Freeze drying has become an increasingly important unit operation in the manufacture of injectable pharmaceutical product over the past generation or so, along with the increase in approvals of biotechnology-derived new therapeutic agents. Freeze drying lends itself to a first-principles approach to developing deep expertise in the subject matter. This includes the importance of states of matter – crystalline vs. amorphous - and how this can affect solid state stability of freeze-dried drug products. Sublimation of ice is discussed with reference to the phase diagram of water. Phase diagrams of solutions of water and a single solute are discussed, particularly in the context of eutectic mixture formation and the influence of the eutectic mixture on freeze drying behavior. For solutes that do not crystallize from a freezing aqueous solution, the state diagram can be used to facilitate understanding of viscoelastic properties of materials – particularly the role of the glass transition of the maximally freeze-concentrated solute, or Tg’, in freeze drying. Non-equilibrium behavior – not captured in a phase diagrame – is also important in understanding the science of freeze-drying, particularly in the concept of supercooling and why this is important in the freezing phase of freeze drying. Annealing in freeze drying is based on the concept of Ostwald ripening. This applies to both ice crystals and crystals of a component of the formulation.
Characterization of frozen systems is discussed, with emphasis on low temperature thermal analysis and freeze dry microscopy. Rate processes in freeze drying include both heat transfer and mass transfer. These are discussed with reference to the unifying principle that a flow term is equal to a driving force term and a conductance (or resistance) term. Understanding the controlling resistance is important in optimizing freeze drying; that is, carrying out freeze drying as rapidly as possible without destroying any critical quality attribute.
Learning Objectives:
Know what sublimation is by referring to the phase diagram of water
Be able to explain what a eutectic mixture is, and why this is important in freeze drying.
Explain why the state of a solid – crystalline or amorphous – can be important in the context of solid state stability of a freeze-dried product.