Preparation of Co-amorphous Erlotinib Hydrochloride-L-tryptophan System and Its Pharmacokinetics in Rats
Erlotinib hydrochloride(1)is a novel tyrosine kinase inhibitor characterized by high permeability but low water solubility.The addition of small molecule ligands to prepare co-amorphous drug systems is an effective strategy to enhance the solubility,dissolution rate,and bioavailability of poorly water-soluble drugs.In this study,co-amorphous systems of 1 and L-tryptophan(2)were prepared by rotary evaporation method.The co-amorphous 1-2 system was characterized by Fourier transform infrared spectroscopy(FTIR),powder X-ray diffraction(PXRD),and differential scanning calorimetry(DSC).The PXRD and DSC results confirmed the formation of the co-amorphous system.And FTIR analysis and molecular dynamics simulations further suggested the presence of hydrogen bond interactions between 1 and 2,which could be the potential molecular mechanism for the formation of the co-amorphous system.Compared to the single crystal of 1,the solubility and dissolution rate of 1 in the 1-2 co-amorphous system were significantly improved.The results of pharmacokinetic modeling in SD rats showed that the cmax and AUC0→ t of the co-amorphous system group were 2.8 times and 2.3 times higher than those of the bulk drug group,respectively.Meanwhile,there was no significant increase in the cmax and AUC0→ t of the physical mixture group.In conclusion,the co-amorphous 1-2 system prepared in this study can significantly improve the solubility and oral bioavailability of 1.
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