CN108226324B - 一种盐酸克林霉素的杂质控制方法 - Google Patents

一种盐酸克林霉素的杂质控制方法 Download PDF

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CN108226324B
CN108226324B CN201711336457.XA CN201711336457A CN108226324B CN 108226324 B CN108226324 B CN 108226324B CN 201711336457 A CN201711336457 A CN 201711336457A CN 108226324 B CN108226324 B CN 108226324B
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倪冬胜
刘婧
李刚
戴向荣
李小羿
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Mega eye (Guangzhou) ophthalmic drug Co., Ltd.
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Abstract

本发明提供了一种盐酸克林霉素的杂质控制方法，采用双相高效液相色谱进行测定，其中色谱条件如下：检测波长为200‑220nm；柱温为20‑40℃；流速为0.8‑1ml/min；流动相A：0.025mol/L磷酸二氢钾溶液；流动相B：乙腈；进行梯度洗脱。本发明杂质控制方法能很好的同时解决辅料干扰问题和众多杂质的分离问题，也为本类制剂杂质的质量标准制定提供了一个有效的方法。

Description

一种盐酸克林霉素的杂质控制方法
技术领域
本发明涉及分析化学领域，特别涉及一种盐酸克林霉素的杂质控制方法。
背景技术
盐酸克林霉素(Clindamycin hydrochloride)是盐酸林可霉素7-位羟基被氯原子取代而得的半合成衍生物。抗菌谱与林可霉素相同，抗菌活性较林可霉素强4-8倍，广泛地应用于治疗金黄色葡萄球菌等革兰氏阳性球菌和各种厌氧菌引起的感染。
盐酸克林霉素及其注射液、复方凝胶在临床应用中出现较多的不良反应。药品在临床使用中产生的不良发应除了与药品本身的药理活性有关外，与药品中存在的杂质也有很大关系。任何影响药物纯度的物质均称为杂质，一般而言，杂质是指在生产和储存过程中产生的药物以外的其他化学物质。药品质量标准中的杂质是指在按照经国家有关药品监督管理部门依法审查批准的规定工艺和规定原辅料生产的药品中，由其生产工艺和原辅料带入的杂质，或经稳定性实验确证的在存储过程中产生的降解产物。
杂质检测是药品质量控制的一个重要环节，药品质量当中的含量测定是指测定原料药和制剂中主要成分的含量，有关物质是指原料药和制剂当中的有机杂质。通过有关物质检查，弄清有关物质的来源、性质、检测方法及其限量，可以优化合成路线、实验条件等因素，进而避免其产生有关物质或其降到最低限度，从多方面保证和提高药品质量，减少药物的不良反应。
药物杂质检查分析方法应灵敏、专属。盐酸克林霉素原料稳定性差，因此克林霉素制剂中需要监控的杂质有很多。尤其是盐酸克林霉素的注射液或者凝胶制剂，由于含有水且克林霉素很不稳定，因此在效期内需要监控很多降解杂质。这些杂质如果得不到有效控制，产品将会有巨大风险。《中国药典》中对克林霉素仅仅对杂质的总量进行了限定，对单一杂质研究不具体，而欧盟药品主管部门和FDA均要求对克林霉素原料药中表观含量0.1％及其以上的杂质，进行结构鉴定和安全性验证。
含有克林霉素的单方凝胶或者复方凝胶，由于凝胶基质的复杂性，且各辅料紫外出峰强烈，很难将辅料峰与杂质峰分开，辅料对杂质形成干扰，对杂质控制方法提出了严峻挑战。
专利CN201310392499.0公开了一种注射用盐酸克林霉素杂质的检测方法及含量测定方法，该方法可以解决杂质分离的问题，但无法解决凝胶制剂辅料峰干扰的问题。各国药典的盐酸克林霉素也没有解决上述同样的问题，且目前国内外已经发布的分析检测方法，控制的杂质偏少，对某些杂质还没有能鉴定。
中国药典克林霉素原料方法公布的控制克林霉素杂质的方法，无法同时对凝胶中的多个已知杂质进行控制，且辅料峰对杂质有干扰风险。分析方法为：
色谱柱：C18色谱柱(250×4.6mm,5μm)
A相：0.05M磷酸二氢钾(pH7.5)
B相：乙腈
柱温：30度
波长：210nm
流速：0.8ml/min
等度洗脱：35min(B相45％)
杂质系统适应性分离度实验图见图1。从图1可知复方凝胶中杂质林可霉素和7-表林可霉素出峰的时间附近有辅料出峰，对处方中辅料同时进样确定；因为杂质被辅料干扰，无法判断是否其中存在其他降解杂质，因此需建立一个新的有关物质方法，能够将上述的辅料峰与杂质峰很好的分离。
发明内容
本发明的一个目的是提供一种盐酸克林霉素的杂质控制方法，用双相高效液相色谱进行测定，其中色谱条件如下：
检测波长为200-220nm；
柱温为20-40℃；
流速为0.8-1ml/min；
流动相A：0.025mol/L磷酸二氢钾溶液；
流动相B：乙腈；
梯度洗脱：按梯度：0～35min：B相为10％-25％；35～40min：B相10％-25％→30％-45％；40～78min：B相30％-45％；78～79min：B相30％-45％→10％-25％；79～90min：B相10％-25％进行梯度洗脱。
作为优选，流动相A的pH为7.5。
作为优选，所述柱温为30℃。
作为优选，所述色谱柱以十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)。更优选的，所述色谱柱为waters色谱柱、Thermo色谱柱、Pheromone色谱柱、YMC色谱柱。
作为优选，所述检测波长为210nm。
更优选的，梯度洗脱为按梯度：0～35min：B相为21％；35～40min：B相35％；40～78min：B相35％；78～79min：B相21％；79～90min：B相21％进行梯度洗脱。
本发明所述方法能很好的同时解决辅料干扰问题和众多杂质的分离问题，并根据药理毒理以及临床实验，给出合理科学的杂质限度，为制剂中盐酸克林霉素的杂质控制提供一种解决方法，也为本类制剂杂质的质量标准制定提供了一个有效的方法。
附图说明
图1为中国药典的杂质系统适应性分离度实验图；
绿色:林可霉素对照溶液
青绿色:7-表林可霉素对照溶液
蓝色:克林霉素复方凝胶供试品
图2为实施例1的杂质系统适应性分离度实验图；
黑色为盐酸克林霉素原料供试品；
蓝色为复方凝胶供试品。
图3为实施例5的杂质系统适应性分离度实验图
黑色：空白辅料；
蓝色：林可霉素对照；
红色：7－表林可霉素对照；
咖啡色：复方凝胶供试品。
具体实施方式
本发明公开了一种盐酸克林霉素的杂质控制方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
下面结合实施例，进一步阐述本发明：
实施例1：
waters色谱柱十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)；检测波长为210nm；柱温为30℃，流速为0.8ml/min：A相，0.025mol/L磷酸二氢钾溶液(用磷酸调pH7.5)，B相，乙腈。
流速1.0ml/min，波长210nm。A相：0.025mol/L磷酸二氢钾溶液(用磷酸调pH9.0)-乙腈(78:28)。B相：0.025mol/L磷酸二氢钾溶液(用磷酸调pH至2.5)-甲醇(19:81)。
梯度洗脱如下表：
时间(min) A％ B％
0 100 0
12 100 0
14 0 100
28 0 100
31 100 0
40 100 0
如图2所示，待改进地方：4.7min和5.3min辅料峰干扰杂质检出。
实施例2、色谱条件：
waters色谱柱十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)；检测波长为210nm；柱温为30℃，流速为0.8ml/min：A相，0.025mol/L磷酸二氢钾溶液(用磷酸调pH7.5)，B相，乙腈。按下表进行梯度洗脱。
时间(min) A％ B％
0 80 20
12 80 20
14 0 100
28 0 100
31 100 0
40 100 0
待改进地方：辅料、林可霉素和7-表林可霉素都可以出峰，但林可霉素峰的出峰位置在梯度峰上，位置不合适，且辅料峰对林可霉素和7-表林可霉素的检测有干扰。
实施例3、色谱条件：
waters色谱柱十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)；检测波长为210nm；柱温为30℃，流速为0.8ml/min：A相，0.025mol/L磷酸二氢钾溶液(用磷酸调pH7.5)，B相，乙腈。按下表进行梯度洗脱。
时间(min) A％ B％
0 80 21
12 80 21
14 0 100
28 0 100
31 100 0
40 100 0
待改进地方：辅料、林可霉素和7-表林可霉素都可以出峰，且出峰时间比较适当，且辅料峰对林可霉素和7-表林可霉素的检测均无干扰，2杂质也可以实现有效分离。但是主峰保留时间不恰当，需要重新调整。
实施例4、色谱条件：
waters色谱柱十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)；检测波长为210nm；柱温为30℃，流速为0.8ml/min：A相，0.025mol/L磷酸二氢钾溶液(用磷酸调pH7.5)，B相，乙腈。按下表进行梯度洗脱。
时间(min) A相％ B相％
0 75 25
35 75 25
37 65 30
75 65 30
76 75 25
86 75 25
待改进地方：由于采用B％＝25％时，盐酸克林霉素主峰，保留时间超过60min，表明有机相比例太小，因此调整有机相比例为B％＝30％，但是盐酸克林霉素在52min内仍未出峰，因此还需要升高有机相比例。
实施例5、色谱条件：
waters色谱柱十八烷基硅烷键合硅胶为填充剂(250mm×4.6mm，5μm)；检测波长为210nm；柱温为30℃，流速为0.8ml/min：A相，0.025mol/L磷酸二氢钾溶液(用磷酸调pH7.5)，B相，乙腈。按下表进行梯度洗脱。
时间(min) A相％ B相％
0 79 21
35 79 21
37 65 35
75 65 35
76 79 21
86 79 21
待改进地方：由图3可知，杂质林可霉素和7-表林可霉素出峰时间恰当，辅料峰不干扰杂质检测。35分钟到37分钟升高梯度，太快，梯度峰太陡。因此延长了梯度变化的时间，这样可以使得梯度变化更加平滑。将该梯度变化时间调整为5分钟后，就是最终的梯度方法。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (4)

1.一种盐酸克林霉素的杂质控制方法，其特征在于，采用双相高效液相色谱进行测定，所述色谱柱以十八烷基硅烷键合硅胶为填充剂，250mm×4.6mm，5μm，色谱条件如下：
检测波长为200-220nm；
柱温为20-40℃；
流速为0.8-1ml/min；
流动相A：0.025mol/L磷酸二氢钾溶液，流动相A的pH为7.5；
流动相B：乙腈；
梯度洗脱：
按梯度：0~35 min：B相为10%-25%；35~40 min：B相10%-25%→30%-45%；40~78 min：B相30%-45%；78~79 min：B相30%-45%→10%-25%；79~90 min：B相10%-25%进行梯度洗脱。
2.根据权利要求1所述的杂质控制方法，其特征在于，所述柱温为30℃。
3.根据权利要求1所述的杂质控制方法，其特征在于，所述检测波长为210nm。
4.根据权利要求1所述的杂质控制方法，其特征在于，所述色谱柱为waters色谱柱、Thermo色谱柱、Pheromone色谱柱或YMC色谱柱。
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