Continuous measurement of drying rate of crystalline and amorphous systems during freeze‐drying using an in situ microbalance technique

Abstract

The use of a novel microbalance (Christ) technique to monitor continuously the weight loss of a vial standing on a shelf of a freeze‐dryer has been investigated. The drying rates of the following aqueous solutions were measured during the primary drying phase of a complete freeze‐drying cycle: sucrose (75mg/mL, 2.5‐mL fill volume), sucrose and phenylalanine (1:0.2 by weight, 75mg/mL, 2.5‐mL fill volume), and mannitol (75mg/mL, 2.5‐mL fill volume). The microbalance yields the cumulative water loss, mcu in grams, and the momentary drying rate, Δmcu/Δt in mg/10min, of the frozen cake. The momentary drying rate curves were especially useful for examining how Δmcu/Δt changes with time during primary drying. Initially, Δmcu/Δt rises to a sharp maximum and then decreases in a fashion depending on shelf temperature, chamber pressure, and the nature of the substance being dried. Different drying behavior was observed for the sucrose and sucrose/phenylalanine systems, which was attributed to the presence of crystalline phenylalanine in the amorphous sucrose. At low shelf‐temperature (−24°C) the crystalline mannitol showed lower Δmcu/Δt than with either sucrose or sucrose/phenylalanine. The balance could also detect differences in Δmcu/Δt when using different freezing protocols. ‘Slow’ and ‘moderate’ freezing protocols gave similar drying behavior, but ‘rapid’ freezing in liquid nitrogen produced greatly altered drying rate and internal cake morphology. The balance also could be used to detect the endpoint of primary drying. Different endpoint criteria and their influence on final dried cake properties were examined. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1345–1355, 2001