Modelling the primary drying step for the determination of the optimal dynamic heating pad temperature in a continuous pharmaceutical freeze-drying process for unit doses

In the pharmaceutical industry, traditional freeze-drying of unit doses is a batch-wise process associated with many disadvantages. To overcome these disadvantages and to guarantee a uniform product quality and high process efficiency, a continuous freeze-drying process is developed and evaluated. The main differences between the proposed continuous freeze-drying process and traditional freeze-drying can be found firstly in the freezing step during which the vials are rotated around their longitudinal axis (spin freezing), and secondly in the drying step during which the energy for sublimation and desorption is provided through the vial wall by conduction via an electrical heating pad. To obtain a more efficient drying process, the energy transfer has to be optimised without exceeding the product and process limits (e.g. cake collapse, choked flow). Therefore, a mechanistic model describing primary drying during continuous lyophilisation of unit doses based on conduction via heating pads was developed allowing the prediction of the optimal dynamic power input and temperature output of the electric heating pads. The model was verified by experimentally testing the optimal dynamic primary drying conditions calculated for a model formulation. The primary drying endpoint of the model formulation was determined via in-line NIR spectroscopy. This endpoint was then compared with the predicted model based endpoint. The mean ratio between the experimental and model based predicted drying time for six verification runs was 1.05 +/- 0.07, indicating a good accordance between the model and the experimental data

Thermal imaging as a noncontact inline process analytical tool for product temperature monitoring during continuous freeze-drying of unit doses

Freeze-drying is a well-established technique to improve the stability of biopharmaceuticals which are unstable in aqueous solution. To obtain an elegant dried product appearance, the temperature at the moving sublimation interface T-i should be kept below the critical product temperature T-i,T-crit during primary drying. The static temperature sensors applied in batch freeze-drying provide unreliable Ti data due to their invasive character. In addition, these sensors are incompatible with the continuous freeze-drying concept based on spinning of the vials during freezing, leading to a thin product layer spread over the entire inner vial wall. During continuous freeze-drying, the sublimation front moves from the inner side of the vial toward the glass wall, offering the unique opportunity to monitor T-i via noncontact inline thermal imaging. Via Fourier's law of thermal conduction, the temperature gradient over the vial wall and ice layer was quantified, which allowed the exact measurement of T-i during the entire primary drying step. On the basis of the obtained thermal images, the infrared (IR) energy transfer was computed via the Stefan-Boltzmann law and the dried product mass transfer resistance (R-p) profile was obtained. This procedure allows the determination of the optimal dynamic IR heater temperature profile for the continuous freeze-drying of any product. In addition, the end point of primary drying was detected via thermal imaging and confirmed by inline near-infrared (NIR) spectroscopy. Both applications show that thermal imaging is a suitable and promising process analytical tool for noninvasive temperature measurements during continuous freeze-drying, with the potential for inline process monitoring and control

Lethal and sublethal effects of azadirachtin on the bumblebee Bombus terrestris (Hymenoptera: Apidae)

Background: Lethal and sublethal effects of azadirachtin were studied on Bombus terrestris via oral exposure in the laboratory to bring out the potential risks of the compound to this important pollinator.Results: Microcolonies chronically exposed to azadirachtin via treated sugar water during 11 weeks in the laboratory exhibited a high mortality ranging from 32 to 100 % with a range of concentrations between 3.2 and 320 mg litre-1. No reproduction was scored at concentrations higher than 3.2 mg litre-1. At 3.2 mg litre-1, azadirachtin significantly inhibited the egg laying and, consequently, the production of drones during 6 weeks. When azadirachtin was tested under an experimental setup in the laboratory where bumblebees need to forage for food, the sublethal effects were stronger as the numbers of drones were reduced already with a concentration of 0.64 mg litre-1. Besides, a negative correlation was found between the body mass of male offspring and azadirachtin concentration.Conclusion: Azadirachtin can affect B. terrestris with a range of sublethal effects. This study confirms the need to test compounds on their safety, especially when they have to perform complex tasks such as foraging.Keywords: chronic oral exposure, insect growth regulator (IGR), neem, repellence effect, reproductio

In-line near infrared spectroscopy during freeze-drying as a tool to measure efficiency of hydrogen bond formation between protein and sugar, predictive of protein storage stability

Sugars are often used as stabilizers of protein formulations during freeze-drying. However, not all sugars are equally suitable for this purpose. Using in-line near-infrared spectroscopy during freeze-drying, it is shown here that hydrogen bond formation during freeze-drying, under secondary drying conditions in particular, can be related to the preservation of the functionality and structure of proteins during storage. The disaccharide trehalose was best capable of forming hydrogen bonds with the model protein, lactate dehydrogenase, thereby stabilizing it, followed by the molecularly flexible oligosaccharide inulin 4kDa. The molecularly rigid oligo- and polysaccharides dextran 5kDa and 70kDa, respectively, formed the least amount of hydrogen bonds and provided least stabilization of the protein. It is concluded that smaller and molecularly more flexible sugars are less affected by steric hindrance, allowing them to form more hydrogen bonds with the protein, thereby stabilizing it better