PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS PharmSciTech. 2006 December; 7(4): E105–E111.
Published online 2014 March 30. doi:  10.1208/pt070497
PMCID: PMC2750334

Evaluation of manometric temperature measurement (MTM), a process analytical technology tool in freeze drying, part III: Heat and mass transfer measurement

Abstract

This article evaluates the procedures for determining the vial heat transfer coefficient and the extent of primary drying through manometric temperature measurement (MTM). The vial heat transfer coefficients (Kv) were calculated from the MTM-determined temperature and resistance and compared with Kv values determined by a gravimetric method. The differences between the MTM vial heat transfer coefficients and the gravimetric values are large at low shelf temperature but smaller when higher shelf temperatures were used. The differences also became smaller at higher chamber pressure and smaller when higher resistance materials were being freeze-dried. In all cases, using thermal shields greatly improved the accuracy of the MTM Kv measurement. With use of thermal shields, the thickness of the frozen layer calculated from MTM is in good agreement with values obtained gravimetrically. The heat transfer coefficient “error” is largely a direct result of the error in the dry layer resistance (ie, MTM-determined resistance is too low). This problem can be minimized if thermal shields are used for freeze-drying. With suitable use of thermal shields, accurate Kv values are obtained by MTM; thus allowing accurate calculations of heat and mass flow rates. The extent of primary drying can be monitored by real-time calculation of the amount of remaining ice using MTM data, thus providing a process analytical tool that greatly improves the freeze-drying process design and control.

Keywords: freeze drying lyophilization, manometric temperature measurement, process analytical technology for freeze drying, vial heat transfer coefficient

Full Text

The Full Text of this article is available as a PDF (225K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Pikal MJ. Freeze-drying of proteins Part I: process design. BioPharm. 1990;3:14–26.
2. Tang XC, Pikal MJ. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21:191–200. doi: 10.1023/B:PHAM.0000016234.73023.75. [PubMed] [Cross Ref]
3. Nail SL, Gatin LA, editors. Freeze-drying: principles and practice. New York, NY: Marcel Dekker, Inc; 1993. pp. 163–233.
4. Pikal MJ, Roy ML, Shah S. Mass and heat transfer in vial freeze-drying of pharmaceuticals: role of the vial. J Pharm Sci. 1984;73:1224–1237. doi: 10.1002/jps.2600730910. [PubMed] [Cross Ref]
5. Pikal MJ. Use of laboratory data in freeze drying process design: heat and mass transfer coefficients and the computer simulation of freeze drying. J Parenter Sci Technol. 1985;39:115–139. [PubMed]
6. Pikal MJ, Shah S, Senior D, Lang JE. Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. J Pharm Sci. 1983;72:635–650. doi: 10.1002/jps.2600720614. [PubMed] [Cross Ref]
7. Overcashier DE, Patapoff TW, Hsu CC. Lyophilization of protein formulations in vials: investigation of the relationship between resistance to vapor flow during primary drying and small-scale product collapse. J Pharm Sci. 1999;88:688–695. doi: 10.1021/js980445+. [PubMed] [Cross Ref]
8. Tang X, Pikal MJ, Nail S. Mass transfer in freeze drying: measurement of dry layer resistance by a non-steady state method (the MTM procedure). AAPS PharmSci. 1998;S1:Abstract 2198.
9. Milton N, Pikal MJ, Roy MJ, Nail SL. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J Pharm Sci Technol. 1997;51:7–16. [PubMed]
10. Jancso G, Pupezin J, Van Hook WA. The vapor pressure of ice between 0.01 and −100 C. J Phys Chem. 1970;74:2984–2989. doi: 10.1021/j100709a025. [Cross Ref]
11. Tang XC, Pikal MJ. Evaluation of manometric temperature measurement (MTM) in freeze drying, part II: measurement of dry layer resistance. AAPS PharmSciTech. 2006;7:E93–E93. doi: 10.1208/pt070369. [PMC free article] [PubMed] [Cross Ref]
12. Tang XC, Pikal MJ. Evaluation of manometric temperature measurement (MTM) in freeze drying, part I: product temperature measurement. AAPS PharmSciTech. 2006;7:E14–E14. [PMC free article] [PubMed]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists