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

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 degrees C, 25 degrees C/60% RH and 40 degrees 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 delta-mannitol is formed, which remains physico-chemically stable upon storage for 6 months. With increasing NaCl concentrations more beta-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.