Thermal Analysis of Zoledronic Acid Hydrate

Introduction

Zoledronic acid (or zoledronate) is a drug substance (API) that is used in different pharmaceutical products such as Zometa^® or Aclasta^® to treat osteoporosis (bone diseases) and bone metastases. Zoledronic acid is a white powder and exists as the anhydride, and mono-, sesqui- and trihydrates. In the Internet, values for the melting point of the anhydride range from 193 °C to 204 °C (www.lookchem.com/Zoledronic-Acid/). The decomposition temperature is given as 239 °C (www.pipharm.com/products/ msds/msds-28079.pdf).

This article describes how the thermal behavior of zoledronic acid hydrate was investigated using DSC-Microscopy and TGA-MS.

Experimental Details

The DSC-Microscopy measurements were performed using a DSC 1 equipped with an FRS5 sensor and the microscopy accessory (see UserCom 26 and 30). The TGA measurements were performed using a TGA/DSC 1 with a DTA sensor coupled to a mass spectrometer (Pfeiffer Thermostar). The heating rate was 10 K/min.

Results

Figure 1 shows the DSC curve of zoledronic acid hydrate. From about 100 °C onward, a broad endothermic peak occurs on which a relatively sharp endothermic peak is superimposed at 154 °C. Another endothermic peak is visible at 211 °C. This changes more or less directly into an exothermic peak. The interpretation of the DSC curve is not so easy. Measurement of the sample mass before and after the DSC measurement showed that the sample loses about 10% of its initial mass during the heating run. The consistency and color change of the sample indicated that it melted during heating and underwent partial composition. The temperatures at which these processes occur cannot be determined from the DSC curve alone.

Additional information is clearly needed to reliably interpret the DSC curve. Melting and decomposition processes can be easily observed by DSC-Microscopy.

Figure 2 shows images of a sample of zoledronic acid hydrate captured at different temperatures on heating. The images indicate no sign of melting up to 211 °C. Closer examination of the images recorded between 190 °C and 211 °C however shows that certain crystallites have shifted slightly (as example: yellow circles). Additional reflections on the surface of the crystals are also observed (see red circles).

Furthermore, the color of the sample at 211 °C has changed slightly. The first indication of melting is observed at about 214 °C and is accompanied by a change in color of the sample. The images also show that the sample is apparently not homogeneous: certain crystals retain their white color appreciably longer and have not (completely) melted at 220 °C.

From about 217 °C onward, the formation of gas bubbles increases with increasing temperature.

These results allow us to draw the following conclusions:

1. None of the overlapping peaks between 100 °C and 160 °C can be explained by assuming a melting process.

2. The sample begins to decompose above 196 °C in at least two steps. An actual melt is not observed until about 214 °C. Apparently, the decomposition products of zoledronic acid are liquid at this temperature.

To obtain additional information, the thermal behavior of zoledronic acid hydrate was investigated using a TGA/ DSC 1 coupled to a Thermostar mass spectrometer.

Conclusions

The interpretation of the DSC curve of zoledronic acid hydrate is not immediately clear. DSC-Microscopy and TGA-MS measurements provide additional information on the thermal behavior of the substance.

For example, DSC-Microscopy showed that the anhydride of zoledronic acid decomposes from about 211 °C onward and that the decomposition products are liquid.

The TGA-MS measurements proved quite clearly that the original product was zoledronic acid monohydrate. The measurements furthermore indicated that the decomposition of the anhydride occurs in several steps in which first water and then immediately afterward CO₂ are eliminated.

^{Thermal Analysis of Zoledronic Acid Hydrate | Thermal Analysis Application No. UC 333 | Application published in METTLER TOLEDO Thermal Analysis UserCom 33}