Ternary Cocrystals Research Articles

Manipulating the dynamics of mechanochemical ternary cocrystal formation.

The mechanism of ternary cocrystal formation, and the potential role of intermediate binary phases, has been debated for some time. We report here the first in situ real-time monitoring of two prototypic ternary cocrystals. Our results suggest that the question is more complicated than previously considered. The mechanism of mechanochemical ternary cocrystal formation depends on the milling conditions, here the milling frequency and addition of liquid. Binary phases can form under certain conditions, but do not act as intermediates in the formation of the ternary cocrystals. Rather, binary phases are competitive with the ternary phase, and their formation appears to compete with that of the ternary components. The presence of binary phases leads to an increase in the overall reaction time. The results reported here offer the first insights into the true complexities of mechanochemical multi-component synthesis of higher order multi-component crystals and demonstrate a new understanding of the influence of milling condition for the study of mechanisms and kinetics.

Combining two distinctive intermolecular forces in designing ternary co-crystals and molecular salts of 1,3,5-trinitrobenzene, 9-anthracenecarboxylic acid and ten substituted pyridines

Coloured three component complexes are made using both charge transfer and hydrogen bonding intermolecular interactions.

Multifacial Recognition in Binary and Ternary Cocrystals from 5-Halouracil and Aminoazine Derivatives

A systematic analysis using single crystal X-ray diffraction was performed to explore the role exerted by potential intercomponent proton-transfer reactions in the supramolecular structures of A–B cocrystals formed by 5-haloderivatives of uracil (A), coupled with 2-aminoadenine simulants (aminoazines, B). Twelve new heterodimers were synthesized in different stoichiometries and cocrystallized by solvent cogrinding followed by solution crystallization. In the binary cocrystals, uracil or 1-methyluracil with halide modification at the 5 position (F, Cl, Br, I) was coupled with amino-aromatic N-heterocycles (melamine, 2,4,6-triaminopyrimidine, 2,6-diaminopyridine) as a multivalent site for pyrimidine nucleobase recognition. The crystallographic analysis showed that, next to the expected neutral three-point hydrogen bonds (TPI), ionized TPI, favored by A → B proton transfer, can be used for WC multifacial recognition. Noteworthy, the formation of the charged TPI, which depends on the acid/base properties of t...

Controlling topological polymorphism and dynamic behavior in ternary cocrystals

Controlling topological polymorphism and dynamic behavior in ternary cocrystals

Binary and ternary co-crystals and molecular salts of 3,5-dinitrobenzoic acid: A many-faceted supramolecular reagent

The co-crystallization of 3,5-dinitrobenzoic acid (DNBA) to form binary and ternary complexes is reported. Binary complexes (DNBA) (flouranthene) (1), (DNBA) (9-bromoanthracene) (2), (DNBA) (9-methylanthracene) (3) and (DNBA) (9-anthroic acid) (4) are all sustained by charge-transfer interactions. By introducing three different pyridine complexes, the ternary complexes (DNBA) (flouranthene) (5-nitro-2-aminopyridine) (5), (DNBA) (9-anthracenecarboxylic acid)∙(3-bromo-2-aminopyridinium) (6) and (DNBA) (9-anthroic acid) (3-nitro-2-aminopyridine) (7) were synthesized utilizing an additional classical hydrogen bond from the DNBA to the pyridine. Compound 6 formed a molecular salt via proton exchange between the DNBA and 3-bromo-2-aminopyridine, whereas all other complexes are neutral (co-crystals).

Drug-Bridge-Drug Ternary Cocrystallization Strategy for Antituberculosis Drugs Combination

Realizing combination drugs at a molecular level via drug–drug cocrystallization opens a new pathway for effective therapeutic hybrids. A “drug-bridge-drug” strategy is developed to cocrystallize two first-line antitubercular drugs isoniazid and pyrazinamide using fumaric acid as the bridge, overcoming the issue of hardly cocrystallizing two different drugs. The first example of ternary cocrystal with combination drugs exhibits optimized formulation capacity and in vitro/vivo synergistic effects, which provides a new insight into antituberculosis combination drugs.

Supramolecular Synthons in Bumetanide Cocrystals and Ternary Products

A novel design strategy for cocrystals of the diuretic sulfonamide drug bumetanide (BUM) with carboxamides is reported based on reliable supramolecular synthons. Binary cocrystals of BUM with pyridine carboxamides, pyridones, and cytosine were obtained by solvent-assisted grinding followed by solution crystallization. All cocrystal structures exhibit hydrogen bonding of the coformer with the carboxylic acid group of BUM via heterosynthons which replace the acid homodimer in the drug crystal structure. Pyridones are inserted as N–H···O dimers which are in turn bonded to the acid group of BUM, while the pyridine amide coformers interact via the acid–amide heterosynthon. Cocrystal polymorphs were obtained for bumetanide–isonicotinamide cocrystal structure with the sulfonamide–pyridine and sulfonamide–acid synthons. Careful crystal packing analysis of BUM structure and nine new binary adducts gave an idea for the design ternary cocrystals, and subsequently four new ternary crystalline products were crystalliz...

Cocrystals: A Review of Recent Trends in Pharmaceutical and Material Science Applications

Over the last two decades, the design of multicomponent molecular crystals or cocrystals has grown out to be an interesting and promising area of research in pharmaceuticals and material science. Cocrystallization is at the interface of crystal engineering and supramolecular chemistry and allows us to vary the physicochemical properties of solids according to the need, through manipulation of various intermolecular interactions. In this short review, we focus on some recent reports on pharmaceutical cocrystals and emerging subclasses of cocrystals, namely: Charge transfer cocrystals, Energetic cocrystals, and Ternary cocrystals and discuss about their methods of characterization and applications of importance in the industry.

Modular assembly of porous organic cage crystals: isoreticular quasiracemates and ternary co-crystal

Co-crystallisation of helically chiral porous organic cage molecules has enabled the formation of isoreticular quasiracemates and a rare porous organic ternary co-crystal.

Supramolecular reactivity in the solid state: step-wise assembly of ternary cocrystals through hydrogen and halogen bonding

Supramolecular reactivity in the solid state: step-wise assembly of ternary cocrystals through hydrogen and halogen bonding

ChemInform Abstract: Pharmaceutical Cocrystals: Walking the Talk

AbstractReview: 105 refs.

Systematic Construction of Ternary Cocrystals by Orthogonal and Robust Hydrogen and Halogen Bonds

A carefully designed strategy is presented for the construction of ternary cocrystals, based on the orthogonality of two supramolecular interaction modes: hydrogen bonding between crown ethers and thioureas and the halogen bonding between thioureas and perfluorohalocarbons. Tested on a set comprising two crown ethers, two thioureas and five halogen bond donors, the strategy resulted in a high, 75% success rate, with 15/20 component combinations yielding at least one cocrystal. Crystal structure analysis revealed the interplay between the hydrogen and halogen bonding motifs, also shedding light on the variables affecting their formation.

Binary and ternary cocrystals of sulfa drug acetazolamide with pyridine carboxamides and cyclic amides.

A novel design strategy for cocrystals of a sulfonamide drug with pyridine carboxamides and cyclic amides is developed based on synthon identification as well as size and shape match of coformers. Binary adducts of acetazolamide (ACZ) with lactams (valerolactam and caprolactam, VLM, CPR), cyclic amides (2-pyridone, labeled as 2HP and its derivatives MeHP, OMeHP) and pyridine amides (nicotinamide and picolinamide, NAM, PAM) were obtained by manual grinding, and their single crystals by solution crystallization. The heterosynthons in the binary cocrystals of ACZ with these coformers suggested a ternary combination for ACZ with pyridone and nicotinamide. Novel supramolecular synthons of ACZ with lactams and pyridine carboxamides are reported together with binary and ternary cocrystals for a sulfonamide drug. This crystal engineering study resulted in the first ternary cocrystal of acetazolamide with amide coformers, ACZ-NAM-2HP (1:1:1).

Quaternary and senary sub-assemblies in cocrystals and salts of quinoline-4-carbaldoxime with aromatic carboxylic acids

Quaternary sub-assemblies in cocrystals and salts of quinoline-4-carbaldoxime with aromatic carboxylic acids are analysed. Quinoline-4-carbaldoxime formed a 1:1 cocrystal with 2-methylbenzoic acid, whereas with 2-hydroxybenzoic acid, 3-nitrobenzoic acid, 4-nitrobenzoic acid, 2,3- or 2,4-dihydroxybenzoic acid, it formed 1:1 salts. A ternary cocrystal with 2-nitrobenzoic acid composed of a neutral 2-nitrobenzoic acid and 2-nitrobenzoate with protonated quinoline-4-carbaldoxime is observed. Accommodation of additional neutral 2-nitrobenzoic acid is due to the extension of quaternary sub-assemblies to senary sub-assemblies to achieve an appropriate packing pattern. Whereas, assemblies of hydrated salts can be considered to comprise senary sub-assemblies formed between water molecules and quaternary sub-assemblies. In such senary sub-assemblies, water molecules are held in the hydrophobic junctions formed by oximes and carboxylic acids.

Pharmaceutical cocrystals: walking the talk.

Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability. In this feature review, we highlight some prominent examples of drug cocrystals which exhibit variable hardness/softness and elasticity/plasticity depending on coformer selection, improvement of solubility and permeability in the same cocrystal, increase of the melting point for solid formulation, enhanced color performance, photostability and hydration stability, and a longer half-life. Cocrystals of flavanoids and polyphenols can make improved pharmaceuticals and also extend to the larger class of nutraceuticals. The application of crystal engineering to assemble ternary cocrystals expands this field to drug-drug cocrystals which may be useful in multi-drug resistance, mitigating side effects of drugs, or attenuating/enhancing drug action synergistically by rational selection. The advent of new techniques for structural characterization beyond the standard X-ray diffraction will provide a better understanding of drug phases which are at the borderline of crystalline-amorphous nature and even newer opportunities in the future.

Design and Synthesis of Ternary Cocrystals Using Carboxyphenols and Two Complementary Acceptor Compounds

A strategy combining a ditopic hydrogen-bond donor with two different hydrogen-bond acceptor molecules is proposed for the assembly of simple trimeric building blocks used in the construction of ternary cocrystals. The crystallization of each of three different low symmetry carboxyphenols (3-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, and ferulic acid) with acridine and 2-amino-4,6-dimethylpyrimidine yielded ternary cocrystals where the three components are joined by phenol-pyridine and carboxylic acid-amidine synthons. The use of pKa values, beta values, and synthon histories in the selection of the acceptor compounds is discussed. Significant challenges to the growth of the desired ternary products from solution were presented by competing crystalline phases, including the individual components, a variety of binary phases, salts, and hydrates. Molecular electrostatic potentials were used to analyze the donating and accepting abilities of the competing synthons.

Engineering ternary cocrystals by orthogonal hydrogen and halogen bonds

Engineering ternary cocrystals by orthogonal hydrogen and halogen bonds

From a binary salt to salt co-crystals of antibacterial agent lomefloxacin with improved solubility and bioavailability.

The cocrystallization of lomefloxacin (Lf) with barbituric acid (HBA) and/or isophthalic acid (H2ip) leads to novel binary and ternary salts via hydrogen-bonding recognition. X-ray single-crystal diffraction analyses show that zwitterionic lomefloxacin can adjust itself to fulfill a different supramolecular array in either binary salts or ternary salt co-crystals, formulated as [HLf]·[Hip]·H2O (1), [HLf]·[BA]·[HBA]·H2O (2) and [HLf]·[BA]·[H2ip]·CH3OH·H2O (3). These pharmaceutical agents present uniform charge-assisted hydrogen-bonding networks between HLf cations and acidic coformers with the lattice capturing water molecules. Structural comparison of (2) and (3) indicated that a delicate balance of geometries and hydrogen-bonding partners is required for stacking to favor the formation of ternary salt co-crystals. Cocrystallization was able to overcome the water insolubility of lomefloxacin. Both the salt co-crystals display enhanced solubility and better pharmaceutical applicability.

Combinatorial selection of molecular conformations and supramolecular synthons in quercetin cocrystal landscapes: a route to ternary solids.

The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O-H⋯N and O-H⋯O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular 'confusion' that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution.

Modularity and three-dimensional isostructurality of novel synthons in sulfonamide-lactam cocrystals.

The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide-lactam cocrystals (SO2NH2⋯CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N-H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N-H⋯O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide-lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.