Freeze drying process design of pharmaceutical dispersions

Supervised by:
  1. José María Franco Gómez Director
  2. Edmundo Brito de la Fuente Director

Defence university: Universidad de Huelva

Fecha de defensa: 10 March 2020

  1. Concepción Valencia Barragán Chair
  2. Susana Simal Florindo Secretary
  3. Antoni Mulet Pons Committee member

Type: Thesis


During a freeze-drying process, the formulation is first frozen and, then, the frozen solvent is removed by a sublimation process at a reduced pressure, followed by a desorption process for the removal of the unfrozen solvent. Therefore, two equally important major processes are taking place during a complete freeze-drying process: (1) freezing, during which the majority of the solvent is converted into a frozen solid; and (2) drying, during which almost all the solvent (frozen and unfrozen) is removed from the formulation. Depending on the drying mechanism, the drying process is further classified into two steps, namely; sublimation process (primary drying) and desorption process (secondary drying). Although the use of a freeze-drying process in the pharmaceutical and biopharmaceutical industries is increasingly growing, it is an energy and time consuming process. Therefore, due to the high investment and running cost, there is a considerable economic motivation to design a robust and optimum freeze-drying process. With this regard, the present study addresses three key issues, which are relevant during freeze-drying process design, optimization and scale-up: (1) understanding of the freezing step and its impact on the subsequent drying process; (2) detailed analyses and understanding of mass and heat transfer during the primary drying; and (3) detailed analyses, understanding and optimization of the secondary drying step. The freezing step dictates the ice crystal morphology, size, and size distribution, which, in turn, influences several freeze-drying related critical parameters. The nature of the degree of supercooling during the freezing step affects the ice habit and results in vial-to-vial and batch-to-batch ice habit heterogeneity. This, in turn, adds significant challenges during development, optimization, and scale-up of the freeze-drying process. Therefore, understanding and controlling the freezing step is of paramount importance. In the present study, several technologies, developed with the aim of controlling the degree of supercooling, have been extensively discussed. The primary drying step is the longest and most critical step. Consequently, it significantly influences the product quality and process economy of the entire freezedrying process. Heat and mass transfers are the core principles of the sublimation process. Thus, a better fundamental understanding of the mass and heat transfer during the primary drying allows a greater efficiency during the process design, optimization and scale-up. Sublimation studies were performed to examine and to establish a fundamental understanding of the relationship between the primary drying input and output parameters. Furthermore, studies on the effect of vial position on the primary drying output parameters revealed significant differences between vials located at the center and edge of the vial array. This fundamental understanding of the mass and heat transfer during the primary drying step was the foundation to the development of a novel approach, called temperature ramp approach (TRA), to design an optimum and robust freeze-drying process. Freezedrying process design using the TRA for two model formulations demonstrated that an effective freeze-drying process could be designed using very few experimental setups. In addition, the present study discussed a novel approach for the development of a process design space (PDS) for the primary drying step a freezedrying process. Although most of the solvent is removed during the primary drying step, there might still be significant amount of solvent, related to the unfrozen solvent, remained at the end of the primary drying. Therefore, an additional drying step at an elevated temperature is necessary to reduce the residual moisture content of the product to an acceptable level. In the context of the freeze-drying process, this additional drying step is termed as secondary drying. Experimental studies using a pharmaceutical drug formulation were performed to examine and to understand the relationship between the secondary drying input and output parameters. The results of these studies were then utilized to develop a process design space (PDS) for the secondary drying step, from which optimum processing parameters could be selected.