A New Approach to Achieve Controlled Ice Nucleation of Supercooled Solutions During the Freezing Step in Freeze‐Drying

Abstract

Controlled ice nucleation of supercooled solutions has recently attracted a lot of interest in the field of freeze‐drying. 1. CPPR. 2012. Freeze‐drying of pharmaceuticals and biologicals. Conference program. Accessed on 08‐25‐2012, at: http://nipte.org/docs/FreezeDrying%20Revised%20Program.pdf. Google Scholar , 2. Konstantinidis A.K. Kuu W. Otten L. Nail S.L. Sever R.R. Controlled nucleation in freeze‐drying: Effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate. J Pharm Sci. 2011; 100: 3453-3470 Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar , 3. Patel S. Bhugra C. Pikal M. Reduced pressure ice fog technique for controlled ice nucleation during freeze‐drying. AAPS PharmSciTech. 2009; 10: 1406-1411 Crossref PubMed Scopus (71) Google Scholar , 4. Kasper J.C. Friess W. The freezing step in lyophilization: Physico‐chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eur J Pharm Biopharm. 2011; 78: 248-263 Crossref PubMed Scopus (321) Google Scholar Ice nucleation is a stochastic event and the probability of spontaneous ice crystal formation is, among others, dependent on the presence of foreign particles. 5. Rambhatla S. Ramot R. Bhugra C. Pikal M. Heat and mass transfer scale‐up issues during freeze drying: II. Control and characterization of the degree of supercooling. AAPS PharmSciTech. 2004; 5: 54-62 Crossref Scopus (190) Google Scholar Thus, ice nucleation becomes a major issue during scale‐up from laboratory‐scale to almost particle‐free clean room production environment. 6. Roy M.L. Pikal M.J. Process control in freeze drying: Determination of the end point of sublimation drying by an electronic moisture sensor. PDA J Pharm Sci Technol. 1989; 43: 60-66 Google Scholar Controlling ice nucleation at a certain product temperature is expected to lead to a more uniform product because the degree of supercooling and nucleation temperature is influencing product parameters, for example, cake resistance, 5. Rambhatla S. Ramot R. Bhugra C. Pikal M. Heat and mass transfer scale‐up issues during freeze drying: II. Control and characterization of the degree of supercooling. AAPS PharmSciTech. 2004; 5: 54-62 Crossref Scopus (190) Google Scholar specific surface area, and residual moisture. 2. Konstantinidis A.K. Kuu W. Otten L. Nail S.L. Sever R.R. Controlled nucleation in freeze‐drying: Effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate. J Pharm Sci. 2011; 100: 3453-3470 Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Reduction of cake resistance is greatly reducing primary drying time 6. Roy M.L. Pikal M.J. Process control in freeze drying: Determination of the end point of sublimation drying by an electronic moisture sensor. PDA J Pharm Sci Technol. 1989; 43: 60-66 Google Scholar and therefore saves energy, time, and money because primary drying usually is the longest step in a freeze‐drying cycle.