Experimental Study and Modeling of Freeze-Drying in Syringe Configuration. Part II: Mass and Heat Transfer Parameters and Sublimation End-Points

Abstract

This work concerns the experimental study in syringe configuration of the sublimation period for a model formulation under operating conditions commonly used for pharmaceutical proteins freeze-drying. Different methods for the detection of the sublimation end-point were compared. This exhaustive comparison has shown that the Lyotrack sensor (Annecy, France) had the best sensitivity and presented the best signal-to-noise ratio followed by the Pirani gauge; a significant advantage of Lyotrack sensor relies on the possibility of sterilization. The scale method, which is based on continuous weighing of a single syringe or a single vial, underestimated largely the sublimation times and, consequently, was not representative at all of the whole syringe (or vial) set behavior. Consequently, caution should be taken for its use for setting up laboratory data and for scaling up these data for the optimization of commercial freeze-drying cycles. Moreover, four standard freeze-drying cycles with different values of main operating parameters (shelf temperature and total gas pressure) were investigated in order to determine overall heat and mass transfer coefficient values in syringe configuration. As expected, higher shelf temperature resulted in higher sublimation rates, but higher total gas pressures led to lower sublimation rates; nevertheless, the total gas pressure influence was less pronounced than the shelf temperature influence. The influence of syringe location in the supporting rack on drying rate values was also investigated: no front/back location influence was observed, but a small side location effect was observed, as syringes located at the edge and at the center of the rack presented slightly higher mean sublimation rates. The two main sublimation parameters, namely, the water vapor mass transfer resistance, noted Rp, and the overall heat transfer coefficient, noted Kv, were determined by the pressure rise analysis method (PRA method) by using on-line and in situ pressure rise tests. The Kv values were higher when the gas temperature or the total gas pressure increased but the Rp values remained quite constant as a function of these two parameters. A comparison between syringe and vial configuration data proved that when glass vials were used instead of syringes, the values of the sublimation rates and of the permeability of the freeze-dried matrix did not change significantly.