Peptides without mannitol filler – a scientific perspective

What is Mannitol ?

Mannitol  is a sugar alcohol (polyol) that is useful for freeze drying proteins and other biomolecules,  It is widely used as an excipient in pharmaceutical applications. During freeze drying, Mannitol provides an amorphous (non-crystalline) matrix, which allows water to escape from samples, while simultaneously preventing the collapse of the sample.  When using this excipient, proteins remain undisrupted during processing and channels form for water sublimation. Mannitol is also a filler that builds up the appearance of peptides in vials, makes peptides more visible in vials.

Why do peptides differ in appearance?

Each aliquot of a peptide is deposited into each vial via a machine. The vial is then stoppered and moved inside the lyophilizer. Once in the lyophilizer, the vial is then given a nitrogen flush to rid any contaminates. This is the phase that will determine the appearance of the contents. Sometimes the water vapour can escape the vial where it goes from a solid to a gas without ever going through a liquid phase. This will make the contents adhere to the sides of the vial leaving very little to see by the naked eye. Other times, depending on several other factors including temperature, the appearance can look like a solid puck, a few smaller pucks, a powder material, or even just a few specks, but the amount of actual material is the same. When freeze-drying products without any matrix (sucrose or mannitol for example) sometimes the residual water of hydration will cause a collapse via hydration of product before it fully dries (Collapse does not mean degradation od peptide). In other words, when the water from the ice crystals is removed what remains prior to secondary drying (when the chamber is warmed) can combine and solubilize the remaining material causing it to collapse. Sometimes it forms crystals and sometimes it forms films dependent upon how much there is local melting and what the temperature and vacuum levels are at the time of the collapse. Very complicated but it tends to happen far less when sucrose or mannitol, for example, is around since the sugar hydrogen bonds to the protein/peptide like the water did and thus less water remains bound as the water of hydration.

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References / Links

1. Pikal, M. J. (1990). Freeze-drying of proteins. Part I: Process design. BioPharm, 3(7), 18–27. PubMed
2. Allison, S. D., & Chang, B. (1999). Stabilization of lyophilized proteins by sugars and polyols: Mechanisms of stabilization. Advanced Drug Delivery Reviews, 46(1-3), 129–150. ScienceDirect
3. Franks, F. (1998). Freeze-drying of bioproducts: Putting principles into practice. European Journal of Pharmaceutics and Biopharmaceutics, 45(3), 221–229. PubMed
4. Wang, W. (2000). Lyophilization and development of solid protein pharmaceuticals. International Journal of Pharmaceutics, 203(1-2), 1–60. PubMed
5. Carpenter, J. F., Pikal, M. J., Chang, B. S., & Randolph, T. W. (1997). Rational design of stable lyophilized protein formulations: Some practical advice. Pharmaceutical Research, 14(8), 969–975. PubMed