摘要
片剂是制药行业最受欢迎的口服固体剂型,葛根素一水合物(puerarin monohydrate,PUEM)是天然抗高血压药物葛根素的市售固体形式,但低水溶性阻碍了其片剂剂型的研发.本研究采用反应结晶法成功制备出葛根素钠螯合物(PUE-Na·7H2O),通过单晶技术表征了其晶体结构,明确了其金属螯合物的结构特性.热力学研究表明,PUE-Na·7H2O的形成包括PUE的脱质子、PUE-和Na+的络合两步,且这两步反应几乎是同时发生,该过程是一个自发放热反应,温度的降低有利于螯合物形成;成核动力学研究表明,在低温、高浓度及高转速的环境中,该螯合物分子更易于成核结晶.与市售PUEM相比,PUE-Na·7H2O的水溶性得到显著提升,溶解度增加了 33.5倍,特性溶出速率提高了 37.6倍.本研究表明,药物-钠螯合物是一种能显著改善药物水溶性的固体形式.通过明确其热力学和动力学形成机制,不仅为相关产品的研发提供了新的策略,也展现了巨大的商业前景.
Abstract
Tablets represent the most widely used oral solid dosage form in the pharmaceutical industry.Puerarin monohydrate(PUEM),a solid form of the natural antihypertensive drug puerarin,is commercially available.However,the low solubility of PUEM poses a significant challenge for the development of its tablet dosage form.In this study,we successfully prepared the sodium chelates of puerarin(PUE-Na·7H2O)using reactive crystallization techniques.The crystal structure of PUE-Na·7H2O was analyzed using single crystal technology,which revealed the structural characteristics of its metal chelate.Our thermodynamic studies demonstrated that the formation of PUE-Na·7H2O involved the simultaneous deprotonation of PUE and the chelation of PUE-and Na+.This reaction process was spontaneous and exothermic(ΔG＜0,ΔH＜0),and reducing the temperature facilitated the formation of the chelate.Nucleation kinetics studies revealed that chelate molecules were more likely to nucleate and crystallize under low temperature,high concentration,and high rotational speed conditions.Compared to commercially available PUEM,PUE-Na·7H2O showed significantly improved water solubility,with a 33.5-fold increase in solubility and a 37.6-fold decrease in intrinsic dissolution rate.Our study identified drug-sodium chelation as an effective means for improving drug solubility and elucidated the mechanisms governing its formation kinetics and thermodynamics.These findings could provide new solutions for related product development and tremendous commercial opportunities.
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