High pressure is of increasing interest to the pharmaceutical industry due to the impact it has during the manufacturing process. During the processes, such as compaction to form tablets, materials can undergo phase transitions, potentially impacting their physicochemical properties and hence their ability to deliver the active ingredient. A team of scientists from University of Strathclyde, Diamond Light Source and the PEARL instrument at ISIS used a combination of synchrotron and neutron diffraction to investigate the effect of pressure on hydrogen bonding in cocrystals.
Pharmaceutical cocrystals involve combining an active pharmaceutical material (API) with coformers, which need not be structurally similar but should engage in compatible interactions with the API. This combination, often guided by hydrogen bonding motifs, modulates a materials stability. Understanding the hydrogen bonding interactions, particularly under varying pressure and temperature conditions, is crucial for assessing material robustness during co-crystal development and its potential changes through processing. The team used pyrazine and a series of dicarboxylic acids as a model to investigate the effect of pressure on the acid-pyrazine interaction in cocrystallisation of pharmaceutical materials. The acid-pyrazine motif is a common hydrogen bonding interaction in pharmaceutical cocrystals. Using this simplified model system, the hydrogen bonding motifs could be probed exclusively to study the impact of pressure whilst minimising the impact of packing effects and other interactions.
They surveyed five pyrazine dicarboxylic acid systems and observed that hydrogen bonding compresses at a similar rate in all the systems, despite the change in the molecular structures and the starting interaction distances. The changes in structure when compressed suggest that the layers move along the major slip planes in the structure. The pyrazine:malonic acid system displays phase transitions: either deteriorating when compressed as seen in the powder samples of the 1:1 and 2:1 system or supercompression beyond the phase boundary in the 2:1 single crystal sample. This highlights that the change in behaviour depending on crystallite size, such as the one observed in this study, is an important and common occurrence in organic materials and a consideration in evaluating the observation of phases. This work is one of the first systematic studies of cocrystalline structures under high pressure, which will aid the discovery of new active pharmaceutical materials.