Pharmaceutical Technology
Controlled nucleation in freeze‐drying: Effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate

https://doi.org/10.1002/jps.22561Get rights and content

ABSTRACT

A novel and scalable method has been developed to enable control of the ice nucleation step for the freezing process during lyophilization. This method manipulates the chamber pressure of the freeze dryer to simultaneously induce nucleation in all product vials at a desired temperature. The effects of controlled nucleation on the drying rate of various formulations including 5% (w/w) mannitol, 5% (w/w) sucrose, and a mixture of 3% (w/w) mannitol and 2% (w/w) sucrose were studied. For a 5% (w/w) mannitol, uncontrolled ice nucleation occurred randomly at product temperatures between −8.0°C and −15.9°C as the vials were cooled to −40°C. Controlled ice nucleation was achieved at product temperatures between −2.3°C and −3.7°C. The effect of nucleation control on the effective pore radius (re) of the cake was determined from the product temperature profiles using a pore diffusion model in combination with a nonlinear parameter estimation approach reported earlier. Results show that the value of re for 5% (w/w) mannitol was enlarged from 13 to 27 μm by uniformly inducing nucleation at higher temperatures. Applying the resistance parameters obtained from the pore diffusion model for 5% (w/w) mannitol, optimized cycles were theoretically generated and experimentally tested, resulting in a 41% reduction in primary drying time. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3453–3470, 2011

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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