How to measure the thermal stability of pharmaceuticals?

How to measure the thermal stability of pharmaceuticals?

Thermal stability is a concept that is easy to conceive. But how to measure and quantify it? A fast and safe method for this is to use a thermobalance.

A material is thermally stable if it doesn’t decompose under the influence of temperature. Although the concept of thermal stability is easy to conceive, its determination is not trivial. One possibility for this is to use a TGA (thermogravimetric analyzer).

The standard ASTM E2550 describes the thermal stability of a material as the “temperature at which the material starts to decompose or react and the extent of mass change using thermogravimetry“. It adds that “the absence of reaction or decomposition is used as an indication of the thermal stability”.

Figure 1 displays the TGA curve of acetylsalicylic acid during heating to 600°C in a nitrogen atmosphere. Two mass-loss steps are detected (closed line). The calculation of the first derivative (DTG, dashed line) indicates the rate of mass Change.

Each of these steps is determined by:

  • Temperature at which the mass loss occurs
  • Mass change occurring during the step

For more information about the decomposition mechanism of acetylsalicylic acid, please click here.

One mass-loss step, 3 characteristic temperatures:

Theoretically, three temperatures can be displayed for a mass-loss step:

  • Peak temperature of the DTG (1st derivative of the TGA curve)
  • Extrapolated onset temperature according to the standard ISO 11358-1. This is “the point of intersection of the starting-mass baseline and the tangent to the TGA curve at the point of maximum gradient”
  • Onset temperature according to ASTM E2550. This is the “point in the TGA curve where a deflection is first observed from the established baseline prior to the thermal event”

In the presented example, the first mass-loss step occurs at 161°C (peak of the DTG curve, figure 1), at 143°C (extrapolated onset temperature of the TGA curve, figure 1) or 102°C (onset temperature according to ASTM E2550, figure 2). This third value is used for evaluation of the thermal stability.

 

Figure 1. TGA measurement on acetylsalicylic acid, sample mass: 5.18 mg, crucible: Aluminum oxide (open), heating to 600°C at 10 K/min in a dynamic nitrogen atmosphere
Figure 2. TGA measurement on acetylsalicylic acid, zoom from figure 1

 

Please note that the method is limited to materials that react or decompose in the investigated temperature range, and cannot be used for sublimation or vaporization.

Notes regarding the measurement conditions:

As the results are affected by the sample mass, the atmosphere (gas and flow rate), the heating rate and the crucible type, it is crucial to mention the measurement conditions. For the same reason, the results for two samples can only be compared if the measurements are carried out under exactly the same conditions.

The following measurement conditions are recommended:

  1. Sample mass: between 1 and 10 mg, for example, 5 mg
  2. Heating rate: 10 to 20 K/min (lower for energetic reactions)
  3. Flow rate of the atmosphere: 20 to 100 ml/min

In the presented example, the thermal stability at 102°C for acetylsalicylic acid is given for a measurement in a dynamic nitrogen atmosphere (gas flow: 40 ml/min) carried out on a 5 mg-sample at a heating rate of 10 K/min.

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