Crystal Engineering of Ionic Cocrystals Sustained by the Phenol–Phenolate Supramolecular Heterosynthon
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ABSTRACT:
SUBMITTER: Jin S
PROVIDER: S-EPMC9347308 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B-A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B-C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31-46 kJ mol-1. The azolium-triazole ICC (A+B-C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.
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Project description: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.
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Project description:Aniline-phenol recognition is studied in the crystal engineering context in several 1:1 cocrystals that contain a closed cyclic hydrogen-bonded [⋯O-H⋯N-H⋯]2 tetramer supramolecular synthon (II). Twelve cocrystals of 3,4,5- and 2,3,4-trichlorophenol with one of eight halogenated anilines have been characterized. Ten of these cocrystals contain an extended octamer synthon that is assembled with hydrogen bonding and π⋯π stacking that defines a Long-Range Synthon Aufbau Module (LSAM). The design strategy is, therefore, based on the construction and transferability of the LSAM, which is a dimer of tetramers. Using the LSAM concept, two short cell axes in the crystal structures can be predicted. Whilst one of them is dictated by synthon II, the other one is dominated by π⋯π interactions. The third cell axis can also be predicted, in some cases, by systematic tuning of the halogen bonds. The design strategy is also verified in cocrystals of non-halogenated precursors. The observation of this large synthon in so many structures points to its stability and possible existence in solution. To this end, one-dimensional (1)H and (15)N NMR studies, performed on the 3,4,5-trichlorophenol-3,5-dichloroaniline cocrystal in CDCl3, show characteristic downfield shifts that point to a π⋯π stacked structure and to the robustness of the hydrogen-bonded aggregates. Nuclear Overhauser effects point to hydrogen bonding between aniline and phenol molecules in the aggregates. Diffusion-ordered spectroscopy and T 1 inversion recovery experiments show that stacking is present in concentrated solution and lost at a certain dilution. A sequence of events is therefore established: molecules of the aniline and the phenol associate via hydrogen bonding to form tetramers, and tetramers subsequently stack to form octamers.
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Project description:Approximately 80% of active pharmaceutical ingredients (APIs) studied as lead candidates in drug development exhibit low aqueous solubility, which typically results in such APIs being poorly absorbed and exhibiting low bioavailability. Salts of ionizable APIs and, more recently, pharmaceutical cocrystals can address low solubility and other relevant physicochemical properties. Pharmaceutical cocrystals are amenable to design through crystal engineering because supramolecular synthons, especially those sustained by hydrogen bonds, can be anticipated through computational modeling or Cambridge Structural Database (CSD) mining. In this contribution, we report a combined experimental and CSD study on a class of cocrystals that, although present in approved drug substances, remains understudied from a crystal engineering perspective: ionic cocrystals composed of dihydrogen phosphate (DHP) salts and phosphoric acid (PA). Ten novel DHP:PA ionic cocrystals were prepared from nine organic bases (4,4'-bipyridine, 5-aminoquinoline, 4,4'-azopyridine, 1,4-diazabicyclo[2.2.2]octane, piperazine, 1,2-bis(4-pyridyl)ethane, 1,2-bis(4-pyridyl)xylene, 1,2-di(4-pyridyl)-1,2-ethanediol, and isoquinoline-5-carboxylic acid) and one anticonvulsant API, lamotrigine. From the resulting crystal structures and a CSD search of previously reported DHP:PA ionic cocrystals, 46 distinct hydrogen bonding motifs (HBMs) have been identified between DHP anions, PA molecules, and, in some cases, water molecules. Our results indicate that although DHP:PA ionic cocrystals are a challenge from a crystal engineering perspective, they are formed reliably and, given that phosphoric acid is a pharmaceutically acceptable coformer, this makes them relevant to pharmaceutical science.
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Project description:Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml-1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO-) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability.
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Project description:In this work we develop photoreactive cocrystals/salts of a commercially-important diacetylene, 10,12-pentacosadiynoic acid (PCDA, 1) and report the first X-ray crystal structures of PCDA based systems. The topochemical reactivity of the system is modified depending on the coformer used and correlates with the structural parameters. Crystallisation of 1 with 4,4'-azopyridine (2), 4,4'-bipyridyl (3), and trans-1,2-bis(4-pyridyl)ethylene (4) results in unreactive 2 : 1 cocrystals or a salt in the case of 4,4'-bipiperidine (5). However, salt formation with morpholine (6), diethylamine (7), and n-butylamine (8), results in highly photoreactive salts 12·7 and 1·8 whose reactivity can be explained using topochemical criteria. The salt 1·6 is also highly photoreactive and is compared to a model morpholinium butanoate salt. Resonance Raman spectroscopy reveals structural details of the photopolymer including its conformational disorder in comparison to less photoactive alkali metal salts and the extent of solid state conversion can be monitored by CP-MAS NMR spectroscopy. We also report an unusual catalysis in which amine evaporation from photopolymerised PCDA ammonium salts effectively acts as a catalyst for polymerisation of PCDA itself. The new photoreactive salts exhibit more reactivity but decreased conjugation compared to the commercial lithium salt and are of considerable practical potential in terms of tunable colours and greater range in UV, X-ray, and γ-ray dosimetry applications.
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Project description:The most abundant polyphenol in green tea, epigallocatechin-3-gallate (EGCg), has recently received considerable attention due to the discovery of numerous health-promoting bioactivities. Despite reports of its poor oral bioavailability, EGCg has been included in many dietary supplement formulations. Conventional preformulation methods have been employed to improve the bioavailability of EGCg. However, these methods have limitations that hinder the development of EGCg as an effective therapeutic agent. In this study, we have utilized the basic concepts of crystal engineering and several crystallization techniques to screen for various solid crystalline forms of EGCg and evaluated the efficacy of crystal engineering for modulating the pharmacokinetics of EGCg. We synthesized and characterized seven previously undescribed crystal forms of EGCg including the pure crystal structure of EGCg. The aqueous solubility profiles of four new EGCg cocrystals were determined. These cocrystals were subsequently dosed at 100 mg EGCg per kg body weight in rats, and the plasma levels were monitored over the course of eight hours following the single oral dose. Two of the EGCg cocrystals were found to exhibit modest improvements in relative bioavailability. Further, cocrystallization resulted in marked effects on pharmacokinetic parameters including Cmax, Tmax, area under curve, relative bioavailability, and apparent terminal half-life. Our findings suggest that modulation of the pharmacokinetic profile of EGCg is possible using cocrystallization and that it offers certain opportunities that could be useful during its development as a therapeutic agent.
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Project description:The title compound, C(2)H(8)N(+)·C(6)H(4)NO(3) (-)·C(6)H(5)NO(3), was synthesized from dimethyl-amine and 4-nitro-phenol in an overall yield of 85%. The dihdral angles between the nphenyl rings and their attached nitro groups are 5.7 (6) and 2.5 (7)°. In the crystal, there are strong hydrogen bonds between the ammonium group and the nitro-phenol and nitro-phenolate O atoms, and between the nitro-phenol and nitro-phenolate O atoms, forming a chain along the b-axis direction.
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Project description:In the crystal structure of the title compound, C(6)H(9)N(2) (+)·C(6)H(4)NO(3) (-)·C(6)H(5)NO(3), ions and mol-ecules are connected via inter-molecular N-H⋯O, N-H⋯N, O-H⋯O and C-H⋯O hydrogen bonds into a three-dimensional network.
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Project description:In the title 1:1 adduct, C9H12N2O2·C6H6O, the dihedral angle between the benzene ring and the salicylic amide group is 6.68 (6)°. The conformation of the amide group is supported by two intra-molecular N-H⋯O hydrogen bonds, which close S(6) and S(7) rings. In the crystal, the components are linked by O-H⋯O and N-H⋯O hydrogen bonds, generating (100) sheets.
| S-EPMC3629528 | biostudies-literature