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Publication date: 22 October 2012
Author(s): Henning Gieseler, Associate Professor at the Division of Pharmaceutics, University of Erlangen & CEO, GILYOS GmbH and Peter Stärtzel, Pharmaceutical Scientist, GILYOS GmbH
Controlled nucleation in freeze-drying
The stochastic nature of nucleation during the freezing step of the freeze-drying process has been regarded as a demerit in a process which is considered under rigorous control. The freezing performance of a product can impact its subsequent drying behaviour and the final product quality attributes. Hence, the idea to control this stochastic event and thus to directly influence the product morphology seems highly appealing. Sound understanding of the nature of nucleation and its link to drying performance, as well as the choice of a suitable technical concept, is of fundamental importance and the prerequisite to profit from the opportunities offered by controlled nucleation.
Freeze-drying is a commonly used method within the pharmaceutical industry. One of the key steps of the entire process is the initial freezing procedure. During freezing of an aqueous solution, the formation of ice does not start at the equilibrium freezing temperature, Tf (Figure 1). Instead, the solution shows supercooling below Tf until the first ice nuclei are formed at the nucleation temperature, Tn. Nucleation itself proceeds in a three-phase process. ‘Primary nucleation’ describes the point where initial crystal nuclei appear from molecular clusters exceeding a critical size1,2. The formed nuclei are further grown to ice crystals by secondary nucleation (also referred to as ‘crystallisation’) passing through the already nucleated volume1.
ABB Analytical Measurement Analytik Jena AG Aptalis Pharmaceutical Technologies ASM - Aerosl-Service AG Azbil BioVigilant, Inc. B&W Tek, Inc. bioMérieux BioTrends – Archilex SA BMG LABTECH GmbH Bruker Daltonik GmbH CAMO Software AS Catalent Pharma Solutions Chemspec Europe Ltd CI Precision Dow Chemical Company Ltd EUROGENTEC FOSS NIRSystems, Inc. GE Analytical Instruments Gerresheimer Group HAMAMATSU PHOTONICS EUROPE I Holland Limited IDBS IONIMED Analytik GmbH LI-COR Biosciences Lonza Natoli Engineering Company, Inc. Pall Life Sciences PANalytical B.V. Patheon Inc PhyNexus, Inc. ReAgent Roche Sirius Analytical Instruments Ltd Vala Sciences Veltek Associates Inc.