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

Authors : Fakhri YOUSEF

Pages : 1544-1558

View : 13 | Download : 11

Publication Date : 0000-00-00

Article Type : Research Paper

Abstract :The affinity of irbesartan insert ignore into journalissuearticles values(IRB); to form inclusion complexes with $\beta $-cyclodextrin insert ignore into journalissuearticles values($\beta $-CD);, hydroxypropyl-$\beta $-cyclodextrin insert ignore into journalissuearticles values(HP-$\beta $-CD);, and $\gamma $-cyclodextrin insert ignore into journalissuearticles values($\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 insert ignore into journalissuearticles values(imidazolinone ring moiety); and p$K_{a2\, }=$ 4.70 insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(PSDs); were obtained for IRB in aqueous buffered solutions of $\beta $-CD, HP-$\beta $-CD, and $\gamma $-CD at pH 4.1 insert ignore into journalissuearticles values(zwitterionic IRB);, pH 1.7 insert ignore into journalissuearticles values(protonated IRB);, and pH 7.0 insert ignore into journalissuearticles values(deprotonated IRB);. Rigorous nonlinear regression analysis of IRB/CD PSDs at pH 4.1, where IRB is poorly soluble, yielded estimates of complex formation constants insert ignore into journalissuearticles values($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