Conformational and crystal energetics of a polymorphic cyclized product of Napafenac: The Z′ and crystal stability correlation

A Spontaneous Single-Crystal-to-Single-Crystal Polymorphic Transition Involving Major Packing Changes

“…In order to compare the stability of polymorphs α and β, it is necessary to get the total energies of polymorphs which is sum of conformer energy and packing energy. 8 Energy of S26 each conformer was calculated individually at B3LYP/6-31G(d,p) level of theory using Guassian09 package. 9 For these calculations, the crystallographic co-ordinates of these conformers are used.…”

“…Packing energy is calculated for each polymorph by using unified pairpotentials (UNI) force-field parameters in Mercury (version 3.3). 8 The position of hydrogen atoms are normalised to standard value of neutron diffraction bond distances. Both average conformer energy and packing energy were found to be lower for polymorph β indicating that the polymorph β is more stable than polymorph α. ΔG α→β was measured based on the differential solubility of polymorphs in same solvent as reported.…”

“…Comparison of relative energy of polymorphs, α & β.Nanbolu et al analysed 5.33 version of CSD to compare the stability of polymorphs of organic compounds 8. This analysis returned 83 polymorphic systems for which the thermodynamic stability data is available.…”

Conformational Polymorphism in Safinamide Acid Hydrochloride (Z′ = 3 and Z′ = 1) and Observation of a Temperature-Dependent Reversible Single-Crystal to Single-Crystal Phase Transformation of High-Z′ form (Z′ = 3 ↔ Z′ = 2 via an Intermediate Z′ = 4)

“…Organic molecules which crystallize with multiple molecules in the asymmetric unit, referred to as Z ′ > 1 or high- Z ′ structures, − continue to fascinate researchers, although several groups in the past have attempted to understand the Z ′ > 1 phenomenon. − The Cambridge Structural Database (CSD) reached a major milestone by depositing the millionth crystal structure in 2019 . The recent statistics of Z ′ > 1 in the CSD continue to be approximately 10–11% in organic structures and 8% in total CSD structures. − ,, A proper understanding of Z ′ and the expectation of a possible Z ′ > 1 crystal structure based on the molecular structure, functional groups, shape, and symmetry is regarded as an important strategy for an accurate crystal structure prediction (CSP) of drug molecules, − a structure determination by the powder X-ray diffraction (PXRD) method, − and the development of chiral materials. , The Z ′ > 1 structures are often termed as “frustrated” structures which are thought to arise from packing difficulties to crystallize as a single molecular entity .…”

“…The recent statistics of Z ′ > 1 in the CSD continue to be approximately 10–11% in organic structures and 8% in total CSD structures. − ,, A proper understanding of Z ′ and the expectation of a possible Z ′ > 1 crystal structure based on the molecular structure, functional groups, shape, and symmetry is regarded as an important strategy for an accurate crystal structure prediction (CSP) of drug molecules, − a structure determination by the powder X-ray diffraction (PXRD) method, − and the development of chiral materials. , The Z ′ > 1 structures are often termed as “frustrated” structures which are thought to arise from packing difficulties to crystallize as a single molecular entity . Steed wrote two detailed reviews on high- Z ′ structures, and the reasons for Z ′ > 1 occurrence are attributed to awkward molecular shape, the choice of slightly different molecular conformations, conflict from strong intermolecular interactions and crystal packing, pseudosymmetry, disorder, and temperature effects. , Experimental conditions under which the crystals are grown are shown to have a strong correlation with Z ′ > 1 behavior. , The connection between high- Z ′ structures and strong hydrogen bonds was noted by Gavezzotti, Nangia, Desiraju, Brock, , and others. , …”