CN108675931A - 一种低钡他汀钙及其制备方法 - Google Patents

一种低钡他汀钙及其制备方法 Download PDF

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CN108675931A
CN108675931A CN201810477305.XA CN201810477305A CN108675931A CN 108675931 A CN108675931 A CN 108675931A CN 201810477305 A CN201810477305 A CN 201810477305A CN 108675931 A CN108675931 A CN 108675931A
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程开生
张蓉
汪吴林
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Anhui Jiexi Pharmaceutical Co ltd
Hefei Cosource Pharmaceutical Co ltd
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Abstract

本发明提供了一种低钡他汀钙，他汀钙中钡含量不大于140ppm；其中钡含量以钡元素分子量137.33计含量占他汀钙样品的重量百分比计；钡含量优选不大于100ppm，更优选不大于50ppm。本发明提供了一种安全性高的低钡他汀钙，符合ICH Q3D关于人用药品元素杂质的要求。

Description

一种低钡他汀钙及其制备方法
技术领域
本发明涉及抗高血脂药物领域，具体涉及一种低钡他汀钙及其制备方法。
背景技术
他汀类药物即3-羟基-3-甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂，其本身或代谢物结构与HMG-CoA相似，因此可于胆固醇合成的早期阶段竞争性的抑制HMG-CoA还原酶的活性，而他汀类药物对此酶的亲和力比HMG-CoA强10000倍，从而使内源性胆固醇的合成减少，降低血浆中总胆固醇的水平。肝脏是内源性胆固醇合成的主要场所，由于肝细胞合成胆固醇减少而阻碍了极低密度脂蛋白的合成和释放；同时，通过自身调节机制，代偿性的增加了肝细胞膜上低密度脂蛋白受体的数目、活性以及与低密度脂蛋白的亲和力，使血浆中大量的低密度脂蛋白被摄取，经代谢排出体外，进一步降低了血浆低密度脂蛋白胆固醇、极低密度脂蛋白胆固醇和总胆固醇水平。大量临床证据表明他汀类药物可大幅度降血脂，采用他汀类药物治疗临床获益显著：(1)减少主要冠脉事件；(2)减少冠心病死亡率；(3)减少PCI/CABG需求；(4)减少中风；(5)减少总死亡率。
自从1976年第一个他汀类药物——美伐他汀在霉菌培养液中被分离，他汀类药物已发展至第三代。第一代用发酵法得到，包括洛伐他汀、辛伐他汀和普伐他汀；第二代为人工合成的消旋体，代表药物为氟伐他汀；第三代为人工合成的对映体，有阿托伐他汀、瑞舒伐他汀等。他汀类药物的结构可分为3个部分：一个与酶的底物HMG-CoA中HMG结构类似的的β，δ-二羟基戊酸结构，即侧链；一个与酶变构后产生的疏水性浅沟相结合的疏水性刚性平面结构，即主环；以及两者之间的连接部分。常见他汀类药物名称与结构。
他汀的合成一般采用主环加侧链的对接汇聚合成路线，CN102311376A公开了一种阿托伐他汀钙的制备工艺，第一步，在正庚烷、四氢呋喃、甲苯组成的混合溶剂中先加入(4R-cis)-6-氨乙基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯与特戊酸反应；第二步，再加入4-氟-α-[2-甲基-1-氧丙基]-γ-氧代-N,β-二苯基苯丁酰胺，升温反应。CN1687087公开了瑞舒伐他汀及其中间体的制备方法，该方法通过将侧链醛化合物与三苯基磷叶里德试剂化合物进行关键的缩合反应，高产率地制备得到瑞舒伐他汀化合物。
这些他汀的侧链均为羧酸，由于稳定性原因，一般均制备成金属盐尤其是钙盐供药用，即他汀钙，如普伐他汀钙、西立伐他汀钙、氟伐他汀钙、阿托伐他汀钙、匹伐他汀钙、瑞舒伐他汀钙。制备钙盐的方法一般采用的路线为，他汀侧链羧酸酯在碱性下水解脱去保护基后，再引入钙源，生成他汀钙。
CN101203496公开了一种制备纯的无定形瑞舒伐他汀钙的方法，包括：a)在非质子溶剂的存在下用碱，或在非质子溶剂和水的混合物的存在下用碱，将瑞舒伐他汀的C 1至C5烷基酯水解以获得瑞舒伐他汀盐的溶液，b)用钙源将由此获得的瑞舒伐他汀盐转化，以获得瑞舒伐他汀钙，c)分离无定形瑞舒伐他汀钙。
CN103508946A公开了匹伐他汀钙的制备方法，以匹伐他汀内脂通过碱水解反应成羧酸，再与钙盐(氯化钙)成盐反应，得到匹伐他汀钙。
CN105693587A公开了一种阿托伐他汀钙的制备方法，阿托伐他汀叔丁酯((3R,5R)-7-[2-异丙基-4-苯基-5-(4-氟苯基)-3-(苯胺基甲酰基)-1氢-吡咯-1-基]-3，5-二羟基庚酸叔丁酯)用氢氧化钠在加热下水解后，滴加乙酸钙的水溶液，得阿托伐他汀钙产品。
这些他汀钙均使用了钙源，常用钙源为氯化钙、醋酸钙。食品医药级的氯化钙(王忠华.氯化钙的制备工艺及应用[J].乙醛醋酸化工,2017(4):21-24.)采用盐酸石灰石法制备。氯化钙国标(GB 1886.45-2016食品安全国家标准食品添加剂氯化钙)及醋酸钙国标(GB1903.15-2016食品安全国家标准食品营养强化剂醋酸钙(乙酸钙))均并未对钡(Ba)元素杂质进行控制。而人用药品注册技术要求国际协调会议(ICH)Q3D要求对药品的元素杂质进行控制，因此应当控制他汀类药物他汀钙中的元素杂质钡，不符合该要求的药品将不符合ICH要求。另外，而钡离子是一种极强的肌肉毒，它对骨骼肌、平滑肌、心肌均有过度刺激和兴奋作用，最后导致肌肉麻痹，钡离子如进入细胞内，会使血清钾降低，可导致低钾血症(陈斌,潘俊芳,林峰,等.注射用磷酸肌酸钠中的微量钡含量测定研究[J].中国药品标准,2011,12(4):252-254.)。目前尚未有研究报道他汀钙中钡的控制，也未见低钡他汀钙。
发明内容
本发明的所要解决的技术问题在于提供了一种安全性高的低钡他汀钙，符合ICHQ3D关于人用药品元素杂质的要求。
本发明采用以下技术方案解决上述技术问题的：
一种低钡他汀钙，他汀钙中钡含量不大于140ppm；其中钡含量以钡元素分子量137.33计含量占他汀钙样品的重量百分比计。
进一步地，所述他汀钙中钡含量不大于100ppm。
进一步地，所述他汀钙中钡含量不大于50ppm。
进一步地，所述他汀钙为普伐他汀钙、西立伐他汀钙、氟伐他汀钙、阿托伐他汀钙、匹伐他汀钙、瑞舒伐他汀钙中的一种或几种。
这种低钡他汀钙的制备方法，步骤包括他汀羧酸或其碱金属盐与低钡可溶性钙源反应生成他汀钙。该反应可如下式表示：
他汀均含有侧链羧酸，该羧酸基团均可与钙离子反应，生成他汀钙。也包括他汀的一些异构体，只要具有他汀羧酸或其碱金属盐，均可与可溶性钙盐反应，如下所示：
有时候，也会采用他汀的某些中间体来制备他汀钙中间体，最后去除这些基团，比如如下这种种中间体：
进一步地，所述低钡可溶性钙源为氯化钙或醋酸钙中的一种或两种。
进一步地，所述低钡可溶性钙源中钡的含量不大于80ppm；其中钡含量以钡元素分子量137.33计含量占钙源样品的重量百分比计。
进一步地，所述低钡可溶性钙源中钡的含量不大于50ppm。
本发明还提供了一种他汀钙中钡含量的检测方法，步骤包括：取他汀钙加硝酸静置后微波消解，微波消解后的消解液置120-140℃加热板上赶酸，将赶酸后的溶液稀释后采用原子吸收分光光度火焰法进行测定；原子吸收光源采用钡元素空心阴极灯，波长选择550-560nm，原子化器采用石墨炉原子化器，石墨管类型为热解涂层石墨管。
进一步地，所述微波消解程序为110-130℃保持3-7分钟，150-170℃保持100-140分钟。
下表为ICH Q3D要求中各元素杂质允许限度。他汀类药物一般口服给药，因此其钡元素杂质限度为140ppm。当然钡的限度还有其他计算方式，但是该方式是首选方式。
表1 ICH Q3D要求中各元素杂质允许限度
本发明的优点在于：
提供了一种安全性高的低钡他汀钙，符合ICH Q3D关于人用药品元素杂质的要求，还提供了灵敏准确的钡含量检测方法。
具体实施方式
下面结合具体实施方式对本发明做进一步说明，以下实施例旨在说明本发明而不是对本发明的进一步限定。
一种低钡他汀钙，所述他汀钙中钡含量小于140ppm；优选地，钡含量小于100ppm；更优选地，钡含量小于50ppm。
他汀钙为普伐他汀钙、西立伐他汀钙、氟伐他汀钙、阿托伐他汀钙、匹伐他汀钙、瑞舒伐他汀钙中的一种或几种。
低钡他汀钙的制备方法是将他汀羧酸或其碱金属盐与低钡可溶性钙源反应生成他汀钙；低钡可溶性钙源为氯化钙或醋酸钙中的一种或两种。
下面以具体实施例分别叙述不同的可溶性钙源、不同的制备步骤得到不同的低钡他汀钙，但是本发明不限于这些实施例，由于原料和制备方法不能一一列举，仅以下列实施例作为进一步说明。
钡含量测定法
如下各实施例中制备得到的他汀钙及钙源均可以使用原子吸收分光光度火焰法(《中国药典》2015年版四部通则0406第一法)来测定钡含量，具体的测试方法如下：
计算方法：标准曲线法
标准曲线溶液(STD)配置：精密移取1000μg/ml钡标准溶液，加溶剂稀释成浓度为0、20、50、100、200、300ng/ml，作为线性溶液；这些线性溶液依次命名为Blank-STD、STD1、STD2、STD3、STD4和STD5。
微波消解程序：120℃保持5分钟，160℃保持120分钟。
瑞舒伐他汀钙样品溶液(SSol)配置：精密称取瑞舒伐他汀钙0.1g，加5ml硝酸，静置过夜，按微波消解程序进行消解，取消解液置130℃加热板上赶酸，将赶酸后的溶液转移置10ml量瓶中，用水稀释至刻度，摇匀，作为母液，浓度为10mg/ml；精密移取1.0ml，置10ml量瓶中，加水稀释至刻度，摇匀，即得，浓度为1mg/ml。
氯化钙、醋酸钙样品溶液配置：取氯化钙或醋酸钙0.1g加溶剂溶解并定容至100ml，即得(1mg/ml)。
样品空白溶液(Blank-SSol)配置：取5ml硝酸，静置过夜，按微波消解程序进行消解，取消解液置130℃加热板上赶酸，将赶酸后的溶液转移置10ml量瓶中，用水稀释至刻度，摇匀，作为母液；精密移取1.0ml，置10ml量瓶中，加水稀释至刻度，摇匀，即得。
标准空白溶液(Blank-STD)：2％硝酸溶液。
进样顺序：Blank-STD、STD1、STD2、STD3、STD4、STD5、Blank-SSol、SSol。
计算方法：以对照品的吸收度为纵坐标，浓度为横坐标，绘制标准曲线，拟合线性方程。将供试品溶液的吸收度代入线性方程后计算供试品溶液中的钡含量。
具体的仪器和使用条件如下：
仪器：原子吸收分光光度计(岛津AA-6800型)
光源：钡元素空心阴极灯
原子化器：石墨炉原子化器
分析参数：
元素：钡
波长：553.6nm
测定方法：石墨炉法
石墨管类型：热解涂层
背景校正：D2
石墨炉程序：
石墨炉升温程序
表2石墨炉升温程序
定量参数：
线性拟合：1级
通过零点：否
浓度单位：mg/ml
信号处理：峰高
溶剂：2％硝酸水溶液
进样体积：20μl
钡含量计算方式：测得钡的浓度*稀释倍数/待测样品称样量，钡浓度以钡元素(Ba)分子量137.33计算，不含钡盐酸根分子量。
实施例1
低钡阿托伐他汀钙的制备
向干燥洁净的烧瓶中加入75ml乙腈和30ml纯化水，然后加入9.2g(3R,5R)-7-[2-异丙基-4-苯基-5-(4-氟苯基)-3-(苯胺基甲酰基)-1氢-吡咯-1-基]-3，5-二羟基庚酸叔丁酯(阿托伐他汀叔丁醇酯,15mmol)和0.68g氢氧化钠，使体系加热至50-55℃，然后向反应釜中滴加醋酸钙的水溶液，加热使体系回流，在回流状态下继续搅拌1小时，降温至50-55℃，过滤，10ml乙腈淋洗涤，把滤液转移到烧瓶中，向烧瓶中滴加60ml纯化水，室温搅拌1小时，过滤，滤饼用20ml纯化水洗两次，再用20ml无水乙醚洗两次，减压抽干，在60℃下真空干燥得阿托伐他汀钙产品5.0g。改变所用醋酸钙的批次，同法操作，并测定阿托伐他汀钙产品的钡含量，结果表列如下(阿托伐他汀叔丁醇酯投料均为9.2g(15mmol))。
表3醋酸钙对阿托伐他汀钙中钡含量的影响
实施例2
低钡瑞舒伐他汀钙制备
将3.0g，6mmol瑞舒伐他汀钠溶于30ml水，滴加0.5ml 1.0M HCl，将溶液pH值调节至7～8。室温下逐滴添加0.79g一水醋酸钙水溶液，以沉淀瑞舒伐他汀钙。在完全添加后，将悬浮液在室温下继续搅拌45分钟。滤出白色沉淀物，用20ml水洗涤并在真空中于40℃下干燥，以得到2.55g瑞舒伐他汀钙，瑞舒伐他汀钙收率为85.0％。
取不同配比及不同钡含量的药用醋酸钙或氯化钙依上法试验，瑞舒伐他汀钠均采用同一批，投料量均为3.0g，并测定成品中瑞舒伐他汀钙中钡含量，考察醋酸钙或氯化钙中钡含量对瑞舒伐他汀钙中钡含量的影响，结果如下表4和表5所示：
表4醋酸钙对瑞舒伐他汀钙中钡含量的影响
表5氯化钙对瑞舒伐他汀钙中钡含量的影响
从上表中可以看出，尽管主要批次醋酸钙和氯化钙的钡含量均小100ppm，也符合药用级要求，瑞舒伐他汀钙多批次钡的含量均大于ICH Q3D中原料药的限度140ppm，即不符合ICH要求。另外发现，钡在瑞舒伐他汀钙中产生了明显蓄积(比钙源醋酸钙、氯化钙原料中钡含量高)，其累计与钙源比例有关，比例越大，累积越严重，然而比例越低收率越低。可见仅按现有药用标准控制钙源中钡含量(80～125ppm)，无法保证成品原料中瑞舒伐他汀钙中钡的限度符合ICH要求。因此应控制钙源中钡含量才可得到低钡他汀钙，钙源中钡含量最优选不大于50ppm，即可保证制备得到低钡他汀钙，他汀钙收率也较高。
最后应说明的是：以上实施例仅用以说明本发明而并非限制本发明所描述的技术方案；本领域的普通技术人员应当理解，仍然可以对本发明进行修改或等同替换；而一切不脱离本发明的精神和范围的技术方案及其改进，其均应涵盖在本发明的权利要求范围中。

Claims (10)

1.一种低钡他汀钙，其特征在于，他汀钙包括他汀钙及其异构体，他汀钙中钡含量不大于140ppm；其中钡含量以钡元素分子量137.33计含量占他汀钙样品的重量百分比计。
2.根据权利要求1所述的一种低钡他汀钙，其特征在于，所述他汀钙中钡含量不大于100ppm。
3.根据权利要求1所述的一种低钡他汀钙，其特征在于，所述他汀钙中钡含量不大于50ppm。
4.根据权利要求1所述的一种低钡他汀钙，其特征在于，所述他汀钙为普伐他汀钙、西立伐他汀钙、氟伐他汀钙、阿托伐他汀钙、匹伐他汀钙、瑞舒伐他汀钙中的一种或几种。
5.一种如权利要求1-4任一项所述的低钡他汀钙的制备方法，其特征在于，步骤包括他汀羧酸或其碱金属盐与低钡可溶性钙源反应生成他汀钙。
6.根据权利要求5所述的一种低钡他汀钙的制备方法，其特征在于，所述低钡可溶性钙源为氯化钙或醋酸钙中的一种或两种。
7.根据权利要求5所述的一种低钡他汀钙的制备方法，其特征在于，所述低钡可溶性钙源中钡的含量不大于80ppm。
8.根据权利要求5所述的一种低钡他汀钙的制备方法，其特征在于，所述低钡可溶性钙源中钡的含量不大于50ppm。
9.根据权利要求1-8任一项所述的低钡他汀钙钡含量的检测方法，其特征在于，步骤包括：取他汀钙加硝酸静置后微波消解，微波消解后的消解液置120-140℃加热板上赶酸，将赶酸后的溶液稀释后采用原子吸收分光光度火焰法进行测定；原子吸收光源采用钡元素空心阴极灯，波长选择550-560nm，原子化器采用石墨炉原子化器，石墨管类型为热解涂层石墨管。
10.根据权利要求9所述的低钡他汀钙钡含量的检测方法，其特征在于，所述微波消解程序为110-130℃保持3-7分钟，150-170℃保持100-140分钟。
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