Using Thermal Analysis to Reduce Testing Time of Shelf Life in Pharmaceutical Drugs

The amount of time a product can be stored and still be considered as safe and effective for use is called the shelf life. The shelf life of pharmaceuticals is affected, amongst others, by:

  • Gas atmosphere
  • Humidity
  • Temperature conditions
  • Light

How Can You Establish the Shelf Life of Drugs Without Long Testing Times?

By utilizing thermogravimetric measurements with kinetics evaluation, the preliminary predictions concerning the shelf-life thermal stability can be gathered. This will take hours or in some instances, days.

Requirements for a Five Year Forecast Within Hours

  • Kinetics Neo, a software that establishes the kinetics of the decomposition reaction
  • A thermobalance, which is a device that stores the mass variations of the sample during its heating

Procedure

  1. Take TGA measurements at different heating rates
  2. Perform the kinetics evaluation using Kinetics Neo
  3. Use the kinetics model to forecast the sample behavior for certain times and temperatures
  4. Validate the kinetic model by comparing the curve calculated by Kinetics Neo with a measurement at an isothermal temperature

Below the procedure is described in detail based on potassium clavulanate. This pharmaceutical substance is typically utilized with the antibiotic amoxicillin to enhance its effectiveness.

1. TG Measurements at Different Heating Rates

The TGA and DTG (first derivative) curves of the measurement on potassium clavulanate at 10 K/min and in a dynamic nitrogen atmosphere are shown in Figure 1. The first mass-loss step, identified between room temperature and 120 °C, is because of the evaporation of surface water. In addition, the three mass-loss steps identified between 120 °C and 600 °C are because of the decomposition of potassium clavulanate.

TGA measurement on potassium clavulanate in pierced crucibles at 10 K/min in a dynamic nitrogen atmosphere, solid lines: TGA, dashed lines: DTG.

Figure 1. TGA measurement on potassium clavulanate in pierced crucibles at 10 K/min in a dynamic nitrogen atmosphere, solid lines: TGA, dashed lines: DTG.

The TGA and DTG (first derivative) curves of the measurements on potassium clavulanate at heating rates of 1, 3, 5 and 10 K/min are shown in Figure 2. The mass-loss steps are shifted to higher temperatures with increasing heating rates (kinetic influence). As an example of this, during a heating rate of 1 K/min, the first decomposition step happens at 167 °C (DTG peak), whilst during a heating rate of 10 K/min, it happens at 184 °C (DTG peak).

TGA measurement on potassium clavulanate in pierced crucibles at different heating rates in a dynamic nitrogen atmosphere, solid lines: TGA, dashed lines: DTG.

Figure 2. TGA measurement on potassium clavulanate in pierced crucibles at different heating rates in a dynamic nitrogen atmosphere, solid lines: TGA, dashed lines: DTG.

2. TG Measurements and Kinetics Neo

With the aid of NETZSCH Kinetics Neo software, the dependence of the decomposition on the heating rate permits evaluation of the decomposition kinetics. Kinetics Neo suggests a kinetic model with five consecutive steps of nth order. It measures the kinetics parameters of each step (activation energy, pre-exponential factor etc.) For the calculation, the water release is not taken into account.

The calculated curves (solid lines) with the measured TGA curves (dotted lines) of the chosen 5-step model are compared in Figure 3. The correlation between calculated and measured curves is excellent.

Kinetic evaluation of the decomposition of potassium clavulanate. Dotted lines: measured curves; solid lines: calculated curves based on a five-step reaction of nth order. The correlation coefficient between measured and calculated curves amounts to />0.999.

Figure 3. Kinetic evaluation of the decomposition of potassium clavulanate. Dotted lines: measured curves; solid lines: calculated curves based on a five-step reaction of nth order. The correlation coefficient between measured and calculated curves amounts to >0.999.

3. Kinetics Neo Predicts the Sample Behavior During Storage at Specified Temperatures

The calculation is utilized by Kinetics Neo to predict how the sample would behave at different temperatures in long-time storage. The five year forecast of the decomposition process of potassium clavulanate is shown in Figure 4. This plot took days to produce, taking into account the measurements and evaluation with Kinetics Neo.

Five-year forecast of the decomposition process of potassium clavulanate in a nitrogen atmosphere between 20 °C and 80 °C

Figure 4. Five-year forecast of the decomposition process of potassium clavulanate in a nitrogen atmosphere between 20 °C and 80 °C.

4. The Validation of the Kinetics Model Ensures the Accuracy of the Calculation

For the prediction of the decomposition behavior under isothermal conditions, the kinetic model calculated by Kinetics Neo should be checked. To do this, a potassium clavulanate sample of 9.23 mg was heated to 200 °C and then for two hours it was kept isothermal.

The mass losses established via prediction (Kinetics Neo) to those established via measurement are compared in Figure 5. The comparison exhibits good agreement between the two curves and hence, the reliability of the calculation.

Comparison of the measured and predicted mass change of potassium clavulanate during heating to 200 °C and isothermal segment; the release of surface water is not monitored.

Figure 5. Comparison of the measured and predicted mass change of potassium clavulanate during heating to 200 °C and isothermal segment; the release of surface water is not monitored.

This information has been sourced, reviewed and adapted from materials provided by NETZSCH.

For more information on this source, please visit NETZSCH.

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