title: Application of gas pycnometry for the density measurement of freeze-dried products.
abstract: Gas pycnometry is applied to determine the density of solid materials. The analysis of lyophilisates is particularly challenging because of their porous structure. In this study, the density of raw materials and freeze-dried products was determined using different pycnometric methodologies and gases [helium (He), nitrogen (N2 ), sulfur hexafluoride]. The number of purges was set to 60 independent of the gas used. Intact and ground lyophilisates were examined, and major differences were found between use of He and N2 . For example, the density of sucrose lyophilisates measured using He remained almost constant before (1.51 g/cm(3) ) and after (1.52 g/cm(3) ) grinding. In contrast, the density of a sucrose lyophilisate before grinding determined with N2 was 1.33 g/cm(3) . On the basis of μCT and scanning electron microscopy pictures, it appears likely that the majority of pores are interconnected, with only a small fraction of closed pores. Helium is able to penetrate deep into the freeze-dried matrix and is supposedly absorbed by the material. The N2 molecules were not able to penetrate closed pores; therefore, the skeletal density of an intact lyophilisate was determined. Reproducibility of the established method was verified, and freeze-dried orally disintegrating tablets of different compositions were analyzed.
authors.affiliation: Freeze Drying Focus Group (FDFG), Division of Pharmaceutics, D-91058 University of Erlangen, Erlangen, D-91058, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stange
authors.forename: Maike
authors.initials: M
authors.lastname: Scherf-Clavel
authors.forename: Henning
authors.initials: H
authors.lastname: Gieseler
mesh_terms: D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying / Q000379:methods; D005740:Gases / Q000737:chemistry; D006371:Helium / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry; D016062:Porosity; D013046:Specific Gravity; D013395:Sucrose / Q000737:chemistry*; D013607:Tablets / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D005079:Excipients; D005740:Gases; D013607:Tablets; D006371:Helium; D013395:Sucrose; D009584:Nitrogen
keywords: amorphous; density; excipients; freeze-drying/lyophilization; gas pycnometry; helium; micromeritics; nitrogen; μCT