Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Experimental Determination of the Key Heat Transfer Mechanisms in Pharmaceutical Freeze-Drying

https://doi.org/10.1002/jps.23514Get rights and content

ABSTRACT:

The study is aimed at quantifying the relative contribution of key heat transfer modes in lyophilization. Measurements of vial heat transfer rates in a laboratory-scale freeze-dryer were performed using pure water, which was partially sublimed under various conditions. The separation distance between the shelf and the vial was systematically varied, and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of separation distance between the vial and the shelf and linearly dependent on pressure in the free molecular flow limit, realized at low pressures (<50 mTorr). However, under higher pressures (>120 mTorr), heat transfer rates were independent of pressure and inversely proportional to separation distance. Previous heat transfer studies in conventional freeze-drying cycles have attributed a dominant portion of the total heat transfer to radiation, the rest to conduction, whereas convection has been found to be insignificant. Although the measurements reported here confirm the significance of the radiative and gas conduction components, the convective component has been found to be comparable to the gas conduction contribution at pressures greater than 100 mTorr. The current investigation supports the conclusion that the convective component of the heat transfer cannot be ignored in typical laboratory-scale freeze-drying conditions.

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

qheat flux (Wm−2)
αaccommodation coefficient
Ppressure (Pa)
Tshshelf temperature (K)
Tvvial temperature (K)
kBoltzmann constant (m2 kgs−2 K−1)
Kheat conductivity of the gas (Wm−1 K−1)
lseparation between the shelf and vial (m)
σStefan–Boltzmann constant (Wm−2 K−4)
εemissivity
Rspecific 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.

REFERENCES (16)

There are more references available in the full text version of this article.

Cited by (0)

View full text