Improving co-amorphous drug formulations by the addition of the highly water soluble amino Acid, proline.

Katrine Jensen,Thomas Rades,Korbinian Löbmann,Holger Grohganz

doi:10.3390/pharmaceutics6030416

Abstract

Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 °C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP–TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP–ARG. In comparison to crystalline NAP, binary NAP–TRP and NAP–ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations.

Highlights

Several approaches have been described for how to overcome the challenges in preparing oral formulations of poorly water-soluble drugs [1]
The high Tg of amorphous TRP confirmed that this amino acid could be advantageous as a stabilizer in co-amorphous mixtures
This was not found for NAP–TRP, which could not be fully converted into a co-amorphous system

Summary

Introduction

Several approaches have been described for how to overcome the challenges in preparing oral formulations of poorly water-soluble drugs (categorized as Class II and Class IV drugs in the Biopharmaceutics Classification System, BCS) [1]. One of these approaches is the transformation of a crystalline drug into its amorphous form, taking advantage of the improved solubility and, subsequently, potentially higher bioavailability of this form. The most common approach to overcome this stability problem is to incorporate the amorphous drug into a water-soluble, amorphous polymer, creating a glass solution [4]. The strengths and weaknesses of various amorphous formulation approaches were recently reviewed in several articles [8,9]

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Conclusion