Modeling of freezing step during freeze‐drying of drugs in vials

A mathematical model that simulates temperature profiles during freezing process of standard pharmaceutical formulations (mannitol and BSA based) was set up in two-dimensional axsymmetric space, and the ice crystal mean sizes were semi empirically estimated from the resulting temperature profiles. Water vapor mass transfer permeability values during sublimation step were also estimated from ice phase morphological parameters. All these numerical data were compared with experimental data, and a quite good agreement was observed that confirmed the adequacy of the present model calculations. It was confirmed that, for a given formulation, the mass transfer parameters during freeze-drying were strongly dependent on morphological textural parameters, and consequently, on the nucleation temperatures that fix the ice phase morphology. The influence of freezing rate was also predicted from the simulations, proving that an increase of cooling rates led to slower primary drying rates. © 2007 American Institute of Chemical Engineers AIChE J, 2007

[1]  J. Andrieu,et al.  Experimental and theoretical study of model food freezing. Part II. Characterization and modelling of the ice crystal size , 1998 .

[2]  D. Reid.  Cryomicroscopic studies of the freezing of model solutions of cryobiological interest , 1982 .

[3]  Ingo Heschel,et al.  The influence of the freezing process on vapour transport during sublimation in vacuum-freeze-drying of macroscopic samples , 1993 .

[4]  Ingo Heschel,et al.  The influence of the freezing process on vapour transport during sublimation in vacuum-freeze-drying , 1991 .

[5]  Julien Andrieu,et al.  A Direct Characterization Method of the Ice Morphology. Relationship Between Mean Crystals Size and Primary Drying Times of Freeze-Drying Processes , 2004 .

[6]  J. Andrieu,et al.  Characterization of ice cream structure by direct optical microscopy. Influence of freezing parameters , 2003 .

[7]  John J. J. Chen,et al.  Simulation and experiment of the unsteady heat transport in the onset time of nucleation and crystallization of ice from the subcooled solution , 2003 .

[8]  J. Carpenter,et al.  Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine T(g)' in pharmaceutical lyophilization. , 2001, Journal of pharmaceutical sciences.

[9]  C. J. King,et al.  Heat and mass transport in the freezing of apple tissue , 2007 .

[10]  J. Andrieu,et al.  Experimental study and modelling of the ice crystal morphology of model standard ice cream. Part I: Direct characterization method and experimental data , 2001 .

[11]  M. Pikal,et al.  Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. , 1983, Journal of pharmaceutical sciences.

[12]  Julien Andrieu,et al.  Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying , 2006 .

[13]  Julien Andrieu,et al.  Freeze-Drying of Pharmaceutical Proteins in Vials: Modeling of Freezing and Sublimation Steps , 2006 .

[14]  J. Carpenter,et al.  The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. , 2001, Journal of pharmaceutical sciences.