.任宝华.抗青光眼新药葛根素滴眼液的研究进展[J].眼科新进展,2000,20(6):454~455.
[30]王锦,李颖,杨丽彬.氮酮对葛根素透皮吸收作用的研究[J].药学实践杂志,1995,13(2):93~95.
[31]曾贵云,谷万章,林茂等.葛根素注射液的研究[J].中国科学院学报,1995,(1):59.
[32]黄绮红,胡容融,葛根黄豆苷元分散片的制备及其溶出度测定[J].广东药学院学报,2001,17(2):87~88.
[33]马云淑,林以宁.葛根素及其磷脂复合物的体外透皮实验研究[J].中国中药杂志,2000,13(2):93~95.
[34]Threlfall TL. Analysis of organic polymorphs[J]. Analyst (Cambridge, U.K.), 1995,120(10):2435
[35]Toscani S. Thoren S, Agafonov Ⅴ. et al Thermodynamic study of sulfanilamide Polymorphism: (Ⅰ) monotropy of the a-variety[J] Pharm Res 1995,12(10):1453
[36]刘崇悌 药物的晶型改变与晶癖以及它们对药品质量及临床药效的重要影响[J],国外医学药学分册,1980,4:207
[37]Kalinkova GN, Stoeva SV. Polymorphism of azlocillin sodium[J] Int J Pharm
1996,135(1,2): 111
[38]Burger A. Lettenbichler A. Polymorphism and pseudopoly morphism of acemetacin[J] Pharmazie, 1993,48(4):262
[39]Ogawa K, Yui T, Miya M et al. Dependence on the preparation procedure of the polymorphism and crystalllinity of chitosan membranes[J]. Biosci Biotechnol Biochem, 1992,56(6): 858
[40]Gubskaya VA, Chishko AK, Lisnyak VY st. et al. Effects of cryogrinding on physico-chemical properties of drugs: particles sizes and polymorphic transition[J]. Drug Dev Ind Pharm: 1995,21(17): 1965
[41]Kossovaky N, Gelman A, Rajguru S, et al. Control of molecular polymorphisms by a structured carbohydrate ceramic delivery vehicle-aquasomes[J] J controlled Release, 1996,39(2-3): 383
[42]Bergren MS, Chao RS, Meulman PA, et al. Solid Phases of delavirdine mesylate[J]. Pharm. Sci. 1996,85(8): 834
[43]Kristl A, Srcic S, Vrecer F, ef al. Polymorphism and pseudopoly morphism: Influencing the dissolution properties of the guanine derivative acyclovir[J], 1996,139(1,2):231
[44]Kitaoka H Wada C Morli R. et al. Effect of dehydration on the formtion of levofloxacin pseudopolymorphs [J]. Chem Pharm Bull,1995,43(4):649
[45]高崇凯,张汝华.皮质激素类药物的多品型及其片剂的溶出度研究[J].医药工业,1987,18(7):301
[46]东国满.无味氯霉素的多晶型物[J].药学通报,1982,17(2):29
[47]程卯生,王敏伟,廖锦来,等.法莫替丁的多晶型与生物利用度[J].中国药物化学杂志,1994,4(2):110
[48]殷恭宽.物理药学.北京医科大学中国协和医科大学联合出版社[M].1993:161-167
[49]周维书.有机药物伍变化的化学键理论基础,科学出版社[M].
[50]GrandyLT, HaysSE, KingRH, et al. Drug Purity pro-files[J]. J Pharm Sci, 1973, 62(3):456
[51]杨腊虎.差示扫描量热法测定药物纯度[J].药物分析杂志,1988,8(6):345
[52]郑俊民,杨丽,何有清等.应用DSC测定硝苯地平的纯度[J].沈阳药科大学学报,1995,1291):10
[53]徐莉英,苏德森,李绍顺.多沙唑嗪的多晶型研究[J].中国药物化学杂志,1995,5(4):266
[54]郑俊民,张连珠,周晖.用热分析技术和红外光谱法鉴别花鹿茸的研究[J].沈阳药科大学学报,1996,13(3):196
[55]袁锡灿,姜德和,沈海葆等.红外光谱法和X-射线粉末衍射法研究棉酚的多晶型[J].药学学报,1991,26(2):152
[56]王晋,张汝华,孙淑英.尼莫地平多晶型的研究[J].药学学报,1995,30(6):443
[57]Paruta AN, Sciarrone BJ, Lordi NG. Dielectric solubility profiles of acetanilide and several derivatives in ioxane--water mixtures[J]. J Pharm Sci 1965,54(9):1325-33
[58]Plaizier-Vercammen JA. Interaction of povidone with aromatic compounds Ⅳ: effects of macromolecule molecular weight, solvent dielectric constantm, and ligand solubility on complex formation[J]. J Pharm Sci 1983,72(9):1042-4
[59]上海医药工业研究院药物制剂部和药物制剂国家工程研究中心,药用辅料应用技术,中国医药科技出版社[M],2002:30-46
[60]中华人民共和国药典2000年二部,化学工业出版社[M]