Study On Preparation And Physi-chemical Properties Of Puerarin Succinate

As one of the important active components of pueraria lobato (Wild) Ohwi., puerarin (4', 7-dihydroxy-8-C-β-D-gluco-isoflavone) has broad pharmacological activities, such as vasodilating function, distinct improving brain microcirculation, peripheral circulation, etc. It is applied clinically for cardiovascular diseases, such as cardiac angina, miocardial infarction, blood hyperviscosity, etc. Furthermore, it is of low toxicity and quick metabolism. However, due to the structure characteristics of isoflavones, puerarin has bad solubility and low oral bioavailability, which restrict the clinical application.To improve the solubility and bioavailability of puerarin, the research selects puerarin as the lead compound and synehtesises puerarin succinate at one of the hydroxy with hydroxyethylation and esterification. The introduced group changes the planar rigid structure of puerarin and improves the derivative solubility much than puerarin. Moreover, the new sodium salt gained from the single carboxyl of puerarin succinate has improved water solubility. The chemical structure of target compound,puerarin succinate is confirmed by U.V., I.R., 1HNMR and 13CNMR. It is an innovative compound that not been reported before. The Puerarin derivatives are separated and purified with TLC and silica gel column chromatography. And the optimal synthesis process is gained through single factor test and orthogonal test.The basic physi-chemical properties and stability of puerarin derivative are researched. The melting points for derivativeⅠandⅡare 142.5±1.5℃and 116.1±2.9℃, respectively, which are both lower than puerarin's. Compared with puerarin, derivativeⅡhas better lipid-solubility. Its solubility improves by 1.87 times in methanol, 3.01 times in ethanol and 4.86 times in 1-octanol. The water solubility of sodium derivativeⅡis 141.63mg/ml, which is 53.24 times than Puerarin. The stability of derivativeⅡand its sodium salt are basically good but they are likely to absorb moisture under the experiment conditions.The dissolution rate in vitro, lipid/aqueous partition coefficient and dissociation constant (pKa) of puerarin derivative are researched for pharmacology. Drug dissociation in body fluid is also calculated and evaluated. DerivativeⅡdissolution trend in vitro is similar with puerarin in 0~24h,but about 2 times than puerarin in 0~1h, and the final dissolution rate of derivativeⅡis 79.03% at 24h; pKa of derivativeⅡis 6.14, which accords with the fundamental property of the drug compound; derivativeⅡis not easy to dissociate in stomach fluid, and the non-dissociation state of derivativeⅡis 993 times than that of puerarin in intestinal fluid, which indicates that intestines absorption of derivativeⅡshould be improved greatly; lipid/aqueous partition coefficient of derivativeⅡshows that it has relatively good lipid solubility and we could regulate pH to change the distribution of medicine.It is validated through the research that the new compound puerarin succinate and its sodium salt obtained through structure design and modification from puerarin have better solubility and physi-chemical properties, which could help to improve drug distribution in vivo, the bioavailability and enhance the pharmacological activities. Consequently, puerarin succinate as a new puerarin derivative has unambiguous structure, steady-going performance, security and good effect. It can be researched further for new drug R&D and this work also has great theoretical value and social significance.