Pharmaceutical TechnologyControlled nucleation in freeze‐drying: Effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate
Section snippets
INTRODUCTION
The degree of supercooling for an aqueous solution can be defined as the temperature difference between the thermodynamic freezing point of the solution and the temperature at which ice nucleation first occurs.1,2 The onset of ice nucleation is a stochastic or random event with the range of supercooling depending on the solution properties and process conditions.3 The degree of supercooling is important because it determines the number of ice nuclei formed during the ice nucleation step and
Freeze‐drying Cycles
Freeze‐drying cycle runs were performed using a Tofflon freeze dryer with five product shelves, having a total surface area of 5 m2 (Shanghai Tofflon Science and Technology Company, Shangai, China). The freeze dryer is located and preparation activities took place in a clean room, where particulate levels are maintained at Class 100 conditions, similar to a pharmaceutical cGMP manufacturing environment. The freeze dryer also has the capability of recording product temperatures using 19
Comparison of Nucleation Behavior
Visual inspection verified that depressurization of the lyophilization chamber consistently nucleated all samples in the chamber for all formulations. The nucleation event using controlled nucleation has been monitored previously by a digital video camera placed inside the freeze dryer. Sequential images following depressurization are shown in Figure 2 for a set of 10 mL vials containing 5 mL of water held at a shelf temperature of approximately −8°C. Using controlled nucleation, the ice
CONCLUSIONS
Controlled nucleation has been successfully implemented to uniformly control the nucleation temperature of water in the formulation during the freezing step of the lyophilization process. The controlled nucleation method utilized a sequence of pressurization and depressurization steps with an inert gas to achieve uniform ice nucleation throughout all samples in a freeze dryer at the desired temperature. Using this technology, very consistent nucleation temperatures were observed in vials at
APPENDIX 1
Freeze‐Drying Procedure for Uncontrolled Nucleation Cycles in this Study
(Note the cycle does not include the optimized cycle for 5% mannitol using Tf = −13.0°C and Pc = 60 mTorr, as described in the section entitled “Effect of Controlled Nucleation on Sublimation Rate”)
- (1)
Load vials onto the freeze dryer shelf at room temperature.
- (2)
Cool shelf to 5°C and hold for 60 min.
- (3)
Ramp shelf at 0.5°C/min to −40°C.
- (4)
Hold shelf at −40°C for:
5% mannitol: 150 min
5% sucrose and 3% mannitol/2% sucrose: 180 min
- (5)
Upon
APPENDIX 2
Freeze‐Drying Procedure for Controlled Nucleation Cycles in this Study
(Note the cycle does not include the optimized cycle for 5% mannitol using Tf = −3.0°C and Pc = 60 mTorr, as described in the section entitled “Effect of Controlled Nucleation on Sublimation Rate”)
- (1)
Load vials onto the shelf at room temperature.
- (2)
Purge air from product chamber twice by pressurizing at 14 psig (197.8 kPa) with argon gas and then depressurizing.
- (3)
Pressurize the chamber with argon gas to approximately 28 psig
ACKNOWLEDGEMENTS
We would like to acknowledge Professor Michael J. Pikal and his students for the BET work and useful discussion as well as Mr. Bryce Rampersad for engineering support.
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