Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy.

Marcin Skotnicki,Jacek Kujawski,Bartłomiej Milanowski,Barbara Jadach,Lidia Tajber,Marek Pyda,Agnieszka Skotnicka

doi:10.3390/pharmaceutics13010118

Abstract

The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of Tg value of co-amorphous system using the Couchman–Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability.

Highlights

The principal cause of death in developed countries is attributed to cardiovascular diseases (CVDs)
The identification of possible interactions between APIs in the fixed-dose combination is of paramount importance at an early stage of the formulation development process [1]
An unusual behavior was observed for ATR, as the intrinsic dissolution rate (IDR) of ATR from the co-amorphous formulation was slightly lower than the IDR of amorphous ATR on its own

Summary

Introduction

The principal cause of death in developed countries is attributed to cardiovascular diseases (CVDs). CVDs are the disorders of heart and blood vessels, including heart failure, coronary heart disease, hypertension, cerebrovascular disease, or congenital heart disease [1]. One of the recently implemented strategies to treat CVDs is to address multiple risk factors simultaneously, for example, by introducing a fixed-dose combination (FDC), i.e., a combination of drugs in one dosage form [1]. Such a combination may contain a statin and a blood pressure lowering agent

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