As discussed above, the key mechanism of stabilization from the water replacement theory is the hydrogen bonding formation between protein and sugar. As such, good miscibility between protein and sugars at a molecular level is suggested to ensure the protective effects of sugars. Any protein and sugar immiscibility or heterogeneous distribution could result in detrimental effects on product stability due to a lack of sufficient interaction. It has been reported that higher rates of protein aggregation were seen with low miscibility. The sugar selection and drying techniques play a critical role in the final product miscibility. For example, the crystallization of one or more components in the matrix, such as mannitol crystallization, can introduce heterogeneity in freeze-dried formulations. Additionally, heterogeneities can also be introduced by the drying technique, such as the heterogeneously distribution of protein from surface to inner core induced by spray drying process. In such a case, the loss of protein-sugar interaction can lead to significant alterations in protein structure. As such, from a formulation design point of view, the crystallization of sugar needs to be avoided and sugars with a low tendency to crystallize are often preferred.