The collapse temperature in freeze drying: Dependence on measurement methodology and rate of water removal from the glassy phase

Accurate determination of the maximum allowable product temperature during primary drying is critical to optimization of the freeze drying process. For an amorphous solute system, this maximum temperature is normally the collapse temperature. Methodologies for determining the collapse temperature involve direct microscopic observation of collapse during freeze drying and methods which, in effect, determine the glass transition temperature of the amorphous phase. While one might be tempted to assume that the collapse temperature is a property only of the material, and independent of details of the measurement method, both theoretical concepts and limited experimental observations suggest that this assumption may not be wholly correct. The main objective of this research is to determine the magnitude of variations in measured collapse temperature caused by variations in experimental methodology. The approach taken is both experimental, using moxalactam di-sodium formulated with 12% mannitol as a model, and theoretical. The theoretical analysis is based on two fundamental concepts. Firstly, for collapse to be observed, viscous flow of the amorphous phase must occur over a finite distance during the measurement time. Secondly, during a freeze drying process, water is removed from the amorphous phase once the ice-vapor boundary recedes past the region of interest. Since water removal increases viscosity, viscous flow, and therefore, collapse is partially arrested, and the effective collapse temperature will be increased, the effect being greater the faster the sublimation rate. A quantitative model based on these concepts is developed with key parameters being evaluated by experimental studies. The observed variation in collapse temperature of moxalactam di-sodium with sublimation rate is quantitatively predicted by the theory. The theory is used to investigate differences between collapse temperatures determined by laboratory procedures and the observation of collapse in production processes. The collapse temperature will increase as the sublimation rate increases (i.e., as the solute concentration decreases), and at constant sublimation rate, the collapse temperature may increase as the surface area of the solid increases. In general, product freeze drying in a vial will collapse at a slightly higher temperature than collapse measured by the microscopic method. However, the calculated variations in collapse temperatures are modest (1–3°C). Collapse temperature and glass transition temperature, T′g, are not identical, the latter being slightly lower when measured at low rates of temperature increase. A secondary but important experimental result is that, contrary to some opinion in the literature, water in a glassy system has sufficient mobility to be in approximate 'equilibrium' with the ice phase during the relatively slow temperature changes relevant to freeze drying operations.