Īnother method is X-ray Powder Diffraction (XRD), where an X-ray diffractogram of the freeze-dried product is recorded. Particularly in glasses where Arrhenius kinetics cannot be applied, this could lead to incorrect predictions. Of course, the onset of crystallization measured above T g can be used as a surrogate for isothermal crystallization tendencies, but dominant reactions at high temperatures, especially above T g, are not always the leading reactions at lower temperatures below T g. With this method, the T g and its onset as well as the energy of crystallization above T g can be determined. ĭifferential scanning calorimetry (DSC) is one method to estimate the crystallization tendency of a formulation. Consequently, methods that predict crystallization in the early stage of development are needed to discover formulations and process conditions that are prone to result in crystallization upon storage, which frequently lasts up to 2 years or more. Therefore, it is important to avoid crystallization of the excipients during the life time of the pharmaceutical formulation. However, during storage, crystallization of sugars can occur, even if the storage temperature is significantly below the glass transition temperature (T g). To fulfil this stabilizing effect, the sugar has to stay amorphous during the storage time of the product. In particular, sugars can mimic water with their hydroxyl groups, thereby supporting the native conformation of the antibody upon lyophilization based on the water replacement theory.
Those excipients are able to protect and sustain the structure of biotherapeutics, including antibodies. To successfully freeze-dry those materials, sugars, such as sucrose or trehalose, are used as bulking agents and lyoprotectants. Thus, freeze- or spray-drying can be used to achieve long-term stability of these products upon removal of water. Those entities face degradation problems during shipment and long-term storage when kept in their liquid formulation. The amount of biological therapeutics has strongly increased in recent years. Furthermore, the study shows that polysorbate 20 strongly accelerates crystallization of sucrose and that the freezing step itself has a strong impact on the relaxation phenomena that is not levelled out by primary and secondary drying. Samples that crystallized during the study time of 12 months showed a promising correlation between their relaxation time and crystallization behavior upon storage.
The amorphous formulations were created by different freeze-drying processes only differing in their freezing step (random nucleation additional annealing step of 1.5 h and 3 h, controlled nucleation quench cooling). Storage conditions of 25 ☌ and 40 ☌ are examined and five model formulations containing either sucrose or trehalose with different concentrations of an IgG 1 antibody are investigated.
The relaxation curve of a fresh sample recorded within 12 h after lyophilization is correlated with the long-term crystallization time at the same temperature. This study applies isothermal microcalorimetry to predict long-term crystallization during product storage time. There is a lack of methods to predict the isothermal crystallization behavior of amorphous freeze-dried formulations stored below the glass transition temperature.
0 kommentar(er)
