Infrared Thermography for Monitoring of Freeze Drying Processes—Part 2: Monitoring of Temperature on the Surface and Vertically in Cuvettes during Freeze Drying of a Pharmaceutical Formulation

Abstract

The coupling of an infrared (IR) camera to a freeze dryer for monitoring of the temperature of a pharmaceutical formulation (sucrose/mannitol solution, 4:1%, m/m) during freeze-drying has been exploited further. The new development allows monitoring of temperatures simultaneously at the surface as well as vertically, (e.g., in depth) along the side using custom-made cuvettes. The IR camera was placed on the chamber roof of a process-scale freeze dryer. Monitoring of cuvettes containing the formulation took place from above where one side of each cuvette was equipped with a germanium window. The Ge-window was placed next to an IR mirror having a 45° angle. The long-wave infrared radiation (LWIR) coming from the inside of the cuvette was reflected upwards toward the IR camera. Accurate recording of the temperature along the cuvettes’ depth profile was therefore possible. Direct imaging from −40 °C to 30 °C took place every 60 s on the surface and on the side with a 2 × 2 mm resolution per IR pixel for 45 h resulting in 2700 thermograms. Results are presented for freeze-drying of a pharmaceutical formulation as a function of time and spatially for the entire side (depth) of the cuvette. As the sublimation process was progressing, the spatial resolution (84 IR pixels for the side-view and 64 pixels for the surface-view) was more than sufficient to reveal lower temperatures deeper down in the material. The results show that the pharmaceutical formulation (a true solution at the onset) dries irregularly and that the sublimation front does not progress evenly through the material. During secondary drying, potential evaporative cooling of upper layers could be detected thanks to the high thermal and spatial resolution.

On the Use of Temperature Measurements as a Process Analytical Technology (PAT) for the Monitoring of a Pharmaceutical Freeze-Drying Process

“…If placed outside the chamber on the top of the freeze-dryer, the sensor, through a germanium window, was able to measure the product temperature on the top surface of the upper shelf, the only one that the camera could see [ 40 ]. In order to also measure the whole axial temperature profile, Emteborg et al [ 41 ] used custom-made cuvettes with a germanium window on one side, placed close to an IR mirror with a 45° angle in such a way that the IR radiation from the cuvette was reflected upwards to the IR camera. It is evident that such a system requires strong hardware modifications and is not widely applicable.…”

“…The main drawback is represented by the harsh conditions that are experienced by the sensor in the drying chamber, i.e., a temperature that may reach values as low as −40 °C or −50 °C (in the freezing step) during the cycle, a low pressure, and a gas composition that is about 100% water vapor. For these reasons, Emteborg et al [ 40 , 41 ] placed the camera outside the drying chamber, on the top of the freeze-dryer, using a germanium window. In addition, also Van Bockstal et al [ 42 ] placed the infrared camera outside the freeze-dryer, although in their case, a continuous freeze-drying process was monitored.…”

Visualizing and understanding batch heterogeneity during freeze-drying using shelf-scale infrared thermography

“…This contribution introduces a shelf-scale monitoring technique based on infrared thermography for this purpose. We build on earlier techniques that have been employed to monitor the thermal evolution of a large number of vials at the same time during freeze-drying: [25][26][27][28][29] Emteborg et al 25 cut a hole into the top of a freeze-dryer to install an infrared camera for the monitoring of the top-most shelf with 2D resolution. Lietta et al 27 developed a camera module that fits inside a freeze-dryer and monitors the vials from the side, effectively measuring the temperature of the glass vial.…”

Thermal Effect of Probes Present in a Pharmaceutical Formulation during Freeze-Drying Measured by Contact-Free Infrared Thermography

“…First, it is a single-point measurement, and second, the presence of the probe itself affects the drying process [4]. In two previous articles from 2014 and 2022, Emteborg et al described the coupling of an IR camera to a freeze-dryer, thereby measuring the product temperature contact-free and with superior spatial resolution [5,6]. The work from 2014 described the first application of this kind [5].…”