A review on experimental determination and optimization of physical quality factors during pharmaceuticals freeze-drying cycles

ABSTRACT

This review concerns description of determination methods and presentation of some significant recent experimental data related to the important parameters involved in the optimization and control of freeze-drying cycles of pharmaceuticals contained in vials.

Concerning ice morphology characterization—generally ignored or neglected by the R&D engineers—the authors strongly recommend greater use of the cold chamber microscopy, which has proven to be an inexpensive and efficient method for determination of ice crystal morphology.

Selected important experimental data relating the influence of the freezing protocol: freezing rates, nucleation temperature, annealing treatment, and freezing configuration—vial size and type, filling height etc.—on ice crystal morphology of the frozen sample and on the morphology and mass transport properties of the final freeze-dried cake are presented and analyzed.

Furthermore, we compare some methods of determination—especially the transient pressure rise methods (PRA or MTM)—of the two main physical parameters, namely the overall water vapor mass transfer resistance, R_p, and the overall heat transfer coefficient, K_v—that control the mean temperature of the product which is the most important parameter that controls the main physical, biological or pharmaceutical properties of the freeze-dried product.

Next, some experimental data concerning the influence of vial type and total gas pressure on the overall heat transfer coefficient, K_v, which is generally the main controlling parameter in the case of freeze-drying of thermosensible proteins at very low total gas pressure and sublimation temperature (vaccines, serums, etc.), are presented. Also included is a critical comparison of the different methods of determination of the end-sublimation period.

Finally, this review analyses some recently published data showing the influence of shelf temperature and the total gas pressure on classical sublimation kinetics curves which allow one to determine the main mechanism of heat and mass transfer that governs the sublimation process; these data are essential to choose the most convenient and efficient parameters for the control of an industrial freeze-dryer.

KEYWORDS:

• Drying cycle’s optimization
• freeze-drying
• heat transfer coefficients
• ice morphology
• mass transfer resistance