ABSTRACT

The freezing step of lyophilization is of paramount importance, It is the principal dehydration and it determines the and pore sizes of the ice and In the desired attributes of a

and if of active lyophilization; appropriate crystal-

glass transition temperature di"C'i,th, to residual

II. PROCESS PHYSICS-THE SUPPLEMENTED PHASE DIAGRAM

A discussion of freezing, annealing, and lyophilization is aided by viewing the process through the "supplemented phase diagram" first described by MacKenzie [2). It is an equilibrium freezing point depression diagram supplemented with the glass transition curve (and solute crystallization and/ or precipitation curve(s) as appropriate). Shown in Figure I is such a diagram for sucrose using data from Blond et al. [3) and Searles et al. [4). The x axis is solute concentration in the non-ice phase, and the y axis is temperature. Sucrose does not crystallize during freeze concentration, so there is no eutectic point shown in Figure I. If crystallizing solutes are being used (e.g., mannitol or glycine) then it would be important to add the appropriate eutectic points and phase lines for the crystallizing solute. The diagram will be explained in the context of freezing, annealing, and lyophilizing a 10% (w/w) sucrose solution.