CN115466235B - 一种抗坏血酸共晶及其制备方法 - Google Patents
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及药物共晶技术领域，具体公开一种抗坏血酸共晶及其制备方法。所述共晶，以抗坏血酸为药物活性成分，以苯甲酸类化合物、烟酸或异烟酸类化合物中的一种为共晶形成物。本发明提供的抗坏血酸共晶。与抗坏血酸单体相比，抗坏血酸共晶物提高了抗坏血酸的稳定性，有效改善了抗坏血酸稳定性差的问题。
Description
技术领域
本发明涉及有机药物共晶技术领域，尤其涉及一种抗坏血酸共晶及其制备方法。
背景技术
抗坏血酸，英文名为L(+)-Ascorbic acid，又称维生素C，简称VC，能够治疗坏血病并且具有酸性，结构式如下：
抗坏血酸即维生素C是一种水溶性的维生素，人体不能合成，必须通过膳食来获取，天然的维生素C主要来源于新鲜的蔬菜水果中，如西红柿、菜花、苦瓜、柑橘、柚子、酸枣等都含有丰富的维生素C。人工合成的维生素C于1933年瑞士化学家Tadeus Reichstein合成。维生素C在体内外都发挥着重要的作用，研究表明，维生素C具有治疗贫血、治疗脓毒症、预防动脉粥硬化、治疗重症胰腺炎、抗炎的功效。除此之外，维生素C还广泛用于化妆品行业中，具有美白淡斑，去除黑色素沉积的问题。
然而，维生素C有较强的还原性,分子中含有两个手性碳原子，其水溶液易发生互变异构，故维生素C非常容易受外界环境的影响，比如温度、光照、pH的干扰都会使其稳定性变差。因此，提供一种可有效改善抗坏血酸稳定性差问题的方法意义重大。
发明内容
针对现有抗坏血酸稳定性差的问题，本发明提供一种抗坏血酸共晶及其制备方法。
为达到上述发明目的，本发明采用了如下的技术方案：
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以苯甲酸类化合物、烟酸或异烟酸类化合物中的一种为共晶形成物，所述抗坏血酸与共晶形成物的摩尔比为1～2：1～2。
进一步地，所述苯甲酸类化合物为3,4-二羟基苯甲酸、间羟基苯甲酸、间氨基苯甲酸、2,5-二羟基苯甲酸中的一种。
进一步地，所述烟酸或异烟酸类化合物为烟酸或异烟酸中的一种。
进一步地，所述抗坏血酸与共晶形成物通过氢键作用结合。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以3,4-二羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为19.8°、30.02°、14.76°、25.28°、17.44°、26.6°、35.54°、10.48°的位置存在特征峰。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以间羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为28.06°、26.58°、16.74°、30.02°、23.7°、25.28°、17.44°、28.42°的位置存在特征峰。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以间氨基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为19.78°、16.62°、17.38°、8.28°、28.46°、27.18°、24.32°、8.28°的位置存在特征峰。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以2,5-二羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为
19.78°、26.9°、16.02°、23.54°、28.84°、17.42°、35.52°、31.14°的位置存在特征峰。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以烟酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为28.08°、16.56°、12.48°、18.78°、27.36°、30.16°、11.28°、21.72°的位置存在特征峰。
进一步地，所述抗坏血酸共晶，以抗坏血酸为药物活性成分，以异烟酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为12.82°、19.28°、17.94°、25.8°、21.12°、27.92°、31.14°、23.54°的位置存在特征峰。
相对于现有技术，本发明提供的抗坏血酸共晶，抗坏血酸与苯甲酸类化合物、烟酸或异烟酸类化合物通过分子间氢键作用，形成稳定的氢键网络结构，组成共晶，与抗坏血酸单体相比，抗坏血酸共晶物提高了抗坏血酸的稳定性，有效改善了抗坏血酸稳定性差的问题。
本发明还提供上述抗坏血酸共晶的制备方法，包括以下步骤：将抗坏血酸与共晶形成物置于研磨管中，以乙醇或纯水作为研磨介质，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以50～60HZ的速率震动研磨15～25min，经研磨后，50～60℃真空干燥3.5～4.5h，得到抗坏血酸共晶。
相对于现有技术，本发明提供的抗坏血酸共晶的制备方法，采用溶剂辅助研磨法，工艺简单，操作方便，绿色环保，安全可靠，在缓和的工艺条件下可得到稳定性好的抗坏血酸共晶。
附图说明
图1至6为分别为本发明实施例1至6提供的共晶、抗坏血酸及共晶形成物的IR谱图；
图7至12分别为本发明实施例1至6提供的共晶、抗坏血酸及共晶形成物的PXRD谱图；
图13为本发明实施例6提供的共晶中氢键示意图；
图14至19分别为本发明实施例1至6提供的共晶、抗坏血酸及共晶形成物的DSC图；
图20至25分别为本发明实施例1至6提供的共晶、抗坏血酸的稳定性图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
为了更好的说明本发明实施例提供的抗坏血酸共晶及其制备方法，下面通过实施例做进一步的举例说明。
实施例1
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以3,4-二羟基苯甲酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和3,4-二羟基苯甲酸154.1mg，置于2mL的研磨管中，向其中加入适量的乙醇，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-PCA)。
实施例2
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以间羟基苯甲酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和间羟基苯甲酸138.1mg，置于2mL的研磨管中，向其中加入适量的研磨溶剂纯水，加入研磨珠，放置于研磨仪的不锈钢
罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-MHBA)。
实施例3
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以间氨基苯甲酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和间氨基苯甲酸137.1mg，置于2mL的研磨管中，向其中加入适量的乙醇，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-MABA)。
实施例4
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以2,5-二羟基苯甲酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和2,5-二羟基苯甲酸154.1mg，置于2mL的研磨管中，向其中加入适量的纯水，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-DHB)。
实施例5
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以烟酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和烟酸123.1mg，置于2mL的研磨管中，向其中加入适量的纯水，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-NA)。
实施例6
一种抗坏血酸共晶，以抗坏血酸为药物活性成分，以异烟酸为共晶形成物，该抗坏血酸共晶的制备方法，包括以下步骤：
精密称取抗坏血酸176.1mg和异烟酸123.1mg，置于2mL的研磨管中，向其中加入适量的乙醇，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以53HZ的速率进行震动研磨。研磨20min，制备完成后置于真空干燥器中在55℃干燥4h，得到抗坏血酸共晶(VC-INA)。
为了更好的说明本发明实施例提供的抗坏血酸共晶的特性，下面将实施例1制备的抗坏血酸共晶进行相应性能的测试。
为证实共晶化合物的形成，采用傅利叶红外光谱(FT-IR)：PerkinElmer Spectrum100 Spectrometer，常温，KBr压片，波长4,000～450cm-1，对实施例1至6所得的共晶与抗坏血酸及其各自的共晶形成物单体进行了傅利叶红外光谱(FT-IR)对照，主要考察与—OH，—NH，—C＝O对应的伸缩振动频率在2500～3400,1500～1750cm-1范围内的变化，如图1至图6，结果发现3,4-二羟基苯甲酸、间羟基苯甲酸、间氨基苯甲酸、2,5-二羟基苯甲酸、烟酸、异烟酸的共晶混合物和其单体在以上波长范围内有较明显的差异，初步预示了共晶化合物的形成。
利用粉末衍射仪(PXRD)：Rigaku Smartlab 9kw，CuK辐射，石墨单色器，对实施例1至6所得的共晶与抗坏血酸进行测试，获得具有以2θ角值表示的粉末X-射线衍射图，参见图7至图12，以抗坏血酸为药物活性成分，以3,4-二羟基苯甲酸为共晶形成物，形成的坏血酸共晶XRD谱图在衍射角2θ为19.8°、30.02°、14.76°、25.28°、17.44°、26.6°、35.54°、10.48°的位置存在特征峰；以抗坏血酸为药物活性成分，以间羟基苯甲酸为共晶形成物，形成的抗坏血酸共晶XRD谱图在衍射角2θ为28.06°、26.58°、16.74°、30.02°、23.7°、25.28°、17.44°、28.42°的位置存在特征峰；以抗坏血酸为药物活性成分，以间氨基苯甲酸为共晶形成物，形成的抗坏血酸共晶XRD谱图在衍射角2θ为19.78°、16.62°、17.38°、8.28°、28.46°、27.18°、24.32°、8.28°的位置存在特征峰；以抗坏血酸为药物活性成分，以2,5-二羟基苯甲酸为共晶形成物，形成的抗坏血酸共晶XRD谱图在衍射角2θ为19.78°、26.9°、16.02°、23.54°、28.84°、17.42°、35.52°、31.14°的位置存在特征峰，以抗坏血酸为药物活性成分，以烟酸为共晶形成物，形成的抗坏血酸共晶XRD谱图在衍射角2θ为28.08°、16.56°、12.48°、18.78°、27.36°、30.16°、11.28°、21.72°的位置存在特征峰；以抗坏血酸为药物活性成分，以异烟酸为共晶形成物，形成的抗坏血酸共晶XRD谱图在衍射角2θ为12.82°、19.28°、17.94°、25.8°、21.12°、27.92°、31.14°、23.54°的位置存在特征峰，其中，抗坏血酸的XRD谱图在衍射角2θ为10.38°、25.24°、28.04°、17.38°、29.98°、34.74°、35.68°、19.74°的位置存在特征峰。
同时，实施例6所得的共晶经X射线单晶衍射仪检测，证实API与CCF的摩尔比为1:1，并具有以下晶胞参数：
抗坏血酸-异烟酸共晶：单斜晶系，空间群C2， α＝γ＝90°，β＝101.250(5)°，体积/> Z＝12，R1＝0.0830,wR2＝0.2078。分子氢键连接模式显示，异烟酸以内盐形式存在，其N—H作为氢键给体与相邻抗坏血酸的内酯O形成氢键，抗坏血酸又与相邻抗坏血酸分子的烯醇羟基两两形成分子间氢键作用，从而形成稳定的氢键网络结构(如图13所示)。
利用差示扫描量热仪(DSC)：Mettler Toledo DSC3，温度30-300℃，升温速率10K/min，保护氮气20.0mL/min，对实施例1至6所得的共晶进行DSC分析。分别如图14至图19所示，差示扫描量热DSC结果表明，各共晶中形成了明显不同于单体的新的吸热峰或衍射峰，证实了共晶中新相的生成。
此外，对实施例1至6所得的共晶进行稳定性测定，包括光照、温度、PH等几方面：
光照具体实施步骤如下，分别精密称取抗坏血酸和抗坏血酸共晶物各30mg，用蒸馏水定容至15mL，将样品分别置于日光、紫外(波长为253.7nm)下放置2h、4h和6h，随后于245波长处测定吸光度，计算残留率。
温度具体实施步骤如下，分别精密称取抗坏血酸和抗坏血酸共晶物各30mg，用蒸馏水定容至15mL,将样品分别置于4℃、25℃和60℃避光条件下放置2h、4h和6h，随后于245nm波长处测定吸光度，计算残留率。
pH具体实施步骤如下，分别精密称取抗坏血酸和抗坏血酸共晶物各30mg，用蒸馏水定容至15mL,加入适量的0.1％HCl或0.1％NaOH使样品溶液的PH为3.0、7.0、9.0，避光条件下放置2h、4h和6h，随后于245nm波长处测定吸光度，计算残留率。
结果如图20至图25所示，与抗坏血酸单体相比，抗坏血酸共晶物提高了抗坏血酸的稳定性。
由以上数据可知，抗坏血酸与苯甲酸类化合物、烟酸或异烟酸类化合物通过分子间氢键作用组成共晶，提高了抗坏血酸的稳定性，有效改善了抗坏血酸稳定性差的问题。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.一种抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以苯甲酸类化合物、烟酸或异烟酸类化合物中的一种为共晶形成物，所述抗坏血酸与共晶形成物的摩尔比为1：1，所述苯甲酸类化合物为3,4-二羟基苯甲酸、间羟基苯甲酸、间氨基苯甲酸、2,5-二羟基苯甲酸中的一种；所述烟酸或异烟酸类化合物为烟酸或异烟酸中的一种。
2.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以3,4-二羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为19.8°、30.02°、14.76°、25.28°、17.44°、26.6°、35.54°、10.48°的位置存在特征峰。
3.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以间羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为28.06°、26.58°、16.74°、30.02°、23.7°、25.28°、17.44°、28.42°的位置存在特征峰。
4.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以间氨基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为19.78°、16.62°、17.38°、8.28°、28.46°、27.18°、24.32°、8.28°的位置存在特征峰。
5.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以2,5-二羟基苯甲酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为19.78°、26.9°、16.02°、23.54°、28.84°、17.42°、35.52°、31.14°的位置存在特征峰。
6.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以烟酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为28.08°、16.56°、12.48°、18.78°、27.36°、30.16°、11.28°、21.72°的位置存在特征峰。
7.如权利要求1所述的抗坏血酸共晶，其特征在于：以抗坏血酸为药物活性成分，以异烟酸为共晶形成物，所述抗坏血酸共晶XRD谱图在衍射角2θ为12.82°、19.28°、17.94°、25.8°、21.12°、27.92°、31.14°、23.54°的位置存在特征峰。
8.一种权利要求1至7任一项所述的抗坏血酸共晶的制备方法，其特征在于：包括以下步骤：将抗坏血酸与共晶形成物置于研磨管中，以乙醇或纯水作为研磨介质，加入研磨珠，放置于研磨仪的不锈钢罐内，室温下以50～60HZ的速率震动研磨15～25min，经研磨后，50～60℃真空干燥3.5～4.5h，得到抗坏血酸共晶。
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