Modeling of heat and mass transfer processes for the gap-lyophilization system using the mannitol-trehalose-NaCl formulation.

Gap freezing (GF) is a new concept that was developed to reduce the primary drying time using an alternative freezing process. The purpose of this investigation was to determine the gap-tray heat transfer coefficient, Kgtr , and to investigate the effect of gap lyophilization on cycle reduction of a mannitol-trehalose-NaCl (MTN) formulation. The values of Kgtr were measured using the product temperature profiles in three different configurations: (1) shelf freezing followed by shelf drying (denoted as SF-SD), (2) GF followed by SD (denoted as GF-SD), and (3) GF followed by gap drying (denoted as GF-GD). For the lyophilization cycle using shelf drying (SF-SD), 80% of the heat transferred during primary drying was from the bottom shelf to the vial, versus 20% via radiation from the top shelf. For the lyophilization cycle using gap drying (GF-GD), only 37% of the heat transferred during primary drying was from the bottom shelf to the vial versus 63% via radiation from the top shelf. Furthermore, GF in conjunction with annealing significantly reduces the dry layer resistance of the MTN formulation, which is the opposite of what was observed with a conventional freezing cycle.

Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept.

During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose).

Synthesis of Isocoumarins and alpha-Pyrones via Palladium-Catalyzed Annulation of Internal Alkynes.

A number of 3,4-disubstituted isocoumarins and polysubstituted alpha-pyrones have been prepared in good yields by treating halogen- or triflate-containing aromatic and alpha,beta-unsaturated esters, respectively, with internal alkynes in the presence of a palladium catalyst. Synthetically, the methodology provides an especially simple and convenient, regioselective route to isocoumarins and alpha-pyrones containing aryl, silyl, ester, tert-alkyl, and other hindered groups. The reaction is believed to proceed through a seven-membered palladacyclic complex in which the regiochemistry of the reaction is controlled by steric factors. A number of 3,4-disubstituted isocoumarins and polysubstituted alpha-pyrones have been prepared in good yields by treating halogen- or triflate-containing aromatic and alpha,beta-unsaturated esters, respectively, with internal alkynes in the presence of a palladium catalyst. Synthetically, the methodology provides an especially simple and convenient regioselective route to isocoumarins and alpha-pyrones containing aryl, silyl, ester, tert-alkyl, and other hindered groups. The reaction is believed to proceed through a seven-membered palladacyclic complex in which the regiochemistry of the reaction is controlled by steric factors.