Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects.

Jiale Li,Zengming Wang,Aiping Zheng,Ting Wang,Conghui Li,Xiang Gao,Hui Zhang

doi:10.3390/polym14030495

Abstract

Azithromycin (AZI) is one of the most commonly used macrolide antibiotics in children, but has the disadvantages of a heavy bitter taste and poor solubility. In order to solve these problems, hot-melt extrusion (HME) was used to prepare azithromycin amorphous solid dispersion. Preliminary selection of a polymer for HME was conducted by calculating Hansen solubility parameter to predict the miscibility of the drug and polymer. Eudragit® RL PO was chosen as the polymer due to its combination of taste-masking effect and dissolution. Moreover, the solubility was improved with this polymer. Design of experiments (DoE) was used to optimize the formulation and process, with screw speed, extrusion temperature, and drug percentage as independent variables, and content, dissolution, and extrudates diameter as dependent variables. The optimal extrusion parameters were obtained as follows: temperature—150 °C; screw speed—75 rpm; and drug percentage—25%. Differential scanning calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies of the powdered solid dispersions showed that the crystalline AZI transformed into the amorphous form. Fourier transform infrared spectroscopy (FTIR) results indicated that the formation of a hydrogen bond between AZI and the polymer led to the stabilization of AZI in its amorphous form. In conclusion, this work illustrated the importance of HME for the preparation of amorphous solid dispersion of AZI, which can solve the problems of bitterness and low solubility. It is also of great significance for the development of compliant pediatric AZI preparation.

Highlights

7 million children under the age of 5 die every year, usually from treatable diseases [1]
The results demonstrate that the combined application of Eudragit® RL PO and hotmelt extrusion (HME) is a good solution to the above problems, while the AZI is converted from the crystalline to the amorphous state
Mechanical energy combined with thermal energy provides energy for the active pharmaceutical ingredients (API), but mechanical energy itself does not cause the degradation of the API, which is mainly influenced by thermal energy

Summary

Introduction

7 million children under the age of 5 die every year, usually from treatable diseases [1]. Special attention should be paid to the bitterness of drugs in the development of pediatric preparation [1,5]. AZI has a heavy bitter taste, which leads to poor oral compliance in children [7]. Some studies have shown the use of physisorption technique [7], ion exchange resin technique [10], and reverse micelles technique [11] to mask the bitterness of AZI. These techniques are operationally complex and, there is a necessity for a simpler approach to develop more compliant AZI preparation for children

Methods

Results

Discussion

Conclusion