Improved in vitro and in vivo properties of telmisartan in the co-amorphous system with hydrochlorothiazide: A potential drug-drug interaction mechanism prediction

Abstract

The aim of this study is to improve in vitro and in vivo properties of an antihypertensive poorly soluble drug Telmisartan (TEL) by co-amorphization with a pharmacologically relevant drug Hydrochlorothiazide (HCT), and to improve the stability of single amorphous drugs. Herein, TEL-HCT co-amorphous systems (CAMs) (1:1, 2:3, 1:2, 1:3) were prepared by solvent evaporation. The apparent solubility and the dissolution of TEL in the TEL-HCT CAM (1:3) were increased by 79 times and 10 times compared to crystalline TEL, which showed the optimal properties. Cmax and AUC0-48h value of TEL-HCT CAM (1:3) were 10-fold and 3-fold as the crystalline state. Moreover, TEL-HCT CAM (1:3) remained stable in 60 °C, 0 % RH (30 days), 40 °C, 75 % RH (90 days) and 25 °C, 0 % RH (180 days). Positive ΔTgs were observed in all CAMs, suggesting the existence of potential intermolecular force. Fourier Transform-Infrared and Raman spectra were used to further prove the drug-drug interaction and predict potential mechanisms. Therefore, in the strategy of combined medication, CAM provides a promising way to transfer drugs with poor properties into systems with enhanced dissolution, greater bioavailability, and stabilized amorphous state, which has been proven in this study.