Development of Freeze-Drying Cycles for Pharmaceutical Products Using a Micro Freeze-Dryer

Abstract

This article aims to investigate how a small-scale freeze-dryer can be used for process design. The system encompasses a temperature controlled metallic ring that surrounds a small batch of vials, in contact with the external vials through removable thermal conductors. The temperature of the ring can be modified to keep a constant difference with the temperature of one or more vials of the batch. In this article, an extensive validation of the system is given, considering 10% w/w sucrose and 5% w/w mannitol solutions, processed in different types of vials (6 R and 20 R) and in different operating conditions. The micro freezedryer was also shown to be able to provide accurate estimates of the overall heat transfer coefficient from the shelf to the product in the vials (K v) and of the resistance of the dried cake to vapor flux (R p): both values appeared to be very close to those obtained for the same case studies in a pilot-scale unit. Finally, the use of the micro freeze-dryer to control product temperature and drying time values to simulate a pilot-scale unit was addressed, thus demonstrating the adequacy of this system for process scaleup.

Micro Freeze-Dryer and Infrared-Based PAT: Novel Tools for Primary Drying Design Space Determination of Freeze-Drying Processes

“…The resulting K v found in that study was 16.7 ± 2.3 W/m 2 K (33). In this present study, the non-gravimetric K v estimation resulted in 16.2 ± 1.8 W/m 2 K. For the MicroFD®, using the −5°C offset setting for the LyoSim®, K v values in the MicroFD® were found correspondent to REVO® central batch ones (35). The observed R p values found in this study were also in good agreement with previously reported values (18,28).…”

“…The use of the MicroFD® with a LyoSim® offset temperature of −5°C with respect to the product temperature resulted in good batch homogeneity (46). Moreover, this offset setting was found to be a good emulator of central batch conditions in the REVO® freeze-dryer (35). This −5°C setting was also found to represent well the temperature profiles and K v values of central batch vials in another freeze-drying equipment of similar scale, the LyoStar® III lyophilizer (SP Scientific, Warminster, PA, USA) (30).…”

“…4) may be used once K v and R p are known. With respect to the overall heat transfer coefficient K v , a gravimetric test may be carried out as described by many in the literature (16,24,35). In such tests, the total heat received by the vials (Q) is assumed to be used for water sublimation, quantified by the weight loss (Δm) in each vial after a truncated sublimation cycle:…”

Analysis of Energy Consumption of the Lyophilizer System Using Solar Absorption Refrigeration

“…Whether it is electric heating or steam heating, the cost is much lower. While heating the materials in the freeze-drying box, it is necessary to use the refrigeration unit to cool the cold trap of the freeze-drying machine at a low temperature, so as to freeze the water vapor generated in the heating sublimation process, maintain the vacuum in the freeze-drying machine, and maintain the vacuum conditions for the continuous sublimation of ice crystals [18,19]. While the refrigeration unit cools the cold trap, it also needs to discharge the heat of the refrigeration unit to the outside through the condenser and absorber.…”

Evaluation of the Robustness of A Novel NIR-based Technique to Measure the Residual Moisture In Freeze-dried Products

“…[8][9][10][11] At the end of the process, a typical freeze-dried product has a low RM, even lower than 1%, 10,12 but a wide distribution of RM values can be found in the vials of the same batch. 13 In fact, pressure gradients between shelves, 14 non-uniformity of temperature of shelf surface, 15 and different heat fluxes to the vials according to their position in the dryer 16,17 are responsible of non-uniform pressure and temperature conditions in the drying chamber, particularly in large scale equipment. 14 As a consequence, taking also into account non-uniform nucleation temperature, 18 sublimation rate and product temperature are different from sample to sample 19 and, thus, the RM.…”