Ionic Cocrystals Research Articles

Structure of ionic cocrystals piperidinium 2-thiobarbiturate–2-thiobarbituric acid

The structure of ionic cocrystals of piperidinium 2-thiobarbiturate with 2-thiobarbituric acid PipeH+(HTBA−)H2TBA (I) (H2TBA is 2-thiobarbituric acid, Pipe is piperidine) is determined. The asymmetric unit of I contains a H2TBA molecule in the form of thionemonocarbonyl tautomer, the HTBA–ion, and the PipeH+ piperidinium ion. The structure is stabilized by the intermolecular O–H•••O, N–H•••S, and N–H•••O hydrogen bonds (HBs) forming a three-dimensional framework. The results of single crystal XRD and IR spectroscopy indicate the formation of strong O–H•••O HB. The topological analysis of the HB network in I is performed.

Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization

Vinpocetine is a poorly water soluble weakly basic drug (pKa = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability.

The Future of Structural Chemistry Nucleates in the Present

AbstractA personal view of nearly four decades of structural chemistry is presented. The rise of molecular crystal engineering as an independent cross‐disciplinary field of research at the intersection of crystallography with supramolecular chemistry and solid‐state reactivity is discussed in light of the development of theoretical and instrumental tools and the need for novel molecular materials. The exchange of ideas and experience within the structural chemistry community has played a fundamental role in reaching the present high level of understanding of the factors that control crystal formation and stability. Crystal‐oriented synthetic strategies, including solvent‐free mechanochemical methods, have been developed, as well as screening methods and computational approaches. Some drawbacks and limitations are also discussed. The wealth of multiple crystal forms, from single‐molecule crystals to solvates, co‐crystals, salts and ionic co‐crystals, and their polymorphs, is both an open challenge to the crystal engineering paradigm and a source of discovery and innovation.

ChemInform Abstract: Pharmaceutical Cocrystals: Along the Path to Improved Medicines

AbstractReview: [158 refs.

Interactions of alkali- and alkaline earth-halides with carbohydrates in the crystalline state – the overlooked salt and sugar cocrystals

Ionic cocrystals have recently gained attention as multi-component pharmaceutical materials capable of improving the physicochemical properties of the respective pharmaceutically active compound. Contrastingly, ionic cocrystals between common carbohydrates and alkali or alkaline earth halides have been investigated since the beginning of chemistry. This is well reflected in the multitude of denominations attached to this class of crystalline species over the years, e.g. adducts, binary compounds, complexes, cocrystals, ionic cocrystals or metal–organic frameworks. Throughout several centuries, these compounds have been inspected with the specific perspective of contemporary interest. In most cases, they can conveniently be prepared from the ionic salt and the respective neutral carbohydrate via solution crystallization or mechanochemical approaches and therefore offer an opportunity for fundamental studies in the fields of crystal engineering and solid state chemistry, bridging traditional organic and inorganic chemistry. Certainly ionic cocrystals remain an underexplored class of compounds and this review gives an in-depth overview of the work that has been performed until today, hoping to elicit further contributions in the discipline.

From isomorphous to “anisomorphous” ionic co-crystals of barbituric acid upon dehydration and return

The isomorphous hydrated ionic co-crystals (ICCs) of barbituric acid (BA) of the formula BA·MBr·2H2O (M = Na, K, Rb) can be easily dehydrated to the corresponding anhydrous ICCs BA·MBr (M = Na, K, Rb). The three anhydrous crystals possess different structures that revert to the isomorphous crystals upon hydration. Only BA·RbBr is stable in air, making it possible to determine its crystal structure from single-crystal X-ray diffraction. BA·NaBr and BA·KBr rapidly absorb water from air and convert to the hydrated form. The crystal structures of BA·NaBr and BA·KBr have been determined by X-ray powder diffraction in sealed capillaries. Solid-state NMR spectroscopy was fundamental in determining the number of independent molecules in the asymmetric unit for the structural determination of the ICC BA·NaBr. The dehydration process was characterized by variable temperature X-ray powder diffraction, DSC and TGA.

Hydrogen Bond Hierarchy: Persistent Phenol···Chloride Hydrogen Bonds in the Presence of Carboxylic Acid Moieties

Crystal engineering strategies have been delineated during the past decade for the design of multi-component molecular crystals (molecular cocrystals, MCCs). However, the same depth of understanding has not yet been established for cocrystals that are comprised of at least one ionic compound (ionic cocrystals, ICCs). We address this long known but understudied class of cocrystals through the use of organic cation chloride salts as cocrystal formers with carboxylic acids and phenols. Such ICCs are of particular interest for both fundamental and applied reasons. With respect to the former, carefully selected molecular cocrystal formers (coformers) enable systematic study of the hierarchy of hydrogen bonds. With respect to the latter, chloride anions, phenol groups, and carboxylic acid moieties are prevalent in biologically active drug substances and nutraceuticals. In this contribution, we evaluated the propensity to form chloride···carboxylic acid vs chloride···phenol hydrogen bonds (supramolecular heteros...

Ionic Cocrystals of Pharmaceutical Compounds: Sodium Complexes of Carbamazepine

Three inorganic cocrystal (ICC) forms of carbamazepine (CBZ) have been synthesized, and their crystal structures are described. [Na(CBZ)4(MeOH)][I]·H2O, [Na(CBZ)5][I3], and [Na(CBZ)5][C13H10N][IBr2]2 are the first CBZ structures that contain metal cations, and the latter example also contains acridinium, which is a known metabolite of CBZ. All three Na complexes have distorted square pyramidal NaO5 coordination geometries but different conformations of the four basal ligands and different hydrogen bonding interactions for the apical ligand. The hydrogen bonded synthons that have been identified for other species that contain neutral CBZ molecules are absent in all these Na containing ICC phases and are replaced by Na–O dative bonds. However, previously identified nonpolar supramolecular constructs in the form of stacks and dimers are shared with other CBZ containing structures.

Physical Stability Enhancement and Pharmacokinetics of a Lithium Ionic Cocrystal with Glucose

Current lithium drugs are plagued with a narrow therapeutic window and tend to be hygroscopic. However, they remain the gold standard for treating manic episodes in bipolar disorder. In this contribution, we report a crystal engineering study aimed at the preparation and characterization of ionic cocrystals (ICCs) of lithium chloride (LIC) and lithium bromide (LIB) with glucose (GLU). The structure of LIBGLU was studied by single-crystal X-ray diffraction and found to be isostructural with related sodium chloride–glucose ICCs. The physical stability of LICGLU was compared to that of LIC at 50% RH and 25 °C and through dynamic vapor sorption analysis. The blood and brain pharmacokinetics of LICGLU were compared to those of LIC in rat models and revealed little change in performance. This study reveals that ICCs can modestly improve the solid-form stability of lithium salts without impacting in vivo performance, a step toward enabling the development of the next generation of lithium therapeutics.

Cocrystallization of photosensitive energetic copper(II) perchlorate complexes with the nitrogen-rich ligand 1,2-Di(1H-tetrazol-5-yl)ethane.

Two recently introduced concepts in the design of new energetic materials, namely complexation and cocrystallization, have been applied in the synthesis and characterization of the energetic copper(II) compound "[Cu(dt-5-e)2(H2O)](ClO4)2," which consists of two different complex cations and can be described as a model energetic ionic cocrystal. The presence of both the N-rich 1,2-di(1H-tetrazol-5-yl)ethane ligand and oxidizing perchlorate counterion results in a new type of energetic material. The ionic complex cocrystal consists of a mononuclear and a trinuclear complex unit. It can be obtained by precipitation from perchloric acid or by dehydration of the related mononuclear coordination compound [Cu(dt-5-e)2(H2O)2](ClO4)2·2H2O at 70 °C in the solid state. The transformation starting at 60 °C was monitored by X-ray powder diffraction and thermal analysis. The energetic ionic cocrystal was shown to be a new primary explosive suitable for laser ignition. The different coordination spheres within the ionic cocrystal (octahedral and square pyramidal) were shown by UV/vis/NIR spectroscopy to result in excellent light absorption.

Enhancing the Solubility of 6-Mercaptopurine by Formation of Ionic Cocrystal with Zinc Trifluoromethanesulfonate: Single-Crystal-to-Single-Crystal Transformation

An antitumor drug, 6-mercaptopurine monohydrate (MP·H2O), has a low oral bioavailability due to its poor aqueous solubility. In order to improve its solubility, two ionic cocrystals of 6-mercaptopurine with zinc trifluoromethanesulfonate (Zn(CF3SO3)2), [Zn(MP)2(H2O)2](CF3SO3)2·2H2O (1) and [Zn(MP)2](CF3SO3)2 (2), were prepared. Slow evaporation of the methanol solution containing 1 gave the crystals of [Zn(MP)2(H2O)(MeOH)](CF3SO3)2·H2O (1a). Single-crystal-to-single-crystal transformation occurred under certain conditions, in which 1a transformed to 1 in the open air around 10 °C, and 1 further transformed to [Zn(MP)2(H2O)](CF3SO3)2 (1b) at room temperature (∼25 °C) and low RH%. The structures of 1, 1a, and 1b were determined by single crystal X-ray diffraction, in which MP and Zn(CF3SO3)2 were assembled via coordination bonds and hydrogen bonds, and the coordination geometry of Zn(II) changed from octahedron in 1 and 1a to square pyramid in 1b. After the formation of ionic cocrystals of 1 and 2, both the...

Direct investigation of halogen bonds by solid-state multinuclear magnetic resonance spectroscopy and molecular orbital analysis.

Noncovalent interactions play a ubiquitous role in the structure, stability, and reactivity of a wide range of molecular and ionic cocrystals, pharmaceuticals, materials, and biomolecules. The halogen bond continues to be the focus of much attention, due in part to its strength and unique directionality. Here, we report a multifaceted experimental and computational study of halogen bonds in the solid state. A series of cocrystals of three different diiodobenzene molecules and various onium halide (Cl(-) or Br(-)) salts, designed to exhibit moderately strong halogen bonds (C-I···X(-)) in the absence of competing hydrogen bonds, has been prepared and characterized by single-crystal X-ray diffraction. Interestingly, a wide range of geometries about the halide anion are observed. (35/37)Cl and (79/81)Br solid-state NMR spectroscopy is applied to characterize the nuclear quadrupolar coupling constants (C(Q)) and asymmetry parameters (η(Q)) for the halogen-bonded anions at the center of bonding environments ranging from approximately linear to distorted square planar to octahedral. The relationship between the halogen bond environment and the quadrupolar parameters is elucidated through a natural localized molecular orbital (NLMO) analysis in the framework of density functional theory (DFT). These calculations reveal that the lone pair type orbitals on the halogen-bonded anion govern the magnitude and orientation of the quadrupolar tensor as the geometry about the anion is systematically altered. In -C-I···X(-)···I-C- environments, the value of η(Q) is well-correlated to the I···X(-)···I angle. (13)C NMR and DFT calculations show a correlation between chemical shifts and halogen bond strength (through the C-I distance) in o-diiodotetrafluorobenzene cocrystals. Overall, this work provides a chemically intuitive understanding of the connection between the geometry and electronic structure of halogen bonds and various NMR parameters with the aid of NLMO analysis.

Ionic co-crystals of racetams: solid-state properties enhancement of neutral active pharmaceutical ingredients via addition of Mg2+ and Ca2+ chlorides

Mechanochemical and solution based reactions of solid brivaracetam (BRV) and seletracetam (SEL), antiepileptic drugs from UCB's pipeline, with the inorganic salts MgCl2 and CaCl2, yield ionic co-crystals with changed or improved physico-chemical properties with respect to pure drugs (melting point, hygroscopicity, crystal morphology). All co-crystals are characterized via a combination of solid-state techniques, i.e. single crystal and powder X-ray diffraction, variable temperature X-ray diffraction, DSC, TGA and hot-stage microscopy (HSM).

Crystal form selectivity by humidity control: the case of the ionic co-crystals of nicotinamide and CaCl2

Post-synthesis (de)hydration techniques were used here to explore further hydrated forms of ionic co-crystals (ICCs) of nicotinamide with CaCl2.

Improving Lithium Therapeutics by Crystal Engineering of Novel Ionic Cocrystals

Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium’s polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics.

Further studies on ionic co-crystals: dehydration and hydration behaviour

Further studies on ionic co-crystals: dehydration and hydration behaviour

Understanding the Effects of Ionicity in Salts, Solvates, Co-Crystals, Ionic Co-Crystals, and Ionic Liquids, Rather than Nomenclature, Is Critical to Understanding Their Behavior

The incorporation of active pharmaceutical ingredients (APIs) into multicomponent solid forms (such as salts and co-crystals) or liquid forms (such as ionic liquids (ILs) or deep eutectic mixtures) is important in optimizing the efficacy and delivery of APIs. However, there is a current debate regarding the classification of these multicomponent systems based on their ionicity which could interfere with their consideration in important applications. Multicomponent systems of intermediate ionicity can show a combination of properties, leading to behavior that is neither strictly typical of either purely ionic or purely neutral compounds, nor easily described as intermediate between the two. In this perspective, we attempt to illustrate the problems in classifying multicomponent APIs based on one of two categories by discussing selected literature regarding solid and liquid multicomponent APIs and presenting the crystal structures of some relevant systems as case studies. It is clear that a focus on restric...

Building multi-component crystals from cations and co-crystals: the use of chaperones

Ternary crystalline complexes consisting of both salts and ionic co-crystals have been created through the crystallisation of the binary co-crystal 3,5-dinitrobenzoic acid–4-(dimethylamino)benzoic acid with group 1 or ammonium cations. The size and charge density of the cation can be used to adjust the protonation level and local geometry of the acid pair. The selectivity and coordination geometry of the chaperone cation may be further adjusted by the inclusion of a crown ether to reduce the number and location of potential binding sites.

Novel pharmaceutical compositions through co-crystallization of racetams and Li+ salts

Grinding of solid brivaracetam (BRV) and seletracetam (SEL) with inorganic lithium salts yields original ionic co-crystals (ICCs) characterized by markedly different thermal properties with respect to pure racetams; solid products have been characterized by single crystal crystallography. It is suggested that co-crystallizing lithium with some racetams could lead to a pharmacologically relevant synergetic association and to development of an original drug substance.

Bis(imidazolium) L‐Tartrate: A Hydrogen‐Bonded Displacive‐Type Molecular Ferroelectric Material

A hydrogen-bonded ionic cocrystal with imidazole as molecular rotator and L-tartaric acid as homochiral component is reported as a displacive-type ferroelectric material. It undergoes a paraelectric-ferroelectric phase transition at 252 K with exceptional dielectric responses triggered by atomic displacements.