Physical characterization of pharmaceutical formulations in frozen and freeze-dried solid states: techniques and applications in freeze-drying development.

Physical characterization of formulations in frozen and freeze-dried solid states provides indispensable information for rational development of freeze-dried pharmaceutical products. This article provides an overview of the physical characteristics of formulations in frozen and freeze-dried solid states, which are essential to both formulation and process development. Along with a brief description of techniques often used in physical characterization for freeze-drying development, applications of and recent improvements to these techniques are discussed. While most of these techniques are used conventionally in physical characterization of pharmaceuticals, some techniques were designed or modified specifically for studies in freeze-drying. These include freeze-drying microscopy, freeze-drying X-ray powder diffractometry and cryoenvironmental scanning microscopy, which can be used to characterize the physical properties of the formulation under conditions similar to the real vial lyophilization process. Novel applications of some conventional techniques, such as microcalorimetry and near infrared (NIR) spectroscopy, which facilitated freeze-drying development, receive special attention. Research and developmental needs in the area of physical characterization for freeze-drying are also addressed, particularly the need for a better understanding of the quantitative correlation between the molecular mobility and the storage stability (shelf life).