Keywords: Pharmaceutical, Compatibility, Interaction, Apparent Melting
TA494
Abstract
Differential scanning calorimetry (DSC) can be used to study interactions between materials used as pharmaceutical APIs and excipients. Modulated DSC™ Techniques can be used to investigate these interactions through heat capacity changes. The approach may also be applied to other fields, such as in the use of energetic materials. This paper first investigates acetylsalicylic acid, magnesium stearate, and sucrose using these techniques and explores the impact of material morphology.
The effect of the morphology changes was studied using DSC and thermogravimetric analysis (TGA).
The use of differential scanning calorimetry is well established for investigating material interactions. This includes energetic materials [1] and pharmaceutical materials [2,3]. The simple approach is that if two materials are used, the result will be the sum of the signals for the individual materials. If there’s an interaction between the materials, there will be a different result.
This technique has been extended to use Quasi-Isothermal Modulated DSC (QI MDSC™) to study the change in sample heat capacity as a function of time. If there is no interaction, then the heat capacity at a fixed temperature will remain constant. Interaction will result in a change in molecular mobility and therefore a change in the heat capacity.
Previous studies [2,3] demonstrated that a mix of acetylsalicylic acid and crystalline sucrose did not undergo any interaction. This was compared to a mix of acetylsalicylic acid and magnesium stearate, which showed a clear interaction. However, it was noted that a change in the material morphology [1] may have an impact on the stability. This paper will further explore the effects of morphology on stability of sucrose.
1. Material interaction testing
A TA Instruments™ Discovery™ DSC 25 was used to measure samples of acetylsalicylic acid, magnesium stearate, and sucrose on their own and with 50:50 mixes of magnesium stearate and sucrose with the acetylsalicylic acid.
Dry mixing of the acetylsalicylic acid with the magnesium stearate and sucrose was achieved by loading 40 mg of each into a small vial and stirring with a spatula. The sample for DSC characterization was taken from this.
Samples of mass 5 mg were prepared in TZero™ Hermetic Pans and heated from 25 °C to 170 °C at 1 °C/min. Given the difference in particle size between the sucrose and the acetylsalicylic acid, the particle size of the sucrose was reduced prior to mixing by gently grinding the sucrose using a small sample agate pestle and mortar.
A second set of tests looked at the change in heat capacity of the mixed materials using QI MDSC Technique using an underlying isothermal temperature of 60 °C with a temperature modulation amplitude of ±2 °C and a modulation period of 120 seconds. The samples were held under these conditions for four hours. In these tests the aspirin/magnesium stearate mix and the aspirin/sucrose (as supplied) mix were used.
Figure 1 shows the DSC thermograms for acetylsalicylic acid, magnesium stearate, and the 50:50 combination of the two. This shows clearly that there is an interaction between the two materials with the thermogram showing a very different response. From previous data this result is expected [2].
Figure 2 shows the DSC thermograms for acetylsalicylic acid, sucrose, and the 50:50 combination of the two. It was unexpected that this appears to also show an interaction in the mixed materials. However, in this case, the particle size of the sucrose had been reduced to maximize the interaction potential. It is possible that the particle size reduction affected the sample morphology, possibly generating amorphous material and impacting the response.
To check this effect, a second mix of acetylsalicylic acid and sucrose was generated without reducing the sucrose particle size. Figure 3 shows the DSC thermograms for the acetylsalicylic acid and the two acetylsalicylic acid and sucrose mixes. Here it can be seen that with the acetylsalicylic acid and sucrose as supplied shows no interaction with the temperature at which the loss of crystalline structure of the acetylsalicylic acid unaffected.
In previous studies [2,3], the usefulness of the QI MDSC Technique was demonstrated. Changes in the reversing heat capacity as a function of time would be indicative of an interaction in the materials. Figure 4 shows the heat flow and reversing heat capacity signals for the 50:50 acetylsalicylic acid: magnesium stearate mix. There is a small heat flow effect, but it is only in the order of 8 μW/g; however, there is a significant change in the heat capacity. Figure 5 shows the same detail for the 50:50 acetylsalicylic acid: sucrose mix. In this case, the mix contained the sucrose as supplied, which showed no interaction in the ramp DSC data. The heat flow shows a variation of 0.8 μW/g and the heat capacity change is negligible (0.008 J/g°C).
As a visual comparison, Figure 6 shows the overlay of the heat capacity signals for the two mixes. This clearly shows the difference between the two blends.
2. Studies of Sucrose in As Supplied and Milled Forms
The material interaction testing showed a change in the interaction between the acetylsalicylic acid and the sucrose when the particle size was reduced. Following this work, a brief investigation into the changes within the sucrose was carried out. Samples of sucrose as supplied and with the reduced particle size were analyzed by DSC (DSC25) and thermogravimetric analysis TGA (Discovery TGA550). Initial testing used 5 mg of sample in Tzero Hermetic Pans and were heated from -20 °C to 230 °C at 10 °C/min. Figure 7 shows the DSC thermograms for the sucrose as supplied and the sucrose with reduced particle size. There is a clear difference in the temperature at which the loss of crystalline structure occurs. Focusing on the baseline between 100 and 120 °C, the particle size reduced sample shows a small exotherm, suggesting a recrystallisation of amorphous material generated in the grinding process.
Based on the observations in the initial testing it was clear that the reduction of the particle size was impacting the stability of the sucrose.
It is generally accepted that the endothermic transition in sucrose in the loss is crystalline structure, which is a decomposition and not a true melting process [4,5]. Given the onset temperature in the reduced particle size sample endotherm at just over 150 °C, a series of experiments were carried out incorporating isothermal holds at 130 °C to see if any decomposition could be observed.
Initial experiments used isothermal TGA for 24 hours to look at the weight loss. Whilst this does not definitely define decomposition, it does indicate the level of volatile loss. The TGA overlay of the as supplied and particle size reduced sucrose held isothermal at 130 °C is shown in Figure 8. It should be noted that the overall weight loss is less than 0.6% but there is a difference in the rate of volatile release. The crossover at about 1300 minutes was noted but it is unclear if this is a real effect or experimental variation.
Following the TGA experiments, a mixed aging/ramp DSC testing protocol was carried out, based on a previously used protocol [5]. In the experiment the sucrose samples were heated to 130 °C and held for three hours. The sample was then cooled and reheated back to the isothermal test temperature. This was repeated in sequential steps so that the total isothermal aging time was 24 hours. The isothermal aging was carried out under Modulated DSC conditions so that the change in heat capacity could be observed; the heating segments to investigate change in morphology were carried out at 10 °C/min.
Figure 9 shows the first ramp, before any isothermal aging had taken place. Here, the recrystallisation in the particle size reduced sucrose can again be seen. There were no other clear transitions observed. Figure 10 shows the reversing heat capacity signals of the two sucrose samples during the isothermal holds at 130 °C. It is clear in both samples that there is an increase in the heat capacity as a function of time. This suggests a structural change in both samples, but this change also occurs earlier in the particle size reduced material, suggesting a reduction in stability.
Figures 11 and 12 show the initial ramp data and the ramp data after each of the three-hour isothermal holds. In both samples, except for the recrystallization during the first heat of the particle sized reduced sucrose, the initial heat and the heat after three hours aging do not show any significant structural change.
However, after six hours and longer, the presence of a glass transition can be observed, indicating the development of amorphous material. There is a general trend that the glass transition decreases in temperature and increases in step height, indicating a decomposition of the material and an increase of the degree of amorphous material. Figure 13 shows the change in the midpoint temperature (half height) and Figure 14 shows the delta Cp value (reflection of the degree of amorphous material) for the as supplied and particle size reduced sucrose samples. In both figures, the data starts after the six hours of aging as this is where the glass transition was first noted.
This application note revisited some historical data looking at DSC and MDSC Techniques to investigate material interactions and noted a potential influence of material morphology. This was then extended to investigate the effect of morphology on the stability of the single material (sucrose).
References
- STANAG 4741:0 Chemical Compatibility of Ammunition Components with Explosives and Propellants (Non-Nuclear Application).
- Aubuchon, S. R. and Thomas, L. C. A New Approach to Measurement of Drug-excipient Incompatibility. TA Applications Notes TA 348
- Len Thomas and Hang Kuen Lau, Drug – Excipient Incompatibility with Discovery X3. TA Applications Notes TA442
- Lee, J.W. et al.; Investigation of the heating rate dependency associated with the loss of crystalline structure in sucrose, glucose, and fructose using a thermal analysis approach (Part I). J. Agric. Food. Chem. 2010. DOI: 10.1021/jf1042344
- DSC Characterization of Crystalline Structure in Foods and Pharmaceuticals: Apparent Melting (Part 2 of 3) – TA Instruments
Acknowledgement
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This paper was written by Philip Davies, Principal Applications Scientist, TA Instruments.
Modulated DSC, MDSC, TA Instruments, Discovery, and TZero are trademarks of Waters Technologies Corporation.
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