(603q) The Application of Novel Characterization Techniques to Understand Formulation-Process-Performance Interplay in Spray Dried Pharmaceutical Product Development

Spray drying has enabled the development of many poorly soluble compounds in the pipeline both for formulation of marketed products and as a delivery vehicle for safety studies. Non-uniformity/phase separation within the spray dried particles (SDP) could occur during the spray drying process, and may cause failure in product stability and performance. To fully characterize the SDPs to build understanding of formulation-process-performance interplay, however, remains an exceptionally difficult task. In this work, X-ray photoelectron spectroscopy (XPS) and high resolution focused ion beam scanning electron microscopy (FIB-SEM) were explored to close this gap.

 XPS is a quantitative surface analysis technique with a penetration depth of 5-10 nm. During the formulation development of compound A and B, the surface concentration of SDP was investigated by XPS. In compound A, under extreme manufacturing conditions, the SDPs displayed "whiskers" by scanning electron microscopy, and significantly higher active pharmaceutical ingredient concentration on the surface by XPS which is consistent with surface crystallization. Further, SDPs of compound B prepared using different spray drying processes showed differences in surface composition, even in the absence of detectable crystallization, and the results were consistent with observed differences in dissolution performance. In addition, a single spray dried particle was cross-sectioned to obtain complete 3D structural and chemical imaging with FIB-SEM, which is a first in the pharmaceutical arena. Particles with size less than 25 um appear to be uniform, while the ones that are greater than 25 um consistently showed contrast in the backscattered images in their shells which is confirmed to correspond to phase separation by EDX.

  Significant progress has been made in understanding the spray drying process through these new characterization tools, and this can lead to better QbD risk assessment and rational design of spray drying process. In the future, the expertise and knowledge will enable elaborate particle engineering, and drug product differentiating.