Theophylline monohydrate and the anhydrous form
Measuring cells: DSC820 or TGA850
Pan: DSC - aluminum 40 µl, hermetically sealed; TGA - aluminum 100 µl, with pierced lid
Sample preparation: As received, or storage of the monohydrate at a rel. humidity of 53% and 92%
DSC measurement: Heating from 20 °C to 300 °C at 20 K/min
TGA measurement: Heating from 30 °C to 300 °C at 20 K/min, blank curve corrected
Atmosphere: Nitrogen, DSC: 50 cm3/min, TGA: 80 cm3/min
It can be shown from the TGA curves (diagram 46a) that the percentage content of water of crystallization is dependent on the storage conditions. The monohydrate remains stable when stored at a relative humidity greater than 92% and shows a loss of about 9% water, as expected from a stoichiometric calculation. Storage at lower humidity results in the partial loss of water of crystallization. For comparison, the curve of the anhydrous form is shown. As expected, this shows no weight loss.
The loss of moisture is determined from the TGA steps.
Sample | Step, % | Evaluation range, °C | Inflection pt, °C |
---|---|---|---|
Anhydrous form | < 0.1 | 30 - 150 | - |
Monohydrate | 8.7 | 30 - 150 | - |
1 Day 92% r.h. | 8.7 | 32 - 130 | 82.6 |
5 Months 92% r.h. | 8.9 | 34 - 124 | 99.6 |
5 Months 53% r.h. | 7.2 | 33 - 123 | 95.7 |
In the DSC curves (diagram 46b), it can be seen that storage at higher relative humidity results in a significant increase in the enthalpy of the first peak (loss of water of crystallization). The second peak followed by a baseline shift is caused by the pan bursting as a result of the pressure of the water vapor. In the evaluation, the ΔH values for these peaks are therefore put in brackets. The anhydrous form is produced through the evaporation of the water. This melts at about 272 °C. The pan containing the anhydrous form of theophylline also bursts but at higher temperature (about 290 °C).
The onset temperatures and integrals of all the peaks are evaluated.
Sample | Peak 1 | Peak 2 | Peak 3 | ||
---|---|---|---|---|---|
Onset, °C | ΔH, J/g | ΔH, J/g | Onset, °C | ΔH, J/g | |
Anhydrous form | 63.1 | 2.1 | - | 272.7 | 169.4 |
5 Months 53% r.h. | 73.1 | 40.3 | (121.6) | 270.9 | 138.5 |
5 Months 92% r.h. | 78.7 | 59.3 | (168.8) | 271.3 | 141.0 |
The stability of a form containing water of crystallization can be determined by DSC/ TGA. Information concerning the stability of such hydrated forms is of great importance for the manufacture of pharmaceutical products, because the content of a pharmaceutical preparation can be affected to significant degree. This can have serious consequences especially with highly active drugs that show high activity even in small doses.
Quantification,Theophylline Monohydrate | Thermal Analysis Application No. HB840 | Application published in METTLER TOLEDO TA Application Handbook Pharmaceuticals