Facile formation of co-amorphous atenolol and hydrochlorothiazide mixtures via cryogenic-milling: Enhanced physical stability, dissolution and pharmacokinetic profile

Abstract

The development of poorly water-soluble drugs faces the risk of low bioavailability and therapeutic efficacy. The co-amorphous drug delivery system has recently gained considerable interest because it offers an alternative approach to modify properties of poorly water-soluble drugs. Herein, we developed a co-amorphous system of atenolol (ATE) and poorly water-soluble hydrochlorothiazide (HCT) by means of cryogenic milling. The co-administration of ATE and HCT has been reported to show therapeutic advantages for patients with uncomplicated hypertension. The co-amorphous ATE-HCT sample with 1:1 molar ratio showed excellent physical stability, which could be attributed to the formation of strong molecular interactions between ATE and HCT as evidenced by FT-IR spectra. Compared to the pure crystalline form, amorphous form and physical mixture, HCT in the co-amorphous form exhibited the significantly increased intrinsic dissolution rate, as well as the enhanced bioavailability in the pharmacokinetic study. It was found that the enhanced bioavailability of HCT in the co-amorphous formulation was achieved by the synergistic effect of amorphized HCT and the water-soluble coformer ATE. The present study provides an improved approach to implement the combination therapy of ATE and HCT for potential clinical treatments.

Keywords: Atenolol; Co-amorphous; Cryogenic milling; Hydrochlorothiazide; Intrinsic dissolution rate; Pharmacokinetics; Physical stability.