Investigation of an Unusual Crystal Habit of Hydrochlorothiazide Reveals Large Polar Enantiopure Domains and a Possible Crystal Nucleation Mechanism

Abstract

The observation of an unusual crystal habit in the common diuretic drug hydrochlorothiazide (HCT), and identification of its subtle conformational chirality,has stimulated ad etailed investigation of its crystalline forms.E nantiomeric conformers of HCT resolve into an unusual structure of conjoined enantiomorphic twin crystals comprising enantiopure domains of opposite chirality.The purity of the domains and the chiral molecular conformation are confirmed by spatially revolved synchrotron micro-XRD experiments and neutron diffraction, respectively.M acroscopic inversion twin symmetry observed between the crystal wings suggests apseudoracemic structure that is not as olid solution or al ayered crystal structure,but an unusual structural variant of conglomerates and racemic twins.C omputed interaction energies for molecular pairs in the racemic and enantiopure polymorphs of HCT,a nd the observation of large opposing unit-cell dipole moments for the enantiopure domains in these twin crystals, suggest ap lausible crystal nucleation mechanism for this unusual crystal habit.

The Advent of Quantum Crystallography: Form and Structure Factors from Quantum Mechanics for Advanced Structure Refinement and Wavefunction Fitting

“…HAR confirmed the pyramidal geometry and the approximate IAM position unambiguously (Fig. 23, unpublished results) [159]. The pyramidal geometry around the sultam N atom was initially found from HAR and was confirmed by the structural model from the neutron diffraction data [159].…”

“…23, unpublished results) [159]. The pyramidal geometry around the sultam N atom was initially found from HAR and was confirmed by the structural model from the neutron diffraction data [159]. Although HAR is a new technique, it is now sufficiently well tested for scientific referees in the crystallography/structural chemistry community to begin trusting its benefits.…”

“…Crystals of the diuretic drug hydrochlorothiazide (HCT), a sulfonamide, show an unusual enantiomorphic twin crystal growth and the crystal structure indicates a subtle chirality phenomenon at the nitrogen atom (Fig. 23) [159]. The focus of this study was the geometry at the N atom and hence the location of the proton attached to it.…”

Metastable Chiral Azobenzenes Stabilized in a Double Racemate

“…In contrast to enantiopure organic materials, which have specific requirements, racemic systems have convenient properties, for example, ease of crystallization, and have therefore gained significance in recent years . Since Pasteur's first observation of enantioselective crystal formation from a racemic solution, termed conglomerates, a variety of crystalline packing arrangements originating from racemic mixtures have been reported (Scheme ) . Racemic crystallography, since the first theoretical prediction of it in 1995, has been widely applied for protein‐structure determination and structural elucidation of nucleic acids in the past decade …”

“…[7] Since Pasteurs first observation of enantioselective crystal formation from ar acemic solution, termed conglomerates, [8,9] av ariety of crystalline packing arrangements originating from racemic mixtures have been reported (Scheme 1). [10][11][12] Racemic crystallography,s ince the first theoretical prediction of it in 1995, [13,14] has been widely applied for protein-structure determination and structural elucidation of nucleic acids in the past decade. [14,15] Ac rystalline supramolecular assembly with two or more distinct molecules connected by various non-covalent interactions,t hat is,acocrystal, holds tremendous potential for novel functionalities that ensue from the synergy of its components.Racemic A + /A À molecular units in the presence of additional chiral or achiral (B + /B) agents have ag eneral tendency to retain the inherent chiral/achiral nature of the added co-formers while assembling either into the same crystal system (diastereomeric,S cheme 1a,f-i)o rs eparate as different crystalline units (Scheme 1b,e).…”