KSEF RDE: Systematic Investigation of Drug-Excipient Interactions in Lyophilized Formulations

Freeze drying or lyophilization is commonly used as a method to stabilize pharmaceutical formulations. Currently, many lyophilized formulations are prepared by trial and error, where a protein or vaccine is formulated using a variety of excipients, and the stability is determined by evaluating the stability of the end product. We propose to use advanced analytical techniques, such as SOlid-state NMR spectroscopy, to study the interactions of the protein, peptide, or small molecule to see how the excipients and solvents influence the lyophilization process and the stability of the final product. Specifically, we will study how the dynamics of peptides and proteins change upon lyophilization, and whether the propensity of degradation is a function of how the peptides and proteins interact with the excipients. This will address two of the most common theories for protein stabilization: vitrification, where the molecules are frozen in place by being surrounded by excipient, and water substitution, where the waters of hydration for the protein are removed and substituted with the hydroxyl groups from carbohydrate-based excipients. We have had extensive experience in studying the influence of lyophilization on the crystallization of proline, and have discovered several new crystalline forms generated by this process. We have also extensively studied the crystallization of various excipients, such as trelahose, mannitol, and sucrose, upon lyophilization. We have also collaborated with many of the leading experts in the field of lyophilization. The results generated from this research will lead to the submission of NIH and NSF proposals to study this work in greater detail. Also, there may be new combinations of excipients discovered that will dramatically improve the ability of proteins to be stabilized, leading to potential new intellectual property