Purpose: Pharmaceutical unit operations such as drying, milling and compaction can often generate disordered regions in API crystals, which can ultimately affect a number of important pharmaceutical properties including dissolution, stability, and hygroscopicity etc. Historically, a range of “bulk” analytical techniques have been used to understand the extent of disorders in pharmaceutical solids including X-ray powder diffraction, density, heat of solution, infrared spectroscopy, dissolution rate, Raman spectroscopy, solid state NMR, dynamic mechanical analysis, differential scanning calorimetry, and water vapor sorption. The disorders generated during these pharmaceutical unit operations sometimes are more local in nature, and are not always easily detectable with the aforementioned methods. It is, therefore, important for pharmaceutical industry to investigate and develop analytical methods that are capable of accurately detecting and assessing the extents of subtle changes in API local structures that can be linked with product stability and performance. In this work, synchrotron-based total scattering pair distribution function (TS-PDF) analysis was applied to assess structural orders of a number of API crystals that were subjected to different drying, milling and compaction conditions.
Methods: Synchrotron total scattering and pair distribution function (TS-PDF) analysis were applied on crystals of three different APIs to assess the effects of drying (sequential drying and humidification vs parallel humidified drying), milling (pin milling and cryo milling) and compaction (force 5 to 55 kN) processing conditions on their structural orders. Nanoindentation and in-situ scanning probe microscopy were also used to determine the mechanical properties of API crystals. Furthermore, the principal component analysis (PCA) was used to analyze the PDF transformed diffraction data to discover latent trends among the data.
Results: TS-PDF data revealed that the hard crystals of compound 1 (Young’s modulus = 10.4 Gpa and hardness = 0.43 Gpa) exhibited very little to no structural disorder under typical dry milling (pin mill speed 9000 rpm to 36000 rpm) and compaction (force 5 kN to 55 kN) conditions. The soft crystals of compound 2 (Young’s modulus = 2.7 Gpa and hardness = 0.15 Gpa), on the other hand, displayed obvious disorders when the dry milling speed exceeded 9000 rpm or the compaction force was greater than 5 kN. For compound 3, PDF analysis revealed that parallel humidified drying process, compared to sequential drying and humidification process, provides much control on preserving product crystallinity.
Conclusion: TS-PDF analysis is a valuable and effective tool for detecting and monitoring process induced subtle changes in API structural orders. Coupled with principal component analysis, it provides a useful approach to assess the impact of mechanical properties and process conditions on the stability and performance of pharmaceutical crystals.