Submerged Eutectic-Assisted, Solvent-Free Mechanochemical Formation of a Propranolol Salt and Its Other Multicomponent Solids.

Klaudia Bialek,Lidia Tajber,Marcin Skotnicki,Brendan Twamley,Marian Paluch,Zaneta Wojnarowska

doi:10.3390/pharmaceutics13122125

Abstract

Salt preparation via a solid-state reaction offers a solution to challenges posed by current pharmaceutical research, which include combining development of novel forms of active pharmaceutical ingredients with greener, sustainable synthesis. This work investigated in detail the mechanism of salt formation between propranolol (PRO) and capric acid (CAP) and explored the solid eutectic phases comprising this salt, propranolol caprate (PRC). The salt structure was solved by X-ray diffraction, and the properties in the crystalline and supercooled states were fully characterised using thermal analysis, nuclear magnetic resonance, Fourier-transform infrared spectroscopy and broadband dielectric spectroscopy (BDS). PRC forms via a submerged eutectic phase composed of PRO and CAP, below room temperature, by mechanochemistry without an extra input of energy. Two other solid eutectic phases are composed of PRC and either CAP or PRO, at 0.28 and 0.82 mol fraction of PRO, respectively. BDS indicated that the supercooled PRC has ionic character, whereas the supercooled PRC-PRO eutectic had predominantly non-ionic properties despite comprising the salt. In conclusion, knowledge of the mechanism of formation of multicomponent systems can help in designing more sustainable pharmaceutical processes.

Highlights

Propranolol (PRO, Figure 1) is a first-generation nonselective β-blocker, blocking both β1-adrenergic and β2-adrenergic receptors [1]
We made a successful attempt to determine the structure of this form, propranolol caprate (PRC), grown from an ethanolic solution, by single-crystal
The crystal structure of the salt formed between PRO and capric acid (CAP)–propranolol caprate was solved, confirming that the salt stoichiometry is 1:1

Summary

Introduction

Propranolol (PRO, Figure 1) is a first-generation nonselective β-blocker, blocking both β1-adrenergic and β2-adrenergic receptors [1]. It is primarily used in the treatment of cardiovascular conditions such as hypertension, cardiac arrhythmias and angina pectoris [2]. It has recently been approved as a first line therapy drug for treatment of infantile haemangioma (IH) [3]. In the context of IH, even though the PRO·HCl oral solution is effective in the treatment of this ailment, the salt is poorly bioavailable (13–23%) and shows extensive hepatic first pass metabolism [8].

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Conclusion