Selecting a non-interacting buffer for α-cyclodextrin containing solutions

Many active pharmaceutical ingredients suffer from poor water solubility, short plasma half-life, low permeability, or limited chemical stability in aqueous solutions, posing significant challenges for drug formulation. Cyclodextrins (CDs) can form inclusion complexes with various drugs, enhancing both their solubility and chemical stability in aqueous environments. In pharmaceutical formulations, pH control is crucial, and buffers are commonly used to maintain solution stability. However, previous studies suggest that certain buffers can interact with CDs, leading to competitive binding that may affect drug complexation. This study examines the effects of twelve pharmaceutically relevant buffers on the inclusion complex between α-cyclodextrin (α-CD) and 1,9-nonanediol using isothermal titration calorimetry to determine complexation constants and thermodynamic parameters. The results indicate that the complexation constant is buffer species-specific. Four carboxylic acid-based buffers-fumaric acid, succinic acid, maleic acid, and malic acid-demonstrated competitive interactions with α-CD, significantly reducing its ability to complex 1,9-nonanediol. In contrast, phosphate, MES, Tris, and tartaric acid showed minimal interaction. Additionally, the data suggests that increased polarity from additional hydroxyl groups in carboxylic acids decreases their competitive binding affinity. Complexation with hydroxypropylated α-cyclodextrin (HP-α-CD) consistently showed lower binding constants, attributed to steric hindrance and increased cavity hydrophilicity. These findings highlight the importance of buffer selection in cyclodextrin-based drug formulations and suggest that buffer-CD interactions are dependent on both buffer structure and CD cavity size.