A correctly lyophilized cake needs to have uniform appearance, well stocked to the walls of the vial without falling off from it. It should not have cavities at the bottom and the color should be uniform all around the lyophilized cake, maybe presenting slight differences because of the crystals formed during the freezing steps, being dendritic or very small and amorphous.
Lyophilized formulation is designed around its API and in most of the cases include a number of excipients, such as buffers, stabilizers, bulking agents and tonicity modifiers. So we can say that a well-chosen excipient formula can prepare a lyophilized product for a long shelf-life and a stable level of biological activity. Excipients are the integral part of pharmaceutical product development to achieve the desired product profile (stability and efficacy).
The main goal of the lyophilized formulation it is to have the formulation as simple and stable as possible while reaching acceptable chemical, physical, and microbiological stability.
In many pharmaceutical formulations, buffers are used to stabilize pH. Choosing a correct buffer is especially crucial in lyophilized formulations, since some buffers can undergo dramatic pH shifts during the freezing process. Regardless of buffer selection, the concentration of buffer used in lyophilization should be reduced to the minimum amount needed to control pH in order to prevent instability resulting from concentrated regions during the lyophilization process.
In formulations with a low concentration of API, a bulking agent helps create a larger, firmer cake structure. Crystalline bulking agents are more common because can produce well-formed cakes with good mechanical properties. Bulking agents, such as mannitol and glycine, are utilized in lyophilized formulations to provide structure to the lyophilized cake, preventing the collapse. But it is important to understand that bulking agents can be dangerous for lyophilized products, because they tend to destabilize emulsions, proteins and liposomes.
For example, when using mannitol, it is essential to ensure that it is fully crystallized. If mannitol crystallizes post-lyophilization, it can release the water associated with it back into the cake, potentially accelerating destabilization of the product.
The suitability of particular stabilizers varies for each formulation, the stabilizer itself induces specific stresses during the lyophilization process, notably chemical and osmotic stress and pH shift during crystallization.
A good example are disaccharides, they form an amorphous sugar glass, which helps stabilize liposomes and proteins throughout the lyophilization process. Sucrose and trehalose have proven especially stabilizing in liposome and virus formulations. This property makes disaccharides highly desirable as stabilizers throughout the lyophilization process.
The tonicity adjuster of choice can be dictated by the stability requirements of the bulk solution, or by the route of administration. In either case, excipients like mannitol, sucrose, glycine, glycerol and sodium chloride can all serve as useful tonicity adjusters. They can be included in the diluent rather than in the formulation itself. At the same time, they’re major contributors to the rapid solubility and absorption that have proven to be such major selling point for lyophilized products.
In summary, a careful balance of buffers, stabilizers, bulking agents and tonicity adjusters is necessary to ensure beneficial interactions with the API throughout each stage of the lyophilization process. But throughout the process, potency, safety and sterility remain crucial concerns for dosage preparations of lyophilized drugs, where the potential for contamination abounds.