Cyclodextrin complexes of the anticonvulsant agent valproic acid

Abstract

Six cyclodextrin (CD) complexes of the antiepileptic drug valproic acid (VAL) were prepared by kneading and/or co-precipitation methods and characterized by thermal analysis, powder X-ray diffraction and spectroscopic (¹H NMR and FT-IR) techniques. The complexes (with host–guest stoichiometries in parentheses) included α-CD·VAL (2 : 1), β-CD·VAL (1 : 1), γ-CD·VAL (3 : 4), DMB·VAL (1 : 1), TMB·VAL (1 : 1) and TMA·VAL (1 : 1). Single crystal X-ray structures of four of the complexes were determined, those with β-CD and γ-CD featuring severely disordered guest molecules. Instead, the VAL molecules in the complexes with dimethylated β-CD (DMB) and permethylated α-CD (TMA) could be modelled, revealing modes of inclusion of valproic acid in CDs for the first time. The aqueous solubility values at 27 °C for VAL in the form of the solid complexes α-CD·VAL, β-CD·VAL and γ-CD·VAL were in the range 0.26–0.58 times that of the pure liquid phase of VAL. The merits of CD inclusion of VAL (e.g. transformation of the liquid guest into a solid, potential for reduction of adverse side effects) are discussed.