Interaction of piroxicam with micelles: Effect of hydrophobic chain length on structural switchover

Molecules, whose pKa values can be easily fine-tuned by their microenvironment, are expected to be profoundly affected by the heterogeneous environments of membranes. Membrane parameters can have a strong effect in choosing a particular structural form of a molecule for incorporation/interaction. A case study has been presented for piroxicam, a non-steroidal anti-inflammatory drug of oxicam group, whose targets are cyclooxygenases, which are membrane active proteins. The structural dynamism of piroxicam is reflected in the ease with which it can switchover or convert from one prototropic form to the other guided by its environment. In this work we have studied the effect of varying hydrophobic chain length and surface charges in fine-tuning the interaction of piroxicam with micelles. Interaction of piroxicam with three types of micelles with identical negatively charged head groups and varying tail lengths viz., sodium dodecyl sulfate (S12S), sodium decyl sulfate (S10S) and sodium octyl sulfate (S8S) shows that there is a shift in the apparent pKa in the direction that favors the switchover or conversion from the anionic form to the global neutral form. The binding constants of piroxicam with three micelles show a linear dependence on chain length. Interaction was also studied with micelles having oppositely charged head groups and different chain lengths viz., dodecyl N,N,N-trimethyl ammonium bromide (DTAB) and cetyl N,N,N-trimethyl ammonium bromide (CTAB). For micelles having identical chain lengths but oppositely charged head groups viz., S12S and DTAB, pKa shifts in two opposite directions compared to that in the absence of any surfactant. This is expected when electrostatic force is the only driving force. This case study demonstrates the effect of hydrophobic chain length and surface charges in fine-tuning the equilibrium between different structural forms of piroxicam. Our results also imply that for structurally dynamic drugs like piroxicam the nature of the biomembranes, characterized by different membrane parameters, should play a crucial role in choosing a particular structural form of the drug that will be finally presented to their targets.