How to Monitor Phase Transitions in Pharmaceuticals

Polymorphism in pharmaceutical solids is the ability of a substance to exist in more than one molecular arrangement, resulting in numerous polymorphic forms which differ in their physiochemical properties such as solubility, melting point, stability, etc. It has a big impact on both the performance and processing of solid pharmaceutical products.1

The polymorphic forms could differ in their relative stabilities depending on these arrangements; with the metastable forms eventually changing to the most stable form.1,2. Examining these phase transformations is crucial to understand the properties of these polymorphic forms.

Several methods could be employed for this purpose but Differential Scanning Colorimetry is the most common and efficient technique as it allows following these transformations as a function of temperature or time, in addition to its high sensitivity.3

However, using only the heat flow signal provided by the DSC, sometimes it can be a challenge to create a clear picture of what is happening to the sample as it goes through a phase transition from, and so visualizing these processes would be valuable. Furthermore, subtle transitions such as solid-solid transitions could be missed in the DSC if they occur over a wide temperature range.


Visualization of the sample during a DSC experiment is permitted by the Linkam DSC450 stage. So this system was utilized for examining flufenamic acid, which is one of the most polymorphic pharmaceuticals with a record of nine known polymorphic forms2.

The aim of this study was to observe crystallization from the amorphous phase obtained by melt quenching. Form I was gathered by spray drying and was first heated in the DSC450 up to the melt, then it was left to cool down to room temperature before re-heating at a 10 °C/min heating rate.


Form I melted at ca. 132 °C whilst the re-heated sample melted at a lower temperature (onset of ca. 122 °C) which is shown in Figure 1. No re-crystallization was observed in the second heating cycle, which established that a metastable form recrystallized from the melt upon cooling.

The heating of spray dried FFA a) first heating, b) re-heating both at 10 °C/min).

Figure 1. The heating of spray dried FFA a) first heating, b) re-heating both at 10 °C/min).

In Figure 2, the effect of adding a polymer (PVP) is apparent, where it looked as though the sample did not crystallize upon cooling but instead formed an amorphous phase. The re-crystallization of FFA followed by a solid-solid transition and then a melt was caused by heating the amorphous phase. These events are observed to be two exothermic transitions followed by a sharp endotherm.

In the DSC thermogram the solid-solid transition is subtle but is extremely clear from the signal gathered by using an image analysis method (Thermal Analysis by Surface Characterization, TASC) shown in Figure 2c. The melting peak has an onset temperature of ca. 119 °C, which is less than that of the form crystallized from the melt without the presence of the polymer. The TASC signal also shows that before the DSC signal starts to change, melting is identified visually.

Spray dried FFA with 10% PVP a) first heating, b) re-heating and c) with TASC analysis of the reheating cycle (green line).

Figure 2. Spray dried FFA with 10% PVP a) first heating, b) re-heating and c) with TASC analysis of the reheating cycle (green line).


In this study, polymorphic transitions in the pharmaceutical active flufenamic acid were examined using Linkam DSC450 stage, which combines differential scanning calorimetry with optical microscopy. The power of the complementary method was apparent with the increased sensitivity for detecting subtle transitions such as solid-solid transition by analyzing the optical images.

References and Further Reading

  1. Rodrı́g uez-Spong, B., Price, C. P., Jayasankar, A., Matzger, A. J. and Rodrı́guez-Hornedo, N. r. 2004. General principles of pharmaceutical solid polymorphism: A supramolecular perspective. Advanced Drug Delivery Reviews 56(3): 241-274.
  2. López-Mejías, V., Kampf, J. W. and Matzger, A. J. 2012. Nonamorphism in øufenamic acid and a new record for a polymorphic compound with solved structures. Journal of the American Chemical Society 134(24): 9872-9875.
  3. Gaisford, S. and Saunders, M. 2012. Physical form i – crystalline materials. Essentials of pharmaceutical preformulation, John Wiley & Sons, Ltd: 127-155.


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

For more information on this source, please visit Linkam Scientific.


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