The Application of Thermoanalytical Techniques to the Study of the Freeze-Drying Proces

The Application of Thermoanalytical Techniques to the Study of the Freeze-Drying Proces
Vicky Kett, Ph.D,.The School of Pharmacy, Queen's University of Belfast
A key challenge facing the pharmaceutical industry is the production of biotechnological therapeutics such as proteins in a stable form. Freeze-drying (lyophilization) is preferred for manufacturing such products because of the possibility of producing a stable ?solid? form of the protein that may be easily reconstituted prior to injection. Freeze-drying may be divided into three parts: freezing of solvent, its subsequent removal at reduced pressure and removal of solvent from the remaining unfrozen matrix [3, 4]. The rationale being that the low temperatures used minimize degradation during drying. However, the protein may still degrade during the process necessitating the inclusion of a cryoprotectant, which stabilizes during freezing, or a lyoprotectant, which stabilizes throughout the whole process [13]. In the studies presented here, a range of thermal analysis techniques have been used to investigate the properties of formulations to be freeze-dried and the resultant products. This approach has allowed insight into the key parameters required for design of formulations and processes that will generate the optimum products.
Mannitol in Freeze-Drying
Mannitol is a hexahydric alcohol that has been extensively used as an excipient for the freeze-drying of pharmaceuticals [8] because of the elegant cakes produced, the promotion of efficient freeze-drying due to the high melting temperature of the eutectic produced and the possibility of mannitol exhibiting cryoprotective properties. However, its crystallization upon reheating has led to problems including vial cracking [15, 16] and reduced cryoprotective ability in protein formulations, since it results in removal of the sugar from the protein phase [6, 7].
Previous studies have indicated that mannitol can exist in three polymorphic forms designated as a, b and, d [12] corresponding to modifications II, I and III as characterized by Burger et al (2000, who have also demonstrated that other reported polymorphs correspond to those already reported, either alone or as mixtures) [1]. Hydrate formation has also been proposed [17]. Therefore, precise knowledge of the subambient transitions occurring in a given mannitol formulation is important. With this in mind, the properties of frozen mannitol solutions (3% w/v) have been explored.
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