The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle i... more The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle in an effective manner where deep understanding is gained through building a scalable freezing step in terms of ice nucleation along with the generation of a primary drying design space. Applying QbD to the design of the cycle allows for the consideration of scalability up front, removing the traditional “trial-and-error” approach, while understanding the performance of the large-scale freeze-dryer. To achieve this, the heat transfer coefficient (K v) of the vial and the product cake resistance (R p) are needed for the mathematical modeling in order to obtain an accurate design space. This chapter explores the latest development and scale-up of the lyophilization process for protein therapeutics in the vial using a QbD approach. Ice nucleation, heat and mass transfer, lyophilization cycle design, and scalability are discussed. A case study is presented for a protein product using both theoretical modeling and experimental scale-down model approach to obtain a wide design space.
Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows... more Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows the online monitoring of critical process parameters to ensure acceptable product quality attributes. This chapter provides a systematic review of latest PAT tools for freeze-drying, with emphasis on suitability for large-scale manufacturing process. Common process monitoring devices such as product temperature sensors (including wireless sensors), Pirani gauge, manometric temperature measurement (MTM), tunable diode laser adsorption spectroscopy (TDLAS), plasma emission spectroscopy (Lyotrack), near-infrared (NIR), and Raman et al. are reviewed in terms of the operation mechanism, major applications, and limitations. These PAT tools are then compared based on their capabilities, practical advantages, and scalability to a large-scale freeze dryer. The criteria of an “ideal” future PAT tool for freeze-drying are then proposed in order to be compliant with the QbD requirements. Finally, the current status of PAT implementation in both development scale and manufacturing scale lyophilizer is discussed, and future implementation of promising PAT tools is proposed.
The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle i... more The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle in an effective manner where deep understanding is gained through building a scalable freezing step in terms of ice nucleation along with the generation of a primary drying design space. Applying QbD to the design of the cycle allows for the consideration of scalability up front, removing the traditional “trial-and-error” approach, while understanding the performance of the large-scale freeze-dryer. To achieve this, the heat transfer coefficient (K v) of the vial and the product cake resistance (R p) are needed for the mathematical modeling in order to obtain an accurate design space. This chapter explores the latest development and scale-up of the lyophilization process for protein therapeutics in the vial using a QbD approach. Ice nucleation, heat and mass transfer, lyophilization cycle design, and scalability are discussed. A case study is presented for a protein product using both theoretical modeling and experimental scale-down model approach to obtain a wide design space.
Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows... more Process analytical technology (PAT) is an integral part of quality by design (QbD), and it allows the online monitoring of critical process parameters to ensure acceptable product quality attributes. This chapter provides a systematic review of latest PAT tools for freeze-drying, with emphasis on suitability for large-scale manufacturing process. Common process monitoring devices such as product temperature sensors (including wireless sensors), Pirani gauge, manometric temperature measurement (MTM), tunable diode laser adsorption spectroscopy (TDLAS), plasma emission spectroscopy (Lyotrack), near-infrared (NIR), and Raman et al. are reviewed in terms of the operation mechanism, major applications, and limitations. These PAT tools are then compared based on their capabilities, practical advantages, and scalability to a large-scale freeze dryer. The criteria of an “ideal” future PAT tool for freeze-drying are then proposed in order to be compliant with the QbD requirements. Finally, the current status of PAT implementation in both development scale and manufacturing scale lyophilizer is discussed, and future implementation of promising PAT tools is proposed.
The objective of this study was to investigate the impact of heat treatment (annealing) on the mo... more The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
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