Comparison and Rationalization of Droperidol Isostructural Solvate Stability: An Experimental and Computational Study

In order to find a tool for comparison of solvate stability and to rationalize their relative stability, droperidol nonstoichiometric isostructural solvates were characterized experimentally and computationally. For the experimental evaluation of stability, three comparison tools were considered: thermal stability characterized by the desolvation rate, desolvation activation energy, and solvent sorption–desorption isotherms. It was found that the desolvation process was limited by diffusion, and the same activation energy values were obtained for all of the characterized solvates, while the solvent content in the sorption isotherm was determined by the steric factors. Therefore, the only criterion characterizing the solvate stability in this particular system was the thermal stability. It was found that computationally obtained solvent–droperidol and solvent–solvent interaction energies could be used for the rationalization of the isostructural solvate stability in this system and that the solvent–solvent interaction energy has a crucial role in determining the stability of solvates

Experimental and Computational Study of Solid Solutions Formed between Substituted Nitrobenzoic Acids

We present an experimental and computational study of the formation of solid solutions in binary systems of substituted nitrobenzoic acids. Different isomers with a methyl group, hydroxyl group, and chlorine substituents are studied. We show that the solid solution formation likelihood evaluated based on the observed solubility limit is notably affected by both the exchanged functional groups and the location of the substituents in the molecular structure. This demonstrates that the component solubility limit strongly depends on the intermolecular interactions present in the crystal structure and is altered by the molecule replacement. Solid solutions form in all of the studied crystalline phases. Component solubility limits from ∼5% up to 50% were observed. The obtained results indicated that the calculated intermolecular interaction energy change by the functional group replacement does not allow rationalization of the experimentally observed solubilities, considering neither the molecules adjacent to the replace group nor all the molecules within a 15 Å radius. The relative energy of the experimental structures and isostructural phases obtained from the computationally generated structure landscapes calculated at the level providing accurate energy ranking was found to be mostly consistent with the experimentally observed component solubilities

On the Formation of Droperidol Solvates: Characterization of Structure and Properties

A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharamaceutical ingredient droperidol. The solvate screening revealed that droperidol can form 11 different solvates. The analysis of the crystal structures and molecular properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol molecules to pack efficiently. The obtained droperidol solvates were characterized by X-ray diffraction and thermal analysis. It was found that droperidol forms seven nonstoichiometric isostructural solvates, and the crystal structures were determined for five of these solvates. To better understand the structure of these five solvates, their solvent sorption–desorption isotherms were recorded, and lattice parameter dependence on the solvent content was determined. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of two hydrogen-bonded water molecules. Isostructural solvates were formed with sufficiently small solvent molecules providing effective intermolecular interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol molecules. Desolvation of stoichiometric droperidol solvates produced one of the four droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate

Designing Solid Solutions of Enantiomers: Lack of Enantioselectivity of Chiral Naphthalimide Derivatives in the Solid State

The enantiomers of a previously reported naphthalimide derivative are shown in this study to form a solid solution; furthermore, on the basis of the knowledge of solid solution structural aspects other naphthalimide derivatives have been synthesized and shown to lack the enantioselectivity in the solid state. The structural origin of solid solution formation is the same as observed in most of the cases in the literature<i>quasi</i>-centrosymmetric structures form at nonracemic compositions where the most abundant enantiomer adjusts its conformation to mimic the absent one. Such solid solutions belong to the type showing some enantioselectivity. An extended single crystal X-ray diffraction study of the crystals of different enantiomeric compositions reveals the nature of the disorder in studied solid solutions. Intermolecular interactions are analyzed in terms of Hirshfeld surfaces and by means of density functional theory calculations to explore the differences of isostructural <i>quasi</i>-centrosymmetric (enantiopure) and genuine centrosymmetric (racemic) packings to shed light on the energetic aspects of solid solution formation as well as to explain the origin of partial enantioselectivity. Furthermore, lattice energy calculations explain why two structurally distinct solid solutions (around the racemic and near the pure enantiomer regions) form as found for one of the studied compounds

On the Formation of Droperidol Solvates: Characterization of Structure and Properties

A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharamaceutical ingredient droperidol. The solvate screening revealed that droperidol can form 11 different solvates. The analysis of the crystal structures and molecular properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol molecules to pack efficiently. The obtained droperidol solvates were characterized by X-ray diffraction and thermal analysis. It was found that droperidol forms seven nonstoichiometric isostructural solvates, and the crystal structures were determined for five of these solvates. To better understand the structure of these five solvates, their solvent sorption–desorption isotherms were recorded, and lattice parameter dependence on the solvent content was determined. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of two hydrogen-bonded water molecules. Isostructural solvates were formed with sufficiently small solvent molecules providing effective intermolecular interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol molecules. Desolvation of stoichiometric droperidol solvates produced one of the four droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate

Formation and Transformations of Organic Salt Hydrates: Four Encenicline Hydrochloride Monohydrates and Respective Isostructural Desolvates

Encenicline hydrochloride (Enc-HCl) crystallizes in four different monohydrate phases, but at the same time crystallization in a nonsolvated phase is not observed, indicating that water plays a crucial role in guiding the crystallization process and ensuring structure stability. All monohydrate phases show exceptionally high stability, and the main structural motif stays intact even after dehydration, leading to isostructural (for I and II) or isomorphic (for III) desolvates. Three monohydrate phases with determined crystal structure information consists of Enc-HCl-water hexamers that are stacked into similar slabs, that are further packed identically in monohydrates I, II, and III. The features of these hexamer slabs determine the properties of the Enc-HCl monohydrates and dehydrates, the dehydration mechanism, and stability of each phase. It was justified that in the Enc-HCl system efficient intermolecular interactions provided by the incorporation of water in the crystal structure play a crucial role in stabilization of the structures

Single Enantiomer’s Urge to Crystallize in Centrosymmetric Space Groups: Solid Solutions of Phenylpiracetam

A detailed thermochemical and structural study of the phenylpiracetam enantiomer system was performed by characterizing the solid solutions, rationalizing the structural driving force for their formation, as well as identifying a common structural origin responsible for the formation of solid solutions of enantiomers. Enantiomerically pure phenylpiracetam forms two enantiotropically related polymorphs (<i>enant</i>–A and <i>enant</i>–B). The transition point (70(7) °C) was determined based on isobaric heat capacity measurements. Structural studies revealed that <i>enant</i>–A and <i>enant</i>–B crystallize in space groups <i>P</i>1 (<i>Z</i>′ = 4) and <i>P</i>2₁2₁2₁ (<i>Z</i>′ = 2), respectively. However, pseudoinversion centers were present resulting in apparent centrosymmetric structures. The quasi centrosymmetry was achieved by a large variety of phenylpiracetam conformations in the solid state (six in total). As a result, miscibility of the phenylpiracetam enantiomers in the solid state is present for scalemic and racemic samples, which was confirmed by the melt phase diagram. Racemic phenylpiracetam (<i>rac</i>–A) was determined to crystallize in the <i>P</i>1̅ space group being isostructural to <i>enant</i>–A; furthermore, disorder is present showing that enantiomers are distributed in a random manner. The lack of enantioselectivity in the solid state is explained. Furthermore, structural aspects of phenylpiracetam solid solutions are discussed in the scope of other cases reported in the literature

A Maze of Solid Solutions of Pimobendan Enantiomers: An Extraordinary Case of Polymorph and Solvate Diversity

Over 10 polymorphs and solvatomorphs of the chiral pharmaceutically active ingredient pimobendan were found to lack enantioselectivity in the solid state, accordingly, forming solid solutions of enantiomers, which is reported to be a rare phenomenon. Solid form screening was performed on different enantiomeric composition samples to analyze obtained phases with powder X-ray diffraction and thermogravimetric differential scanning calorimetry. For nonsolvated forms, a melt phase diagram has been constructed convincingly showing the existence of stable and metastable solid solutions near the pure enantiomer and around the racemic composition regions. A crystal structure study combined with solid-state NMR experiments was performed to analyze and explain structural aspects of pimobendan solid solutions. Furthermore, the driving force for the existence of such a surprisingly large amount of different solid state phases lacking enantioselectivity for a single compound is elucidated tracking down the origin of their formation to the molecular level