Optimization of Freeze-Drying Cycles of Pharmaceutical Organic Co-Solvent-Based Formulations Using the Design Space Methodology

Abstract

This paper deals with the concept of Design Space, which is an efficient tool for freeze-drying cycle optimization that gathers a combination of product formulation variables and of operating process variables that provide suitable quality attributes of the final freeze-dried product. The Design Space concept is presented as an envelope in a graph, with sublimation rates and total gas chamber pressures on the main (x,y) axis, illustrating the functional relationships between the sublimation rates, the mean product temperatures, and the two principal independent process variables, namely the shelf heat transfer fluid temperature and the total gas pressure. The limits of this design space are determined by the influence of product and process variables on quality attributes of the freeze-dried drug, more precisely by the failure of these attributes under aggressive cycle conditions. In the case of large industrial freeze-dryers, other limits are also imposed by freeze-dryer performances. Next, as an illustration of this concept, we have presented a case study showing the methodology of construction of the Design Space for an ibuprofen organic co-solvent-based formulation realized with a pilot laboratory freeze-dryer. This methodology can reduce the development and the cycle optimization costs of drugs’ freeze-drying processes, especially in the case of costly active principle ingredients that are only available in small quantities.