Directing Crystallization Outcomes of Conformationally Flexible Molecules: Polymorphs, Solvates, and Desolvation Pathways of Fluconazole.

Control over polymorphism and solvatomorphism in API assisted by structural information, e.g., molecular conformation or associations via hydrogen bonds, is crucial for the industrial development of new drugs, as the crystallization products differ in solubility, dissolution profile, compressibility, or melting temperature. The stability of the final formulation and technological factors of the pharmaceutical powders further emphasize the importance of precise crystallization protocols. This is particularly important when working with highly flexible molecules with considerable conformational freedom and a large number of hydrogen bond donors or acceptors (e.g., fluconazole, FLU). Here, cooling and suspension crystallization were applied to access polymorphs and solvates of FLU, a widely used azole antifungal agent with high molecular flexibility and several reported polymorphs. Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful control of the crystallization conditions. For the first time, two types of isostructural channel solvates of FLU were obtained (nine new structures). Type I solvates were prepared by cooling crystallization in Tol, ACN, DMSO, BuOH, and BuON. Type II solvates formed in DCM, ACN, nPrOH, and BuOH during suspension experiments. We propose desolvation pathways for both types of solvates based on the structural analysis of the newly obtained solvates and their desolvation products. Type I solvates desolvate to FLU form I by hydrogen-bonded chain rearrangements. Type II solvates desolvation leads first to an isomorphic desolvate, followed by a phase transition to FLU form II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated phase transformations with structural analysis and solid-state NMR, supported by periodic electronic structure calculations, allowed us to elucidate the interrelations and transformation pathways of FLU.

Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions.

A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including powder and single-crystal X-ray diffraction, solid-state NMR, and thermal analysis were employed, supplemented by periodic ab initio calculations. The molecular conformation in different solvates, types, and hierarchy of intermolecular interactions as well as the crystal packing were investigated to provide data for future research focused on studying protein-ligand interactions. Based on various methods of crystal structure analysis, including the interaction energy calculation and programs using an artificial neural network, a salicylamide fragment was found to be crucial for intermolecular contacts, mostly of dispersion and electrostatic character. A supramolecular 2D kite-type layer of {4,4} topology was found to form in crystals. The closed voids between layers contain disordered solvents, very weakly interacting with the molecule and the layer. It has been postulated that the separation of the layers might be influenced by an increase in temperature or the size of the solvent; hence, only methanol and ethanol hemi-solvates could be obtained from a series of various alcohols.

Salts of HCN-Cyanide Aggregates: [CN(HCN)2 ]- and [CN(HCN)3 ].

Although pure hydrogen cyanide can spontaneously polymerize or even explode, when initiated by small amounts of bases (e.g. CN- ), the reaction of liquid HCN with [WCC]CN (WCC=weakly coordinating cation=Ph4 P, Ph3 PNPPh3 =PNP) was investigated. Depending on the cation, it was possible to extract salts containing the formal dihydrogen tricyanide [CN(HCN)2 ]- and trihydrogen tetracyanide ions [CN(HCN)3 ]- from liquid HCN when a fast crystallization was carried out at low temperatures. X-ray structure elucidation revealed hydrogen-bridged linear [CN(HCN)2 ]- and Y-shaped [CN(HCN)3 ]- molecular ions in the crystal. Both anions can be considered members of highly labile cyanide-HCN solvates of the type [CN(HCN)n ]- (n=1, 2, 3 …) as well as formal polypseudohalide ions.

Crystallization of Esomeprazole Magnesium Water/Butanol Solvate.

The molecular structure of esomeprazole magnesium derivative in the solid-state is reported for the first time, along with a simplified crystallization pathway. The structure was determined using the single crystal X-ray diffraction technique to reveal the bonding relationships between esomeprazole heteroatoms and magnesium. The esomeprazole crystallization process was carried out in 1-butanol and water was utilized as anti-solvent. The product proved to be esomeprazole magnesium tetrahydrate with two 1-butanol molecules that crystallized in P63 space group, in a hexagonal unit cell. Complete characterization of a sample after drying was conducted by the use of powder X-ray diffraction (PXRD), ¹H-nuclear magnetic resonance (NMR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectroscopy (IR), and dynamic vapor sorption (DVS). Investigation by ¹H-NMR and TGA has shown that the solvent content in the dried sample consists of two water molecules and 0.3 butanol molecules per esomeprazole magnesium molecule. This is different from the single crystal X-ray diffraction results and can be attributed to the loss of some water and 1-butanol molecules stabilized by intermolecular interactions. The title compound, after drying, is a true solvate in terms of water; conversely, 1-butanol fills the voids of the crystal lattice in non-stoichiometric amounts.

Hydrogen Peroxide Solvates of 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane.

Two polymorphic hydrogen peroxide solvates of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20; wurtzitane is an alternative name to iceane) were obtained using hydrated α-CL-20 as a guide. These novel H2 O2 solvates have high crystallographic densities (1.96 and 2.03 g cm-3 , respectively), high predicted detonation velocities/pressures (with one solvate performing better than ϵ-CL-20), and a sensitivity similar to that of ϵ-CL-20. The use of hydrated materials as a guide will be important in the development of other energetic materials with hydrogen peroxide. These solvates represent an area of energetic materials that has yet to be explored.

Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.

The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.

New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility.

Salts of the antiviral drug Arbidol (umifenovir) with pharmaceutically relevant benzoate and salicylate anions were obtained, and their crystal structures were described. For Arbidol salicylate, an unstable solvate with acetonitrile was also found and characterized. Analysis of the conformational preferences of the Arbidol molecule in the crystal structures showed that it adopts two types of conformations, namely "open" and "closed", both of which correspond to local conformational energy minima of the isolated molecule. Thermal stability of the Arbidol salicylate solvates with chloroform and acetonitrile was analyzed by means of differential scanning calorimetry and thermogravimetric analysis. The standard thermodynamic functions of the salt formation were determined. The Gibbs energy change of the process was found to be negative, indicating that the formation of the salts from individual components is a spontaneous process. The dissolution study of the Arbidol salts performed in aqueous buffer solutions with pH 1.2 and 6.8 showed that both salts dissolve incongruently to form an Arbidol hydrochloride monohydrate at pH 1.2 and an Arbidol base at pH 6.8, respectively.

Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol.

(13)C, (15)N and (2)H solid-state NMR spectroscopy have been used to rationalize arrangement and dynamics of solvent molecules in a set of isostructural solvates of droperidol. The solvent molecules are determined to be dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. (2)H NMR spectra of deuterium-labelled samples allowed the characterization of the solvent molecule dynamics in the alcohol solvates and the non-stoichiometric hydrate. The likely motion of the alcohol molecules is rapid libration within a site, plus occasional exchange into an equivalent site related by the inversion symmetry, while the water molecules are more strongly disordered. DFT calculations strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent molecule.

Supramolecular synthons in hydrates and solvates of lamotrigine: a tool for cocrystal design.

The molecule of anti-epileptic drug lamotrigine [LAM; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is capable of the formation of multicomponent solids. Such an enhanced tendency is related to the diverse functionalities of the LAM chemical groups able to form hydrogen bonds. Two robust synthons are recognized in the supramolecular structure of LAM itself formed via N-H...N hydrogen bond: homosynthon, so-called aminopyridine dimer or synthon 1 [R22(8)] and larger homosynthon 2 [R32(8)]. The synthetic procedures for a new hydrate and 11 solvates of LAM (in the series: with acetone, ethanol: two polymorphs: form I and form II, 2-propanol, n-butanol, tert-butanol, n-pentanol, benzonitrile, acetonitrile, DMSO and dioxane) were performed. The comparative solid state structural analysis of a new hydrate and 11 solvates of LAM has been undertaken in order to establish robustness of the supramolecular synthons 1 and 2 found in the crystal structure of LAM itself as well as LAM susceptibility to build methodical solid state supramolecular architecture in the given competitive surrounding of potential hydrogen bonds. The aminopyridine dimer homosynthon 1 [R22(8)] has been switched from para-para (P-P) topology to ortho-ortho (O-O) topology in all crystal structures, except in LAM:n-pentanol:water solvate where it remains P-P. Homosynthon 2 [R32(8)] of the LAM crystal structure imitates in the LAM solvates as a heterosynthon by replacing the triazine nitrogen proton acceptor atoms of LAM with the proton acceptors of solvates molecules.

Relating solvatochromism and solvatomorphism in organic dyes using high pressure.

By using complementary experimental methods including in situ high-pressure single-crystal X-ray diffraction and UV-Vis spectroscopy, the intricate connection between solvatochromism and solvatomorphism has been elucidated in a recent publication [Sobczak & Katrusiak (2024). IUCrJ, 11, 528-537]. The connection was demonstrated for an important pigment - Reichardt's dye - with potential applications in nonlinear optoelectronics and molecular pressure sensor development.

Formation of ibrutinib solvates: so similar, yet so different.

The transformation processes of non-solvated ibrutinib into a series of halogenated benzene solvates are explored in detail here. The transformation was studied in real time by X-ray powder diffraction in a glass capillary. Crystal structures of chlorobenzene, bromobenzene and iodobenzene solvates are isostructural, whereas the structure of fluorobenzene solvate is different. Four different mechanisms for transformation were discovered despite the similarity in the chemical nature of the solvents and crystal structures of the solvates formed. These mechanisms include direct transformations and transformations with either a crystalline or an amorphous intermediate phase. The binding preference of each solvate in the crystal structure of the solvates was examined in competitive slurry experiments and further confirmed by interaction strength calculations. Overall, the presented system and online X-ray powder diffraction measurement provide unique insights into the formation of solvates.

Solid Forms of The New Antitrypanosomal 1-(4-Acetamide-Benzenesulfonyl)-Benzimidazole: Preparation and Physicochemical Characterization.

This study aimed to investigate the polymorphism of 1-(4-acetamide-benzenesulfonyl)-benzimidazole (PABZI), a newly developed compound with significant activity against Trypanosoma cruzi, the parasite which causes American trypanosomiasis (Chagas disease). Three different crystalline forms of PABZI [a solvent-free form (form I), three isostructural solvates (from isopropanol; acetonitrile-dichloromethane, and methanol-benzene) and a non-isostructural solvate from methanol] were isolated and characterized. The crystal structure of form I was resolved at 173 K and 300 K by single crystal X-ray diffraction. Physicochemical properties, including solubility, dissolution rate, wettability, and solid-state stability were assessed for the two most viable solid forms of PABZI, viz. form I and the isopropanol solvate (PABZI-isoOH). Form I exhibited a higher solubility and dissolution rate, and superior stability towards moisture (40 °C/75 % relative humidity) and UV-Visible light than PABZI-isoOH. Based on the solid-state stability results, form I was selected over PABZI-isoOH for further preclinical studies.

Praziquantel Fifty Years on: A Comprehensive Overview of Its Solid State.

This review discusses the entire progress made on the anthelmintic drug praziquantel, focusing on the solid state and, therefore, on anhydrous crystalline polymorphs, amorphous forms, and multicomponent systems (i.e., hydrates, solvates, and cocrystals). Despite having been extensively studied over the last 50 years, new polymorphs and the greater part of their cocrystals have only been identified in the past decade. Progress in crystal engineering science (e.g., the use of mechanochemistry as a solid form screening tool and more strategic structure-based methods), along with the development of analytical techniques, including Synchrotron X-ray analyses, spectroscopy, and microscopy, have furthered the identification of unknown crystal structures of the drug. Also, computational modeling has significantly contributed to the prediction and design of new cocrystals by considering structural conformations and interactions energy. Whilst the insights on praziquantel polymorphs discussed in the present review will give a significant contribution to controlling their formation during manufacturing and drug formulation, the detailed multicomponent forms will help in designing and implementing future praziquantel-based functional materials. The latter will hopefully overcome praziquantel's numerous drawbacks and exploit its potential in the field of neglected tropical diseases.

Cocrystals, Salts, and Salt-Solvates of olanzapine; selection of coformers and improved solubility.

Pharmaceutical cocrystals and salts are extensively researched in recent years due to their ability to tune the physicochemical properties of active pharmaceutical ingredients (APIs). A model API, olanzapine, an atypical antipsychotic drug classified as Biopharmaceutical Classification System class II, is used in this study. Cocrystals and salts of olanzapine are discovered using solvent drop grinding and ball milling. Appropriate coformers were selected based on a combination of hydrogen-bond propensity (HBP) and hydrogen-bond coordination (HBC) calculations. Eight new multicomponent phases of olanzapine, including one cocrystal hydrate with phenol; four anhydrous salts with salicylic acid, terephthalic acid, anthranilic acid, 3-hydroxybenzoic acid, and 2-aminoterephthalic acid; one salt dihydrate with terephthalic acid; and one salt solvate with 3-hydroxybenzoic acid and acetonitrile, have been discovered and characterized by PXRD and DSC. One reported cocrystal (olanzapine-resorcinol) has also been considered for the dissolution test. All these newly formed solid phases followed the "ΔpKa rule of 3". The crystal structures of cocrystal/salts were determined by single-crystal X-ray (sc-XRD) diffraction. With the collected single-crystal data, the crystal packings were found to be primarily stabilized via strong hydrogen bonds between carboxyl, phenolic hydroxyl of co-formers/salt-formers with the piperazine and diazepine nitrogen of olanzapine, which confirmed the predicted result from the HBP and HBC calculations. HPLC coupled with UV-vis detector was used in the solubility and dissolution test instead of UV-vis spectroscopy, to avoid the peak overlap between olanzapine and co-formers/salt-formers. A threefold increase in the solubility was observed in olanzapinium 3-hydroxybenzoate and olanzapinium anthranilate, and an almost fivefold increase in solubility of olanzapinium 2-aminoterephthalate.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases.

The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained when crystallized from selected solvents. A combined study using crystal structure and molecule electrostatic potential surface analysis, as well as an exploration of molecular association in solution using spectroscopic methods and molecular dynamics simulations were used to determine the possible mechanism of how the location of the phenolic hydroxyl groups affect the diversity of solid phases formed by the diOHBAs. The crystal structure analysis showed that classical carboxylic acid homodimers and ring-like hydrogen bond motifs consisting of six diOHBA molecules are prominently present in almost all analyzed crystal structures. Both experimental spectroscopic investigations and molecular dynamics simulations indicated that the extent of intramolecular bonding between carboxyl and hydroxyl groups in solution has the most significant impact on the solid phases formed by the diOHBAs. Additionally, the extent of hydrogen bonding with solvent molecules and the mean lifetime of solute-solvent associates formed by diOHBAs and 2-propanol were also investigated.

Solid-State Overview of R-Baclofen: Relative Stability of Forms A, B and C and Characterization of a New Heterosolvate.

A new polymorphic form (Form C) of enantiopure Baclofen was isolated and characterized. Crystal structures of R-Baclofen Form A and Form C were resolved from powder diffraction data, and cell parameters by profile matching for Form B. The relative stability of these three forms is proposed based on structural data, thermal analyses and solvent-mediated conversions. The experiments highlight the stability order A < C < B at 25 °C (A is the most stable form), whereas above 180 °C it would likely be: C < A < B (C being the stable modification). Moreover, a new heterosolvate of the molecule is observed in N,N-DMF/water mixture. This heterosolvate offers a new pathway to isolate pure R-Baclofen Form B provided the lactam impurity does not exceed 3%. Upon mechanical stress Form B tends to evolve to Form C.

Crystal structures of 3ß,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [(5).H2O]: A survey of the structures of related di- and tri-substituted hydroxy derivatives and their solvated compounds.

The crystal structures of 3ß,19-dihydroxyandrost-5-en-17-one, 5, and its monohydrate, [((5).H2O]], are reported. The monohydrate, isolated from a solution of 5 in 50% aqueous methanol, recrystallizes in the orthorhombic space group, P212121, while that of the anhydrous compound, isolated from solutions of THF, Me2CO, EtOAc or dry MeOH, recrystallizes in the monoclinic space group, P21. Apart from the different orientation of the 3-HO group, the conformations of the steroid molecules in 5 and [(5).H2O]: are similar. The two-dimensional structure of 5 consists of sheets of molecules formed from strong classical O3-H3⋯O19(OH) and O19-H19···O3(OH), augmented by weaker C-H⋯O hydrogen bonds. Noticeably the presence of the C19 hydroxyl group results in the replacement of the O3-H3⋯O17(one) hydrogen bonds as the strongest intermolecular interaction found in the stable polymorphs of the mono-hydroxylated compound, 3ß-hydroxyandrost-5-en-17-one (dehydroepiandrosterone). An additional structural difference between 3ß-hydroxyandrost-5-en-17-one and 3ß,19-dihydroxyandrost-5-en-17-one is that the steroid molecules are most strongly linked head-to-tail in the former but head-to-middle fashion in the latter. In the three dimensional structure of [((5).H2O]], each steroid molecule is directly connected to another by a O19-H19⋯O3(OH) hydrogen bond and indirectly to two others via the water molecule. Each water molecule forms three hydrogen bonds, namely O3-H3⋯Ow, Ow-Hw1⋯O17 and Ow-Hw2⋯O19. As found for most hydrated steroids, the hydrate molecules have strong influences on the structure. In addition to the reporting of the crystal structures of 5 and [(5).H2O], we report on a survey of the crystal structures of related di- and tri- hydroxy-17-one derivatives as well as solvated compounds.

High-pressure preference for reduced water content in porous zinc aspartate hydrates.

The zinc aspartate (ZnAsp2) complex, a common dietary supplement, preferentially crystallizes as the dihydrate (ZnAsp2·2H2O) from aqueous solution. Under normal conditions the dihydrate easily transforms into the sesquihydrate (ZnAsp2·1.5H2O). The dihydrate crystal structure is triclinic, space group P1, and the sesquihydrate is monoclinic, space group C2/c. However, their structures are closely related and similarly consist of zinc aspartate ribbons parallel to pores accommodating water molecules. These porous structures can breathe water molecules in and out depending on the temperature and air humidity. High pressure above 50 MPa favours the sesquihydrate, as shown by recrystallizations under pressure and compressibility measured by single-crystal X-ray diffraction up to 4 GPa. This preference is explained by the reduced volume of the sesquihydrate and water compressed separately, compared with the dihydrate. The sesquihydrate undergoes an isostructural phase transition when the voids collapse at 0.8 GPa, whereas no phase transitions occur in the dihydrate, because its pores are supported by increased water content.

Solvation of anions in acetonitrile solutions: FTIR and quantum chemical study for Br-, ClO4-, AsF6-, and CF3SO3.

Anion solvation in acetonitrile solutions was comparatively studied using FTIR spectroscopy and quantum chemical calculations at the RTF + MP2/6-311G** level of theory with solvation model density (SMD) corrections. Infrared spectra for all stable anionic complexes X-(CH3CN)n (where X- = Br- (monatomic halide), ClO4- (polyatomic tetrahedral), AsF6- (polyatomic octahedral), CF3SO3- (polyatomic ethane-like) and n = 1-8) were calculated and subsequently used in the analysis of the FTIR spectra of (Bu4N)X and LiX acetonitrile solutions across a wide range of concentrations. Spectroscopic manifestations of solvation were established for all X- examined. The results for all four anions under investigation were generalized to reveal the regularities of anion solvation by acetonitrile.