## 1 Introduction
However, when combined with the custom-made cuvettes equipped with one side made of germanium as reported previously [6], minute differences in temperature and positions can be recorded at the surface of the material itself adjacent to the Ge-window inside the cuvette. In the current study, a new IR camera with a 640 \(\times\) 480 pixel microbolometer and 40 mm lens was coupled to a freeze-dryer and used together with the custom-made glass cuvettes with one side made of germanium [6]. This set-up allowed the monitoring of the gradual change in temperature through a full freeze-drying cycle based on 2700 thermograms with a field-of-view of about 140 \(\times\) 180 mm. The side view of these cuvettes (filled with formulation) was approximately 18 \(\times\) 30 mm (65 \(\times\) 105 IR-pixels), resulting in approximately 6825 IR-pixels, which is an 80-fold increase in comparison with previous work. The surface view consisted of 4225 pixels in cuvettes without a probe, and it was exploited for comparing and quantifying the thermal effect that the presence probes had on the material during ice-nucleation, freezing and primary drying. If a probe is present, part of the surface view was not visible because of the wires, and the number of available pixels was reduced somewhat. The resolution and thermal images were of sufficient detail to reveal temperature gradients near the probes and across the surface, especially during primary drying. To our knowledge, this is the first time it has been possible to clearly display and measure the temperature differences prevailing around probes during a freeze-drying cycle. Attention was paid not to monitor the wire of the probes still making sure that meas-urements took place as close as possible to the probes. The probes were immersed about 8 mm into the pharmaceutical formulation in order to obtain a measurable temperature effect closer to the surface using the IR camera. The probes were consequently not placed at the bottom of the vial, which would be the most logical position [4]. The Pt100 probe is a small metal cylinder of 3 mm diameter and 6 mm height. It occupies a volume of 42 \(\upmu\)L and thereby makes up about 0.5% of the total fill volume of pharmaceutical formulation. The LyoRX probe is also a cylinder (equipped with two pins) but is made of a polymer material. It has a diameter of 6.5 mm and a height of 9 mm. It occupies a volume of 300 \(\upmu\)L and thereby makes up about 3.5% of the total fill volume of pharmaceutical formulation. For both sensors, the connecting wires were not considered when calculating their volumes (present inside the material). Monitoring took place on the material next to the wires, whereas the bulk of the sensor was below the surface. The current work also provides a better resolution of local temperature differences along the depth profiles (e.g., of the side view) during a drying cycle as compared to previous work [6]. The freeze-drying cycle employed here consisted of the four steps listed below, and any freeze-drying cycle must always consist of steps 1, 3 and 4. Freezing of the water present in the matrix at ambient pressure (without causing severe phase separation and too-small ice crystals. The ice-nucleation temperature and uniform freezing conditions are crucial for achieving excellent and uniform product quality after drying [16; 17])  
Annealing of ice to achieve crystals of larger and uniform size [18]. Sublimation (primary drying), whereby the water evaporates from solid ice in the material and is captured on the ice-condenser under soft vacuum. Secondary drying during which most of the remaining water is removed under hard vacuum and a shelf temperature of 20 to 30 \({}^{\circ}\)C.