New Crystal Forms for Biologically Active Compounds. Part 2: Anastrozole as N-Substituted 1,2,4-Triazole in Halogen Bonding and Lp-π Interactions with 1,4-Diiodotetrafluorobenzene

Mariya A Kryukova,Mikhail Krasavin,Alexander S Novikov,Alexander V Sapegin,Daniil M Ivanov

doi:10.3390/cryst10050371

Abstract

For an active pharmaceutical ingredient, it is important to stabilize its specific crystal polymorph. If the potential interconversion of various polymorphs is not carefully controlled, it may lead to deterioration of the drug’s physicochemical profile and, ultimately, its therapeutic efficacy. The desired polymorph stabilization can be achieved via co-crystallization with appropriate crystallophoric excipients. In this work, we identified an opportunity for co-crystallization of anastrozole (ASZ), a well-known aromatase inhibitor useful in second-line therapy of estrogen-dependent breast cancer, with a classical XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB). In the X-ray structures of ASZ·1.5 (1,4-FIB) co-crystal, different non-covalent interactions involving hydrogen and halogen atoms were detected and studied by quantum chemical calculations and QTAIM analysis at the ωB97XD/DZP-DKH level of theory.

Highlights

The generation of a new salt form is a proven way to modify the physical and chemical properties of an active pharmaceutical ingredient (API) [1]
In continuation of our efforts to identify new crystalline forms for APIs that would be stabilized by halogen bonding [14,15], we turned our attention to screening of crystallization conditions for the title compound, anastrozole
Slow evaporation of a MeOH solution of ASZ with 1,4-FIB taken in a 1:1 ratio leads to the formation on single crystals of ASZ·1.5(1,4-FIB) suitable for the X-ray diffraction experiment

Summary

Introduction

The generation of a new salt form is a proven way to modify the physical and chemical properties of an active pharmaceutical ingredient (API) [1]. Despite the emergence of this intriguing supramolecular interaction, halogen-bonded API co-crystals remain relatively scarce. This may have to do with the limited range of pharmaceutically acceptable excipients containing polarized halogen atoms [13]. In continuation of our efforts to identify new crystalline forms for APIs that would be stabilized by halogen bonding [14,15], we turned our attention to screening of crystallization conditions for the title compound, anastrozole (IUPAC name 2,20 -(5-((1H-1,2,4-triazol-1-yl)methyl)-1,3-phenylene)bis(2-methylpropanenitrile), abbreviated as ASZ), which is an aromatase inhibitor useful in second-line therapy of estrogen-dependent breast cancer [16,17,18]

Methods

Results

Conclusion