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 822e 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 822e 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 822e 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(Cp) = heat due to component’s heat capacity
ΔHSA = heat due to salicylic acid heat capacity
ΔHMgSt = heat due to magnesium stearate heat
capacity
MSA = mass of salicylic acid in mixture
MMgSt = 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 822e 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].