Effect of pH on the complexation of irbesartan with $\beta $-, hydroxypropyl-$\beta $-, and $\gamma $-cyclodextrin: solubility enhancement and physicochemical characterization


Abstract: The affinity of irbesartan (IRB) to form inclusion complexes with $\beta $-cyclodextrin ($\beta $-CD), hydroxypropyl-$\beta $-cyclodextrin (HP-$\beta $-CD), and $\gamma $-cyclodextrin ($\gamma $-CD) was investigated in aqueous buffered solutions at pH 1.7, 4.1, and 7.0. Analysis of the UV absorption-pH profiles revealed that IRB has two p$K_{a}$ values: p$K_{a1\, }=$ 3.60 (imidazolinone ring moiety) and p$K_{a2\, }=$ 4.70 (tetrazole moiety). In the presence of 5.0 mmol L$^{-1} \beta $-CD, the tetrazole moiety became more acidic, indicating its inclusion within the $\beta $-CD cavity. Phase-solubility diagrams (PSDs) were obtained for IRB in aqueous buffered solutions of $\beta $-CD, HP-$\beta $-CD, and $\gamma $-CD at pH 4.1 (zwitterionic IRB), pH 1.7 (protonated IRB), and pH 7.0 (deprotonated IRB). Rigorous nonlinear regression analysis of IRB/CD PSDs at pH 4.1, where IRB is poorly soluble, yielded estimates of complex formation constants ($K_{11})$ that followed the decreasing order of HP-$\beta $-CD > $\gamma $-CD > $\beta $-CD. The highest solubility enhancement of IRB was achieved by complexation with HP-$\beta $-CD at pH 4.1. The formation of the IRB/$\beta $-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 moiety within the $\beta $-CD cavity.

Keywords: Irbesartan, irbesartan-cyclodextrin complexes, irbesartan p$K_{a}$ values, phase solubility analysis

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