Molecular interactions in amorphous paracetamol

This is a resubmission of RB1820402, which has been terminated due to the inability to finalise the experiment within 5 years. This is due to problems of the D-lab providing deuterated sample (including set-back due to the fire).
The appearance of multiple crystal forms is one of the bottlenecks in pharmaceutical formulation. To date the result of a crystallisation experiment cannot be predicted and we do not understand the influence of the amorphous phase (solution or melt) on the crystal form. A lot of attention has been paid to crystallisation from solution, which is currently the standard method in industry, whilst crystallisation from the melt has been widely neglected. However, this crystallisation pathway frequently leads to unique crystal forms that are not accessible through any other route. In this proposal we want to measure the melt phase of paracetamol, which presents the only path to obtain the metastable form III. By using SANDALS to obtain total scattering data and connected EPSR simulations, we will connect the molecular interactions in the melt with those in the crystal structure.

本提交为RB1820402项目的重新申请，原项目因未能在5年内完成实验而终止。终止原因为提供氘代样品（deuterated sample）的D实验室出现相关问题，其中包括火灾导致的实验进度延误。
多晶型现象是药物制剂研发的核心瓶颈之一。截至目前，结晶实验的结果仍无法被精准预测，学界尚未明确非晶相（溶液或熔融态）对晶型形成的具体影响。当前工业界以溶液结晶为标准结晶方法，相关研究已获得大量关注，但熔融态结晶却长期被广泛忽视。然而，该结晶路径往往能够生成其他结晶途径无法获得的独特晶型。
在本次申请中，我们拟对对乙酰氨基酚（paracetamol）的熔融相开展表征，这是获取其亚稳态晶型III的唯一可行路径。我们将利用SANDALS仪器获取全散射数据，并结合关联式经验势结构精修（EPSR）模拟，建立熔融态分子相互作用与晶体结构分子相互作用之间的关联。