Solvent Effect on the Preparation of Ionic Cocrystals of dl-Amino Acids with Lithium Chloride: Conglomerate versus Racemate Formation

Oleksii Shemchuk,Dario Braga,Fabrizia Grepioni,Enrico Spoletti

doi:10.1021/acs.cgd.1c00216

Abstract

The hydrophobic dl-amino acids alanine, valine, leucine, and isoleucine have been cocrystallized with LiCl via solid-state and solution methods, and the effect of preparation conditions and solvent choice on the racemic versus conglomerate formation has been investigated. For the sake of comparison, enantiopure l-amino acids have also been reacted with LiCl in the same experimental conditions. With dl-alanine only, a racemic ionic cocrystal of formula dl-alanine·LiCl·H2O is obtained, irrespective of the preparation conditions, while the amino acids dl-valine and dl-leucine undergo spontaneous chiral resolution when MeOH is used in ball milling conditions, yielding monohydrated conglomerates, which at ambient conditions convert over time into the racemic ionic cocrystals dl-Val·LiCl·H2O and dl-Leu·LiCl·1.5H2O; these racemic ionic cocrystals (ICCs) are otherwise obtained in a single step if water is employed instead of MeOH, both in ball milling and solution conditions. dl-Isoleucine behaves differently, and product characterization is complicated by the presence of dl-alloisoleucine (dl-aIle) in the commercial starting material; solution crystallization in the presence of excess LiCl, however, unexpectedly results in the formation of the alloisoleucine conglomerate d-aIle·LiCl·H2O and l-aIle·LiCl·H2O, together with unreacted dl-isoleucine. Solid-state syntheses of the ionic cocrystals proceed in most cases via formation of intermediate metastable polymorphs; phase identification and structural characterization for all ICCs have been conducted via single crystal and/or powder X-ray diffraction.

Highlights

Cocrystallization has developed into an extremely attractive approach toward the formulation of new materials with active principles, providing a means to tune their physicochemical properties in their solid state
Cocrystals, both molecular and ionic, find applications, among others, in the fields of pharmaceuticals,[1−4] agrochemicals,[5−7] high-energy materials,[8−10] and nutraceuticals.[11−13] Ionic cocrystals (ICCs) constitute a class of multicomponent crystalline solids composed of neutral organic molecules and organic or inorganic salts in a defined stoichiometric ratio.[14−20] Pharmaceutical ICCs are of particular interest since the addition of charged components to the active pharmaceutical ingredient (API) of interest in its crystal can help in modulating the physicochemical and biological properties of the API.[21−24]
In order to investigate the possibility of spontaneous chiral resolution, the racemic amino acids DL-alanine (DL-Ala), DL

Summary

■ INTRODUCTION

Cocrystallization has developed into an extremely attractive approach toward the formulation of new materials with active principles, providing a means to tune their physicochemical properties in their solid state. Four DL-Amino Acids in Their Zwitterionic Forms Reacted with LiCl in the Solid State and in Solution, and the Effect of the Solvent Used on Conglomerate (D-ICC + L-ICC) and Racemic Compounds (DL-ICC) Formationa aSolvent used: H2O: blue arrows; MeOH: red arrows. X-ray diffraction patterns were collected on a PANalytical X’Pert Pro automated diffractometer with transmission geometry equipped with a focusing mirror and PIXcel detector, using Cu Kα radiation (λ = 1.5418 Å) without a monochromator in the 2θ range 3−60° It should be noted here that a full structural characterization of the two ICCs LLeu·LiCl·H2O form II and DL-Leu·LiCl·1.5H2O was only obtained by a combination of PXRD and single crystal X-ray diffraction data. Crystal data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ REFERENCES