title: Effect of the design of the stopper including dimension, type, and vent area on lyophilization process.
abstract: The objective of this study was to examine the role of dimension and design of stoppers on the vapor transfer rate during the lyophilization process. Glass vials (100 cc, 28-mm neck diameter) containing mannitol solutions (4% w/w) were fitted with specially designed Teflon discs with circular holes (area ranging 0.12 to 41.80 mm(2)) instead of stopper vents, which served as the vent for water vapor transfer. The rate of vapor transfer across the vent, the temperature of the frozen product, and the vapor pressure inside the vial were monitored during the early primary drying phase. It was observed that the rate of vapor transfer from the vial increased as the cross-sectional area of the vent was increased. However, this increase tapered off as the area of the vent approached approximately 6 mm(2) in the case when the shelf temperature was at 0 °C and 10 mm(2) in the case when the shelf temperature was at 25 °C. Despite the higher accumulated pressure inside the vial and the corresponding higher temperatures of the frozen product, the rate of water vapor transfer across the vents was lower at the smaller vents, suggesting that the vapor transfer flow regime was under the choked conditions. Mathematical modeling using the observed water vapor pressure values inside the vial indicated that the flow pattern transitioned from the choked to non-choked pattern at a point where the ratio of pressure in the vial to pressure in the chamber, P(vial)/P(chamber), was 2.5. In another set of drying experiments using stoppers with various vent configurations (1-leg, 2-leg, and 3-leg) in glass vials (100 cc, 20-mm neck diameter) containing 4% w/w mannitol solutions, there was no statistical difference in the rate of drying among the three stoppers. The temperature of the frozen product/vial pressure profiles was also similar. This is due to the fact that the vent areas in all the cases were above ∼20 mm(2) and coincided with the plateau region where mass transfer was not the rate-limiting factor across the vent areas. Partial blockage of the vent areas, even up to 50%, did not affect the rate of drying in any of the stoppers, whereas blockage of the vent areas of >75% did decrease the sublimation rate by 25%.
  The objective of this study was to investigate if the dimension and the design of stoppers may affect the moisture vapor transfer rate during the lyophilization process. The rate of vapor transfer across the vent, the temperature of the frozen product, and the vapor pressure inside the vial were monitored during the early primary drying phase in vials that were fitted with specially designed Teflon discs with circular holes (area ranging from 0.12 to 41.80 mm(2)) instead of stoppers. It was observed that although the rate of vapor transfer from the vial increased with the cross-sectional area of the vent, the increase tapered off as the area of the vent approached approximately 6 mm(2) in the case when the shelf temperature was at 0 °C and 10 mm(2) in the case when the shelf temperature was at 25 °C. Despite the higher accumulated pressure inside the vial and the corresponding higher temperatures of the frozen product, the rate of water vapor transfer across the vents was lower at the smaller vents, suggesting that the vapor transfer flow regime was under the choked conditions. Studies with various stopper configurations (1-leg, 2-leg, and 3-leg) and vent areas also showed that as long as the vent areas are greater than the critical mass transfer restriction threshold then there should not be any difference in the overall drying behavior and that substitution of stoppers within the range should yield similar drying cycles.
authors.affiliation: Biopharmaceutics-R&D, Bristol Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903.
authors.forename: Amol
authors.initials: A
authors.lastname: Mungikar
authors.forename: Miron
authors.initials: M
authors.lastname: Ludzinski
authors.forename: Madhav
authors.initials: M
authors.lastname: Kamat
mesh_terms: D003890:Desiccation; D004867:Equipment Design; D005612:Freeze Drying; D005898:Glass; D008353:Mannitol; D011312:Pressure; D013696:Temperature; D014867:Water
chemical_list: D014867:Water; D008353:Mannitol