The objective of this study was to investigate the effects of different freeze-drying parameters on the rate of sublimation and on sublimation end-point by using a microbalance placed inside the product chamber. The freeze-drying process was carried out in organic medium constituted by a mixture of tert-butanol alcohol (TBA) and water. Experiments were conducted on the basis of a full factorial design by varying four parameters: the initial organic solvent concentration (TBA), the shelf temperature, the total gas pressure and the volume of the solution filled in the vials and the vials size. We observed that the use of an organic co-solvent (tert-butanol) reduced considerably the sublimation times around 2 h30, these values being 10-11 times lower than the values observed with pure aqueous solvent formulations under the same operating conditions of pressure and temperature. Thus, the freeze-drying times with organic co-solvent formulations become comparable with drying times observed with agitated vacuum contact dryers. Furthermore, the high value of the glass transition temperature of the maximally freeze concentrated solute (T-g') led to adequate mechanical freeze-dried cake structure without any collapse phenomenon. in addition, both the shelf temperature and to a lesser degree, the chamber total gas pressure had significant impact on sublimation times. The higher shelf temperature the higher sublimation rates, regardless of the total chamber gas pressure; nevertheless, the sublimation rate was not a continuous increasing function of the total gas pressure as it reached a maximum value at the intermediate total gas pressure equal to 15 Pa and then it decreased. (C) 2008 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.