CN114262337A - 普鲁卡因青霉素及其制备方法、杂质及杂质控制方法 - Google Patents
普鲁卡因青霉素及其制备方法、杂质及杂质控制方法 Download PDFInfo
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Abstract
本发明提供了一种普鲁卡因青霉素及其制备方法、杂质及杂质控制方法,所述普鲁卡因青霉素中RRT0.24杂质的含量小于0.13%。所述制备方法为控制所用原料盐酸普鲁卡因中RRT0.24杂质的含量不高于0.05%,所述RRT0.24杂质为2‑{[2‑(4‑氨基苯甲酰氧基)乙基](乙基)氨基}乙基‑4‑氨基苯甲酸酯。所述产品普鲁卡因青霉素中RRT0.24杂质的含量y与原料盐酸普鲁卡因中RRT0.24杂质的含量x之间满足线性关系模型y=2.4835x,其中模型R2=0.9546。本发明认识了一种普鲁卡因青霉素新杂质,对普鲁卡因青霉素的质量控制起到重要作用。
Description
技术领域
本发明涉及药物制备技术领域,具体地说是涉及一种普鲁卡因青霉素及其制备方法、杂 质及杂质控制方法。
背景技术
普鲁卡因青霉素,其化学名为:对氨基苯甲酸2-(二乙氨基)乙酯(6R)-6-(2-苯基乙 酰氨基)青霉烷酸盐一水合物。结构式为:
普鲁卡因青霉素为青霉素的普鲁卡因盐,其抗菌活性成分为青霉素,为青霉素长效品种。 青霉素通过抑制细菌细胞壁合成发挥杀菌作用。制备方法为:青霉素钾溶液与盐酸普鲁卡因 溶液进行复分解反应,经结晶,洗涤,干燥,得普鲁卡因青霉素结晶粉末。
药物一致性评价,即药品一致性研究,就是仿制药必须和原研药“管理一致性、中间过 程一致性、质量标准一致性等全过程一致”的高标准要求。
目前,普鲁卡因青霉素中杂质研究还不完善,因此对其杂质组成进行深入研究,对于药 品质量监测及药品的一致性评价具有重要意义。
发明内容
本发明的目的是提供一种普鲁卡因青霉素及其制备方法、杂质及杂质控制方法,以提供 一种质量更高的普鲁卡因青霉素的制备方法,解决现有技术中普鲁卡因青霉素杂质不明确, 质量监测难度大的问题。
本发明技术方案为:一种普鲁卡因青霉素,所述普鲁卡因青霉素中RRT0.24杂质的含量 小于0.13%,所述RRT0.24杂质的结构式如下所示:
上述普鲁卡因青霉素的制备方法,其是将青霉素钾溶液与盐酸普鲁卡因溶液进行复分解 反应,经结晶、洗涤、干燥后,得到普鲁卡因青霉素结晶粉末,所用盐酸普鲁卡因中RRT0.24 杂质的含量不高于0.05%。
所述普鲁卡因青霉素结晶粉末中RRT0.24杂质的含量y与盐酸普鲁卡因中RRT0.24杂质 的含量x之间满足线性关系模型y=2.4835x,其中模型R2=0.9546。
所述制备方法包括:分别配制盐酸普鲁卡因溶液和青霉素钾溶液,然后将盐酸普鲁卡因 溶液流加至青霉素钾溶液中,流加完毕后养晶40-80min,结晶液抽滤后进行洗涤、干燥,即 得普鲁卡因青霉素结晶粉末;其中,所述盐酸普鲁卡因与青霉素钾盐的用量比为15.3g: 18-22g。
青霉素钾溶液为青霉素钾的磷酸缓冲溶液;在开始流加盐酸普鲁卡因溶液时,向青霉素 钾溶液中加入普鲁卡因青霉素晶种;所述盐酸普鲁卡因溶液浓度为0.20-0.35g/mL,所述青霉 素钾溶液浓度为0.15-0.30g/mL。
所述流加工艺为:流加速度18-22mL/h,流加5-15min;调节流加速度为30-35mL/h,流 加3-7min;之后每流加3-7min,流速增加12-15mL/h,直至流加结束。
依次用纯化水、正丁醇、乙酸乙酯对晶体进行洗涤,干燥条件为72±2℃真空干燥1-3h。
一种普鲁卡因青霉素杂质,所述杂质为RRT0.24杂质,中文名为2-{[2-(4-氨基苯甲酰氧 基)乙基](乙基)氨基}乙基-4-氨基苯甲酸酯,其结构式如下所示:
上述普鲁卡因青霉素杂质的检测控制方法,其通过检测原料盐酸普鲁卡因中RRT0.24杂 质的含量,对产品普鲁卡因青霉素中RRT0.24杂质的含量进行控制,所述产品普鲁卡因青霉 素中RRT0.24杂质的含量y与原料盐酸普鲁卡因中RRT0.24杂质的含量x之间满足线性关系 模型y=2.4835x,其中模型R2=0.9546。
将盐酸普鲁卡因用水溶解后,负载在色谱柱上,然后用流动相进行梯度洗脱并进行检测, 所述色谱柱为C18柱,检测波长为220-230nm,柱温为48-52℃,流速为1.3-1.7mL/min;流 动相A:68g/L pH=3.4磷酸二氢钾溶液50mL+300mL水+150mL甲醇;流动相B:68g/LpH=3.4 磷酸二氢钾溶液50mL+175mL水+275mL甲醇。
所述梯度洗脱的程序如下:
时间(min) | 流动相A%(V/V) | 流动相B%(V/V) |
0-7 | 70 | 30 |
7-17 | 70→0 | 30→100 |
17-22 | 0 | 100 |
22.01-35 | 70 | 30 |
本发明采用EP10.0普鲁卡因青霉素有关物质项下方法检测普鲁卡因青霉素原料药,发现 于杂质A后、RRT约0.24(相对青霉素峰)处,有一未知杂质。通过研究发现该杂质的工艺 去除率低;且现有文献及专利中无针对该杂质的相关研究,其结构、毒性及控制方法均属未 知。因此,为了保证普鲁卡因青霉素的安全性,对RRT0.24杂质进行有效控制,本发明研究 确定了RRT0.24杂质的结构、基因毒性,并分析其来源,从而进行控制。
相对于现有技术,本发明具有以下技术效果:
(1)本发明认识了一种普鲁卡因青霉素新杂质,确定了其结构式,增加了对普鲁卡因青 霉素杂质谱的认识;通过结构判断,该杂质无基因毒性,有无其他毒性需进一步研究;
(2)本发明完成了该杂质溯源,确定了该杂质为原料盐酸普鲁卡因引入,在其合成过程 中产生,为起始物料二乙胺中存在的乙胺发生环氧乙烷加成生成N,N‘-二(2-乙醇基)乙胺, 进一步与二分子对硝基苯甲酸发生酯化反应,之后还原产生。
(3)本发明确定了该杂质的控制方法以及一种高质量普鲁卡因青霉素的制备方法,利用 盐酸普鲁卡因-普鲁卡因青霉素RRT0.24杂质含量关系模型y=2.4835x(R2=0.9546),及95% 置信区间估计误差,对盐酸普鲁卡因中RRT0.24杂质进行检测控制,可实现普鲁卡因青霉素 中的杂质控制。对普鲁卡因青霉素的质量控制起到重要作用。
附图说明
图1为本发明RRT0.24杂质LC-MS分析的质谱图。
图2为本发明RRT0.24杂质的核磁氢谱图。
图3为本发明RRT0.24杂质的核磁碳谱图。
具体实施方式
下面结合实施例对本发明做进一步的阐述,在下述实施例中未详细描述的过程和方法是 本领域公知的常规方法,实施例中所用原料或试剂除另有说明外均为市售品,可通过商业渠 道购得。
实施例1
一种普鲁卡因青霉素杂质,经定性为式(1)所示化合物,该化合物英文 名:2-{[2-(4-aminobenzoyloxy)ethyl](ethly)amino}ethyl-4-aminobenzoate。中文名:2-{[2-(4-氨基 苯甲酰氧基)乙基](乙基)氨基}乙基-4-氨基苯甲酸酯。分子式:C20H25N3O4。分子量:371。
结构确认:对RRT0.24杂质进行LC-MS分析,[M+H]+=372,分子量为371,见附图1。对RRT0.24杂质进行核磁共振分析,数据见表1,图谱见附图2、3。氢谱数据解析:(1)结构中共有1个甲基:与亚甲基相邻(三重峰),化学位移为δ1.11ppm。(2)结构中有5个亚甲基:与杂原 子相邻,分为3组信号,化学位移δ2.7-4.4ppm之间。(3)结构中有8个芳氢质子:化学位移值 在δ6-8ppm之间。(4)二维谱均显示了合理的相关点。碳谱数据解析:(1)结构中有1个甲基:为 邻碳甲基,化学位移位于δ12.73ppm。HSQC谱显示与它们的质子相关。(2)结构中有5个亚 甲基:化学位移值介于δ50-64ppm之间。HSQC谱显示与它们的质子相关。(3)结构中有8个芳 香碳:化学位移值介于δ115-133ppm之间,HSQC谱显示与它们的质子相关。(4)结构中有6个 季碳:其中2个羰基碳,化学位移δ169.16ppm;4个芳香碳化学位移为δ119.06ppm、δ155.25ppm。 (5)碳谱的碳原子数和其类型与该化学结构相符,二维谱均显示合理的相关点。
表1 NMR数据信息
注:核磁谱图中有水和甲醇残留溶剂峰。
普鲁卡因青霉素RRT0.24杂质的官能团与普鲁卡因类似,无基因毒性警示结构,无基因 毒性。
实施例2
普鲁卡因青霉素RRT0.24杂质的合成过程如下所示:
该杂质由原料盐酸普鲁卡因引入,在盐酸普鲁卡因合成过程中生成。在盐酸普鲁卡因合 成过程中,使用二乙胺发生环氧乙烷加成得到二乙胺基乙醇,再与对硝基苯甲酸通过酯化形 成中间体,后还原得普鲁卡因。因起始物料二乙胺中存在乙胺,在环氧乙烷加成过程中生成 N,N‘-二(2-乙醇基)乙胺,进一步与二分子对硝基苯甲酸发生酯化反应,后还原产生RRT0.24 杂质。普鲁卡因青霉素生产工艺不具备该杂质的生成条件。
实施例3
普鲁卡因青霉素的制备:
(1)配制盐酸普鲁卡因溶液:检测原料盐酸普鲁卡因中RRT0.24杂质的含量,其含量为 0.036%,室温下将15.3g盐酸普鲁卡因加入41mL纯化水中,超声溶解至澄清后,补水至53mL。
(2)配制青霉素钾盐缓冲液:将0.47g缓冲盐(Na2HPO4和NaH2PO4质量比为6:1即0.40g Na2HPO4+0.067g NaH2PO4)加入61mL纯化水中,再加入0.067g NaCl,超声溶解至澄清后,室温下,加入20g青霉素钾盐,超声溶解至澄清后,补水至93mL。
(3)结晶单元:分别将0.2mL盐酸普鲁卡因溶液和0.024g晶种缓慢加入到青霉素钾盐 缓冲液中,养晶7min。向青霉素钾盐缓冲液中流加盐酸普鲁卡因溶液,调节流加速度20mL/h, 流加10min;再调节流加速度为33.3mL/h,流加5min;之后每流加5min,流速增加13.3mL/h, 直至流加结束。之后静止养晶60min。
(4)洗涤单元:结晶液抽滤后,分别用36ml纯化水,18ml正丁醇,21ml乙酸乙酯21洗涤晶体各两次。
(5)干燥单元:72(±2)℃真空干燥2h。
实施例4
RRT0.24杂质的检测:
仪器设备:Waters ACQUITY Arc-WFMA
色谱柱:C18 packed 0.15m×4.6mm×3.0μm
检测波长:225nm
柱温:50℃
流速:1.5mL/min
进样量:20μL
流动相A:68g/L pH=3.4磷酸二氢钾溶液50mL+300mL水+150mL甲醇
流动相B:68g/L pH=3.4磷酸二氢钾溶液50mL+175mL水+275mL甲醇
梯度洗脱表
时间(min) | 流动相A%(V/V) | 流动相B%(V/V) |
0-7 | 70 | 30 |
7-17 | 70→0 | 30→100 |
17-22 | 0 | 100 |
22.01-35 | 70 | 30 |
盐酸普鲁卡因样品溶液:称取盐酸普鲁卡因116mg,用水稀释至50ml。
普鲁卡因青霉素样品溶液:称取普鲁卡因青霉素250mg,用25ml甲醇超声溶解,用水稀 释至50ml。
普鲁卡因青霉素对照溶液:称取普鲁卡因青霉素标准品50mg,用25ml甲醇超声溶解, 用水稀释至50ml。取5ml,用50%甲醇水稀释至100ml。
RRT0.24杂质含量计算公式:
(式中:Ai-RRT0.24杂质峰面积;At-对照溶液普鲁卡因峰面积;Ar-对照溶液青霉 素G峰面积;Ct-对照溶液普鲁卡因浓度mg/mL;Cs-对照溶液普鲁卡因青霉素浓度mg/mL; Ci-样品溶液浓度mg/mL。)
实施例5
盐酸普鲁卡因中RRT0.24杂质与普鲁卡因青霉素中RRT0.24杂质的关联性:
a.收集EP10.0方法下盐酸普鲁卡因及普鲁卡因青霉素中RRT0.24杂质含量,建立盐普— 普青RRT0.24杂质含量关系模型,所得模型为:y=2.4835x(R2=0.9546)。取95%置信区间, 计算普鲁卡因青霉素中RRT0.24杂质含量估计误差和估计上、下限。见表2。
表2:盐普—普青RRT0.24杂质含量关系模型(部分)数据
b.取3批盐酸普鲁卡因原料,按照实施例4的方法检测其RRT0.24杂质含量,然后利用 原料按照实施例3的方法合成普鲁卡因青霉素,并测定其RRT0.24杂质含量(检测参数与原 料检测参数一致),与所建关系模型的预测平均值基本一致,证明所建立的关系模型预测性 好。见表3。
表3:盐普—普青RRT0.24杂质含量关系模型预测性评价数据
本发明从杂质生成机理和检测数据均证明普鲁卡因青霉素中RRT0.24杂质含量与盐酸普 鲁卡因中该杂质含量密切相关。利用盐酸普鲁卡因—普鲁卡因青霉素RRT0.24杂质含量关系 模型:y=2.4835x(R2=0.9546),及95%置信区间估计误差,对盐酸普鲁卡因中RRT0.24杂质 进行检测控制,可实现普鲁卡因青霉素中的杂质控制。
Claims (10)
2.权利要求1所述普鲁卡因青霉素的制备方法,其特征在于,将青霉素钾溶液与盐酸普鲁卡因溶液进行复分解反应,经结晶、洗涤、干燥后,得到普鲁卡因青霉素结晶粉末,所用盐酸普鲁卡因中RRT0.24杂质的含量不高于0.05%。
3.根据权利要求2所述的普鲁卡因青霉素的制备方法,其特征在于,所述普鲁卡因青霉素结晶粉末中RRT0.24杂质的含量y与盐酸普鲁卡因中RRT0.24杂质的含量x之间满足线性关系模型y=2.4835x,其中模型R2=0.9546。
4.根据权利要求2所述的普鲁卡因青霉素的制备方法,其特征在于,所述制备方法包括:分别配制盐酸普鲁卡因溶液和青霉素钾溶液,然后将盐酸普鲁卡因溶液流加至青霉素钾溶液中,流加完毕后养晶40-80min,结晶液抽滤后进行洗涤、干燥,即得普鲁卡因青霉素结晶粉末;其中,所述盐酸普鲁卡因与青霉素钾盐的用量比为15.3g:18-22g。
5.根据权利要求4所述的普鲁卡因青霉素的制备方法,其特征在于,青霉素钾溶液为青霉素钾的磷酸缓冲溶液;在开始流加盐酸普鲁卡因溶液时,向青霉素钾溶液中加入普鲁卡因青霉素晶种;所述盐酸普鲁卡因溶液浓度为0.20-0.35g/mL,所述青霉素钾溶液浓度为0.15-0.30 g/mL;所述流加工艺为:流加速度18-22mL/h,流加5-15min;调节流加速度为30-35mL/h,流加3-7min;之后每流加3-7min,流速增加12-15mL/h,直至流加结束。
6.根据权利要求4所述的普鲁卡因青霉素的制备方法,其特征在于,依次用纯化水、正丁醇、乙酸乙酯对晶体进行洗涤,干燥条件为72±2℃真空干燥1-3h。
8.权利要求7所述普鲁卡因青霉素杂质的控制方法,其特征在于,通过检测原料盐酸普鲁卡因中RRT0.24杂质的含量,对产品普鲁卡因青霉素中RRT0.24杂质的含量进行控制,所述产品普鲁卡因青霉素中RRT0.24杂质的含量y与原料盐酸普鲁卡因中RRT0.24杂质的含量x之间满足线性关系模型y=2.4835x,其中模型R2=0.9546。
9.根据权利要求8所述的控制方法,其特征在于,将盐酸普鲁卡因用水溶解后,负载在色谱柱上,然后用流动相进行梯度洗脱并进行检测,所述色谱柱为C18柱,检测波长为220-230 nm,柱温为48-52℃,流速为1.3-1.7mL/min;流动相A:68g/L pH=3.4磷酸二氢钾溶液50mL+300 mL水+150 mL甲醇;流动相B:68g/L pH=3.4磷酸二氢钾溶液50 mL+175 mL水+275mL甲醇。
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