Pharmaceutics, Drug Delivery and Pharmaceutical TechnologyExperimental Determination of the Key Heat Transfer Mechanisms in Pharmaceutical Freeze-Drying
Section snippets
INTRODUCTION
Although freeze-drying of injectable products in the primary container system is an essential unit operation in the manufacture of parenteral dosage forms, the process is currently very inefficient. This is because of the inefficient heat transfer from the heat source, a shelf through which heat transfer fluid is circulated, and the primary product container—usually a glass vial. Nail1 identified poor thermal contact between the vial and the shelf as the rate limiting resistance to heat
MATERIALS AND METHODS
This section describes the materials and procedures for quantifying the heat transfer contributions at varying shelf temperatures and chamber pressures. Four sets of experiments are described and their process parameters are summarized in Table 1. Set 1 consists of a setup with vial–shelf separation ranging from direct contact to 3 mm for a shelf temperature of 25°C with a total load of about 30 g. Set 2 consists of measurements at shelf temperatures of −20°C and 25°C for a large load of 400 g.
THEORY AND DATA ANALYSIS
Currently, most industrial pharmaceutical freeze-drying processes use a freeze-drying chamber that contains the product in vials, which are in direct contact with heated shelves. For cycles in which vials are loaded on the shelf, the stainless steel shelf on which the vial is placed serves as a primary source of heat for drying. However, for suspended vials or for products in syringes, direct contact with the shelf is eliminated and the walls of the freeze-dryer, the shelf above the vials, and
Set 1: Contribution of Conduction, Convection, and Radiation in Primary Drying
Table 2 summarizes the measured sublimation rates for chamber pressures of 10, 15, 20, 60, 100, and 200 mTorr. The product was allowed to sublime until about 22%–25% of the initial mass was lost. Once the individual sublimation rates were obtained, the heat flux across an individual vial was calculated using the heat of sublimation and the total vial area. Figure 7 illustrates the experimentally measured heat flux for different pressures and separation distances. As predicted by the analytical
CONCLUSIONS
The current work elaborates on the contribution of the different modes of heat transfer during primary drying. Apart from the proximity to the plexiglass door, separation from the shelves plays an important role in determining the sublimation rate. The vials placed directly on the shelf had the highest sublimation rate, which reduced as the separation from the bottom shelf increased. The heat transfer in the free molecular limit was found to be independent of separation, and hence, at low
NOMENCLATURE
q heat flux (Wm−2) α accommodation coefficient P pressure (Pa) Tsh shelf temperature (K) Tv vial temperature (K) k Boltzmann constant (m2 kgs−2 K−1) K heat conductivity of the gas (Wm−1 K−1) l separation between the shelf and vial (m) σ Stefan–Boltzmann constant (Wm−2 K−4) ε emissivity R specific gas constant (J kg−1 K−1)
Acknowledgements
The research was supported by National Science Foundation, CBET/GOALI-0829047, Baxter Pharmaceutical Solutions, LLC, and Purdue's Center for Advanced Manufacturing. The authors would also like to thank Ms. Lisa Hardwick and Drs. Mike Akers and Gregory Sacha of Baxter Pharmaceutical Solutions (Bloomington, Indiana) for extremely useful discussions of freeze-drying hardware.
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