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A dramatic improvement of the solubility of PAB (about 600 folds) by CDs complexation has been found.The complexation was characterized by DSC, XRD, 1H NMR and molecular simulation, and validated by the in vitro degradation tests.The PAB/HP-β-CD inclusion complex prepared in our study could greatly improve the solubility of PAB, which will result in great improvement of the in vivo administration of PAB as a liquid solution.As one of the most important technologies to improve the solubility of poorly water-soluble drugs, the solubilization effects of cyclodextrins (CDs) complexation are, on occasions, not as large as expected, which tends to detract from the wider application of CDs. In this study, a dramatic improvement of the solubility of pseudolaric acid B (PAB) by CDs has been found with a 600 fold increase by HP-β-CD complexation. In addition, the solubility enhancement of PAB by various CDs, including α-CD, β-CD, γ-CD, HP-β-CD and SBE-β-CD was investigated by phase solubility studies. The inclusion complex of PAB/HP-β-CD was prepared by different methods and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (XRD), nuclear magnetic resonance spectroscopy (1H NMR) together with molecular simulation. The results indicated that the solubility of PAB was increased to 15.78 mg mL−1 in the presence of 30% HP-β-CD, which is a 600 fold increase compared with that in pure water. And the chemical stability of PAB in PBS (pH 7.4) can be enhanced. The results of DSC and XRD showed the absence of crystallinity in the PAB/HP-β-CD inclusion complex prepared by the saturated water solution method. The results of 1H NMR together with molecular simulation indicated the conjugated diene side-chain of PAB was included into the cavity of HP-β-CD, with the free energy of −20.34 ± 4.69 kJ mol−1. While the enzymatic degradation site of the carboxyl polar bond is located in the hydrophilic outer of HP-β-CD resulted in no significant difference for the enzymatic degradation rate between PAB and PAB/HP-β-CD complexes in rat plasma. In summary, the PAB/HP-β-CD inclusion complex prepared in this study can greatly improve the solubility and chemical stability of PAB, which will result in the in vivo administration of PAB as a liquid solution.