Drug excipient compatibility: Try it with thermal analysis

Drug excipient compatibility studies ensure that the efficacy of the active ingredient is not affected by the excipients. Interaction between a drug and the excipients can alter the stability of the drug and affect its safety and/or its efficacy. You get first information about compatibility by means of DSC and TG measurements.

How To Measure Drug Excipient Interaction?

1. Prepare 10 mg of each sample (drug/excipient) in Concavus crucibles;
2. Prepare a mixture drug + excipient (e.g., with a mass ratio of 1:1);
3. Measure your drug, your excipient and the mixture of both with your DSC;
4. Compare the DSC curves.

If the thermal effects of the mixture correspond to the effects of the single samples, then both substances do not interact. This indicated good drug excipient compatibility. Let us apply this method on a mixture of diclofenac sodium and magnesium stearate.

Measurement Conditions

• Instrument: DSC 204 F1 Phoenix
• Active ingredient: Diclofenac sodium
• Excipient: Magnesium stearate
• Mixture: Diclofenac sodium + magnesium stearate, weight ratio 1:1
• Temperature program: Heating to 300°C at 10 K/min under a nitrogen atmosphere

What Do the DSC Curves Look Like?

Figure 1 displays the resulting curves.

• Diclofenac: The sample melts at 281°C (onset temperature of the endothermal peak). It decomposes immediately after melting (exothermal effect).
• Magnesium stearate: Evaporation of water and melting are overlapped between 30°C and 130°C. At higher temperatures, no thermal effect occurs any more.
• Mixture: The effects between 30 and 130°C are due to the release of water and melting of magnesium stearate. However, neither the typical melting peak of diclofenac nor the exothermic decomposition are detected. Instead, an endothermic peak was found between 230°C and 300°C.

The thermal effects of magnesium stearate are depicted in the mixture, whereas melting and decomposition of diclofenac are no longer found. This means that both components of the 1:1 mixture interact.

What Happens in the Mixture at 264°C?

The same samples (and the mixture) are measured with a thermobalance (TG 209 F1 Libra) to 600°C (10 K/min) under nitrogen. Figure 2 shows the resulting curves.

• Diclofenac: The mass loss occurring at 303°C indicates the thermal decomposition.
• Magnesium stearate: Water is released between 80°C and 180°C. The decomposition begins at 351°C.
• Mixture: The release of water is detected. Decomposition starts earlier (279°C) than for the single substances.

The interaction of both components lead to an earlier thermal decomposition process. The DSC Peak at 164°C is due to the melting and decomposition of the mixture.

Conclusion

The DSC and TGA measurements on the drug, the excipient, and the 1:1 mixture show that at this mixing ratio, magnesium stearate influences the melting and decomposition temperatures of diclofenac. This is often due to structural changes and indicates interaction and incompatibilities between the compounds. Thus, DSC and TGA yield first Information about the drug excipient compatibility.

References

Application of Thermal Analysis to Study the Compatibility of Sodium Diclofenac with Different Pharmaceutical Excipients, Bogdan Toita, Adriana Fulias, Geza Bandur, Ionut Ledeti, Dumitru Tita, Revista de Chimie, 62, pages 443-454 (2011)

https://www.kunststoffe.de/en/journal/archive/article/systematic-approach-to-the-selection-of-nucleating-agents-6216076.html