New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity.

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.

Macrocycle-Based Charge Transfer Cocrystals with Dynamically Reversible Chiral Self-Sorting Display Chain Length-Selective Vapochromism to Alkyl Ketones.

Chirality-driven self-sorting plays an essential role in controlling the biofunction of biosystems, such as the chiral double-helix structure of DNA from self-recognition by hydrogen bonding. However, achieving precise control over the chiral self-sorted structures and their functional properties for the bioinspired supramolecular systems still remains a challenge, not to mention realizing dynamically reversible regulation. Herein, we report an unprecedented saucer[4]arene-based charge transfer (CT) cocrystal system with dynamically reversible chiral self-sorting synergistically induced by chiral triangular macrocycle and organic vapors. It displays efficient chain length-selective vapochromism toward alkyl ketones due to precise modulation of optical properties by vapor-induced diverse structural transformations. Experimental and theoretical studies reveal that the unique vapochromic behavior is mainly attributed to the formation of homo- or heterochiral self-sorted assemblies with different alkyl ketone guests, which differ dramatically in solid-state superstructures and CT interactions, thus influencing their optical properties. This work highlights the essential role of chiral self-sorting in controlling the functional properties of synthetic supramolecular systems, and the rarely seen controllable chiral self-sorting at the solid-vapor interface deepens the understanding of efficient vapochromic sensors.

Morphological Diversity of Dps Complex with Genomic DNA.

In response to adverse environmental factors, Escherichia coli cells actively produce Dps proteins which form ordered complexes (biocrystals) with bacterial DNA to protect the genome. The effect of biocrystallization has been described extensively in the scientific literature; furthermore, to date, the structure of the Dps-DNA complex has been established in detail in vitro using plasmid DNA. In the present work, for the first time, Dps complexes with E. coli genomic DNA were studied in vitro using cryo-electron tomography. We demonstrate that genomic DNA forms one-dimensional crystals or filament-like assemblies which transform into weakly ordered complexes with triclinic unit cells, similar to what is observed for plasmid DNA. Changing such environmental factors as pH and KCl and MgCl2 concentrations leads to the formation of cylindrical structures.

Halogen Bonding in Sulphonamide Co-Crystals: X···π Preferred over X···O/N?

Sulphonamides have been one of the major pharmaceutical compound classes since their introduction in the 1930s. Co-crystallisation of sulphonamides with halogen bonding (XB) might lead to a new class of pharmaceutical-relevant co-crystals. We present the synthesis and structural analysis of seven new co-crystals of simple sulphonamides N-methylbenzenesulphonamide (NMBSA), N-phenylmethanesulphonamide (NPMSA), and N-phenylbenzenesulphonamide (BSA), as well as of an anti-diabetic agent Chlorpropamide (CPA), with the model XB-donors 1,4-diiodotetrafluorobenzene (14DITFB), 1,4-dibromotetrafluorobenzene (14DBTFB), and 1,2-diiodotetrafluorobenzene (12DITFB). In the reported co-crystals, X···O/N bonds do not represent the most common intermolecular interaction. Against our rational design expectations and the results of our statistical CSD analysis, the normally less often present X···π interaction dominates the crystal packing. Furthermore, the general interaction pattern in model sulphonamides and the CPA multicomponent crystals differ, mainly due to strong hydrogen bonds blocking possible interaction sites.

An Intragastric Delivery Device Employing FDM Technology: 3D-Printed Tablet Containing Green Developed Mosapride-Saccharin Co-crystals.

Mosapride citrate (MC) is a poorly soluble short half-life drug with more pronounced absorption in the stomach. The present study aimed to incorporate MC co-crystals with enhanced solubility into 3D-printed floating tablets. MC co-crystals were prepared via the green method using Saccharin sod. as a co-former at a (1:1) molar ratio. The prepared co-crystals were assessed for solubility, FTIR, thermal behavior, and SEM. Then, it was incorporated into zero % infill 3D-printed tablets of different configurations at two thickness levels by the FDM printing technique. Printed tablets were evaluated for dimensions, weight deviation, friability, and in vitro floating behavior. Drug release and kinetic of the MC release were also assessed. Solubility study of the co-crystals showed a significant (p value < 0.05) increased solubility over pure MC. FTIR and thermal behavior confirmed hydrogen bonding formation during co-crystallization. The obstructed particles had an erratic protrusion form, similar to a nodule, as illustrated by SEM. The printed tablets showed acceptable physicochemical properties. Tablets floated for about ≥ 12 h without floating lag time. In vitro drug release exhibited variable extended release profiles with different lag times depending on the configuration indicating that the tablet's wall thickness and surface area were the factors manipulated to control drug release. Kinetic analysis of the release data displayed intermediate kinetics between zero-order and diffusional kinetics. The intragastric extended release profile for MC co-crystals of improved solubility could be successfully, economically, and quickly developed utilizing the 3D printing technique.

Robust S4 ⋠⋠⋠O Supramolecular Synthons: Structures of Radical-Radical Cocrystals [p-XC6 F4 CNSSN]2 [TEMPO] (X=F, Cl, Br, I, CN).

Cocrystallization of the dithiadiazolyl (DTDA) radicals p-XC6 F4 CNSSN (X=F, Cl, Br, I, CN) with TEMPO afforded the 2 : 1 cocrystals [p-XC6 F4 CNSSN]2 [TEMPO] (1-5) whose structures all reflect a common S4 ⋅⋅⋅O supramolecular motif. The nature of this interaction was probed by DFT calculations (M06/aug-cc-pVDZ) on 1 which revealed that the enthalpy of formation of the [C6 F5 CNSSN]2 [TEMPO] supramolecular motif from [C6 F5 CNSSN]2 and TEMPO is substantial (-54.0 kJ mol-1 ). Electronic structure calculations revealed a TEMPO-based doublet S= 1 / 2 configuration as the ground state with limited spin density on the DTDA rings (2.4 %). The corresponding spin quartet state is +78.9 kJ mol-1 higher in energy. An atoms-in-molecules analysis reveals four bond critical points (BCPs) between the TEMPO O and the DTDA S atoms as well as additional BCPs between selected DTDA S atoms and methyl H atoms of the TEMPO molecule. Herein, the structures of 2-5 are considered within the context of a hierarchical view of competing and complementary intermolecular interactions; in particular, the established supramolecular CN⋅⋅⋅S-S synthon is sacrificed in order to form the new S4 ⋅⋅⋅O interaction.

Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs.

PURPOSE: Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate. METHODS: Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling. RESULTS: 300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 µg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal. CONCLUSIONS: The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

HPMC improves protective effects of naringenin and isonicotinamide co-crystals against abdominal aortic aneurysm.

PURPOSE: Abdominal aortic aneurysm (AAA) rupture is one of the most common causes of mortality in cardiovascular diseases, but currently there is no approved drug for AAA treatment or prevention in the clinic. Naringenin (NGN) has been reported to have anti-AAA effects. However, water solubility and in vivo absorption of NGN are not satisfactory, which leads to its low bioavailability, thus affecting its pharmacological effects. In this project, the improving effects of isonicotinamide (INT) co-crystal and hydroxy propyl methyl cellulose (HPMC) or polyvinyl pyrrolidone (PVP) on the solubility, in vivo absorption, and anti-AAA effects of NGN were evaluated. METHODS: In the current study, co-crystals of naringenin-isonicotinamide (NGN-INT) were prepared, and effects of PVP or HPMC on precipitation rate, supersaturation, and bioavailability of NGN were explored. In addition, with or without HPMC supply, the effects of NGN-INT co-crystal on anti-AAA efficacy of NGN were investigated on an elastase-induced AAA mouse model, and the results were compared with the efficacy of the NGN crude drug. RESULTS: Our results demonstrate that NGN-INT formulation, compared to the NGN crude drug, enhanced the dissolution rate of NGN and significantly increased Cmax and AUC(0-∞) of NGN by 18 times and 1.97 times, respectively. Addition of PVP or HPMC in NGN-INT co-crystal further increased bioavailability of NGN in NGN-INT. The in vivo pharmacodynamic study showed that NGN-INT with HPMC significantly improved the inhibitory effects of NGN against AAA. CONCLUSION: NGN-INT significantly improved the absorption and aortic protective effects of NGN. The supersaturation-prolonging effect of HPMC further enhanced bioavailability and anti-AAA effects of NGN-INT.

Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co-crystals of solvate-like compounds with specific structure - A tandem resolution.

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25-mol equivalent of (R,R)-tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half-equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)-tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re-resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co-crystals in the structure of the diastereomeric salts. The used solvate-former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA-EGA-MS, and -FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key-intermediate crystalline diastereomeric salts-as solvates and co-crystals-inherit a kind of structural similarity from their related additives-solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively.

The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?

This review is aimed to provide to an "educated but non-expert" readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of an API is relevant not only for the selection of the best solid material to carry through the various stages of drug development, including the choice of dosage and of excipients suitable for drug development and marketing, but also in terms of intellectual property protection and/or extension. This is because the physico-chemical properties, such as solubility, dissolution rate, thermal stability, processability, etc., of the solid API may depend, sometimes dramatically, on the crystal form, with important implications on the drug's ultimate efficacy. This review will recount how the scientific community and the pharmaceutical industry learned from the catastrophic consequences of the appearance of new, more stable, and unsuspected crystal forms. The relevant aspects of hydrates, the most common pharmaceutical solid solvates, and of co-crystals, the association of two or more solid components in the same crystalline materials, will also be discussed. Examples will be provided of how to tackle multiple crystal forms with screening protocols and theoretical approaches, and ultimately how to turn into discovery and innovation the purposed preparation of new crystalline forms of an API.

Novel Ascorbic Acid Co-Crystal Formulations for Improved Stability.

A series of co-crystals of ascorbic acid were prepared with equimolar amounts of co-crystal formers (CCFs), including isonicotinic acid, nicotinic acid, 3,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid and m-hydroxybenzoic acid, by slow solvent evaporation and solvent-assisted grinding. The co-crystals were characterized by single-crystal X-ray diffraction spectroscopy, powder X-ray diffraction, IR spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Molecular dynamics (MD) simulations further validated the interaction energy and the possible intermolecular hydrogen bonds among VC and CCFs. The co-crystals showed improved stability when exposed to different wavelengths of light, pH and temperatures compared to the free analogue, especially at higher pH (~9) and lower temperature (~4 °C).

Supramolecular cis-"Bis(Chelation)" of [M(CN)6]3- (M = CrIII, FeIII, CoIII) by Phloroglucinol (H3PG).

Studies on molecular co-crystal type materials are important in the design and preparation of easy-to-absorb drugs, non-centrosymmetric, and chiral crystals for optical performance, liquid crystals, or plastic phases. From a fundamental point of view, such studies also provide useful information on various supramolecular synthons and molecular ordering, including metric parameters, molecular matching, energetical hierarchy, and combinatorial potential, appealing to the rational design of functional materials through structure-properties-application schemes. Co-crystal salts involving anionic d-metallate coordination complexes are moderately explored (compared to the generality of co-crystals), and in this context, we present a new series of isomorphous co-crystalline salts (PPh4)3[M(CN)6](H3PG)2·2MeCN (M = Cr, 1; Fe, 2; Co 3; H3PG = phloroglucinol, 1,3,5-trihydroxobenzene). In this study, 1-3 were characterized experimentally using SC XRD, Hirshfeld analysis, ESI-MS spectrometry, vibrational IR and Raman, 57Fe Mössbauer, electronic absorption UV-Vis-NIR, and photoluminescence spectroscopies, and theoretically with density functional theory calculations. The two-dimensional square grid-like hydrogen-bond {[M(CN)6]3-;(H3PG)2}∞ network features original {[M(CN)6]3-;(H3PG)4} supramolecular cis-bis(chelate) motifs involving: (i) two double cyclic hydrogen bond synthons M(-CN⋅⋅⋅HO-)2Ar, {[M(CN)6]3-;H2PGH}, between cis-oriented cyanido ligands of [M(CN)6]3- and resorcinol-like face of H3PG, and (ii) two single hydrogen bonds M-CN⋅⋅⋅HO-Ar, {[M(CN)6]3-;HPGH2}, involving the remaining two cyanide ligands. The occurrence of the above tectonic motif is discussed with regard to the relevant data existing in the CCDC database, including the multisite H-bond binding of [M(CN)6]3- by organic species, mononuclear coordination complexes, and polynuclear complexes. The physicochemical and computational characterization discloses notable spectral modifications under the regime of an extended hydrogen bond network.

"Rim-Differentiated" Pillar[6]arenes.

A "rim-differentiated" pillar[6]arene (RD-P[6]) was obtained successfully, with the assistance of a dimeric silver trifluoroacetate template, among eight different constitutional isomers in a direct and regioselective manner. The solid-state conformation of this macrocycle could switch from the 1,3,5-alternate to a truly rim-differentiated one upon guest inclusion. This highly symmetric RD-P[6] not only hosts metal-containing molecules inside its cavity, but also can form a pillar[6]arene-C60 adduct through co-crystallization on account of donor-acceptor interactions. The development of synthetic strategies to desymmetrize pillararenes offers new opportunities for engineering complex molecular architectures and organic electronic materials.

Modulating Supramolecular Charge-Transfer Interactions in the Solid State using Compressible Macrocyclic Hosts.

Modulating intermolecular charge-transfer (ICT) interactions between specific donor and acceptor species in host-guest systems is a big challenge and full of research value in supramolecular chemistry and materials science. In this work, a strategy to modulate the supramolecular ICT interactions in the solid state is developed by compressing the binding cavity of a macrocyclic host named perethylated leaning pillar[6]arene (p-EtLP6). The solid-state ICT affinities of p-EtLP6 toward multi-types of electron-deficient planar guests could be significantly enhanced by transforming the macrocyclic backbone from the original para-bridged mode into a hybrid para- and meta-bridged isomeric form (m-EtLP6). X-ray single-crystal structural analyses incorporating theoretical calculation demonstrate that the improved ICT affinities are mainly attributed to the superior host-guest size fit arising from the compressed binding cavity in m-EtLP6 as compared with p-EtLP6.

Superstructures of Organic-Polyoxometalate Co-crystals as Precursors for Hydrogen Evolution Electrocatalysts.

Molybdenum-based carbides and nitrides have been considered as catalysts for the hydrogen evolution reaction (HER). One of the challenges in using Mo-based HER electrocatalysts is establishing well-defined precursors which can be transformed into Mo-based carbides/nitrides with controllable structure and porosity. We report the synthesis of a series of superstructures consisting of organic-polyoxometalate co-crystals (O-POCs) as a new type of metal-organic precursor to synthesize Mo-based carbides/nitrides in a controlled fashion and to use them for efficient catalytic hydrogen production. This protocol enables to create electrocatalysts composed of abundant nanocrystallites and heterojunctions with tunable micro- and nanostructure and mesoporosity. The best performing electrocatalyst shows high HER activity and stability with a low overpotential of 162 mV at 100 mA cm-2 (in comparison to Pt/C with 263 mV), which makes it one of the best non-noble metal HER catalysts in alkaline media and seawater.

Recent Progress in Polycyclic Aromatic Hydrocarbon-Based Organic Co-Crystals.

Recently, the development of polycyclic aromatic hydrocarbon (PAH)-based organic co-crystals has attracted increasing interest due to their unique packing modes, optic-electronic properties and various potential applications in electronic, optic-electronic and magnetic devices. In this account, we mainly discuss the definition, classification, packing patterns, preparation methods, and applications of PAH-based co-crystals. Specifically, the main categories of PAH-based organic co-crystals, the frequent methods to prepare them, three main packing patterns, their optical and electrical properties, and their potential applications will be presented. Finally, an outlook of this field is provided.

An industrial perspective on co-crystals: Screening, identification and development of the less utilised solid form in drug discovery and development.

Active pharmaceutical ingredients are commonly marketed as a solid form due to ease of transport, storage and administration. In the design of a drug formulation, the selection of the solid form is incredibly important and is traditionally based on what polymorphs, hydrates or salts are available for that compound. Co-crystals, another potential solid form available, are currently not as readily considered as a viable solid form for the development process. Even though co-crystals are gaining an ever-increasing level of interest within the pharmaceutical community, their acceptance and application is still not as standard as other solid forms such as the ubiquitous pharmaceutical salt and stabilised amorphous formulations. Presented in this chapter is information that would allow for a co-crystal screen to be planned and conducted as well as scaled up using solution and mechanochemistry based methods commonly employed in both the literature and industry. Also presented are methods for identifying the formation of a co-crystal using a variety of analytical techniques as well as the importance of confirming the formation of co-crystals from a legal perspective and demonstrating the legal precedent by looking at co-crystalline products already on the market. The benefits of co-crystals have been well established, and presented in this chapter are a selection of examples which best exemplify their potential. The goal of this chapter is to increase the understanding of co-crystals and how they may be successfully exploited in early stage development.

Structural Rearrangement of Dps-DNA Complex Caused by Divalent Mg and Fe Cations.

Two independent, complementary methods of structural analysis were used to elucidate the effect of divalent magnesium and iron cations on the structure of the protective Dps-DNA complex. Small-angle X-ray scattering (SAXS) and cryo-electron microscopy (cryo-EM) demonstrate that Mg2+ ions block the N-terminals of the Dps protein preventing its interaction with DNA. Non-interacting macromolecules of Dps and DNA remain in the solution in this case. The subsequent addition of the chelating agent (EDTA) leads to a complete restoration of the structure of the complex. Different effect was observed when Fe cations were added to the Dps-DNA complex; the presence of Fe2+ in solution leads to the total complex destruction and aggregation without possibility of the complex restoration with the chelating agent. Here, we discuss these different responses of the Dps-DNA complex on the presence of additional free metal cations, investigating the structure of the Dps protein with and without cations using SAXS and cryo-EM. Additionally, the single particle analysis of Dps with accumulated iron performed by cryo-EM shows localization of iron nanoparticles inside the Dps cavity next to the acidic (hydrophobic) pore, near three glutamate residues.

Intermolecular Forces Driving Hexamethylenetetramine Co-Crystal Formation, a DFT and XRD Analysis.

Interest in co-crystals formation has been constantly growing since their discovery, almost a century ago. Such success is due to the ability to tune the physical-chemical properties of the components in solid state by avoiding a change in their molecular structure. The properties influenced by the co-crystals formation range from an improvement of mechanical features and chemical stability to different solubility. In the scientific research area, the pharmacological field is undoubtedly one of those in which an expansion of the co-crystal knowledge can offer wide benefits. In this work, we described the crystalline structure of hexamethylenetetramine co-crystallized with the isophthalic acid, and we compared it with another co-crystal, showing the same components but different stoichiometry. To give a wider overview on the nature of the interactions behind the observed crystal packing and to rationalize the reasons of its formation, a computational analysis on such structures was carried out.

A Contribution to the Solid State Forms of Bis(demethoxy)curcumin: Co-Crystal Screening and Characterization.

Bis(demethoxy)curcumin (BDMC) is one of the main active components found in turmeric. Major drawbacks for its usage are its low aqueous solubility, and the challenging separation from other curcuminoids present in turmeric. Co-crystallization can be applied to alter the physicochemical properties of BDMC in a desired manner. A co-crystal screening of BDMC with four hydroxybenzenes was carried out using four different methods of co-crystal production: crystallization from solution by slow solvent evaporation (SSE), and rapid solvent removal (RSR), liquid-assisted grinding (LAG), and crystallization from the melt phase. Two co-crystal phases of BDMC were obtained with pyrogallol (PYR), and hydroxyquinol (HYQ). PYR-BDMC co-crystals can be obtained only from the melt, while HYQ-BDMC co-crystals could also be produced by LAG. Both co-crystals possess an equimolar composition and reveal an incongruent melting behavior. Infrared spectroscopy demonstrated the presence of BDMC in the diketo form in the PYR co-crystals, while it is in a more stable keto-enol form in the HYQ co-crystals. Solubility measurements in ethanol and an ethanol-water mixture revealed an increase of solubility in the latter, but a slightly negative effect on ethanol solubility. These results are useful for a prospective development of crystallization-based separation processes of chemical similar substances through co-crystallization.