Lyophilization Optimization Using DSC and MT-DSC - Lyophilization Articles & Reports

Lyophilization Optimization Using DSC and MT-DSC
January/February 2004
A. Rameau, A. Chevalier, and C. Neves
Applied Physics, Pharmaceutical Sciences, Paris Research Center
Aventis Pharma
APR
Introduction
Since the early 1940s, freeze-drying (lyophilization) has become a standard method for the stabilization of valuable but labile products. The fact that it is a time consuming process, with high cost in capital and energy, leads to establish a pragmatical approach for the optimization of lyophilization cycles instead of following a simple trial and error method [1,2].
An adequate freeze-drying process can't be defined without the knowledge of the chemical and physical properties of the formulation. For this purpose, Differential Scanning Calorimetry [3] and the more recent technique of DSC with Modulation of Temperature give subsequent information to evaluate crystalline versus amorphous systems.
This paper reviews some basics on state diagrams and illustrates different cases of solutions and lyophilized products characterization.
Binary State Diagrams
To obtain a freeze-dried product of good quality (i.e. a dry product which occupies the same volume than the solution, with an homogeneous porous aspect and excellent rehydration properties), the main point is to avoid collapse during the lyophilization process.
The best way to do so is to maintain the solute few degrees below the lowest transition temperature that can take place within the solution all the way through the freezing and dehydration processes.
Excipients can be classified into two main categories: solutes that crystallize and solutes that do not crystallize upon cooling [1,2].
Materials that form eutectic solutions with water enter the first category. Figure 1 gives the scheme of the eutectic behavior. The diagram represents the freezing temperature of a solution as a function of the initial concentration of the solute. When cooling a solution with a concentration below or equal to the eutectic concentration CE, phase segregation occurs: ice crystallizes first. As the temperature decreases, ice formation in solution results in freeze-concentration of solute till the eutectic composition is reached. At that particular point, the interstitial solution crystallizes. Below the eutectic temperature, all the matter is in the solid state and crystalline. After dehydration, eutectic systems remain crystalline.
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