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University of Erlangen-Nuremberg - Articles and news items

Figure 1: Typical product temperature profiles during uncontrolled nucleation indicated by thermocouples placed centre bottom within the vial. 1: degree of supercooling; 2: nucleation temperature, Tn; 3: equilibrium freezing temperature, Tf.

Controlled nucleation in freeze-drying

Issue 5 2012, Lyophilisation / 22 October 2012 / Henning Gieseler, Associate Professor at the Division of Pharmaceutics, University of Erlangen & CEO, GILYOS GmbH and Peter Stärtzel, Pharmaceutical Scientist, GILYOS GmbH

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, page 64). 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.

Process Analytical Technology (PAT) in Freeze Drying: Tunable Diode Laser Absorption Spectroscopy as an evolving tool for Cycle Monitoring

Issue 6 2009, Past issues / 12 December 2009 /

The most important critical product parameter during a freeze-drying process is the product temperature at the ice sublimation interface, Tp1. Once the product temperature in this area of interest exceeds the critical formulation temperature (typically denoted as “collapse temperature”, Tc) during primary drying, a stepwise loss of the cake structure may be observed2,3. This, in turn, can greatly impact the product quality attributes with regard to product appearance, reconstitution times, sub-visible particles and residual moisture content4.

The determination of structural changes of biopharmaceuticals during Freeze-Drying using Fourier Transform Infrared Spectroscopyb

Issue 2 2009, Past issues / 20 March 2009 /

Peptides and proteins are powerful active therapeutic ingredients used in a wide variety of serious conditions and illnesses such as diabetes, arthritis or cancer. The application of these so-called biopharmaceuticals has been rapidly increasing since the middle of the 1990s, facilitated by improvements in modern recombinant DNA technology and biotechnological manufacturing. The worldwide sales of the biotech drug market grew from 43 billion US$ in 2003 to over 75 billion US$ in 2007 according to a recent IMS Health market analysis. The major challenge in the development of stable protein formulations and dosage forms is to ensure their process and shelf life stability.

Application of DSC and MDSC in the development of freeze dried pharmaceuticals

Issue 6 2008, Past issues / 3 December 2008 / Jakob Beirowski, Pharmacist and Dr. Henning Gieseler, Assistant Professor, Division of Pharmaceutics, University of Erlangen-Nuremberg

Freeze drying of pharmaceuticals requires an adequate formulation design to prevent low-temperature, freezing and drying stresses. The goal is to achieve a final product with long storage stability and elegant appearance. To meet these specifications the product temperature must be controlled below the critical formulation temperature during the freeze drying cycle. DSC is an established tool to measure this critical formulation property in the development of freeze dried pharmaceuticals as it allows rapid sample preparation and analysis time. The introduction of modulated DSC (MDSC) by Reading in 1992 has greatly facilitated the interpretation of DSC results. The overlapping transitions in the same temperature range can be distinguished and characterisation of the nature of transitions is facilitated.

A significant comparison between collapse and glass transition temperatures

Issue 5 2008, Past issues / 29 September 2008 /

Rational freeze-drying process design is based on a representative and accurate measurement of the critical formulation temperature. To avoid product shrinkage or collapse, it is indispensable to control the product temperature just below this key temperature during primary drying. Over the last decades, DSC was routinely used to determine the glass transition temperature of the maximally freeze concentrated solute (Tg’), information which was then applied to freeze-drying process design. Recently, Freeze-Dry Microscopy (FDM) was introduced as a new technology to determine an even more representative critical temperature: the collapse temperature (Tc). Today, important technological improvements in FDM even allow more sophisticated observations of collapse behaviour and therefore, further cycle optimization.

PAT for freeze drying: cycle optimisation in the laboratory

Issue 1 2007, Past issues / 25 January 2007 / Dr. Henning Gieseler, PhD., Department of Pharmaceutics, University of Erlangen-Nuremberg

Freeze drying is generally known to be a time consuming and therefore expensive process. In order to lower costs during manufacturing, the effective cycle time must be reduced. This goal can be achieved by optimising a freeze drying cycle in the laboratory – in particular the primary drying phase. Applying PAT in the laboratory can provide valuable information about product and process behaviour and may help to identify the critical process parameters during cycle development and optimisation.


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