Experimental Determination of the Key Heat Transfer Mechanisms in Pharmaceutical Freeze Drying

Freeze-drying is often used in manufacture of pharmaceuticals to remove a solvent in such a way that the sensitive molecular structure of the active substance of a drug is least disturbed, and to provide a sterile powder that can be quickly and completely rehydrated. In this work heat transfer rates in a laboratory-scale freeze-dryer have been measured to investigate the contribution of different heat transfer modes. Pure water was partially dried under low-pressure conditions and sublimation rates were determined gravimetrically. The heat transfer rates were observed to be independent of the separation distance between a product vial and a dryer shelf and linearly dependent on the pressure in the free molecular limit. However, under higher pressures the heat transfer rates were independent of pressure and inversely proportional to the 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 the convection has been found insignificant. While the measurements revealed the significance of the radiative and gas conduction components, the convective component was found to be comparable to the gas conduction contribution at pressures greater than 100mTorr. The current investigation suggests that the convective component of the heat transfer cannot be ignored at typical laboratory-scale freeze-drying conditions

Heat and mass transfer scale-up issues during freeze-drying

The overall objective of this research is to develop useful guidelines and algorithms to allow reliable scale-up of heat and mass transfer effects from laboratory to manufacturing scale lyophilizers. Scale up issues include variations in shelf surface temperature, heterogeneity in heat transfer rates with respect to position on the shelf, freezing variations between manufacturing and laboratory lyophilizers and variations that can occur due to differences in freeze dryer design. ^ Cake shrinkage during freeze-drying is related to the heat and mass transfer characteristics of the product and highlights the importance of product temperature control during drying. A combined experimental and theoretical approach was used to show that conditions of secondary drying impact cake shrinkage and that the product temperature should be maintained below the glass transition temperature throughout secondary drying. ^ Atypical radiation heat transfer experienced by edge vials due to their clear view of a warmer surface is responsible for their higher heat transfer rates and this atypical behavior poses a scale-up issue. Convection heat transfer was not responsible for this atypical behavior. Variation in the degree of supercooling between laboratory and manufacturing cycles may lead to significant variations in primary drying time. A correlation between product resistance during primary drying and the specific surface area of the product provided a quantitative prediction of the impact of freezing variations during scale up. Control of nucleation temperature within vials of the same batch was achieved by using an ice fog technique. ^ Data obtained from controlled sublimation tests on laboratory and manufacturing freeze dryers was used to estimate inter-vial variation in heat transfer rates based on design characteristics. Shelf non-uniformity, variable emissivities of representative surfaces, and the individual resistances offered by chamber, condenser and refrigeration system, are design parameters that were evaluated from sublimation tests. ^ Steady state heat and mass transfer theory was then used to combine data obtained for various scale-up issues in order to provide overall “rules and algorithms” for successful scale up from laboratory to manufacturing scale.

Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling

This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an “ice fog”, there-by facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1°C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scaleup drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization

Heat and mass transfer scale-up issues during freeze-drying, I: Atypical radiation and the edge vial effect

The aim of this study is to determine whether radiation heat transfer is responsible for the position dependence of heat transfer known as the edge vial effect. Freeze drying was performed on a laboratory-scale freeze dryer using pure water with vials that were fully stoppered but had precision cut metal tubes inserted in them to ensure uniformity in resistance to vapor flow. Sublimation rates were determined gravimetrically. Vials were sputter-coated with gold and placed at selected positions on the shelf. Average sublimation rates were determined for vials located at the front, side, and center of an array of vials. Sublimation rates were also determined with and without the use of aluminum foil as a radiation shield. The effect of the guardrail material and its contribution to the edge vial effect by conduction heat transfer was studied by replacing the stainless steel band with a low-thermal conductivity material (styrofoam). The emissivities (ε) of relevant surfaces were measured using an infrared thermometer. Sublimation rate experiments were also conducted with vials suspended off the shelf to study the role of convection heat transfer. It was found that sublimation rates were significantly higher for vials located in the front compared to vials in the center. Additional radiation shields in the form of aluminum foil on the inside door resulted in a decrease in sublimation rates for the front vials and to a lesser extent, the center vials. There was a significant decrease in sublimation rate for goldcoated vials (ε≈0.4) placed at the front of an array when compared to that of clear vials (ε≈0.9). In the case of experiments with vials suspended off the shelf, the heat transfer coefficient was found to be independent of chamber pressure, indicating that pure convection plays no significant role in heat transfer. Higher sublimation rates were observed when the steel band was used instead of Styrofoam while the highest sublimation rates were obtained in the absence of the guardrail, indicating that the metal band can act as a thermal shield but also transmits some heat from the shelf via conduction and radiation. Atypical radiation heat transfer is responsible for higher sublimation rates for vials located at the front and side of an array. However, the guardrail contributes a little to heat transfer by conduction