目的 测定不同来源非洛地平原料药及其制剂的晶型现状,探讨非洛地平的质量、疗效与其晶型状态的关系。方法 采用粉末X射线衍射分析法(PXRD)、红外光谱分析法(IR)、差示扫描量热法(DSC)等技术对不同来源的原料样品进行晶型表征,采用Origin软件分析不同来源制剂样品中原料药晶型的存在形式,并采用整体动物完成了其生物学评价。结果 发现了不同来源非洛地平原料药的晶型状态存在一定的差异,但主成分基本一致,均为晶Ⅰ型;生物学研究显示不同来源的非洛地平缓释片在主要药动学参数呈现显著的差异性,其中ρmax、tmax、t1/2、AUC0-t的最大差异分别达到1.8、1.4、8.2、1.5倍之多。结论 不同来源非洛地平原料药的晶型主成分虽然一致,但经制剂工艺制备后晶型状态明显发生改变,值得进一步研究。实验为指导工艺改进,提高产品质量提供一定的科学依据。
Abstract
OBJECTIVE To clarify the crystal forms of the active pharmaceutical ingredient and preparations of felodipine from different sources, and explore the relationship between quality and efficacy of felodipine and its crystal form. METHODS Crystal form characterization of the active pharmaceutical ingredient from different sources was carried out by powder X-ray diffraction (PXRD), infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The Origin software was used to analyze the crystal forms of felodipine in the sample preparations from different sources. Biological evaluation in vivo was conducted by using whole animals. RESULTS There were some differences in the crystal state of the active pharmaceutical ingredient from different sources, but the main components were basically the same, all of which were type I. Biological studies showed significant differences in the main pharmacokinetic parameters of felodipine sustained release tablets from different sources. Among them, the ρmax, tmax, t1/2, and AUC0-t had maximal 1.8, 1.4, 8.2 and 1.5 times of differences. CONCLUSION Although the main crystal forms of felodipine bulk drug from different origins are consistent, the crystal state significantly changes after the preparation process. This finding is of important scientific significance to guide the improvement of process and product quality.
关键词
二氢吡啶类 /
非洛地平 /
多晶型 /
粉末X射线衍射分析法 /
红外光谱分析法 /
差示扫描量热法 /
药动学
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Key words
DHP /
felodipine /
polymorphism /
powder X-ray diffraction /
infrared spectrum /
differential scanning calorimetry /
pharmacokinetics
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中图分类号：
R917
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参考文献
[1] HU D M. Recent progress in the study of dihydropyridine calcium antagonists[J]. Natl Med Front China (中国医疗前沿),2010,5(13):12-13.
[2] Ch.P(2015) Vol Ⅱ(中国药典2015年版. 二部)[S]. 2015:640.
[3] SHEN W B,WANG Q F,LIAO H P. Study of NMR methods for stereoisomeric determination of pharmaceuticals Ⅰ. Felodipine[J]. Chin J Pharm Anal(药物分析杂志), 1996, 16(4):230-233.
[4] RUNE F. Crystal structure of the dihydropyridine Ca2+ antagonist felodipine. Dihydropyridine binding prerequisites assessed from crystallographic data[J]. J Med Chem,1986,29(2):305-307.
[5] JUDITH M R,ARTUR B. Polymorphism of racemic felodipine and the unusual series of solid solutions in the binary system of its enantiomers[J]. J Pharm Sci,2001,90(7):949-959.
[6] BENYONG L, DAN B, SITARAM P V. Polymorph control of felodipine form Ⅱ in an attempted cocrystallization[J]. Cryst Growth Des,2009,9(3):1254-1257.
[7] ARTEM O S, KATARZYNA A S, ANDREW D B, et al. Crystallization and polymorphism of felodipine[J]. Cryst Growth Des,2012,12:4022-4030.
[8] GERMAN L P, SVETLANA V B, NIKOLAY G M, et al. Polymorphs and solvates of felodipine: analysis of crystal structures and thermodynamic aspects of sublimation and solubility processes[J]. Cryst Eng Comm,2012,14:8577-8588.
[9] KATARZYNA A S, ARTEM O S, GERMAN L P, et al. Felodipine diazabicyclo[2.2.2]-octane-water(1/1/1)[J]. Acta Cryst,2012,C68:456-458.
[10] LÜ Y,DU G H. Polymorphic Drugs(晶型药物)[M]. Beijing: People′s Medical Publishing House,2009:198.
[11] FANG L H, HE G R, WANG Y H, et al. Study on the biological activity of compound crystal in the early evaluation of drug resistance[J]. Chin Pharm J (中国药学杂志),2013,48(7): 497-500.
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脚注
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基金
“重大新药创制”科技重大专项资助(2015ZX09303001)
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