Characterisation and fundamental insight into the formation of new solid state, multicomponent systems of propranolol

Klaudia Bialek,Zaneta Wojnarowska,Brendan Twamley,Lidia Tajber

doi:10.1016/j.ijpharm.2021.120605

Klaudia Bialek, Zaneta Wojnarowska + Show 2 more

Open Access

https://doi.org/10.1016/j.ijpharm.2021.120605

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Abstract

The physiochemical properties of acidic or basic active pharmaceutical ingredients (APIs) can be optimised by forming salts with different counterions. The aim of this work was to synthesise a novel salt of propranolol (PRO) using sebacic acid (SEBA) as the counterion and to gain mechanistic understanding of not only the salt formation, but also its eutectic phase formation with SEBA. Thermal analysis showed a solid-state reaction occurring between PRO and SEBA leading to the formation of dipropranolol sebacate (DPS) melting at app. 170 °C and the eutectic composed of DPS and SEBA melting at app. 103 °C, comprising 0.33 mol fraction of PRO as determined by the Tammann plot. X-ray diffraction and Fourier-transform infrared spectroscopy (FTIR) confirmed the identity of the new multicomponent phases of PRO. DPS can be conveniently obtained by heat-induced crystallisation, grinding and conventional solvent crystallisation. Detailed analysis by FTIR revealed H-bond interactions between DPS and SEBA at the inter-phase in the eutectic. Bravais, Friedel, Donnay and Harker crystal morphology coupled with full interaction maps analysis allowed to understand further the nature of interactions which led to formation of the eutectic phase. This work contributes to furthering research on multicomponent pharmaceutical systems to harness their full potential.

Highlights

Adequate aqueous solubility of orally administrated active pharma ceutical ingredients (APIs) is essential to ensure good bioavailability (Savjani et al, 2012)
Since many drugs are either weak acids or weak bases, the salt formation is by far the easiest way to optimise chemical and physical properties of poorly soluble APIs
We have explored different solvent-free approaches to the salt formation

Summary

Introduction

Adequate aqueous solubility of orally administrated active pharma ceutical ingredients (APIs) is essential to ensure good bioavailability (Savjani et al, 2012). Up to 90% of APIs in the develop ment stage may be considered as poorly soluble (Ting et al, 2018) and are more likely to fail during late-stage drug development. The search for new forms of APIs, which have desirable properties, has become of paramount importance to the pharmaceutical industry in recent years. Since many drugs are either weak acids or weak bases, the salt formation is by far the easiest way to optimise chemical and physical properties of poorly soluble APIs. The salt formation strategy can increase API solubility (Serajuddin, 2007), but it can be used to improve stability (Sigfridsson et al, 2018), permeability (Mannava et al, 2020) and well as efficacy and release profiles

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