CN108863748A - 一种姜黄素共晶及其制备方法 - Google Patents

一种姜黄素共晶及其制备方法 Download PDF

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CN108863748A
CN108863748A CN201810638164.5A CN201810638164A CN108863748A CN 108863748 A CN108863748 A CN 108863748A CN 201810638164 A CN201810638164 A CN 201810638164A CN 108863748 A CN108863748 A CN 108863748A
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CN108863748B (zh
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郑康
姜柳
周娜
张欣茹
朱亚晴
张贤
吕梦雪
纪丽华
李润
刘鹏
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    • C07—ORGANIC CHEMISTRY
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

本发明涉及一种姜黄素‑2’‑羟基苯乙酮共晶及其制备方法。共晶由姜黄素和2’‑羟基苯乙酮通过非共价相互作用结合。共晶的晶体结构属于单斜晶系，轴长a=14.018~14.218Å，b=27.468~27.668Å，c=10.076~10.276Å，轴角α=90°，β=106.89°~107.09°，γ=90°，X‑射线粉末衍射图样中，共晶在衍射角2θ=6.877°，8.813°，17.192°，17.533°，23.063°，24.662°，25.507°处有主要峰处有主要峰。本发明的共晶可通过溶剂助研磨法制得。本发明为在不改变姜黄素共价结构的前提下进行晶型改造提供了可能。

Description

一种姜黄素共晶及其制备方法
技术领域
本发明属于药物共晶技术领域，具体涉及一种新型姜黄素共晶及其制备方法。
背景技术
天然产物是新药研发的宝库，据统计，1981到2014年上市的1562种药物中有50%都直接或间接来源于天然产物。可是，天然产物直接成药的比例相当低，仅有4.3%，这是因为天然产物大多具有不利于成药的性质，如低水溶性和低生物利用度，这些不利的物理、化学和生物学性质成为阻碍高活性天然产物成药的重要限制因素。虽然可以通过化学修饰改善药物的理化性质，但是，化学修饰改变了天然产物的共价结构，可能导致脱靶现象并带来毒副作用。药物共晶是近年来兴起一种新的药物固体形态改造方法，与化学修饰法相比最大的不同是其不改变化合物的共价结构，因而不会对药物原有的作用方式产生影响。药物共晶通过氢键等非共晶键实现药物活性成分和共晶形成物的结合，适用于可电离和不可电离的分子，而且共晶形成物的选择范围广，克服了传统的改造方法适用范围小的缺点。药物共晶已经在药物的处方前研究和剂型设计中扮演了重要的角色。虽然药物共晶用于药物改造已有不少实例，通过形成共晶改善天然来源的药物活性成分的实例尚不多见。
姜黄素是来源于中药姜黄的药物活性成分，具有抗肿瘤、抗炎、抗动脉粥样硬化等多种药理活性，安全性良好。然而，姜黄素水溶性差，水中的溶解度仅有不到0.001 g，导致姜黄素的生物利用度低，低水溶性成为阻碍姜黄素成药的重要因素。通过制备姜黄素共晶可以提高姜黄素的水溶性，进而改善姜黄素的药学性质，为发展新型姜黄素药物提供化学物质基础。
发明内容
本发明的目的在于提供一种新的姜黄素共晶及制备方法。
本发明以姜黄素作为药物活性成分，其化学名是(1E,6E)-1,7-双(4-羟基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮，分子式为C21H20O6，结构式如a所示，选用2’-羟基苯乙酮作为共晶形成物，分子式为C8H8O2，结构式如b所示。
本发明所述的共晶具有如下特征。
姜黄素-2’-羟基苯乙酮共晶由姜黄素和2’-羟基苯乙酮通过非共价相互作用结合生成，在X-射线粉末衍射图样中，共晶在衍射角2θ = 6.877°，8.813°，17.192°，17.533°，23.063°，24.662°，25.507°处有主要峰，在衍射角2θ = 12.215°，13.827°，14.521°，15.077°，15.879°，18.110°，18.769°，19.406°，21.113°，23.645°，26.671°，27.368°，28.214°，29.112°，30.183°处有次要峰，其中2θ值的误差范围为±0.3°。姜黄素-2’-羟基苯乙酮共晶属于单斜晶系，其轴长a = 14.018 ~ 14.218 Å，b = 27.468 ~ 27.668 Å，c =10.076 ~ 10.276 Å，轴角α = 90°，β = 106.89° ~ 107.09°，γ = 90°。
本发明所述的姜黄素-2’-羟基苯乙酮共晶的制备方法为溶剂助研法，其步骤如下。
(1) 质量比为5:1到1:5的姜黄素和2’-羟基苯乙酮置于直径为8 ~ 20 cm的玛瑙研钵内，研磨成100 ~ 400目的粉末。
(2) 用微量移液枪移入50 ~ 500 µL的助研溶剂，均匀研磨1 ~ 3 h。所用有机溶剂为甲醇、乙醇、丙酮、氯仿、二氯甲烷中的一种或几种的混合。
(3) 收集粉末，冷冻干燥1 h，得到黄色粉末即为姜黄素-2’-羟基苯乙酮共晶。
本发明制备的药物共晶继承了姜黄素本身的药理活性，并使其在溶解性方面有明显改进。
本发明中检测药物共晶结构的仪器如下。
粉末衍射图采用的仪器型号为Bruker D8 Advance测定，Cu-Kα (λ = 1.54056Å)，管电压40 kV，管电流40 mA，扫描速度5°/min。
附图说明
图1是姜黄素-2’-羟基苯乙酮共晶的晶体结构图。
图2是姜黄素-2’-羟基苯乙酮共晶的粉末X-射线衍射图。
图3是姜黄素的粉末X-射线衍射图。
图4是2’-羟基苯乙酮的粉末X-射线衍射图。
具体实施方式
下面结合实施实例对本发明做进一步的描述，但并不局限于此。
实施例1。
(1) 准确称取250 mg的姜黄素和250 mg的2’-羟基苯乙酮置于直径为10 cm的玛瑙研钵内，研磨成200目的粉末。
(2) 用微量移液枪移入100 µL的丙酮和乙醇的混合溶液(体积比4:1)，均匀研磨2h。
(3) 收集粉末，冷冻干燥1 h，得到黄色粉末即为姜黄素-2’-羟基苯乙酮共晶。
实施例2。
(1) 准确称取368 mg的姜黄素和136 mg的2’-羟基苯乙酮置于直径为10 cm的玛瑙研钵内，研磨成200目的粉末。
(2) 用微量移液枪移入100 µL乙醇，均匀研磨1 h。
(3) 收集粉末，冷冻干燥1 h，得到黄色粉末即为姜黄素-2’-羟基苯乙酮共晶。
效果实施例1。
对姜黄素-2’-羟基苯乙酮共晶以及姜黄素和2’-羟基苯乙酮进行粉末X-射线衍射表征，测试在德国Bruker公司的D8 Advance型X-射线粉末衍射仪上进行。测试条件：Cu-Kα靶(λ = 1.54056 Å)，管电压40 kV，管电流40 mA，扫描速度5°/min。
实施例1和例2制备的姜黄素-2’-羟基苯乙酮共晶的粉末X-射线衍射结果见图2，特征峰如下。
采用同样方法对姜黄素和2’-羟基苯乙酮进行X-射线粉末衍射表征。姜黄素的X-射线粉末衍射结果见图3，特征峰如下。
2’-羟基苯乙酮的X-射线粉末衍射结果见图4，特征峰如下。
通过比较姜黄素-2’-羟基苯乙酮共晶、姜黄素和2’-羟基苯乙酮的衍射图可知，姜黄素-2’-羟基苯乙酮共晶位于2θ角6.877°和23.063°处的峰继承自2’-羟基苯乙酮，位于2θ角8.813°，17.192°，23.063°，24.662°和25.507°处的峰继承自姜黄素，位于2θ角17.533°处的峰继承自2’-羟基苯乙酮，它的强度相比2’-羟基苯乙酮有明显的增强，为姜黄素-2’-羟基苯乙酮共晶的特征峰。用Expo2014软件根据粉末衍射峰模拟姜黄素-2’-羟基苯乙酮共晶的结构，结果显示姜黄素-2’-羟基苯乙酮共晶属于单斜晶系，其轴长a = 14.118 Å，b =27.568 Å，c = 10.176 Å，轴角α = 90°，β = 106.99°，γ = 90°，模拟的结构见图1。以上结果表明姜黄素-2’-羟基苯乙酮共晶是一种新的物相，证实了共晶的生成。
效果实施例2。
由于姜黄素难溶于水，直接测定姜黄素的溶解度误差太大，为了比较姜黄素-2’-羟基苯乙酮共晶和姜黄素的溶解性，在不同浓度的乙醇溶液中测定了姜黄素-2’-羟基苯乙酮共晶和姜黄素的平衡溶解度，结果如下。
结果显示姜黄素-2’-羟基苯乙酮共晶的溶解度明显优于姜黄素自身，这种提高溶解度的特性可以改善姜黄素的药学性质，在新药研发中具有优势。

Claims (2)

1.一种姜黄素-2’-羟基苯乙酮共晶，其特征在于：姜黄素和2’-羟基苯乙酮通过非共价相互作用结合生成，在X-射线粉末衍射图样中，共晶在衍射角2θ = 6.877°，8.813°，17.192°，17.533°，23.063°，24.662°，25.507°处有主要峰，在衍射角2θ = 12.215°，13.827°，14.521°，15.077°，15.879°，18.110°，18.769°，19.406°，21.113°，23.645°，26.671°，27.368°，28.214°，29.112°，30.183°处有次要峰，其中2θ值的误差范围为±0.3°；姜黄素-2’-羟基苯乙酮共晶属于单斜晶系，其轴长a = 14.018 ~ 14.218 Å，b = 27.468 ~27.668 Å，c = 10.076 ~ 10.276 Å，轴角α = 90°，β = 106.89° ~ 107.09°，γ = 90°。
2.权利要求1所述的姜黄素-2’-羟基苯乙酮共晶的制备方法，其步骤为：
(1) 质量比为5:1到1:5的姜黄素和2’-羟基苯乙酮置于直径为8 ~ 20 cm的玛瑙研钵内，研磨成100 ~ 400目的粉末；
(2) 用微量移液枪移入50 ~ 500 µL的助研溶剂，均匀研磨1 ~ 3 h，所用有机溶剂为甲醇、乙醇、丙酮、氯仿、二氯甲烷中的一种或几种的混合；
(3) 收集粉末，冷冻干燥1 h，得到黄色粉末即为姜黄素-2’-羟基苯乙酮共晶。
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