Compatibility refers to harmony in a relationship, but is also an important term in science, be it in medicine where only a compatible organ can be transplanted to a recipient, or in computing to refer to software packages that can be used together. This concept is also well-known in the pharmaceutical field: Two components (e.g., one API [active pharmaceutical ingredient] and one excipient) are compatible if the presence of one does not affect the properties, stability, efficacy of the other. An interaction between drug and excipient has an impact on the chemical, physical, bioavailability and stability of the dosage form. Therefore, drug-excipient compatibility studies represent an important phase in drug development.
How to get first information about the compatibility of a drug and excipient?
By using thermal analysis, and particularly the DSC and TG methods. To understand how it works, let’s have a look at the DSC curves of 2 ingredients that interact – or not. For that, you carry out a DSC measurement on each component as well as on the mixture of both components (50/50 weight). Figure 1 displays the DSC curves of the API and excipient with melting peak. A resulting DSC curve that shows no interaction between the API and excipient (figure 2) indicates that the excipient is recommended for the formulation using the API. In this case, there is compatibility between API and excipient; the DSC curve will continue to show the melting peaks of the two substances unaltered at the same temperature. The occurrence of a new peak in the mixture, the disappearance of a peak, or a change in melting peak (shape, position, or enthalpy) indicates that there is an interaction between the two components (figure 3). However, this doesn’t necessarily mean that the drug and excipient are not compatible. Additional investigations would have to be carried out with other techniques (X-ray, spectroscopy, chromatography, etc.) to confirm incompatibility.
Faster compatibility check by means of SuperPosition
This software feature allows for depiction of the curve that would be obtained for a mixture if no interaction between the two components occurred. Let‘s apply this function on true DSC curves, for example, on the DSC curves of diclofenac (API) and magnesium stearate (excipient). Figure 4 displays the DSC curves of the two substances during heating. You will find the description of the detected effects in the NETZSCH application notes AN120 and AN116. To get the superimposed curve of both DSC curves, you only have to click on SuperPosition in the NETZSCH evaluation software and select the curves you want to superimpose. You even have the possibility to adjust the mass ratio at will (in our example, we have a mixture of 50/50). Figure 5 compares the measured curve of the mixture (continuous line) with the curve calculated by means of SuperPosition (dashed line). The melting peak typical for diclofenac (at 290°C) is no longer exhibited in the mixture. Instead, a broad endothermal peak with a peak temperature of 264°C is detected. No difference between the two curves (as, for example, for the effects in the temperature range 10°C to 150°C) would indicate a compatible mixture. The fact that there are differences detected in the example indicates that there is an interaction between diclofenac sodium and magnesium stearate.
Drug-excipient compatibility studies are an important part in the development of a dosage form. Thermal analysis, and particularly the DSC and TGA methods, offer an easy and fast way to get information about potential interactions between API and excipients.