Liquid Metastable Precursors of Ibuprofen as Aqueous Nucleation Intermediates.

Eduard Wiedenbeck,Helmut Cölfen,Denis Gebauer,Michael Kovermann

doi:10.1002/anie.201910986

Abstract

The nucleation mechanism of crystals of small organic molecules, postulated based on computer simulations, still lacks experimental evidence. In this study we designed an experimental approach to monitor the early stages of the crystallization of ibuprofen as a model system for small organic molecules. Ibuprofen undergoes liquid–liquid phase separation prior to nucleation. The binodal and spinodal limits of the corresponding liquid–liquid miscibility gap were analyzed and confirmed. An increase in viscosity sustains the kinetic stability of the dense liquid intermediate. Since the distances between ibuprofen molecules within the dense liquid phase are similar to those in the crystal forms, this dense liquid phase is identified as a precursor phase in the nucleation of ibuprofen, in which densification is followed by generation of structural order. This discovery may make it possible to enrich poorly soluble pharmaceuticals beyond classical solubility limitations in aqueous environments.

Highlights

Crystallization, a natural phenomenon observed in everyday life, is crucial to many processes occurring in nature and in the chemical, pharmaceutical, and food industries
Since the distances between ibuprofen molecules within the dense liquid phase are similar to those in the crystal forms, this dense liquid phase is identified as a precursor phase in the nucleation of ibuprofen, in which densification is followed by generation of structural order
The loci of the binodal (0.43 Æ 0.01 mm) and spinodal limits (0.71 Æ 0.01 mm) of the corresponding liquid–liquid miscibility gap were determined by means of 1H NMR spectroscopy due to the different chemical environment of the ibuprofen molecules in the two phases

Summary

Introduction

Crystallization, a natural phenomenon observed in everyday life, is crucial to many processes occurring in nature and in the chemical, pharmaceutical, and food industries. The majority of agrochemical and pharmaceutical products undergo many crystallization steps during their development and manufacture, where corresponding processes serve as versatile techniques in separation, purification, and product design.[1,2] More than 90 % of all active pharmaceutical ingredients (APIs) are small organic molecules in the crystalline state.[2] Notably, the selection of suitable polymorphs of drug components plays a key role in formulation and manufacturing design, and it is crucial for achieving the desired solubility and stability properties.[3] Since solution.

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