Influence of Processing Conditions on the Physical State of Mannitol—Implications in Freeze-Drying

Abstract

The presence of protein as well as the processing conditions (annealing temperature and time, primary and secondary drying temperatures) influenced the physical form of mannitol in the final lyophile. The protein promoted formation of delta-mannitol while inhibiting the formation of mannitol hemihydrate. Since the physical form of mannitol was greatly influenced by the presence of protein, it will be prudent to conduct the preliminary lyophilization cycle development studies in the presence of the protein. If mannitol hemihydrate is formed during annealing, its dehydration may require high secondary drying temperature.

Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol

“…The residual moisture measured for the mannitol lyophilisates was insignificant (0.2% ± 0.1%, w/w) which is ideal for storage stability (Barresi et al, 2009;Tang and Pikal, 2004). This agrees with DSC analysis that showed no endothermic transitions below 100 ºC for all mannitols (Figure 4), confirming the absence of detectable surface (free) water (which would have produced an endotherm at ~ 100 °C) or metastable monoclinic mannitol hemihydrate (which would have produced an endotherm at ~ 80 °C (Liao et al, 2007)). (Figure 6b) indicating that the two techniques were in concurrence.…”

The Impact of Protein Concentration on Mannitol and Sodium Chloride Crystallinity and Polymorphism Upon Lyophilization

“…1,2 Depending on formulation composition and lyophilization conditions, mannitol can crystallize in any one of four different polymorphs (a, b, d and hydrate), or remain amorphous. [3][4][5][6][7][8][9] Much of the focus of mannitol research has been on the meta-stable hemihydrate polymorph, which may convert to an anhydrous form during storage, releasing water into the product. Sodium chloride, at elevated levels, also crystallizes during lyophilization and has been used as a bulking agent in Factor VIII formulations.…”

Lyophilization of Biologics: An FDA Perspective

“…However, these methods are invasive and are not applicable at the commercial scale due to sterility issues. PAT tools that allow for noninvasive control of the freezing step include a scalable method, called ContrLyo™ Technology, which works by rapidly pressurizing and depressurizing the chamber using an inert gas such as argon to uniformly trigger the onset of ice nucleation during freezing [27,32]. This causes the product in the chamber to nucleate simultaneously at a lower degree of supercooling (Fig.…”