Calorimetric investigation of protein/amino acid interactions in the solid state

Stability of Protein Pharmaceuticals: An Update

“…Second, there are recent reports of material other than sugars yielding glassy matrices that might be used for embedding proteins and achieving stable dosage forms. These include many of the naturally occurring amino acids (500)(501)(502). In addition, combinations of compounds provide glassy matrices that have properties superior to the individual components.…”

Mechanisms of protein stabilization in the solid state

“…[140][141][142] In order to improve the solid state stability of a protein, the amino acid, such as histidine or arginine, would need to be present in the same amorphous phase as the protein. 143,144 In a series of amino acid formulations, a good correlation was found between the structural changes of antibody upon drying and the long-term storage stability. 141,142 The data suggest that the amino acids can interact (i.e., hydrogen-bond) with the protein during drying to preserve the native protein structure in the dried state.…”

“…141,142 The data suggest that the amino acids can interact (i.e., hydrogen-bond) with the protein during drying to preserve the native protein structure in the dried state. 144 Therefore, the long-term storage stability of protein is improved via the ''water substitution mechanism'' as described above. However, there are no data addressing the effect of amino acids on molecular mobility in the glassy matrix upon drying or in the final dried product.…”

Amorphous–Amorphous Phase Separation of Freeze-Concentrated Protein and Amino Acid Excipients for Lyophilized Formulations

“…The amino acid molecules concentrated with the proteins in the amorphous mixture phase would provide intermolecular hydrogen bonding that protects the protein conformation from low temperatures and dehydration stresses. [5][6][7][8][9] However, the formation of an amino acid-dominant phase would alter local environment surrounding the protein molecules (e.g., pH, salt concentration) through uneven contribution of third components (e.g., NaCl, phosphate buffer).…”

“…Certain amino acids and their salts are potent stabilizers in the freeze-drying of proteins, frozen storage of liposomes, and spray drying of vaccines. [5][6][7][8][9][10][11] Application of the amino acid excipients that protect proteins through particular mechanisms not achievable by saccharides (e.g., aggregation-reducing effect of L-arginine (L-Arg) in aqueous solution) would increase formulation strategies in lyophilization of marginally stable proteins. 5,8,[12][13][14][15] Physical states (e.g., crystallinity, crystal polymorph) of the components are important factors that determine chemical and conformational stability of proteins during the freeze-drying process and subsequent storage.…”