43Freeze-drying is a popular method of ensuring the stability of proteins that are not stable enough in aqueous solutions during the period required for storage and distribution. 1,2) Various freeze-dried protein formulations contain excipients (e.g., sugars, polymers, and amino acids) that protect proteins from physical and chemical changes. Disaccharides (e.g., sucrose, trehalose) are the most popular among them because they stabilize proteins both thermodynamically and kinetically in aqueous solutions and freeze-dried solids. [3][4][5] The development of freeze-dried protein formulations containing amino acids is often more challenging than the development of formulations with saccharides because of the varied physical and chemical properties (e.g., crystallinity, glass transition temperature) of the freeze-dried amino acids, as well as their tendency to form complexes with other ingredients. 6) Many amino acids are considered to protect proteins basically in similar mechanisms with disaccharides. They thermodynamically stabilize protein conformation in aqueous solutions and probably in frozen solutions by being preferentially excluded from the immediate surface of proteins. 7) Glass-state amorphous solids formed by freeze-drying of the disaccharides or some amino acids protect proteins from structural changes thermodynamically by substituting surrounding water molecules. 8) They also reduce chemical degradation of freeze-dried proteins kinetically by reducing the molecular mobility. 2,8) In addition, some amino acids (e.g., L-arginine) also prevent protein aggregation in aqueous solutions prior to the drying process and after reconstitution. 9) Choosing appropriate counterions that form glass-state solid should be one of the key factors in designing amino acid-based amorphous freeze-dried formulations. 10,11) For example, glass transition temperatures (T g ) of freeze-dried Lhistidine salts depend largely on the counterions. 12) Colyophilization of L-arginine and multivalent inorganic acids (e.g., H 3 PO 4 , H 2 SO 4 ) results in glass-state amorphous solids that protect proteins during the process and storage (e.g., tissue plasminogen activator formulation, PDR 2003). 13) Some organic acid and inorganic cation combinations (e.g., sodium citrates) also form high glass transition temperature amorphous solids. 14) Various functional groups (e.g., amino, carboxyl, hydroxyl) in the constituting molecules contributes significantly to form the glass-state amorphous salt solids. 15) Producing glass-state amorphous solids by freeze-drying of amino acid and organic acid combinations, and their application in pharmaceutical formulations are interesting topics to explore. 15) The purpose of this study was to produce stable amorphous solids that protect proteins by freeze-drying combinations of amino acids and organic acids. The physical properties of frozen solutions and freeze-dried solids containing the popular excipients and model chemicals were studied. The effect of the excipient combinations on the freeze-drying ...
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