An experimental and theoretical study of mechanical properties in pharmaceutical materials

在药物制剂开发中，候选药物可能表现出次优的行为和物理性质，使得商业规模的稳健制造工艺的开发具有挑战性。该开发的关键阶段是固体形式的选择，因为活性药物成分的不同多晶型物可能具有不同的物理化学性质，从而影响最终剂型的成功。虽然在颗粒形成过程中对固体形式进行常规控制，但对通过压片制备片剂时典型生产操作的影响了解较少。通过创建工具来连接固体形式的结构特征，了解如何在制造条件下对其进行修改，将有可能解锁新的机会，以加速制造开发并防止代价高昂的故障。本项目将调查压力对制药材料的影响。在产品微粉化和压片过程中，可在产品加工过程中找到本研究的依据。在这些情况下，固体形式暴露于超过150 MPa的压力下，因此理解在这些条件下固体中可能发生的变化可以帮助全面理解。当考虑到大量的化合物时，这是特别强大的。通过调查许多不同的分子，我们将能够探索不同的分子功能对药物材料压缩的影响。我们将能够使用金刚石对顶砧单元来跟踪固体形式的变化，该金刚石对X射线辐射是透明的。通过单晶分析，可以在压缩下，特别是在流体静力学环境下跟踪药物材料的结构。将使用X射线粉末衍射、纳米压痕和光谱方法探索非流体静力学压缩（更接近于“工作”环境）。计算方法将用于提供系统的能量信息。

In pharmaceutical drug product development drug candidates can exhibit sub-optimal behaviour and physical properties, making the development of commercial scale, robust manufacturing processes challenging. A key stage in this development is the selection of the solid form, as different polymorphs of an active pharmaceutical ingredient can have different physico-chemical properties, thus impacting the success of the final dosage form. While solid form is routinely controlled during the particle formation process, the impact of typical manufacturing operations when making tablets via compression is much less well understood. By creating tools to connect the structural features of a solid form with an understanding of how this can be modified under manufacturing conditions it will be possible to unlock new opportunities to accelerate manufacturing development and prevent costly failures. This project will investigate the impact of pressure on pharmaceutical materials. The rationale for this investigation can be found during the processing of the products during micronisation and tabletting of the product. Under these circumstances the solid form in exposed to pressures in excess of 150 MPa and hence understanding the changes that may occur in a solid under these conditions can aid a global understanding. This is especially powerful when taking into account a larger number of compounds. By surveying many different molecules we will be able to explore the impact that different molecular functionalities have on the compression of the pharmaceutical materials. We will be able to follow changes in solid forms as a function of pressure using a diamond anvil cell where the diamonds are transparent to X-ray radiation. Through single-crystal analysis the structures of the pharmaceutical materials can be followed under compression, in particular, under a hydrostatic environment. Non-hydrostatic compression (which is closer to a "working" environment) will be explored using X-ray powder diffraction, nanoindentation and spectroscopic methods. Computational methods will be used to provide energetic information on the system.