Insight into the Structure and Properties of Novel Imidazole-Based Salts of Salicylic Acid.

Inês C B Martins,Dominik Al-Sabbagh,Michael Maiwald,Klas Meyer,Gudrun Scholz,Franziska Emmerling

doi:10.3390/molecules24224144

Abstract

The preparation of new active pharmaceutical ingredient (API) multicomponent crystal forms, especially co-crystals and salts, is being considered as a reliable strategy to improve API solubility and bioavailability. In this study, three novel imidazole-based salts of the poorly water-soluble salicylic acid (SA) are reported exhibiting a remarkable improvement in solubility and dissolution rate properties. All structures were solved by powder X-ray diffraction. Multiple complementary techniques were used to solve co-crystal/salt ambiguities: density functional theory calculations, Raman and 1H/13C solid-state NMR spectroscopies. In all molecular salts, the crystal packing interactions are based on a common charged assisted +N-H(SA)O−(co-former) hydrogen bond interaction. The presence of an extra methyl group in different positions of the co-former, induced different supramolecular arrangements, yielding salts with different physicochemical properties. All salts present much higher solubility and dissolution rate than pure SA. The most promising results were obtained for the salts with imidazole and 1-methylimidazole co-formers.

Highlights

The discovery of new active pharmaceutical ingredients (APIs) having poor water-solubility and bioavailability has become prevalent during the drug development process [1,2,3]
The responsibility for maintaining a consistent bioavailability throughout product life has led to regulatory requirements for polymorphism-screening experiments, which is described in the ICH Q6A
We intended to obtain new multicomponent crystal forms of salicylic acid (SA), so co-former selection was based in its biological safety, capacity to participate in hydrogensuch bonds (HBs) interactions and ∆pKa selection was based in its biological safety, capacity to participate in HB interactions and ΔpKa rule rule [45]

Summary

Introduction

The discovery of new active pharmaceutical ingredients (APIs) having poor water-solubility and bioavailability has become prevalent during the drug development process [1,2,3]. The responsibility for maintaining a consistent bioavailability throughout product life has led to regulatory requirements for polymorphism-screening experiments, which is described in the ICH Q6A

Methods

Results

Conclusion