Purpose. To understand the role of charge in substrate/cyclodextrin complexation by comparing the binding of neutral and charged substrates to a neutral cyclodextrin, such as hydroxypropyl β–CD (HP–β–CD) with 3.5 degrees of substitution, and an anionically charged cyclodextrin, such as sulfobutyl ether β–CD ((SBE)7M–β–CD) with 6.8 degrees of substitution.
Method. HP–β–CD and (SBE)7M–β–CD were evaluated in their ability to form inclusion complexes with neutral compounds, as well as to cationic and anionic substrates in their charged and uncharged forms. The complexation constants (Kc) were determined via a UV spectrophotometric technique, by monitoring the change in substrate absorbance upon incremental addition of a concentrated cyclodextrin solution. The role of electrostatic interaction was probed by observing Kc as a function of solution ionic strength.
Results. Neutral molecules displayed a stronger interaction with (SBE)7M–β–CD compared to HP–β–CD. In those cases where the guest possessed a charge (positive or negative), HP–β–CD/substrate complexes exhibited a decrease in complexation strength (2 to 31 times lower) compared to the neutral forms of the same substrate. The same was true (but to a larger extent, 41 times lower) for negatively charged molecules binding to (SBE)7M–β–CD due to charge–charge repulsion. However, positively charged molecules interacting with the negatively charged (SBE)7M–β–CD displayed a similar binding capability as their neutral counterpart, due to charge–charge attraction. Further evaluation through manipulation of solution ionic strength revealed strong electrostatic interactions between substrate and cyclodextrin charges. In addition, the studies suggested that on average two sulfonates out of seven may be involved in forming ionic attraction or repulsion effects with the positive charges on prazosin and papaverine, or negative charges of ionized naproxen and warfarin.
Conclusions. Presence of charge on the cyclodextrin structure provides an additional site of interaction compared to neutral cyclodextrins, which may be modified using solution ionic strength.