Stability of Salicylic Acid and Magnesium Stearate by DSC

The first step in developing effective pharmaceutical formulations is the discovery of the active agent. The next development step is to formulate the active ingredient with other materials so that the powder can be formed into a tablet. These ingredients must be stable when mixed in the solid state. Of course, if the active agent reacts with any of the other ingredients, the potency decreases with time. At best, this reduces the shelf life. At worst, this will preclude FDA approval of the new formulation.

This paper shows how the DSC 822^e with the high-sensitivity HSS7 sensor (Mettler-Toledo, Columbus, OH) can detect the heat of reaction between the active ingredient and the filler. In this case, salicylic acid and magnesium stearate will react together after solid mixing. This simple example demonstrates how the test is performed. This test, however, can be used on any pharmaceutical powder formulation.

The shelf-life testing of formulations can be performed faster by increasing the sample temperature during the test. The decomposition reaction will happen very slowly at room temperature. This reaction rate could be so slow as to not be measurable. This study uses differential scanning calorimetry (DSC) to measure the heat of reaction of magnesium stearate and salicylic acid (the acid form of Aspirin^® pain reliever [Simon Carter Accessories, Ltd., Essex, U.K.]).

Experimental

All experiments were performed on the DSC 822^e with the high-sensitivity HSS7 DSC sensor. The DSC was equipped with air cooling. The samples were encapsulated in a sealed 40-μL aluminum crucible.

The magnesium stearate (PN 26454, CAS# 557-04-0) and the salicylic acid (PN 27301, CAS# 69-72-7) were purchased from Sigma-Aldrich (St. Louis, MO) and were used as received. The mixtures were made gravimetrically and ground in a glass mortar and pestle for about 5 min. The powder was placed in an infrared (IR) sample press (part no. 0012-193, International Crystal Laboratories, Garfield, NJ) and the bolts were hand-tightened. The bolts were removed and the solid sample wafer was removed from the press. The wafer was trimmed with a razor blade to fit in the crucible. The wafer was run in the DSC immediately after pressing. Compositions were made at every 10% composition by weight from 0% to 100% magnesium stearate. The compositions were made by weight percentage.

The thermal analysis method was run in a temperature step–isothermal hold manner. The method was as follows: 5 ^°C/min to 45 ^°C, isothermal for 60 min; 5 ^°C/min to 50 ^°C, isothermal for 60 min; 5 ^°C/min to 55 ^°C, isothermal for 60 min; 5 ^°C/min to 60 ^°C, isothermal for 60 min; 5 ^°C/min to 65 ^°C, isothermal for 60 min; 5 ^°C/min to 70 ^°C, isothermal for 60 min. The resulting heat flow was plotted in W/g versus time.

Results and discussion

Figure 1 - Example of the step–isothermal method showing the data and the temperature profile (blue line).

The heat flow curves for all the mixtures are shown in Figure 1. The temperature profile is shown in the blue curve. The largest difference in reactivity appears to be during the 60 ^°C isotherm. The reaction is continuing throughout the 60-min isotherm and into the next temperature step. The initial experiments indicated that the DSC 822^e with the high-sensitivity sensor has more than enough sensitivity to measure this interaction.

Figure 2 - All formulations plotted showing the reaction at 60 and 65 °C. The y-axis scale was changed from that shown in Figure 1 so that the curves could be shifted for better clarity.

The change in this interaction versus composition is better seen in Figure 2. In this figure, only the 60 and 65 ^°C isotherms are shown. The curve for each formulation is shifted on the y-axis so that the peaks are easier to see.

Figure 3 - Plot of all compositions. Total heat of interaction is calculated.

The black dashed line is pure salicylic acid. The blue dashed line is pure magnesium stearate. The pure materials also have an endothermic peak when the temperature is ramped up to the next isothermal temperature. This is due to the heat capacity of the material. A certain amount of heat needs to flow into (endothermic) the sample so that its temperature can increase. The authors decided to integrate the curves from 55 to 360 min. This will include all the heat of reaction even if it is spread out over several temperature steps. The integration results are shown in Figure 3 and more clearly in Table 1.

The heat of reaction must be corrected for the heat capacity of the two components. It is assumed that the heat capacities are additive in linear proportion to the concentration. The following equation was used to calculate the enthalpy due to the heat capacity for each formulation.

where ΔH(C_p) = heat due to component’s heat capacity
ΔH_SA = heat due to salicylic acid heat capacity
ΔH_MgSt = heat due to magnesium stearate heat capacity
M_SA = mass of salicylic acid in mixture
M_MgSt = mass of magnesium stearate in mixture.

Figure 4 - Plot of heat-capacity-corrected total reaction versus magnesium stearate composition. Note: The percentage was not independently checked. The results at 30 and 60% could be a sampling error.

Using Eq. (1) on the data in Table 1 gives the results shown in Table 2. These data are plotted in Figure 4. The largest heat of interaction occurs at 70% magnesium stearate.

Figure 5 - Plot of heat-capacity-corrected total reaction versus molar ratio of magnesium stearate to salicylic acid.

In biochemistry, data are interpreted in units of molar ratio. Figure 5 shows the same data as in Figure 4, except the x-axis is the molar ratio. The chemical reaction for this heat of interaction is the exchange of the magnesium between the stearic acid and the salicylic acid. The salicylic acid has two functional groups that would like to bond to magnesium, an OH and a COOH group. The two groups are close enough that they may also act as a chelate and only bond to one magnesium ion per salicylic acid molecule. The question to be answered is, “Does the magnesium chelate to the salicylic acid or is a magnesium ion bound to both the OH and COOH group?” The heat of interaction reaches a maximum when the best stoichiometry has been obtained. The maximum in Figure 5 is at a molar ratio of one magnesium stearate per two salicylic acids. This indicates that it requires two salicylic acid molecules to form enough chelation power to be in equilibrium with one magnesium stearate molecule.

Conclusion

The DSC 822^e with the high-sensitivity HSS7 sensor has the sensitivity required to detect very small interactions between two solids. The DSC can be used in more complex formulations to detect incompatibilities by simply changing the formulation to see which component is causing the problem. Additionally, the DSC can do these experiments on very small (5–20 mg) sample sizes. By comparison, a microcalorimeter requires 0.5–1 g of sample to obtain similar results. This is an asset when working with expensive materials or materials of limited availability, such as research compounds.

Mr. MacPherson is Technical Sales Representative for the West Coast, Mettler-Toledo, Columbus, OH, U.S.A. Dr. Sauerbrunn is Technical Manager, Mettler-Toledo, 130 Executive Dr., Ste. 2A, Newark, DE 19702, U.S.A.; tel.: 302-283-5638; fax: 614-985-9094; e-mail:[email protected].