Rheological Issues on Oropharyngeal Dysphagia.

There is an increasing proof of the relevance of rheology on the design of fluids for the diagnosis and management of dysphagia. In this sense, different authors have reported clinical evidence that support the conclusion that an increase in bolus viscosity reduces the risks of airway penetration during swallowing. However, this clinical evidence has not been associated yet to the definition of objective viscosity levels that may help to predict a safe swallowing process. In addition, more recent reports highlight the potential contribution of bolus extensional viscosity, as elongational flows also develops during the swallowing process. Based on this background, the aim of this review paper is to introduce the lecturer (experts in Dysphagia) into the relevance of Rheology for the diagnosis and management of oropharyngeal dysphagia (OD). In this sense, this paper starts with the definition of some basic concepts on Rheology, complemented by a more extended vision on the concepts of shear viscosity and elongational viscosity. This is followed by a short overview of shear and elongational rheometrical techniques relevant for the characterization of dysphagia-oriented fluids, and, finally, an in-depth analysis of the current knowledge concerning the role of shear and elongational viscosities in the diagnosis and management of OD (shear and elongational behaviors of different categories of dysphagia-oriented products and contrast fluids for dysphagia assessment, as well as the relevance of saliva influence on bolus rheological behavior during the swallowing process).

Freeze-drying: A relevant unit operation in the manufacture of foods, nutritional products, and pharmaceuticals.

Freeze-drying, a drying unit operation frequently used in food, pharmaceutical, and biopharmaceutical industries to prolong the shelf life of labile products, is an energy-intensive, time-consuming, and expensive process. Although all three steps (freezing, primary drying, and secondary drying) of freeze-drying are important, primary drying is the longest and most critical one. As sublimation during primary drying is mainly described in terms of heat and mass transfer, the present work provides extensive theoretical and experimental analyses of these processes. First, a detailed review of the current state-of-the art of freeze-drying, focusing on the drying stage, is given, which contributes to a fundamental understanding of the drying process. Second, a detailed experimental study of the drying section of the freeze-drying process is discussed, furnishing information on the relationship between input and output process parameters during the primary drying stage and thus aiding freeze-drying process design and optimization. In this regard, the influence of primary drying input parameters (i.e., shelf temperature and chamber pressure) and vial position on output parameters such as product temperature, sublimation rate, overall vial heat transfer coefficient, and resistance to mass transfer of the dried product are extensively discussed. For all combinations of shelf temperature and chamber pressure studied herein, the highest product temperature, sublimation rate, and overall vial heat transfer coefficient are observed in front edge vials, whereas the lowest values are observed in center vials. In general, the highest sublimation rate, at a given product temperature, is observed for low chamber pressure-high shelf temperature combinations.

Use of a temperature ramp approach (TRA) to design an optimum and robust freeze-drying process for pharmaceutical formulations.

Freeze-drying, until now, has been a process that was designed using a trial and error experimental approach. This approach is often material and time consuming, and the resulting freeze-drying processes are neither optimum nor robust. Accordingly, the objective of this study was to develop a simple-to-use and experimental-based approach to design an optimum and robust freeze-drying process for any given formulation. The temperature ramp approach (TRA) detailed in this study involves the implementation of a customized design of experiments (DoE) to perform few (three or four) experiments using a given drug formulation. The DoE results are analyzed to define optimum processing conditions (i.e., shelf temperature and chamber pressure) based on a predefined range of target product temperature for primary drying, which could be defined from formulation characterization at its frozen state. In this study, a successful freeze-drying process of two model formulations using the TRA was designed. Verification experiments at the optimum processing conditions showed excellent agreement in both product temperature and sublimation rate with the values obtained using the TRA. Thus, the TRA detailed in this study offers a significant advantage to reduce development time and material, and enhance the efficiency and robustness of the resulting freeze-drying process.

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals.

The application of quality by design (QbD) is becoming an integral part of the formulation and process development for pharmaceutical products. An essential feature of the QbD philosophy is the design space. In this sense, a new approach to construct a process design space (PDS) for the primary drying section of a freeze-drying process is addressed in this paper. An effective customized design of experiments (DoE) is developed for freeze-drying experiments. The results obtained from the DoE are then used to construct the product-based PDS. The proposed product-based PDS construction approach has several advantages, including (1) eliminating assumptions on the heat transfer coefficient and dried product resistance, as it is constructed from experimental results specifically obtained from a given formulation, yielding more realistic and reliable results and (2) PDS construction based on a narrow range of product temperatures and considering the variations in product temperature and sublimation rate of vials across a shelf. This guarantees the effectiveness and robustness of the process and facilitates the process scale-up and transfer. The PDS developed herein was experimentally verified. The PDS predicted parameters were in excellent agreement with the experimentally obtained parameters.

The Importance of Understanding the Freezing Step and Its Impact on Freeze-Drying Process Performance.

The freeze-drying process is a combination of 2 equally important processes, freezing, and drying. In the past, the effort was mainly focused on optimizing the drying process without considering the possible effects of the freezing step. During freezing, a solution undergoes several physical changes, including a supercooling state. The degree of supercooling of a solution dictates the ice habit (size, number, and morphology) during freezing, which impacts the subsequent drying process, such as the resistance to water vapor flow. Therefore, heterogeneous degree of supercooling leads to heterogeneous ice habits and, in turn, to heterogeneous drying behavior. This poses significant challenges during freeze-drying process development, optimization, and scale up. Hence, controlling the degree of supercooling significantly improves freeze-drying process design. The aim of the current review is to gather existing information on the physicochemical phenomena involved in the freezing process and how these phenomena impact the subsequent drying step of the freeze-drying process. In addition, modification of the freezing process and different techniques used to actively control the degree of supercooling during freezing will be reviewed and discussed. Their impact on freeze-drying process performance will be also addressed.