化药新药研发检测

通过AIMsolution的范围扫描不仅可以显示峰高和面积，而且还可显示基于PCA、MCR等多变量分析结果的多种绘制图像。

质量源于设计 (QbD) 是一种进行药物开发的系统方法，该方法始于预设目标，并应用科学和风险管理使我们对产品和工艺有更深入的了解，最终实现工艺控制。在开发和生产的每一个步骤中均应用 QbD 原理，有助于提高工艺的稳定性，并避免在后续环节中出现问题。

In the modern pharmaceutical industry, it is critically important to identify and quantify impurities with the highest possible confidence given their potential toxic effects on humans. This report describes the performance of the Agilent 6545 Q - TOF LC/MS system in the determination of metoclopramide pharmaceutical impurities. In this, the 6545 Q - TOF and 1290 Infinity LC system are used to determine metoclo pramide impurities (structures below). Metoclopramide standard prepared at 500 ppm was spiked with all known impurities described in European Pharmacopoeia and two additional impurities at 0.05% (w/w) and 0.01% (w/w) levels.

Over the last decades, an increasing number of generic drug formulations have been released on the pharmaceutical market. These products are generally analyzed with compendia methods. This Application Note describes the method transfer of a USP HPLC method for amlodipine besylate tablets to a state-of-the-art UHPLC method. Adjustments on column dimension and method parameters were carried out within the permitted limits in order to avoid the need for a lengthy revalidation process. The Agilent 1290 Infinity II LC facilitated smooth transfer from one method to the other. System suitability criteria were investigated and met with both HPLC and UHPLC.

安捷伦用于药物代谢物鉴定及定量的强大解决方案 安捷伦致力于推出适合大多数应用的系列解决方案，辅以应用开发领域安捷伦无与伦比的独有专业技术，为 ADME/DMPK 研究提供鼎力支持。因此，我们当之无愧地成为制药公司以及合同研究组织 (CRO) 的优秀合作伙伴。

CEM专利的环形电磁场结构设计，使氨基酸构成的卷曲肽链充分展开，进行彻 底的去保护、耦合和裂解，反应变得极其快速，完全，高纯。Liberty BLUE比传统方法提高了近20倍；标准的10肽 ACP 序列合成纯度竟达到 98%，使得许多合成反应甚至可免去纯化步骤；可以完成传统方法不可能实现的困难合成。实现更多更长的氨基酸耦合，防止长链多肽聚合，消除双重耦合和外消旋现象，同时降低树脂的要求。BLUE 开辟了多肽合成的新纪元，使生物化学和蛋白质研究具备了空前的多肽合成的能力，是以前传统合成方法根本无法想象的。市场上没有任何一台多肽合成仪能与 BLUE相媲美。

使用安东帕微波合成仪Monowave 400，详细描述了微波合成在药物合成中的应用。可以明显提高反应效率。

客户所提供三样品分别为氨基丁二酸与杂质A混合溶液、氨基丁二酸不同处理方法溶液及氨基丁二酸单标，由于使用CAPCELL PAK C8DD色谱柱无法将样品①中氨基丁二酸与杂质A分离，因此我们选择使用具有高表面极性、可以对极性样品有良好保留的CAPCELL PAK ADME色谱柱进行尝试

Key Words Acclaim C18 RSLC, Biocompatible UHPLC, Biopharma, Biotherapeutics Characterization, Monoclonal Antibodies, Protein Digest, Vanquish UHPLC System Goal Evaluate the long-term stability of peptide mapping on a Vanquish UHPLC system

The use of near-infrared (NIR) spectroscopy in the pharmaceutical industry has grown rapidly in the past decade. The IMV-4000 Infrared Multichannel Viewer integrated with a NIR capable FT/IR- 4000 or FT/IR-6000 instrument enables NIR Imaging of pharmaceutical tablets, a valuable tool in the estimation of tablet properties, offering measurement data with high specificity and sensitivity. The obtained data can be exported into the Principal Component Analysis (PCA) software for the estimation of tablet characteristics. Instrument: FTIR-6200 with IMV-4000 CaF2 beam splitter, NIR source, etc

因为药物晶体具有很好的储存稳定性，药物公司在新药物配方中倾向采用结晶化合物。然而经常碰到的问题是药物存在多种结晶形式，即通常所说得多晶型。由于多晶型的每种晶型的物理性质、比如分散速率和生物活性有很大的不同，因此控制结晶的形势和含量显得十分重要。

各相温度和热量对预估结果的影响。在相同的条件下对比不同的温控温度，合适的温度控制比设置参数更重要，特比对于UHPLC方法来估计温度。。

开发一个超高效液相色谱（UHPLC）方法来解决主要的生物胺，并在他们的酸性代谢产物微透析样本收集从大鼠脑使用改进吞吐量Thermo Scientific的戴安?的UltiMate??3000平台的高效液相色谱法。 从前额皮质细胞外液的样品中收集的20分钟持续使用2毫米微透析探针。随后的分析通过进行样品生物胺和酸性代谢产物的含量采用了一块2.4?m的，2.1×100毫米C18柱3000的UltiMate HPLC系统。 一个UHPLC方法在微透析神经化学物质的测量样品被开发。主要的生物胺和酸性代谢物使用的电化学组合的细胞外液样品中检测氧化和还原技术。

UHPLC仪器，药品Stribild?，自动进样器线性，制药，HIV，泛型方法 要开发一个易于使用的方法四个主要的快速分离利用最新的UHPLC设备Stribild丸化合物和技术。该方法进一步优化考虑在这种相当的各种可能的杂质同时分析复杂的药物配方。

在生物系统中的蛋白质多样性是相当大的，但短期短期（<1小时），由于特定的刺激会引起变化在非常特殊的蛋白表达的只有细微变化水平。过多的样品处理/处理方法往往添加显著噪声总体的实验结果。在这里，我们使用简单的样品制备技术，极可重复UHPLC系统和强大的群众相结合 系统，分光计平台，得到研究人员使用的能力对于几个量化大规模蛋白质/肽文库千蛋白质。

保留时间的精度只受液相泵的影响。保留时间的精度对于对比结果很重要。尽管如此，有了UHPLC有直接控制这些因素的方法

生物，诊断或治疗感兴趣的糖蛋白欠的关键方面的正常功能，以连接到蛋白质骨架上的寡糖。变化这些聚糖的数量，类型，组合物或联动图案可以用作疾病的生物标志物或影响生物治疗的效力对于本因此，为了正确地识别和测量这些聚糖的能力是科学兴趣，并且这样做可靠，快速且廉价地是实际的好处。此作品探讨直接检测天然聚糖的作为替代的共同 依靠衍生反应技术分析聚糖呈现聚糖检测。在天然聚糖可检测发色团的缺乏是通过使用HPLC用带电气溶胶检测克服，检测器可以定量地测量任何非挥发性化合物

日立F-7000荧光分光光度计具有如高灵敏度（RMS信噪比为800）以及同类产品最高级别的高扫描速（60000nm/min）等许多新功能。目前，荧光分光光度法在各个领域内得到广泛应用：诸如有机电致发光和液晶等工业材料；水质分析等环境相关领域；荧光试剂的合成与开发等制药领域；细胞内钙离子浓度测定等生物技术相关领域。

The development of monoclonal antibody (Mab) based drugs has undergone considerable growth since the release of the first Mab in the mid-eighties. Intuitive biophysical tools that examine and quantify interactions and conformational dynamics are important in demonstrating and understanding local and global conformational changes. The structure of antibodies as well as other macromolecules is related to its function and efficacy therefore control over these parameters is essential. The association of antigens to antibodies or of antibodies to delivery assemblies such as liposomes or gold nanoparticles can be addressed by isothermal titration calorimetry (ITC) while the folding of antibodies can be assayed using differential scanning calorimetry (DSC). Both techniques offer the advantage of using native solutions and both instruments are offered by TA Instruments.

检测细胞与蛋白质类药物的相互作用在药物研发过程中通常是十分重要的。石英晶体微天平可以实时的观测蛋白质药物与细胞的相互作用。

蛋白质类药物通常容易在制造和包装的过程发生聚集。这些蛋白质容易聚集在玻璃表面，塑料表面，管路，袋子，或者金属容器表面等等。所以说全面的理解蛋白在表面的聚集对于制药行业来说至关重要，因为可以最小化贵重药物的损失，最大化药品的活性。在本文中，石英晶体微天平成功的研究了这种蛋白聚集过程。

马钱子主要有效成分士的宁（strychnine）又名番木鳖碱，属于中枢神经兴奋剂，临床用于偏瘫、瘫痪及因注射链霉素引起的骨骼肌松弛、弱视症等和巴比妥类中毒等。此外，添加士的宁的饲料诱饵可用来消灭老鼠等啮齿类有害动物，然而这些动物体内残留士的宁会通过食物链传递, 对整个生态圈造成影响，故有必要对其代谢产物进行深入研究，为临床用药、环保、司法等部门提供可靠的分析手段和数据。 LTQ Orbitrap XL结合了线性离子阱和Orbitrap高分辨质量分析器，具有高灵敏度的多级高分辨能力。Mass Frontier为Thermo专业的结构解析软件，利用其丰富的碎裂数据库，可快速的对士的宁多级碎裂规律进行准确推测和归属，碎片离子检索功能将母药与代谢物相关性与可能的代谢途径有机的结合起来，从繁杂的基质样品质谱信号中准确的筛选到未知代谢物信息，进一步对代谢位点进行推测，最终获得全面的代谢物信息。

Exactive Plus EMR总共具有五档不同的分辨率，供不同分析目的使用。首先，由于在非变性状态下蛋白质样品更不易带电，与变性条件下相比，150kDa的单克隆抗体出峰在m/z 5000-8000的范围内，明显向高质量端移动。Exactive Plus EMR的m/z上限拓展至20000，可轻松胜任非变性条件下单克隆抗体乃至其多聚体的分析需求。其次，即使在最低分辨率下，仍能采集到高信噪比、基线干净的谱图，证明了Orbitrap系统所具有的高灵敏度、高质量精度和高稳定性等优点可以生成高质量、高可信度的原始数据。

PepFinder软件对单克隆抗体进行常规肽图分析的各种应用。结果表明，使用PepFinder软件可以简便快捷的得到序列覆盖度分析的结果，并且可以对脱酰胺等生物医药质控中重要的翻译后修饰进行鉴定以及定量。PepFinder独具的单克隆抗体分子量计算功能及二级谱图智能预测功能大大减少了分析人员花费在数据处理上的时间；在PepFinder2.0版本中，新增的De Novo Sequencing功能和mgf格式文件、pinpoint txt文件输出功能帮助分析人员对数据进行不同平台上的深入挖掘。通过生成快速、全面的肽段表征及自动化的修饰位点总结报告， PepFinder 软件能够大幅减少生物产品详细表征所需的时间和精力。

采用Exactive Plus EMR质谱仪，直接进样方式，突破了传统的RPLC/MS平台无法进行cysteine-linked ADCs分析的瓶颈，建立了cysteine-linked ADCs的精确分子量测定方法，为cysteine-linked ADCs 单抗药物研发和生产检测提供了高效、快速的分析平台。实验结果表明Exactive Plus EMR质谱仪凭借其超高的分辨率、超快的扫描速度、超高的质量精度、超高的灵敏度以及拓展的质量范围，极大地完善和推动了ADCs药物的鉴定分析。

实验表明，得益于主动离子管控技术（AIM），TSQ Quantiva在复杂基质中针对目标肽段的定量灵敏度表现突出，极大地提升了TSQ 质谱平台定量复杂基质中目标肽段的能力，适用于复杂生物学样本中低丰度蛋白质的分析，可用于 潜在生物标志物的确证工作。

Previously it has been shown that glycerol can be regioselectively glucosylated by sucrose phosphorylase from Leuconostoc mesenteroides to form 2-O--d-glucopyranosyl glycerol.A series of compounds related to glycerol were investigated by us to determine the scope of the -glucosylation reaction of sucrose phosphorylase. Both sucrose and glucose 1-phosphate (G1P) were applied as glucosyl donor. Mono-alcohols were not accepted as substrates but several 1,2-diols were readily glucosylated, proving that the vicinal diol unit is crucial for activity. The smallest substrate that was accepted for glucosylation appeared to be ethylene glycol,which was converted to the monoglucoside for 69%. Using high acceptor and donor concentrations (up to 2.5 M), sucrose or G1P hydrolysis (with H2O being the ‘acceptor’) can be minimised. In the study cited above, a preference for glucosylation of glycerol on the 2-position has been observed. For 1,2-propanediol however, the regiochemistry appeared to be dependent on the configuration of the substrate. The (R)-enantiomer was preferentialy glucosylated on its 1-position (ratio 2.5:1), whereas the 2-glucoside is the major product for (S)-1,2-propanediol (1:4.1). d.e.ps of 71–83% were observed with a preference for the (S)-enantiomer of the glucosides of 1,2-propanediol and 1,2-butanediol and the (R)-enantiomer of the glucoside of 3-methoxy-1,2-propanediol. This is the first example of stereoselective glucosylation of a non-natural substrate by sucrose phosphorylase. 3-Amino-1,2-propanediol, 3-chloro-1,2-propanediol, 1-thioglycerol and glyceraldehyde were not accepted as substrates.

A biomimetic approach has been investigated and developed for the total synthesis of azonazine, an unusual marine natural cyclopeptide containing a rigid transannular 10-membered ring. A hypervalent iodine-mediated direct oxidative cyclization was successfully developed and applied to construct the highly strained core, which was the key step in the first total synthesis of ent-(
)-azonazine. Based on the physical evidences of synthesized diastereomer and enantiomer of azonazine, both the relative and absolute configurations of the natural product were revised. Two fluorinated azonazine derivatives were also synthesized in short convenient steps utilizing the same intermediate in this work. The established total synthesis opens a potential opportunity to study the structureeactivity relationship of natural azonazine.

A group of novel taxoids, with modifications at C-7, C-10, C-30 and C-14 positions of paclitaxel, was synthesized in order to improve their biological profile by decreasing their affinity with P-glycoprotein (Pgp) and increasing cellular permeability. Most of the new taxoids demonstrated the similar potent cytotoxic activities in MCF-7 human tumor cell line as paclitaxel in vitro. In the permeability assay with monolayers of Caco-2 cells, most of the compounds demonstrated an increased trans-cellular transport in Ato- B direction in comparison with paclitaxel. Among them the compounds T-13, T-15 and T-26 showed the highest permeability, and with efflux ratios better than that of ortataxel. The interaction of the compounds T-13 and T-26 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1(MDR1) and MDCK-wild-type (WT). The results indicated that T-13 and T-26 were poor substrates for P-gp and possessed inhibiting effects of P-gp mediated efflux. It was thus clear that simultaneous modifications at the C-7, C-10 and C-30 positions of paclitaxel significantly impaired its interactions with P-gp and interfered with P-gp mediated efflux.

Clandestine laboratories constantly produce new synthetic cannabinoids to circumvent legislative efforts,complicating toxicological analysis. No extensive synthetic cannabinoid quantitative urinary methodsare reported in the literature. We developed and validated a liquid chromatography–tandem mass spec-trometric (LC–MS/MS) method for simultaneously quantifying JWH-018, JWH-019, JWH-073, JWH-081,JWH-122, JWH 200, JWH-210, JWH-250, JWH-398, RCS-4, AM-2201, MAM-2201, UR-144, CP 47,497-C7,CP 47,497-C8 and their metabolites, and JWH-203, AM-694, RCS-8, XLR-11 and HU-210 parent com-pounds in urine. Non-chromatographically resolved alkyl hydroxy metabolite isomers were consideredsemi-quantitative.  Glucuronidase hydrolyzed urine was extracted with 1 ml Biotage SLE+ columns.Specimens were reconstituted in 150 L mobile phase consisting of 50% A (0.01% formic acid in water)and 50% B (0.01% formic acid in 50:50 methanol:acetonitrile). 4 and 25 L injections were performed toacquire data in positive and negative ionization modes, respectively. The LC–MS/MS instrument consistedof a Shimadzu UFLCxr system and an ABSciex 5500 Qtrap massspectrometer with an electrospray source.Gradient chromatographic separation was achieved utilizing a Restek Ultra Biphenyl column with a0.5 ml/min flow rate and an overall run time of 19.5 and 11.4 min for positive and negative mode methods,respectively. Quantification was by multiple reaction monitoring with CP 47,497 compounds and HU-210ionized via negative polarity; all other analytes were acquired in positive mode. Lower and upper limitsof linearity were 0.1–1.0 and 50–100 g/l (r2> 0.994).