On-chip terahertz spectroscopy for characterisation of pharmaceutical polymorphs

我们寻求后续资金，以支持原型仪器的商业和技术开发，该仪器适用于药物的非接触表征和监测，无论是在其研究开发阶段，还是在其随后的制造阶段。药物由有机化合物组成，这些有机化合物可以采用各种不同的晶体形式（称为多晶型）。每种多晶型都有一组独特的物理和化学性质，每种多晶型的鉴定对于药物的成功开发和制造至关重要，因为每种形式都可以表现出截然不同的性质（例如，溶解速度，生物利用度和可制造性）。因此，允许多态形式的表征和定量分析的技术对制药公司至关重要。现有的多态分析技术目前被制药行业所采用，每种技术都有明显的局限性。这些限制可能出现在药物的研究阶段或随后的生产过程中。拉曼光谱通常只显示具有相似化学成分的药物之间非常有限的光谱差异。傅里叶变换红外光谱（FTIR）需要昂贵和困难的热量检测，并且受到明显的热背景辐射。虽然粉末x射线分析目前是多晶型鉴别的金标准，但机器体积大，价格昂贵，并且需要大量时间才能获得单一光谱（通常需要数小时）。辐射的电离性质和缓慢的采集时间也使得x射线技术不适合在线过程监测。这些问题的潜在解决方案可以在太赫兹时域光谱（THz-TDS）技术中找到，该技术具有穿透包装材料的独特能力。利用后续资金，我们将开发和利用基于太赫兹频率振动光谱学的片上分析原型仪器，但与自由空间太赫兹光谱学不同。我们的技术能够实时识别、分析和监测药物的组成和多态形式。我们仪器的背景知识产权是在2008年EPSRC资助基础科学研究的最后阶段建立的；研究人员证明了一种芯片上的太赫兹频率分析技术，能够通过太赫兹频率范围内的光谱特征来区分有机化合物。不同的药物多晶在太赫兹光照下表现出不同的吸收响应，这使得它们很容易被区分。与制药行业使用的现有自由空间太赫兹- tds技术相比，我们的片上技术为最终用户提供了几个实质性的好处：-由于其高（<10微米）空间分辨率，它可以确定小得多的样品（通常是体积的千分之一）的组成，这在具有赋形剂的药物的分类和成像中很重要。-它具有增强的频率分辨率（2 GHz，与~40 GHz相比），这对于药物开发过程中低温下多晶型的区分至关重要。-它有可能是一个数量级的便宜，因为它是兼容的低功率（和低成本）激光激发。我们将使用我们的原型仪器来表征一些靶向药物的吸收光谱，建立证明应用数据，我们将在项目过程中吸引许可方。我们的工作还将建立在我们已经取得的基础技术和商业发展的基础上，并提供必要的工作来证明我们的技术在制药工业中的直接应用。

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.