Effect of pH on the complexation of irbesartan with β -, hydroxypropyl-β -, and γ -cyclodextrin: solubility enhancement and physicochemical characterization

Abstract

The affinity of irbesartan (IRB) to form inclusion complexes with β -cyclodextrin (β -CD), hydroxypropylβ -cyclodextrin (HP-β -CD), and γ -cyclodextrin (γ -CD) was investigated in aqueous buffered solutions at pH 1.7, 4.1,and 7.0. Analysis of the UV absorption-pH profiles revealed that IRB has two pKa values: pKa1 = 3.60 (imidazolinonering moiety) and pKa2 = 4.70 (tetrazole moiety). In the presence of 5.0 mmol L −1β -CD, the tetrazole moiety becamemore acidic, indicating its inclusion within the β -CD cavity. Phase-solubility diagrams (PSDs) were obtained for IRBin aqueous buffered solutions of β -CD, HP-β -CD, and γ -CD at pH 4.1 (zwitterionic IRB), pH 1.7 (protonated IRB),and pH 7.0 (deprotonated IRB). Rigorous nonlinear regression analysis of IRB/CD PSDs at pH 4.1, where IRB is poorlysoluble, yielded estimates of complex formation constants (K11) that followed the decreasing order of HP-β -CD >γ -CD>β -CD. The highest solubility enhancement of IRB was achieved by complexation with HP-β -CD at pH 4.1. Theformation of the IRB/β -CD inclusion complex in solution and in the solid state has been proven through NMR, DSC,FT-IR, and XRD studies. Analysis of 1 H and 13 C-NMR spectra indicated the inclusion of the tetrazole-biphenyl moietywithin the β -CD cavity.