金属参与的化学合成原料药元素杂质来源浅析

元素杂质是关乎药品质量重要的因素之一。合理控制药品中元素杂质也成为了业界关注的重点。国际人用药物注册技术协调会（ICH） Q3D明确了药品中可能残留的元素杂质的类型及其限度，这也为药品的开发和生产指明了方向。然而，元素杂质种类繁多，向药物中引入途径复杂，这为科学评估药品中元素杂质的安全性带了极大挑战。在众多的元素杂质引入途径中，原料药的制备工艺可能使用多种类型金属催化剂或无机试剂，这无疑是造成药品中元素杂质残留最为重要的影响因素。因此全面认识和理解不同元素以何种形式参与原料药的生产是科学控制元素杂质的关键。按照ICH Q3D汇总的3类元素杂质为序，介绍了不同金属在原料药合成中参与的反应。同时，建议将“质量源于设计”理念植入到原料药的生产工艺中，确保元素杂质水平符合《中国药典》和指导原则要求。     

ICH Q3D新药制剂元素杂质评估及控制的要点解读

目的：药品中可能有多个来源的元素杂质,由于元素杂质不能给病人提供任何治疗益处,因而药品生产中元素杂质含量应被控制在可接受的限度内。国际人用药物注册技术协调会议（ICH）Q3D元素杂质指南是新药制剂元素杂质控制的质量指南,旨在为新药制剂和其赋形剂中元素杂质的定性和定量控制提供全球性方针。本文介绍Q3D元素杂质指南,对相关要点进行解读。方法：详细描述元素杂质指南的主要内容,侧重于对元素风险评估及设定制剂中各组分元素杂质的限度进行具体分析。根据《美国药典》39和《欧洲药典》9.0中相关金属元素杂质的通则,汇总这些指导性文件与ICH Q3D的不同之处。结果与结论：Q3D主要包括潜在元素杂质的安全性评价、类别、元素杂质的风险评估和控制、日允许暴露量（Permitted Daily Exposure,简称PDE）与浓度限度之间的转换。元素杂质的风险评估应考虑潜在元素杂质的来源和药物服用方式,将特定元素杂质水平与PDE进行比较,评价该元素在药品中存在的可能性。经风险评估需要进行控制的元素杂质,可以根据药物服用剂量和PDE用3种方法设定元素浓度限度,这有利于帮助药品生产企业通过风险评估来决定对哪些元素进行额外控制,从而有效保障药品质量。     

《美国药典》新通则<232>和<233>元素杂质控制新标准和方法介绍及其对医药界的影响

目的:介绍《美国药典》(USP)新通则<232>和<233>中的药品元素杂质控制的新标准和方法,并分析其对医药行业的影响。方法:与现行标准比较USP新通则中元素杂质控制的新标准和方法以及重金属检查法的异同,并分析各元素杂质定量检测方法的优缺点及运行成本,对相关生产厂家提出建议。结果与结论:新通则明确要求测定各元素杂质含量而不是总量,即由半定量转为定量控制,并规定了15种金属元素杂质的每日允许接触限值及原料药和辅料中元素杂质的限量值;新通则推荐的两种重金属检查分析方法为电感耦合等离子体原子发射光谱法和电感耦合等离子体质谱法,可大大提高杂质检出能力,但仪器总运行成本较高。准备进入美国市场或已有产品销售的原料药或制剂生产厂家需对检测分析手段从软件和硬件上进行升级,并开发和验证合适的金属杂质检测方法。新通则的实施能更好地控制药品中的元素杂质含量。     

金莲花的X射线荧光分析及X射线衍射技术研究

目的：建立金莲花中药材内在质量的快速鉴别方法。方法：采用X射线荧光分析方法（XRF）和粉末X射线衍射技术（PXRD）对5个不同来源及产地金莲花样品的元素含量和整体特征进行了测定和分析。结果：5个样品中钾和钙元素含量均较高；而微量元素含量差异较大；道地品中富含钾元素的晶态物质含量最高，晶粒尺寸却最小，约40nm。结论：首次在金莲花中发现了富钾相。2种方法的联合应用不仅可以表达和鉴别药材的产地特征及识别其优劣；也能用于可制成粉末样品的中成药的鉴别、表征和质量控制，而且在质量标准的研究及制定方面具有广阔应用前景。     

ICP-MS法测定盐酸阿芬太尼注射液中25种元素杂质的含量

目的:建立电感耦合等离子体质谱法(ICP-MS),测定盐酸阿芬太尼注射液中25种具有潜在风险的元素杂质的含量。方法:采用Agilent 7800 ICP-MS电感耦合等离子体质谱仪,运用常规调谐模式,射频功率1 550 W,等离子气体流量15 L·min^-1,通过外标方式消除基质效应,样品稀释直接进样测定。结果:该方法能同时测定25种元素杂质含量,其线性关系良好(r>0.99),重复性试验的RSD≤10%(n=6),回收率在80.0%～120.0%(n=9),均满足方法学验证的要求。结论:盐酸阿芬太尼注射液元素杂质含量均低于ICH·Q3D规定限度的30%,不会给药品带来安全性风险,本法为其他相似药品元素杂质的质量控制和风险评估提供了参考。     

分析电子显微镜在医学生物学上的应用

伦琴发现 X 射线后不久,莫斯来即发现元素的原子序数与“特征 X 射线”波长之间存在着简单的数学关系,为 X 射线光谱分析奠定了理论基础。直至1971年以来,水平敏知等为医学生物学真正的 X 射线微区分析开辟了途径。近几年来,有关这方面的研究引起了人们极大兴趣,并取得了令人鼓舞的进展。这是因为,应用分析电镜能够同时在亚细胞水平上对无机元素进行微区定位分析,甚至可以直观无机元素。就是说,这种手段能分     

药品杂志检查研究进展

药品中的杂质影响药品质量,药品标准对药品中杂质均有严格规定.近年来,对药品中杂质的研究和应用水平都有提高.目前常用方法为薄层色谱法、高效液相色谱法、气相色谱法、毛细管电泳、超临界流体色谱及联用技术等,本文对药品杂质的来源、检验方法的建立和验证及应用情况进行了综述.     

航天诱变育种第4代知母的XRF、PXRD分析

目的：通过航天诱变选育优良的知母突变体，定向培育成药用部分品质提升的优良种质资源。方法：利用我国发射的神舟三号宇宙飞船搭载知母种子，回收后在地面上筛选繁育，并对枝叶和产量等方面占优势的第4代太空组及地面组知母药用部分中多种元素含量用X射线荧光光谱（XRF）和粉末x射线衍射（PXRD）法测定并对比分析。结果：太空知母元素种类无改变，但Zn、Sr元素含量比地面组知母分别提高到2．7和1．7倍，Al元素含量降低66．7％；并首次用PXRD技术在知母中鉴别出一水草酸钙晶体，太空知母中该晶体含量和晶粒尺寸比地面组明显减小。结论：航天诱变第4代知母中一水草酸钙晶体的含量明显减少，微量元素指标明显优化。通过航天诱变育种可以筛选出品质优化的知母新品种。     

药物杂质及其对安全性的影响

药物杂质与药品质量、安全性及效能密切相关,杂质控制在药物开发研究中的重要性越来越受到重视。本文综述了药品杂质的来源、杂质对药品安全性的影响及杂质的控制方法,阐明了加强杂质作用研究的意义。     

原料药有机杂质分析与研究流程

药物杂质与药物的临床使用安全性、药品的稳定性密切相关。对药物的杂质进行充分的研究和控制是确保药品安全性的必要环节,在药品杂质中有机杂质一直是研究的重点和难点。本文描述了仿制原料药的分析研究流程,为原料药生产企业进行仿制药有机杂质研究和控制提供了明确有效的途径。     

X-ray fluorescence elemental mapping and microscopy to follow hepatic disposition of a Gd-based magnetic resonance imaging contrast agent

1. Spatially resolved X-ray fluorescence (XRF) spectroscopy with synchrotron radiation is a technique that allows imaging and quantification of chemical elements in biological specimens with high sensitivity. In the present study, we applied XRF techniques at a macro and micro level to carry out drug distribution studies on ex vivo models to confirm the hepatobiliary disposition of the Gd-based magnetic resonance imaging contrast agent B22956/1. 2. Gd presence was selectively quantified allowing the determination of the time dependent disappearance of the drug from blood and its hepatic accumulation in mice after administration. Elemental mapping highlighted the drug distribution differences between healthy and diseased livers. XRF microanalyses showed that in CCl(4) -induced hepatitis, B22956/1 has greatly reduced hepatic accumulation, shown as a 20-fold reduction of Gd presence. Furthermore, a significant increase of Fe presence was found in steatotic compared with healthy livers, in line with the disease features. 3. The present results show that XRF might be useful in preclinical pharmacological studies with drugs containing exogenous elements. Furthermore, quantitative and high-sensitivity elemental mapping allows simultaneous detection of chemical variation, showing pathological conditions. This approach was useful in suggesting reduced B22956/1 accumulation in steatotic livers, thus opening possible new diagnostic perspectives for this drug.     

Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations

Since the discovery of X-ray diffraction and its potential to elucidate crystal symmetry, powder X-ray diffraction has found diverse applications in the field of pharmaceutical sciences. This review summarizes significant achievements of the technique during various stages of dosage form development. Improved understanding of the principle involved and development of automated hardware and reliable software have led to increased instrumental sensitivity and improved data analysis. These advances continue to expand the applications of powder X-ray diffraction to emerging research fields such as amorphous systems, mechanistic understanding of phase transformations, and “Quality by Design” in formulation development.     

高分辨三维X射线显微成像在药物制剂结构分析中的应用

药物制剂的结构研究能够帮助更加全面的评价药物制剂的质量,也有助于新型药物制剂的设计和创新。高分辨三维X射线显微成像技术能够在微米级甚至纳米级空间分辨率上原位、无损的展示粉末、颗粒、片剂、胶囊等固体制剂的三维结构信息,为新型制剂的创新和质量控制提供新方法。本文在介绍高分辨三维X射线显微成像技术的原理、发展及其研究药物制剂结构的基本流程的基础上,综述了其在药物制剂结构研究方面的国内外进展,为相关研究提供参考。     

A fatal copper sulfate poisoning.

An 11-year-old female died within hours of accidentally ingesting a solution of copper sulfate. A postmortem blood sample was found to contain 66 micrograms/mL copper. The initial qualitative identification of this poison in the body organs and fluids was by means of SEM-microprobe analysis (SEM-MPA) and X-ray fluorescence (XRF). The samples were quantified by atomic absorption spectrometry.     

Cellular distribution and degradation of cobalt ferrite nanoparticles in Balb/3T3 mouse fibroblasts

The effect of the concentration of cobalt ferrite (CoFe₂O₄) nanoparticles (NPs) on their intracellular location and distribution has been explored by synchrotron radiation X-ray and fluorescence microscopy (SR-XRF) monitoring the evolution of NPs elemental composition as well. In cells exposed to low concentrations of CoFe₂O₄ NPs, the NPs preferentially segregate in the perinuclear region preserving their initial chemical content. At concentrations exceeding 500 μM the XRF spectra indicate the presence of Co and Fe also in the nuclear region, accompanied by sensible changes in the cellular morphology. The increase of the Co/Fe ratio measured in the nuclear compartment indicates that above certain concentrations the CoFe₂O₄ NPs intracellular distribution could be accompanied by biodegradation resulting in Co accumulation in the nucleus.     

药学质性研究文献数据的信息可视化分析

目的:分析近十年国际上药学质性研究的现状和热点,为国内开展相关研究提供参考。方法:检索PubMed数据库2009-2018年发表的有关药学质性研究的文献,运用BICOMB-2软件对文献资料进行提取和统计,得到高频主题词的词篇矩阵和共现矩阵,利用gCLUTO 1.0进行聚类分析,利用NetDraw 2.089绘制社会网络图,并利用UCINET 6.212进行中心度和多维尺度分析。结果:共纳入157篇文献,刊载在65种期刊上,其中英格兰、美国发文最多;确定了当前研究的五大主题:药学教育课程、医联体教学及体验式教育模式、医院药学服务质量、社区药师沟通能力和社区药师药学服务能力的质性研究。结论:药学质性研究在国际上发文量呈逐年增长趋势,我国可以借鉴国际上的现状和热点,从药学教育课程、教育模式、医院药学服务等方面,开展我国的药学质性研究。     

Solid-state characterization of novel active pharmaceutical ingredients: cocrystal of a salbutamol hemiadipate salt with adipic acid (2:1:1) and salbutamol hemisuccinate salt

The production of salt or cocrystalline forms is a common approach to alter the physicochemical properties of pharmaceutical compounds. The goal of this work was to evaluate the impact of anion choice (succinate, adipate, and sulfate) on the physicochemical characteristics of salbutamol forms. Novel crystals of salbutamol were produced by solvent evaporation: a cocrystal of salbutamol hemiadipate with adipic acid (salbutamol adipate, SA), salbutamol hemisuccinate tetramethanolate (SSU.MeOH), and its desolvated form (SSU). The crystalline materials obtained were characterized using thermal, X-ray, nuclear magnetic resonance, Fourier transform infrared spectroscopy, dynamic vapor sorption (DVS), and elemental analysis. The crystal forms of SA and SSU.MeOH were determined to be triclinic, (Pī), and monoclinic, (P2(1) /n), respectively. DVS analysis confirmed that SSU and SA do not undergo hydration under increased relative humidity. Both thermal and elemental analyses confirmed the stoichiometry of the salt forms. The aqueous solubilities of SA and SSU were measured to be 82 ± 2 mg/mL (pH 4.5 ± 0.1) and 334 ± 13 mg/mL (pH 6.6 ± 0.1), respectively. Measured values corresponded well with the calculated pH solubility profiles. The intrinsic dissolution rate of cocrystallized SA was approximately four times lower than that of SSU, suggesting its use as an alternative to more rapidly dissolving salbutamol sulfate.     

Secondary x-ray fluorescence for in vivo transdermal absorption measurements

A modification of an X-ray fluorescence (XRF) technique that could be applied to the noninvasive measurement of transdermal absorption in human subjects with a low absorbed radiation dose was investigated. Secondary X-rays that were produced in a samarium foil by an isotopic ²⁴¹Am source were used to induce iodine Kα X-rays in an iodine-containing compound. The disappearance of this compound was measured following topical administration to a human volunteer. The use of the secondary X-ray fluorescence technique resulted in an 11-fold reduction in the absorbed radiation dose to the skin compared to conventional XRF bringing the technique within acceptable dosimetry limits for human studies.     

Thermal analysis of the antiretroviral zidovudine (AZT) and evaluation of the compatibility with excipients used in solid dosage forms

Modern thermal analysis techniques are frequently used because of their ability to provide detailed information about both the physical and the energetic properties of a substance. In the present work, the thermal decomposition of zidovudine (AZT) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Thermal analysis was supplemented using elemental analysis (C, H, and N), infrared (IR) spectroscopy, and X-ray powder diffraction to characterize the solid intermediates products. Volatile products of the thermal decomposition of AZT were studied by a system composed of the TG/DTA coupled gas chromatography/mass spectrometry (GC/MS). The physical–chemical properties and compatibilities of several commonly used pharmaceutical excipients with AZT were evaluated using thermal methods. The results showed that the product originated from the first thermal decomposition stage corresponds to the cleavage followed by elimination of the azide group and consequent formation of thymine. The second event corresponds to thermal decomposition of thymine. TG/DTA–GC/MS system identified thymine’s decomposition products as furan and 2-furanmethanol like volatile species. Comparison of the thermoanalytical profiles of the mixtures with individual compounds did not give any evidence of interactions.