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A selection of articles from European Pharmaceutical Review covering Lyophilisation:


Davide Fissore, Department of Applied Science and Technology, Polytechnic University of Turin

Techniques to preserve product quality in pharmaceutical freeze drying

3 July 2014  •  Antonello A. Barresi, Roberto Pisano and Davide Fissore, Department of Applied Science and Technology, Polytechnic University of Turin

In a pharmaceutical freeze drying process, it is mandatory to preserve product quality. This means that for a given formulation that has to be freeze dried, the temperature has to remain below a limit value corresponding to the eutectic temperature for a product that crystallises after freezing, with the goal of avoiding product melting, or to the collapse temperature for a product that remains amorphous at the end of the freezing stage, with the goal of avoiding dried cake collapse, as this could result in a product with unacceptable appearance, and it could cause some concerns during the drying process (e.g. lower sublimation flux and higher residual moisture). The denaturation of the active pharmaceutical ingredient is another issue that has to be accounted for when defining this limit temperature...

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

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.

Figure 1 Schematic illustration of a particle stabilised by a steric stabiliser. Note that it has been reported that both the degree of adsorption and the density / thickness of the steric barrier are essential factors to mitigate freezing and drying stresses

Stabilisation of nanoparticles during freeze drying: The difference to proteins

31 August 2011  •  Jakob Beirowski and Henning Gieseler, University of Erlangen-Nuremberg, Division of Pharmaceutics, Freeze Drying Focus Group

The underlying concept for the stabilisation of proteins during freeze drying is the formation of a glassy matrix in which the macromolecules remain isolated and immobilised. The concept relies on the so-called ‘vitrification hypothesis’ which assumes that the formation of an amorphous phase by lyoprotectants is mandatory to interact with the amorphous protein molecule. The use of lyoprotectants has also been found to be beneficial to preserve the original particle size distribution of nanoparticles during freeze drying. Until today, it has been speculated that the predominant mechanism to suppress physical instabilities of such colloidal particle systems is their embedment in a rigid glass. Today, there are various types of colloidal particles used in drug development, and sometimes the scientific literature gives evidence that glass formation was not necessarily required for stabilisation during freezing thawing or even freeze drying. The purpose of this article is therefore to briefly provide the latest insight into potential stabilisation mechanisms when freeze drying nanoparticles, a key knowledge for rational formulation and process design for such systems.

Figure 1 Kv values at different pressure settings (centre vials, average from two experiments per pressure setpoint). Symbols represent: upper solid line = curve fit TopLyoTM vial, upper dotted line = curve fit ‘standard serum tubing’ vial, lower solid line = curve fit EasyLyoTM vial, lower dotted line = curve fit ‘standard moulded’ vial.

Primary packaging materials for pharmaceutical freeze-drying: Moulded vs. serum tubing vials

19 August 2010  •  Susanne Hibler and Dr. Henning Gieseler, University of Erlangen-Nuremberg, Division ofPharmaceutics, Freeze Drying Focus Group

Pharmaceutical freeze-drying is used to stabilise delicate drugs which are typically unstable in solution over a longer shelf life. The liquid formulation is converted into a solid, highly porous cake which can be easily reconstituted prior to administration. The majority of freeze-dried products in the pharmaceutical industry are used for parenteral application. This route of administration demands high quality for both the drug product and the primary packaging material. Today, glass vials are routinely used for freeze-dried products as they provide some indispensable characteristics. Depending on glass composition, surface treatment, processing and geometry, a vast number of different glass vials are commercially available for customers. Selection of the optimum vial for a given product seems to become more and more difficult as manufacturers of moulded and tubing glass have refined their products over the last decades to fulfil market needs.


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