Freeze-drying theories

M. L. Roy, M. J. Pikal, E. C. Rickard, and A. Maloney, The effects of formulation and moisture on the stability of a freeze-dried monoclonal antibody-vinca conjugate A test of the WLF glass transition theory Dev. Biol. Standards, 74, 323 (1991). 

Most protein stability studies have focused their interpretation on either a thermodynamic mechanism or a pure kinetic mechanism, and consequently there is some controversy and confusion over which mechanism is correct. Since the direction of a formulation development effort may depend on which theory is being followed, clarification of the roles of thermodynamic stabilization and kinetic stabilization in given stability problems would provide some practical benefit. This chapter is an attempt to provide such clarification. To this end, the major stresses, or destabilizing effects, that operate during the freeze-drying process are discussed, selected empirical observations regarding pharmaceutical stability in protein systems are presented, and the structure and dynamics in amorphous protein formulations are discussed. 

A.I. Liapis, R. Bruttini 1994 A theory for the primary and secondary drying stages of the freeze drying of pharmaceutical crystalline and amorphous solutes comparison between experimental data and theory. Separation Technology, 4, 144-155. 

The target polymers 10-20, upon dialysis in aqueous solution and freeze-drying, were obtained as water-soluble solids in yields of 35-90%. Inherent viscosities were typically in the range of 10-15 ml g l, and the degree of ferrocene incorporation, assessed by elemental analysis and NMR data, ranged from about 20 to 75% of theory, depending critically on reactant ratio and type of anchoring function. The polymers showed the characteristic ferrocene CH out-of-plane deformation and skeletal bands at 810 and 500 90 cm"i in the IR spectra. The... 

This reflects the fact that the thermal conductivity of a gas obeying simple kinetic theory is independent of the pressure. The transition in thermal conductivity between asymptotes usually occurs between 0.1 and 100 mmHg, which includes the pressures characteristic of freeze drying processes. The pressure range over which the transition in thermal conductivity between asymptotes occurs is characteristic of the pore size distribution of the void spaces within the freeze-dried material [50]. A smaller pore dimension means that the gas must achieve a higher pressure in order for the mean free path of the gas to become comparable to the pore spacing and, hence, means that the transition between asymptotes will occur at higher pressures. 

The retention of volatile eomponents sueh as organie solvents during freezedrying has been well described in the literature [48-57]. Many of the organie compounds in the food aroma have a vapor pressure higher than water. However, a signifieant number of these eompounds remain with the freeze-dried cake after lyophilization. Two theories whieh are used to explain this phenomenon have been deseribed as selective diffusion [57] and... 

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