Detailed Analysis of Packing Efficiency Allows Rationalization of Solvate Formation Propensity for Selected Structurally Similar Organic Molecules

In structural study of seven bile acids it was identified that their propensity for solvate formation is directly related to the packing efficiency of the unsolvated phases: low packing index, voids, and unsatisfied hydrogen bonding lead to extensive solvate formation, whereas efficient packing leads to the opposite. This was determined to be caused by the presence of OH group attached to carbon C12. Solvate formation was determined to provide a noticeable improvement in the packing efficiency for compounds having ansolvates with inefficient packing

Structural Characterization and Rationalization of Formation, Stability, and Transformations of Benperidol Solvates

Experimental and theoretical characterization and studies of phase transitions and stability of the solvates obtained in solvate screening of the pharmaceutical compound benperidol were performed to rationalize and understand the solvate formation, stability, and phase transitions occurring during their desolvation. The solvate screening revealed that benperidol can form 11 solvates, including two sets of isostructural solvates. The analysis of the solvate crystal structures and molecular properties indicated that benperidol solvate formation is mainly driven by the complications during packing of benperidol molecules in an energetically efficient way in the absence of solvent molecules, as well as by the compensation of an insufficient number of hydrogen bond donor moieties. Analysis of solvate structures, particularly those of isostructural solvates, revealed that both the possible interactions and the size and shape of the solvent molecules were important factors in solvate formation. Stability of the solvate was proved to be associated with the intermolecular interaction energies in the crystal structure. Desolvation studies of benperidol solvates identified two forces determining the polymorph obtained after desolvation: structural similarity with the solvate and the thermodynamic stability

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

Polymorphs and Hydrates of Sequifenadine Hydrochloride: Crystallographic Explanation of Observed Phase Transitions and Thermodynamic Stability

In this study, detailed analysis of crystal structures was used to rationalize the observed stability and phase transformations of sequifenadine hydrochloride polymorphs and hydrates, as well as to understand the observed structural diversity. The performed polymorph and hydrate screening revealed the existence of six polymorphs and four hydrates. Crystal structures of these phases were determined either from single crystal or from powder diffraction data. The different possibilities for packing of sequifenadine cations were found to be the main reason for the observed structural diversity of polymorphs. The hydrate structures were found to be structurally similar and related to those of particular polymorphs, which was consistent with the observed easy phase transitions among the related pairs

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

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

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 and Desolvation Mechanism of Organic Molecule Solvates: A Structural Study of Methyl Cholate Solvates

Solvate formation and the desolvation mechanism of 25 obtained methyl cholate solvates were rationalized using crystal structure analysis and study of the phase transformations. The facile solvate formation was determined to be associated with the possibility for more efficient packing in structures containing solvent molecules. Most of the obtained solvates crystallized in one of the six isostructural solvate groups, with solvent selection based on the solvent capability to provide particular intermolecular interactions along with appropriate size and shape. In crystal structures several different methyl cholate conformers were observed, as apparently more efficient packing could be achieved by diversifying the molecule conformation and even adopting energetically quite unfavorable conformations. Nevertheless, the packing was generally controlled by the steroid ring system, particularly employing hydrogen bonding of the attached hydroxyl groups. Study of the desolvation mechanism showed that the primary desolvation product is determined by the structure similarity with the solvate, with thermodynamic stability of the desolvate having no directly identifiable effect. In the case of the absence of an acceptable structurally similar desolvate, desolvation produced an amorphous phase

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