Component Crystallization and Physical Collapse during Freeze-Drying of L-Arginine–Citric Acid Mixtures

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Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (Tc) approximately 10°C higher than their Tg′s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the Tc. Slower ice sublimation at higher chamber pressures induced the physical collapse from lower shelf temperatures. The large effect of chamber pressures on the collapse-inducing shelf temperatures confirmed significance of the sublimation-related heat loss on the sublimation interface temperature during the primary drying. Drying of the single-solute L-arginine solution resulted in cake-structure solids composed of its anhydrous crystal. Thermal and powder X-ray diffraction (PXRD) analysis suggested slow crystal nucleation of L-arginine dihydrate in the frozen solutions. Characterization of the frozen solutions and freeze-dried solids should enable rational formulation design and process control of amino acid-containing lyophilized pharmaceuticals.