Developing mechanistic understanding of unconventional growth in pharmaceutical crystals using scanning electron microscopy, atomic force microscopy and time-of-flight secondary ion mass spectrometry

Introduction
Crystalline materials play a pivotal role in medicines manufacturing as active pharmaceutical ingredients are commonly formulated in crystalline form and developing a thorough understanding of the mechanisms underlying crystal growth is paramount in ensuring the production of potent medicines. Materials crystallizing in the form of twisted structures have been observed at the nanoscale, mesoscale, and macroscale and pose unique challenges with respect to structural characterization because of their inherent lack of long-range translational order.
In our work, we have explored a combination of characterization techniques to gain insight into the mechanism of growth of unconventional, twisted crystals of oxcarbazepine (OXCBZ), a commercially available antiepileptic drug known to exhibit multiple crystalline forms (polymorphs). Our efforts focused on investigating twisted crystals of the elusive form III of OXCBZ which were grown on a variety of metallic substrates using a physical vapor deposition approach.

Methods
By conducting physical vapor deposition studies of OXCBZ we were able to observe the serendipitous formation of twisted needle and fiber-like form III crystals which were imaged using scanning electron microscopy (SEM), atomic force microscopy (AFM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to obtain detailed information on the structural features present in the crystals and understand their formation mechanism and evolution over the course of the deposition process. Complementary solid state analyses of samples were additionally carried out using powder X-ray diffraction and low-frequency Raman spectroscopy.

Results
SEM and AFM micrographs that we obtained showed that twisted OXCBZ III crystals emerge directly through the apparent aggregation of droplet-like, nanosized precursors arising on a variety of metallic substrates upon physical vapor deposition of OXCBZ. Low-frequency Raman spectroscopy analysis of the nanosized precursors suggested that they are likely of amorphous (non-crystalline) nature. Chemical imaging performed with ToF-SIMS highlighted that the layer of OXCBZ precursors around the formed crystals is depleted, exposing the surface of the metallic substrates underneath.

Conclusion
Our experimental observations suggest that unconventional OXCBZ III crystals with twisted morphologies arise by following a non-classical, multi-step growth mechanism bearing many similarities to ones that have been reported in solution-based crystallization studies of various organic and inorganic materials.