Glossary of Freeze Drying Terminology

A

Ablation
Entrapment and blow-out of product with the vapour flow is termed ablation. This is most common in formulations which have not produced a cohesive cake but remain loose and friable.

Absorption
A process in which one substance permeates another.

Adsorption
Adhesion of the molecules of gases, liquids, or dissolved substances to a solid surface, for example to the freeze dryer or container.

Amorphous
A solid which is not crystalline. An amorphous solid may also be called a glass.

Ampoule
A small glass vessel in which liquids, mainly for injections, are hermetically sealed. Freeze drying can be performed in ampoules, usually attached to a manifold as the ampoules have a round bottom and therefore will not stand up on a shelf.

Annealing
A process involving controlled heating and cooling of a solution to encourage crystallisation.

Aqueous
Containing water; a solution in which the solvent is water.

Aseptic
Free from any living organisms.

B

Back-Filling
After freeze drying the chamber can be filled with an inert gas, i.e. nitrogen, prior to stoppering. This prevents the product oxidising while in storage and also reduces the potential loss of product on opening the vial to atmosphere.

Bulking Agent
A substance that is added to a formulation to increase solute density.

C

Cake
Freeze dried product in a vial is sometimes called a cake or plug.

Collapse
The failure of a frozen product to maintain its structure, due to an unsuitable product temperature during sublimation.Collapse temperatures are often gradual in onset and can be difficult to measure.

Condenser
The part of the freeze dryer that traps the moisture that has been expelled from the product and holds it as ice. It also provides the driving force for the sublimation of the solvent.

Critical Temperature(s)
The temperatures that reflect the points at which key changes occur in a solution, for example freezing point and collapse/eutectic temperature.

Crust
See Skin.

Cryoprotectant
A substance that is added to a formulation in order to protect the active ingredients during the freezing stages.

Crystalline
A structure that is crystalline has a uniform molecular structure.

Cycle
A freeze drying cycle describes operationally the entire freeze drying process. The control of parameters such as shelf temperature, condenser temperature, and chamber pressure (vacuum) is described in a stepwise manner. The aim is to precisely record the process of producing a satisfactorily dried product so that it can be repeated. Freeze drying cycles are programmed direct into a freeze dryer (or freeze dryer control system) and recorded electronically there for recall whenever required.

D

Dehydration
The removal of water from a solution.

Denature
To alter the structure of a molecule so that its biological activity is disrupted or entirely lost.

Drying
The removal of solvent from a solution.
Primary Drying: The first drying stage of the freeze drying process, involving sublimation of mobile (not adsorbed) ice molecules.
Secondary Drying: The second drying stage of the freeze drying process, which aims to remove (or desorb) the water molecules that were adsorbed.

Drying Front
The freeze drying front describes the moving interface within a frozen product where the drying (sublimation) is occurring. Drying starts from the outer edge of the ice and progresses inwards, with the product in the bottom and centre of the container drying last. The freeze drying front can be viewed in real time using the Lyostat2 freeze-drying microscope.

E

Endothermic
A chemical change that is accompanied by an absorption of heat.

Eutectic Point
The temperature at which a crystallise solid melts. Very few solids are purely crystalline, therefore it is more relevant to talk about glass transition and collapse temperatures for the majority of formulations.

Evaporation
The transformation of a liquid into a gas.

Excipient
A substance that is added to a formulation to provide benefits to the processing of the active ingredient, i.e. increase critical temperatures or provide protection. Any component of a finished dosage form other than the active ingredients.

Exothermic
A chemical change that is accompanied by a liberation of heat.

F

Free Water
Water in a solution that is not chemically or physically bound.

Freeze Drying
The process of drying a material by first freezing it and then encouraging the ice within it to sublimate. Also known as lyophilisation.

Freezing
The solidification of a liquid, usually with the removal of heat. A product must be thoroughly frozen for freeze drying to take place effectively. The freezing point is the temperature at which a solution crystallises.

G

Glass
A solid which has a non-crystalline (amorphous) structure. The temperature at which the glass first exhibits a change in viscosity is termed the glass transition temperature.

GMP
Good Manufacturing Practice. The FDA's guidelines on production for various industries, including Biotech and Pharmaceutical. cGMP stands for Current Good Manufacturing Practice.

I

Impedance
A function of capacitance, resistance and inductance that allows detection of changes in the molecular mobility of a product in its frozen state.

L

Lyophilisation
An alternative name for freeze drying.

Lyoprotectant
A substance that is added to a formulation in order to protect the active ingredients. Note that lyoprotectants protect during the drying stages whereas cryoprotectants protect during the freezing stages.

M

Matrix
The system of crystals in a frozen product is called the ice matrix or frozen matrix. The structure created and retained by the product after freeze-drying is called hte freeze-dried matrix.

Meltback
A less common name for collapse and eutectic melting.

Melting
The change from a solid to a liquid. The Melting Point is the temperature at which this occurs. Note that the melting point and the freezing point are not necessarily the same (freezing is a random process).

N

Non-Aqueous
A solution that does not contain water.

Nucleation
The process by which (ice) crystals form. When a product first starts to freeze, crystals initially form on particles in the formulation or cluster around existing crystals, and the ice matrix expands outwards from these nuclei.

P

Phase Diagram
A graph which shows how the phase (solid, liquid, gas) of a substance is related to temperature and pressure.

Process Development
Researching the relevant properties of a product and the processes by which it is obtained, and attempting to refine and streamline production to increase efficiency and improve effectiveness.

Product
A generic term referring to whatever is to be freeze dried. In pharmaceuticals or biotechnology, "product" can refer to either the complete formulation or just the active ingredient.

R

Reconstitution
Adding a solvent to a freeze-dried product to return it to its original wet or liquid condition.

Recrystallisation
The growth of large crystals at the expense of smaller crystals.

Resistivity
The ability of a material to resist the flow of an electric current through itself. Changes in the structure of a substance as its temperature is raised or lowered will affect its resistivity. In freeze drying analysis generally resistance is measured in ohms and resistivity is derived by calculation.

S

Shelf Life
The length of time a product can be stored before it degrades beyond usefulness.

Skin
A layer found on the surface of some freeze dried products caused by a concentration of solute. This can be a result of a high concentration of solute excluded by the ice matrix during freezing. Often relatively impermeable, the formation of a skin impedes the drying of the product below it. Also known as a crust.

Sorption
The taking up of and retention of one substance by another, either absorption or adsorption.

Stopper
Stoppers are ventilated rubber lids for vials. A stopper is partially seated into the vial neck to allow water vapour to escape during drying, and fully inserted at the end of the process to fully seal the vial. "Stoppering" is usually a function carried out by the freeze dryer while a vacuum or partial vacuum is still present, to help preserve the product.

Supercooling
The process of cooling a liquid below its freezing point, without it becoming a solid. Without a nucleation point for a frozen structure to form around, the liquid phase can be maintained at a much lower temperature.

T

Thermal Treatment
Another name for annealing.

Triple Point
A theoretical point at which, due to a precise balance of temperature and pressure, a substance can exist in all three phases (solid, liquid and gas) in thermodynamic equilibrium.

V

Vial
Small, flat-bottomed glass bottle with a short neck. They are usually fitted with a stopper. Vials are perhaps the most convenient and certainly the most common container used for parenteral products. Vials are available in a wide range of sizes and dimensions.

W

WFI
Water For Injection. Water that has been purified to a high degree, for use particularly in drugs that are to be injected.

 
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