The impact of thermal treatment on the stability of freeze dried amorphous pharmaceuticals: I. Dimer formation in sodium ethacrynate.
The objective of this study was to investigate the impact of heat treatment (annealing) on the molecular mobility and chemical stability of dried sodium ethacrynate (ECA). ECA was lyophilized with sucrose or trehalose, and some samples were held as control while others were annealed at temperatures below T(g). Enthalpy recovery was studied with DSC and free volume was estimated based on density measurements. Global mobility was measured by the thermal activity monitor (TAM), and fast local mobility was studied with neutron backscattering. Formation of ECA dimer was measured by reverse phase HPLC. Maximum enthalpy recovery and minimum fictive temperature were observed at about T(g)-15 degrees C for both ECA/saccharide formulations. Annealing ECA in amorphous solids improved chemical stability, as shown by the decrease in degradation rate constant relative to the control. Annealed samples exhibited larger structural relaxation time than the control, and thus annealing decreased global mobility in the system. However, annealing does not significantly impact the local mobility. Chemical stability correlates with structural relaxation time, fictive temperature, and free volume, which suggests that improved stability is mainly a result of the reduced global mobility upon annealing.
Department of Pharmaceutics, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269, USA.
Bingquan
B
Wang
Michael J
MJ
Pikal
D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D019281:Dimerization; D004355:Drug Stability; D004976:Ethacrynic Acid / Q000737:chemistry*; D005079:Excipients; D005612:Freeze Drying; D006358:Hot Temperature; D006813:Humidity; D008968:Molecular Conformation; D009502:Neutrons; D011506:Proteins / Q000737:chemistry; D012542:Scattering, Radiation; D013395:Sucrose / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics; D014199:Trehalose / Q000737:chemistry
D005079:Excipients; D011506:Proteins; D013395:Sucrose; D014199:Trehalose; D004976:Ethacrynic Acid