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DMU LyoGroup

De Montfort University’s LyoGroup specialises in instrumentation technologies for the development of drug product formulations and for monitoring and/or understanding critical process parameters of the freeze-drying cycle. 

When aqueous solutions freeze, which means liquid water turning to crystalline water (ice), they do so by first super-cooling below the equilibrium melting point of ice. At some sub-zero temperature, there will be enough nuclei with sufficient stability to allow ice growth to start. This nucleation temperature, and the cooling rate of the solution, are the two critical process parameters which define how the ice forms and the morphology of the ice crystals that result. The amount of ice that forms is clearly important to the requirements of the primary drying stage, when ice converts directly to vapour via the process of sublimation, including the required capacity of the condenser. However, it’s the ice morphology that has a particular relevance to the sublimation phase, as it creates the initial template for the porosity of the dry layer, which restricts the flow of vapour from the ice interface to the condenser. This resistance to vapour flow is not the only impediment to the free flow of water vapours to the condenser surface, there are also resistances associated with the vent in the stopper and the duct between the drying chamber and the condensing chamber.

The main interest, in terms of the suitability of the formulation for freeze-drying, is the maximum temperature the dried solid can tolerate on heating during the primary and secondary drying stages. This is known as the collapse temperature, or simply the critical temperature, and marks the point of onset of viscous flow within the dry layer that results from the product temperature passing through the glass transition of an amorphous component or the melting point of any crystalline component, whereas the target critical quality attributes (CQAs) of the product at the end of the cycle are the reconstitution time, moisture content, and stability of the ‘dried’ solid form. These requirements are added complications for those formulations intended for lyophilization and come on top of the expected norms of the API stability, pH and tonicity of the liquid form (post reconstitution).

The traditional pharmaceutical freeze-drying process has the drug formulation contained in a glass vial, which are freeze-dried in batches of up to 100,000 vials in the larger scale commercial dryers. The batch process is generally developed using a smaller scale dryer but still within the same container that would be used for the final commercial product. Similarly, the majority of the novel continuous freeze-drying approaches also has the drug product solution contained in a glass vial. However, the assessment of the suitability of the drug product formulation (i.e. the solution to be freeze-dried) is generally undertaken using volumes of liquid that are much smaller than the volume of drug product, in containers that are very different to a glass vial, and under “process” conditions that are far from that experienced within a freeze-dryer. 

Applications

Through our application of a range of off-line and in-line techniques (process analytical technologies, or PAT) we aim to arrive at a more reliable assessment of these formulation and process requirements of freeze-dried drug product formulations.

Our off-line techniques for the development and/or characterization of the drug product formulation, include:

  • Z-FDM : Impedance-spectroscopy-enabled freeze-drying microscopy for the determination of the collapse temperature. This novel adaptation of the classical freeze-drying microscope can also be used to determine ice sublimation rates during primary drying.
  • BDS : Broadband dielectric spectroscopy for determining features of the frozen solution, including the dielectric relaxation of the ice fraction, and the glass transition of the solids (non-ice) fraction.
  • DSC : Differential scanning calorimetry for determining the phase behaviour of the solution during freezing and annealing.
  • SEM : Scanning electron microscopy for assessment of the porous structure of the dried cake (end product)
  • TGA : Thermogravimetric analysis for determination of the dried solids moisture content
  • PXRD : Powder x-ray diffraction for the determination of the polymorphic forms of any crystalline component.
  • THz spectroscopy : Like PXRD this spectroscopy can be used for the determination of the polymorphic forms of any crystalline component

Our in-line approaches for the development of the lyo-cycle (i.e., the process) is to “multiplex” a number of individual PAT systems to determine critical aspects of the product as it under-goes the freeze-drying process.

We work with instrumentation companies specialising in

  • Raman spectroscopy, and
  • near-infrared spectroscopy,

and combine these technologies with our novel impedance technology (known as through-vial impedance spectroscopy, TVIS).

Such combinations of technologies are key to an in-situ evaluation of the different facets of the freeze-drying process, under conditions that are more representative of commercial manufacturing. For example, Raman and terahertz spectroscopies are capable of discriminating between different crystalline states (polymorphic forms) within the solids fraction of the frozen and/or dried product; Infrared is capable of detecting and quantifying the moisture content of the solids fraction (which is an important attribute in terms of the stability of the drug substance during shelf life); whereas impedance spectroscopy measures the (i) dielectric relaxation of ice, and (ii) the percolation of charge through the solids fraction, and is therefore sensitive to the properties of both the ice fraction (inc. ice temperature and ice mass) and the solids fraction (inc. the glass transition and devitrification). Applications for through-vial impedance spectroscopy therefore span the freezing stage (to determine the ice nucleation temperature and ice solidification time), through the annealing stage (to assess devitrification and recrystallization phenomenon), and to the primary drying stage, to determine ice temperatures, sublimation rates and sublimation end points.

Together, or individually, these technologies can be used to good effect in the qualification of the more traditional approaches such as the primary drying batch end point, which uses comparative pressure measurements from Pirani and capacitance manometer gauges. In addition, each spectroscopy can be used in a stand-off mode and is therefore adaptable for use in continuous freeze-drying, especially those production methods whereby single vials (i.e. the final product container) are suspended and passed through a series of chambers in order to first freeze, before drying the product under a partial vacuum.

For further information contact:

Prof. Geoff Smith
Pharmaceutical Technologies Group
Leicester School of Pharmacy
De Montfort University
Leicester
LE1 9BH
United Kingdom

T: +44 (0)116 250 6298
E: gsmith02@dmu.ac.uk