Physico-chemical lyophilization behavior of mannitol, human serum albumin formulations

Physico-chemical lyophilization behavior of mannitol, human serum albumin formulations
Received 23 November 2005; revised 14 February 2006; accepted 18 February 2006. Available online 28 February 2006.
Andrea Hawe, and Wolfgang Frie?
European Journal of Pharmaceutical Sciences
Volume 28, Issue 3 , June 2006
Copyright ? 2006 Elsevier B.V. All rights reserved.
Ludwig-Maximilians-University Munich, Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Butenandtstr. 5-13, House B, 81377 Munich, Germany
Abstract
The lyophilization behavior is influenced by the presence of salts. The impact of NaCl on drying-time and the morphology after lyophilization was studied for formulations with mannitol and HSA, using different freezing-protocols. The drying-process was monitored by thermocouples and microbalance technique. Karl?Fischer titration, DSC, XRD, SEM and turbiditimetry and HP-SEC were used to study the products after lyophilization and 6 months storage at 2?8 ?C, 25 ?C/60% RH and 40 ?C/75% RH.
NaCl decreases the drying-time of mannitol-HSA formulations, indicating morphological changes, which was confirmed by XRD and SEM. Without NaCl exclusively d-mannitol is formed, which remains physico-chemically stable upon storage for 6 months. With increasing NaCl concentrations more ?-mannitol and finally amorphous products are formed, whereby the freezing-protocol determines how much NaCl is needed to achieve an amorphous product. Upon storage, the amorphous state cannot be preserved and mannitol and NaCl crystallize, which can damage proteins in the formulations. However, regarding the stability of HSA in the lyophilized products, monitored by turbidimetry and HP-SEC, the addition of NaCl can prevent increases in turbidity upon storage. Here the benefit of NaCl on HSA stability outbalances the potential drawbacks that morphological changes, like crystallization impose on protein stability in the lyophilized products.
Keywords: Lyophilization; Mannitol; HSA; Morphology; Storage stability

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