On-chip terahertz spectroscopy for characterisation of pharmaceutical polymorphs

用于表征药物多晶型物的片上太赫兹光谱

• 批准号: EP/H007881/1
• 负责人: John Cunningham
• 金额: $ 17.16万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FH007881%2F1
• 关键词: chip; terahertz; spectroscopy; characterisation; pharmaceutical

We seek Follow-on funding to support the commercial and technical development of a prototype instrument suitable for the non-contact characterization and monitoring of pharmaceutical drugs, both during their research development stage, and their subsequent manufacture. Pharmaceuticals comprise organic compounds, which can adopt a variety of distinct crystal forms (called polymorphs). Each polymorph has a set of unique physical and chemical properties, and the identification of each polymorph is critical for the successful development and manufacture of pharmaceutical drugs, since each form can exhibit profoundly different properties (changing, for example, dissolution rate, bioavailability, and manufacturability). Techniques which allow the characterisation and quantitative analysis of polymorphic forms are therefore of fundamental importance to pharmaceutical companies.Existing techniques for the analysis of polymorphs currently being employed by the pharmaceutical industry each have significant limitations. These limitations can appear in the research phase of a drug, or in its subsequent manufacture. Raman spectroscopy typically shows only very limited spectral differences between drugs having similar chemical composition. Fourier transform infrared (FTIR) spectroscopy requires expensive and difficult bolometric detection, and furthermore is subject to significant thermal background radiation. While powder X-ray analysis is currently the gold-standard for polymorph discrimination, the machines are large, expensive, and take substantial time to obtain single spectra (typically hours). The ionizing nature of the radiation and slow acquisition times also make X-ray techniques unsuitable for on-line process monitoring. Potential solutions to these problems can be found in the technique of terahertz time-domain spectroscopy (THz-TDS), which is additionally and uniquely capable of penetrating packaging material.With Follow-on funding, we will develop and exploit an on-chip analysis prototype instrument based on THz frequency vibrational spectroscopy, but distinct from free-space THz spectroscopy. Our technology is capable of identifying, analyzing, and monitoring in real-time the composition and polymorphic form of pharmaceutical drugs. The background IP for our instrument was established in 2008, during the final stages of several EPSRC grants which funded the basic scientific research; the investigators proved an on-chip THz frequency analysis technology capable of distinguishing organic compounds by their spectral signature in the THz frequency range. The distinct absorption response which different pharmaceutical polymorphs show under THz illumination allows them to be distinguished easily.Compared with the existing technique of free-space THz-TDS in use by the pharmaceutical industry, our on-chip technology offers several substantial benefits to end-users:- It can determine the composition of much smaller samples (typically one-thousandth of the volume), owing to its high (<10 micron) spatial resolution, important in the classification and imaging of drugs with excipients.- It has enhanced frequency resolution (2 GHz, compared with ~40 GHz), vital in the discrimination between polymorphs at low temperatures during drug development.- It has the potential to be an order of magnitude cheaper, since it is compatible with low power (and low-cost) laser excitation.We will use our prototype instrument to characterize the absorption spectra of a number of targeted drugs, building up proving application data with which we will attract licensees over the course of the project. Our work will also build on the underpinning technical and commercial developments we have already made, and provide the necessary work to demonstrate direct application of our technology to the pharmaceutical industry.

我们寻求跟进资金，以支持适用于在研究开发阶段及其后续生产的制药药物的非接触式表征和监测的原型仪器的商业和技术开发。药物包括有机化合物，可以采用各种不同的晶体形式（称为多晶型物）。每个多晶型物具有一组独特的物理和化学特性，并且每个多晶型物的识别对于成功开发和制造药物至关重要，因为每种形式都可以表现出明显不同的特性（例如，例如，溶解速率，生物利用度和生产能力）。因此，允许对多态性形式进行表征和定量分析的技术对制药公司至关重要。在制药行业目前使用的多晶型物分析的技术都有很大的限制。这些局限性可能会出现在药物的研究阶段，也可以出现在其随后的生产中。拉曼光谱法通常仅显示具有相似化学成分的药物之间的光谱差异非常有限。傅立叶变换红外（FTIR）光谱需要昂贵且困难的降压检测，此外，还需要明显的热背景辐射。虽然粉末X射线分析目前是多态性歧视的金标准，但这些机器很大，昂贵，并且需要大量时间获得单光谱（通常是小时）。辐射的电离性质和缓慢的获取时间也使X射线技术不适合在线过程监视。在Terahertz时域光谱（THZ-TDS）的技术中，可以找到解决这些问题的潜在解决方案，该技术还可以渗透包装材料。随后，我们将开发并利用基于THZ频率振动的芯片分析原型仪器，但从自由镜头thz Spectrspace thz Spectrspace thz Spectroscopy。我们的技术能够实时识别，分析和监测药物的组成和多态性形式。我们工具的背景IP成立于2008年，是在资助基础科学研究的几项EPSRC补助金的最后阶段。研究人员证明了一种芯片THZ频率分析技术，能够通过其光谱签名在THZ频率范围内区分有机化合物。 The distinct absorption response which different pharmaceutical polymorphs show under THz illumination allows them to be distinguished easily.Compared with the existing technique of free-space THz-TDS in use by the pharmaceutical industry, our on-chip technology offers several substantial benefits to end-users:- It can determine the composition of much smaller samples (typically one-thousandth of the volume), owing to its high (<10 micron) spatial resolution, important in - 它具有提高的频率分辨率（2 GHz，比约40 GHz），对药物开发期间低温下的多晶型物的区分至关重要。毒品，建立证明应用数据，我们将在项目过程中吸引被许可人。我们的工作还将建立在我们已经做出的基础技术和商业发展的基础上，并提供必要的工作，以展示我们的技术直接应用于制药行业。

项目成果

Simultaneous measurement of orthogonal components of polarization in a free-space propagating terahertz signal using electro-optic detection

使用电光检测同时测量自由空间传播太赫兹信号中偏振的正交分量

• DOI: 10.1063/1.3579258
• 发表时间: 2011
• 期刊: Applied Physics Letters
• 影响因子: 4
• 作者: Byrne M

Time-domain measurement of terahertz frequency magnetoplasmon resonances in a two-dimensional electron system by the direct injection of picosecond pulsed currents

通过直接注入皮秒脉冲电流对二维电子系统中太赫兹频率磁等离子共振进行时域测量

• DOI: 10.1063/1.4943173
• 发表时间: 2016
• 期刊: Applied Physics Letters
• 影响因子: 4
• 作者: Wu J

On-chip picosecond pulse detection and generation using graphene photoconductive switches.

• DOI: 10.1021/nl504116w
• 发表时间: 2015-03-11
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Hunter N;Mayorov AS;Wood CD;Russell C;Li L;Linfield EH;Davies AG;Cunningham JE
• 通讯作者: Cunningham JE

Terahertz imaging and spectroscopy

太赫兹成像和光谱学

• 发表时间: 2010
• 期刊: EuCAP 2010 - The 4th European Conference on Antennas and Propagation
• 作者: Davies A.G.

Free-space terahertz radiation from a LT-GaAs-on-quartz large-area photoconductive emitter.

• DOI: 10.1364/oe.24.026986
• 发表时间: 2016-11
• 期刊: Optics express
• 影响因子: 3.8
• 作者: D. R. Bacon;A. Burnett;M. Swithenbank;C. Russell;Lianhe H. Li;C. Wood;J. Cunningham;E. Linfield;A. Davies;P. Dean;J. Freeman