(T1530-04-23) Determination of Binding Constants between Diflunisal and Trazodone and Several Excipients

Purpose: The excipients play an important role in pharmaceutical formulations. In pharmaceutical solid forms the excipient can affect physicochemical properties of the drug as the ionization degree or the solubility. In fact, some excipients like cyclodextrins or plasdones are used as enhancers of drug solubility and this enhancement is attributed, mainly, to interactions between the excipient and the drug. Therefore, knowing the binding constant between the drug and the excipient the compound solubility can be predicted. For ionisable compounds, the excipient-drug interactions can be evaluated by the shift of the dissociation constant (pK_a) of the drug which, in turn, depends on the species which are interacting (neutral, ionic), the type of the ionisable group (acidic, basic) and the excipient. Moreover, the knowledge of the binding constants have interest not only to predict the enhancement of drug solubility, but also to develop models to predict the excipient-drug interaction at any pH. This work focuses on the determination of the binding constant between the excipient and the drug species (neutral and ionic) by studying the pKa-shift of the drug when increasing excipient concentration. Three excipients; two cyclodextrins (captisol and cavasol) and one plasdone (kollidon) and two drugs; diflunisal (containing an acidic group) and trazodone (containing a basic group) have been selected. Moreover, a model to predict the interaction of these drugs with the studied excipients has been developed.

Methods: The ionisation constants were determined using the spectrometric technique. Diflunisal and trazodone were titrated between pH 2.0 – 12.0 at concentrations of 50 – 20 µM under aqueous conditions (at the ionic strength of 0.15 M KCl and at 25°C). A minimum of 8 concentration levels (between 0.1 – 100 mg/mL) of excipient were studied. At least four replicates of each excipient concentration level with each API were also performed. A Pion SiriusT3 and GLpKa-DPAS potentiometers with RefineT3 (v2.0) software were used to perform the dissolution rate measurements and calculations.

Results: The ionisation constant versus the excipient content profiles showed different behaviour depending on the type of the excipient. However, for all three excipients studied, it is observed that the more the concentration of excipient is used the larger shift of the pK_a value is observed. Diflunisal: In the case of the cyclodextrines (cavasol and captisol); the increase of the pK_a-shift with the increase of the excipient content confirmed that the neutral species is the one which is interacting with the excipient decreasing the concentration of the neutral species in solution, disturbing the aqueous equilibria of the drug. This interaction is by the inclusion of diflunisal into the cyclodextrine cavity. In the figure is shown the increase of the pK_a-shift to a higher pHs with the excipient content until a plateau is reached, which represents the complete inclusion of diflunisal into the cavasol cavity, meaning that the maximum pK_a-shift was achieved. Captisol has a bigger cavity and therefore a higher interaction is observed. In the figure the captisol plot has a higher effect on the pK_a-shift than cavasol. The interactions of diflunisal with Kollidon are different in comparison with the cyclodextrine interactions. The pK_a-shift is smaller and negative. This behaviour could be explained due to the fact that the ionic species is mainly the one that is interacting with the excipient. Moreover, the ionic species interaction is weaker than the neutral species affecting the pK_a shift to a lesser extent. Trazodone: Trazodone has a basic ionisable group and so, the pK_a-shift observed with the increase of the excipient was to a lower pH. In the case of the cyclodextrines, the increase of the pK_a-shift with the increase of the excipient content confirms that the neutral species is interacting with the excipient (as it was observed for diflunisal). In the presence of Kollidon, no pK_a-shift was observed, meaning that very small interactions could happen with this excipient or the excipient interactions occur between both the species (the neutral and the ionic) in a similar way.

Conclusion: Interactions between excipient and drugs depends on the type of the ionisable centres (acid, bases); as the basic pK_as shift to a lower pH and acidic pK_as shift to a higher pH. Moreover, the type of excipient interact differently with the neutral and ionic species of the drug and the stronger interaction will control the extent of the pK_a-shift.