Low-Temperature Thermal Analyses are Key to Formulation Design

Low-Temperature Thermal Analyses are Key to Formulation Design
2004
Michael Thomas and Anthony J.Cannon
Pharmaceutical Technology
Product and process development of a lyophilized preparation is a critical step in bringing a new product to market. Because product presentation and formulation dictate the processing conditions,
the thermal properties of a formulation must be characterized as part of product and process development activities.When designing a formulation, it is helpful to have a general knowledge of the thermal characteristics of each excipient as well as an understanding of the potential synergistic effects of various combinations of excipients and active pharmaceutical ingredients. At minimum, one should
identify the thermal behavior of the final formulation before process development. The intent of lowtemperature thermal analysis is to identify the critical values for freezing and primary drying as well as
the characteristics that contribute to the behavior of a product during processing. Methodologies and the instrumentation for identifying the critical temperatures of a formulation to
be lyophilized have technologically progressed from simple devices constructed by the user to sophisticated
instrumentation now commercially available. This article evaluates the instrumentation and
methods now commonly used to determine these critical values and to characterize the thermal behavior
of the product. Examples of the innovations and applications of the various methods are provided.
Several methods can be used to determine the thermal behavior of excipients and the final formulation.
The most frequently used techniques are electrical resistance (ER), low-temperature differential
scanning calorimetry (LT-DSC), and freeze-drying microscopy (FDM). Electrical resistance?which is
perhaps the oldest technique? measures a phase change from solid to liquid that corresponds to a
change in the relative conductivity of an electrical current through a sample. Low-temperature differential
scanning calorimetry measures endothermic and exothermic events that correlate to crystallization and
melting as well a glass transition temperature (Tg). Freeze-drying microscopy allows direct visual observation throughout the freezing and drying steps of the freeze-drying process and correlates observations of a collapse (Tc) or eutectic melt (Tm) to a measured temperature. Each of these measurements reflect various characteristics of the formulation. In addition, they all provide some of the critical information necessary to
successfully lyophilize a product.
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