Formation of low melting point binary systems comprising ketoprofen and an amide local anaesthetic

Anita Umerska,Julija Zotova,Lidia Tajber

doi:10.1016/j.ijpharm.2021.120969

Anita Umerska, Julija Zotova + Show 1 more

Open Access

https://doi.org/10.1016/j.ijpharm.2021.120969

Copy DOI

Abstract

Liquid forms of active pharmaceutical ingredients, ionic liquids (ILs) and deep eutectic mixtures (DEMs), offer several potential benefits in respect to advancing pharmaceutical formulations. The aim of this study was to develop and characterise ILs/DEMs composed of two active molecules: ketoprofen (KET), as the acidic component, and a local anaesthetics (LA), lidocaine (LID), mepivacaine (MEP) or bupivacaine (BUP), which constituted the basic component. A mechanosynthetic approach was successfully applied to obtain LA-KET low melting systems. Composition/temperature phase diagrams were determined by differential scanning calorimetry. The amide LA-KET mixtures showed a eutectic behaviour during heating and formed viscous liquids upon quench cooling. Considering the quench cooled LA-KET mixtures, LA crystallisation was observed only in the LA-rich mixtures. LID, MEP and BUP formed disordered complexes with KET at an approximate 1:2 stoichiometry. Infrared spectroscopy studies revealed that the mixtures were composed mainly of hydrogen bonded acid and base molecules, but small amounts of carboxylate anions were detected. The formation of LA-KET complex not only suppressed the high crystallisation tendency of the LA molecules in the dry state, but also eliminated the crystallisation of KET and LA molecules induced by moisture, as revealed by dynamic vapour sorption studies.

Highlights

Deep eutectic mixtures (DEMs) and ionic liquids (ILs) are emerging as promising strategies to obtain favourable forms of active pharma ceutical ingredients (APIs) (Moreira et al, 2015, Griffin et al, 2014, Balk et al, 2015, Berton et al, 2017, Wojnarowska et al, 2018, Umerska et al, 2020a)
The xylidine-derived amide local anaesthetics (LA)-KET systems investigated in this work can be described as deep eutectics with strong interactions be tween the acid and base molecules resulting in a sudden decrease in melting temperature and deviations from the theoretical Schroder van Laar predictions
The electrostatic in teractions existing between KET and LA molecules were found to reduce the crystallisation tendency of binary mixtures

Summary

Introduction

Deep eutectic mixtures (DEMs) and ionic liquids (ILs) are emerging as promising strategies to obtain favourable forms of active pharma ceutical ingredients (APIs) (Moreira et al, 2015, Griffin et al, 2014, Balk et al, 2015, Berton et al, 2017, Wojnarowska et al, 2018, Umerska et al, 2020a). The dual functional ILs and DEMs, obtained by combining biologically active cations and anions via reversible intermolecular interactions, offer the advantage of lowering either the melting point (Mp) or the glass transition temperature (Tg) of the API in addition to providing a second biological function, an approach very attractive for pharma ceutical combination products (Hough et al, 2007, Hough and Rogers, 2007, Wang et al, 2014, Umerska et al, 2020a). They differ from coamorphous systems as those are defined as single phase amorphous solids. The ionisation degree and the molar ratio between the components are important for pharmaceutical applications since they influence the solubility and pharmacokinetics of the API (Berton et al, 2017)

Objectives

Methods

Results

Conclusion