Weak H-bonds Research Articles

Weak H-Bond Interface Environment for Stable Aqueous Zinc Batteries.

Hydrogen evolution reaction and Zn dendrite growth, originating from high water activity and the adverse competition between the electrochemical kinetics and mass transfer, are the main constraints for the commercial applications of the aqueous zinc-based batteries. Herein, a weak H-bond interface with a suspension electrolyte is developed by adding TiO2 nanoparticles into the electrolytes. Owing to the strong polarity of Ti-O bonds in TiO2, abundant hydroxyl functional groups are formed between the TiO2[110] active surface and aqueous environment, which can produce a weak H-bond interface by disrupting the initial H-bond networks between the water molecules, thereby accelerating the mass transfer of Zn2+ and reducing the water activity. In consequence, the Zn||Zn symmetrical cells display reversible Zn plating/stripping behaviors with a high Coulombic efficiency of 99.7% over 700 cycles. Moreover, the TiO2-based suspension strategy is also applicable to other zinc salt systems and exhibits fast plating/stripping behaviors. The suspension electrolyte enables long-term full cells, including Zn||PANI hybrid capacitors and Zn||ZnVO full batteries.

A Study on the Stability of High Drug Solubility Characteristics of Hydroxyphenyl Adhesives under the Interference of CPEs.

Novel hydroxyphenyl adhesives (HP-PSAs) could significantly increase drug solubility and control drug release through a doubly ionic hydrogen bond (DIH bond) in the patch. However, chemical penetration enhancers (CPEs) always destroy the performance of most adhesives. As a result, this work investigated the stability of both the HP-PSA features and the DIH bond under the interference of the CPEs. Donepezil (DON) was chosen as the model drug, and CPEs with hydroxyl, carboxyl, amido, and ester groups were selected as model CPEs. Unlike the commonly used neutral H-bond, the DIH bond between DON and the HP-PSA was still stable under the interference of the CPEs, resulting in the 2-3-fold drug solubility in the HP-PSA, which was higher than that in the nonfunctional PSA, which reduced the drug crystallization risk and the difficulty of formulation design. FT-IR, 1H NMR, XPS, dynamic simulation, and molecular docking revealed the mechanism of the stability feature of both the DIH bond and the high drug solubility of the HP-PSA, which was that the formed neutral H-bond interaction caused by CPEs is weaker than that of the DIH bond between DON and the HP-PSA. Furthermore, the drug release, skin permeation, and CPE release study showed that the newly formed weak H-bond and strong ionic H-bond interaction promoted or controlled both DON and CPE release, respectively, thereby influencing drug skin permeation, which provided a theoretical basis for drug release regulation. To summarize, besides the reversible, strong features of the DIH bond in our previous study, the stability of the interaction made the HP-PSA's high drug solubility potential to be applied in the TDDS.

An experimental and computational investigation of the cyclopentene-containing peptide-derived compounds: focus on pseudo-cyclic motifs via intramolecular interactions.

Conformational flexibility is one of the main disadvantages of peptide-based compounds. We focus on their molecular 'chameleonicity' related to forming pseudo-cyclic motifs via modulation of weak intramolecular interactions. It is an appealing strategy for controlling equilibrium between the polar open and the nonpolar closed conformations. Within this context, we report here the crystal structure of the (R)-(2-tert-butoxycarbonyl)amino-1-oxo-3-phenyl)propyl)-1-cyclopentene (1), synthesis of which in high yield was achieved by a facile multi-step protocol. Our Cambridge Structural Database (CSD) overview for the peptide-based crystals revealed the exclusivity of this compound from the viewpoint of the unusual pseudo-bicyclic system via C-H…O and C-O…π interactions, in which cyclopentene shields the amide bond. Notably, cyclopentene as a bioisostere of proline is an appealing scaffold in medicinal chemistry. An extensive combined experimental and computational study provided more profound insight into the supramolecular landscape of 1 with respect to similar derivatives deposited in the CSD, including the tendency of cyclopentene for the generation of pseudo-cyclic motifs through weak H-bonding and π-based intramolecular interactions. These weak interactions have been examined by either the quantum theory of 'atoms-in-molecules' (QTAIM) or complex Hirshfeld surface methodology, including enrichment ratios, molecular electrostatic potential surfaces and energy frameworks. In all analysed crystals, all types of H-bonded motifs involving cyclopentene are formed at all levels of supramolecular architecture. A library of cyclopentene-based H-bonding synthons is provided. A molecular docking study depicted vital interactions of cyclopentene with key amino acid residues inside the active sites of two prominent protein kinases, uncovering the therapeutic potential of 1 against breast cancer. To a large extent, dispersion forces have significance in stabilizing the supramolecular structure of both ligand and bio-complex ligand-protein. Finally, the satisfactory in silico bio-pharmacokinetic profile of 1 related to drug-likeness and blood-brain barrier permeation was also revealed.

Hierarchical Self-Organization and Disorganization of Helical Supramolecular Columns Mediated by H-Bonding and Shape Complementarity.

H-bonding, shape complementarity, and quasi-equivalence are widely accepted as some of the most influential molecular recognition events mediating biological and synthetic self-organizations. H-bonds are weaker than ionic but stronger than van der Waals forces. However, the directionality of H-bonds makes them the most powerful among all nonbonding interactions. Here, we selected two taper-shaped self-assembling dendrons, one flexible and one rigid, and equipped them with -CO2CH3, -CH2OH, and -COOH at their apex. They demonstrated the hierarchical way in which shape-complementarity in the presence of -CO2CH3 mediated highly ordered helical self-organization for the case of the rigid building block and less ordered helical arrays for the flexible one. Weak H-bonding by -CH2OH unwound the helix from the rigid dendron, yielding a porous column. Due to its quasi-equivalence, the flexible dendron tolerated better the H-bonding by -CH2OH self-organizing a different helical column. The rigid and the flexible dendrons yielded only disorganized nonhelical columns in the presence of -COOH at the apex. This balance between rigidity, flexibility, and tolerance or lack of it to diverse H-bonding architectures indicates that mechanistic elucidation of the self-organization process helps endow it with the same building block, both helical organizations approaching biological precision, and disorganized nonhelical arrangements.

Effect of high-temperature annealing on terahertz optoelectronic properties of nitrogen-doped polycrystalline diamond

Nitrogen-doped polycrystalline diamond (N-PCD) is one of the most important carbon-based electronic materials. Here we present a systmatic investigation of the effect of high-temperature annealing (HTA) on basic physical properties of N-PCD wafer grown by microwave plasma-enhanced chemical vapor deposition (MPECVD). The metallographic and optical microscopes, X-ray diffraction,Raman spectroscopy and X-ray photoelectron spectroscopy are applied for the characterization of N-PCD before and after HTA. Particularly, we study the optoelectrnic properties of N-PCD before and after HTA by using terahertz (THz) time-domain spectroscopy. THz transmittance, dynamical and static dielectric constants and optical conductivity for N-PCD are measured. For N-PCD before HTA, we can observe a THz absorption peak induced by weak H-bonds in N-PCD, which was predicted theoretically in 1999. For N-PCD after HTA, we find that the corresponding optical conductivity can be rightly descriped by the Drude-Lorentz formula. Thus, via fitting the experimental results with the theoretical formula, we can determine optically the key electronic parameters of N-PCD after HTA, such as the electron density, the electronic relaxation time and the Lorentz frequency. The temperature dependence of these parameters is examined in the range of 80–300 K. This work demondtrates that HTA is a practical and efficient way in improving the electronic and optoelectronic properties of N-PCD. The results obtained from this research can benefit an in-depth understanding of the effect of HTA on physical properties of N-PCD from a viewpoint of semiconductor physics.

Hydrogels with Differentiated Hydrogen-Bonding Networks for Bioinspired Stress Response.

Stress response, an intricate and autonomously coordinated reaction in living organisms, holds a reversible, multi-path, and multi-state nature. However, existing stimuli-responsive materials often exhibit single-step and monotonous reactions due to the limited integration of structural components. Inspired by the cooperative interplay of extensor and flexor cells within Mimosa's pulvini, we present a hydrogel with differentiated hydrogen-bonding (H-bonding) networks designed to enable the biological stress response. Weak H-bonding domains resemble flexor cells, confined within a hydrophobic network stabilized by strong H-bonding clusters (acting like extensor cells). Under external force, strong H-bonding clusters are disrupted, facilitating water diffusion from the bottom layer and enabling transient expansion pressure gradient along the thickness direction. Subsequently, water diffuses upward, gradually equalizing the pressure, while weak H-bonding domains undergo cooperative elastic deformation. Consequently, the hydrogel autonomously undergoes a sequence of reversible and pluralistic motion responses, similar to Mimosa's touch-triggered stress response. Intriguingly, it exhibits stress-dependent color shifts under polarized light, highlighting its potential for applications in time-sensitive "double-lock" information encryption systems. This work achieves the coordinated stress response inspired by natural tissues using a simple hydrogel, paving the way for substantial advancements in the development of intelligent soft robots.

Chasing weakly-bound biological water in aqueous environment near the peptide backbone by ultrafast 2D infrared spectroscopy

There has been a long-standing debate as to how many hydrogen bonds a peptide backbone amide can form in aqueous solution. Hydrogen-bonding structural dynamics of N-ethylpropionamide (a β-peptide model) in water was examined using infrared (IR) spectroscopy. Two amide-I sub bands arise mainly from amide C=O group that forms strong H-bonds with solvent water molecules (SHB state), and minorly from that involving one weak H-bond with water (WHB state). This picture is supported by molecular dynamics simulations and ab-initio calculations. Further, thermodynamics and kinetics of the SHB and WHB species were examined mainly by chemical-exchange two-dimensional IR spectroscopy, yielding an activation energy for the SHB-to-WHB exchange of 13.25 ± 0.52 kJ mol‒1, which occurs in half picosecond at room temperature. Our results provided experimental evidence of an unstable water molecule near peptide backbone, allowing us to gain more insights into the dynamics of the protein backbone hydration.

Competition-Induced Macroscopic Superlubricity of Ionic Liquid Analogues by Hydroxyl Ligands Revealed by in Situ Raman.

High load-bearing capacity is one of the crucial indicators for liquid superlubricants to move toward practicality. However, some of the current emerging systems not only have low contact pressures but also are highly susceptible to further degradation due to water adsorption and even superlubricity failure. Herein, a novel choline chloride-based ionic liquid analogues (ILAs) of a superlubricant with triethanolamine (TEOA) as the H-bond donor is reported for the first time; it obtains an ultralow coefficient of friction (0.005) and high load-bearing capacity (360 MPa, more than 2 times that of similar systems) due to adsorption of a small amount of water (<5 wt %) from the air. In situ Raman combined with 1H NMR and FTIR techniques reveals that adsorbed water competes with the hydroxyl group of TEOA for coordination with Cl-, leading to the conversion of some strong H-bonds to weak H-bonds in ILAs; the localized strong H-bonds and weak H-bonds endow the ILAs with high load-bearing capacity and the formation of ultralow shear-resistance sliding interfaces, respectively, under the shear motion. This study proposes a strategy to modulate the interactions between liquid species using adsorbed water from air as a competing ligand, which provides new insights into the design of ILA-based macroscopic liquid superlubricants with a high load-bearing capacity.

An Investigation into the Stability Source of Collagen Fiber Modified Using Cr(III): An Adsorption Isotherm Study.

The enhanced hydrothermal stability of leather, imparted by little Cr(III), has traditionally been ascribed to strong coordinate bonds. However, this explanation falls short when considering that the heat-induced shrinking of collagen fiber is predominantly driven by rupturing weak H-bonds. This study explored the stability source via adsorption thermodynamics using collagen fiber as an adsorbent. Eleven isotherm models were fitted with the equilibrium dataset. Nine of these models aptly described Cr(III) adsorption based on the physical interpretations of model parameters and error functions. The adsorption equilibrium constants from six models could be transformed into dimensionless thermodynamic equilibrium constants. Based on the higher R2 of the van't Hoff equation, thermodynamic parameters (∆G°, ∆H°, ∆S°) from the Fritz-Shluender isotherm model revealed that the adsorption process typifies endothermic and spontaneous chemisorption, emphasizing entropy increase as the primary driver of Cr(III) bonding with collagen. Thus, the release of bound H2O from collagen is identified as the stability source of collagen fiber modified by Cr(III). This research not only clarifies the selection and applicability of the isotherm model in a specific aqueous system but also identifies entropy, rather than enthalpy, as the principal stability source of Cr-leather. These insights facilitate the development of novel methods to obtain stable collagen-based material.

Effect of aromatic substituents on the H-bonded assembly of diketopyrrolopyrroles at solid-liquid interfaces.

Hydrogen-bonded (H-bonded) self-assembly is a suitable approach for tailoring the solid-state packing and properties of organic semiconductors. Here we studied the H-bonded self-assembly of an important class of organic semiconductors, diketopyrrolopyrrole (DPP) derivatives, diselenophenylDPP (DSeDPP), dithiazolylDPP (DTzDPP), and dithienothiophenylDPP (DTTDPP), at solid-liquid interfaces using scanning tunneling microscopy (STM) and density functional theory (DFT). At the 1-octanoic acid/highly ordered pyrolytic graphite (HOPG) interface, DSeDPP and DTzDPP either co-assemble with the solvent via H-bonding between lactam and carboxyl groups or form homoassemblies through H-bonding between the lactam groups. However, DTTDPP forms two different homoassemblies involving H-bonding between lactam groups or weak H-bonding between the lactam group and the heteroaromatic ring. Enthalpic factors for the formation of homoassemblies and co-assemblies are investigated by evaluating the inter- and intramolecular interactions in the self-assembled lattices using DFT. A homoassembly with a twisted geometry of molecules with intermolecular π-interactions is only observed for DSeDPP. The absence of homoassembly with the twisted geometry of DTzDPP is attributed to the higher strain energy required to acquire out-of-plane twists in this molecule. Our study shows the profound effects aromatic substituents can impart in the supramolecular assembly of DPP molecules, which influences film morphology and hence its properties (e.g. charge transport).

Electrostatic interactions dominate thermal conductivity and anisotropy in three-dimensional hydrogen-bonded organic frameworks

Hydrogen-bonded organic frameworks (HOFs), an emerging class of porous molecular materials assembled through hydrogen bonds (H-bonds), have shown intriguing latent for multifunctional materials or devices. Understanding thermal transport in HOFs is crucial to guiding the functional material design with desired thermal properties. Here, we report thermal transport properties in HOFs and reveal the significance of electrostatic interactions (H-bonds and π-π interactions) to heat conduction with molecular dynamics simulations. It is found that despite relatively weak H-bonds, tetracarboxylic-based frameworks (TCFs), a three-dimensional (3D) HOF, show relatively high thermal conductivity compared with known 3D porous covalent organic frameworks and metal-organic frameworks. Electrostatic interactions in TCFs dominate thermal conductivity and anisotropy but central atoms in the monomers show negligible impact. The structural analysis and x-ray diffraction patterns highlight the importance of electrostatic interactions in maintaining the high crystallinity of TCFs. The vibrational density of states and spectral thermal conductivity further demonstrate that phonon modes with frequencies below 25 THz contribute about 90 % of total thermal conductivity in TCFs, and electrostatic interactions sustain phonon modes with frequencies of 5–25 THz to carry heat. These findings provide a fundamental understanding of structure-thermal conductivity relation in HOFs and advance their applications for multifunctional materials and devices.

Effect of Bacterial Amyloid Protein Phenol-Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer's Disease.

Since the proposal of the brainstem axis theory, increasing research attention has been paid to the interactions between bacterial amyloids produced by intestinal flora and the amyloid β-protein (Aβ) related to Alzheimer's disease (AD), and it has been considered as the possible cause of AD. Therefore, phenol-soluble modulin (PSM) α3, the most virulent protein secreted by Staphylococcus aureus, has attracted much attention. In this work, the effect of PSMα3 with a unique cross-α fibril architecture on the aggregation of pathogenic Aβ40 of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aβ40 in a concentration-dependent manner and changed the aggregation pathway to form granular aggregates. However, PSMα3 oligomers promoted the generation of the β-sheet structure, thus shortening the lag phase of Aβ40 aggregation. Moreover, the higher the cross-α content of PSMα3, the stronger the effect of the promotion, indicating that the cross-α structure of PSMα3 plays a crucial role in the aggregation of Aβ40. Further molecular dynamics (MD) simulations have shown that the Met1-Gly20 region in the PSMα3 monomer can be combined with the Asp1-Ala2 and His13-Val36 regions in the Aβ40 monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aβ40 from the α-helix to β-sheet structure. By contrast, PSMα3 oligomers mainly combined with the central hydrophobic core (CHC) and the C-terminal region of the Aβ40 monomer by weak H-bonding and hydrophobic interactions, which could not inhibit the transition to the β-sheet structure in the aggregation pathway. Thus, the research has unraveled molecular interactions between Aβ40 and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD-related pathogenic Aβ.

The C[sbnd]F⋅⋅⋅H[sbnd]CF2 interaction: A combination of hydrogen bonding and n → σ* stabilization

In this communication, we explore a unique molecule that exhibits a substantial interaction between a CF2H group and a CF group. In medicinal chemistry, CF2H groups are known as weak hydrogen bond donors, and CF groups as weak H-bond acceptors. Seldom are they paired up together in an array such that their unique properties can be examined. In this case, we establish that along with an attractive hydrogen bonding interaction, an n → σ* component anchors the interactions. A unique combination of steric and hyperconjugative effects ‘switches’ the interaction away from previously reported dominant tetrel-type bonding in the case of a CH2F and CF interation towards an unusualy complex hybrid interaction. Crystallographic, computational, and spectroscopic studies illuminate the problem.

Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds.

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain-backbone N-H···N C6γ H-bonds that accompany-and thereby stabilize-C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

Cumulative impact of classical, weak and sulfur-centered H-bonds on structure and energetic: Homodimers of formic acid and its thio derivatives

An extensive computational investigation for homodimers of formic acid along with its mono- and di-thio derivatives has been carried out. Geometries and binding energies have been calculated at CCSD(T)-F12/cc-pVTZ-F12//ωB97X-D/aug-cc-pV(D+d)Z level. The findings are in very good agreement with existing experimental and high-level theoretical results. A total of 99 distinguishable stable conformers have been predicted for all four studied homodimers. Sixteen different noncovalent interactions, including ten types of H-bonds, have been identified. Structures and energetics of the dimers show systematic changes with sequential replacement of the two O atoms by S atoms. Caged structures become more favored over cyclic and linear ones with increasing S atoms. Hydroxyl/thiol groups were found to dictate dimeric properties rather than carbonyl/thiocarbonyl groups.

In Silico Exploration of Alternative Conformational States of VDAC.

VDAC (Voltage-Dependent Anion-selective Channel) is the primary metabolite pore in the mitochondrial outer membrane (OM). Atomic structures of VDAC, consistent with its physiological "open" state, are β-barrels formed by 19 transmembrane (TM) β-strands and an N-terminal segment (NTERM) that folds inside the pore lumen. However, structures are lacking for VDAC's partially "closed" states. To provide clues about possible VDAC conformers, we used the RoseTTAFold neural network to predict structures for human and fungal VDAC sequences modified to mimic removal from the pore wall or lumen of "cryptic" domains, i.e., segments buried in atomic models yet accessible to antibodies in OM-bound VDAC. Predicted in vacuo structures for full-length VDAC sequences are 19-strand β-barrels similar to atomic models, but with weaker H-bonding between TM strands and reduced interactions between NTERM and the pore wall. Excision of combinations of "cryptic" subregions yields β-barrels with smaller diameters, wide gaps between N- and C-terminal β-strands, and in some cases disruption of the β-sheet (associated with strained backbone H-bond registration). Tandem repeats of modified VDAC sequences also were explored, as was domain swapping in monomer constructs. Implications of the results for possible alternative conformational states of VDAC are discussed.

Unusual phosphatidylcholine lipid phase behavior in the ionic liquid ethylammonium nitrate

HypothesisThe forces that govern lipid self-assembly ionic liquids are similar to water, but their different balance can result in unexpected behaviour. ExperimentsThe self-assembly behaviour and phase equilibria of two phospholipids, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), in the most common protic ionic liquid, ethylammonium nitrate (EAN) have been investigated as function of composition and temperature by small- and wide-angle X-ray scattering (SAXS/WAXS) and small-angle neutron scattering (SANS). FindingsBoth lipids form unusual self-assembly structures and show complex and unexpected phase behaviour unlike that seen in water; DSPC undergoes a gel Lβ to crystalline Lc phase transition on warming, while POPC forms worm-like micelles L1 upon dilution. This surprising phase behaviour is attributed to the large size of the EAN ions that solvate the lipid headgroup compared to water changing amphiphile packing. Weaker H-bonding between EAN and lipid headgroups also contributes. These results provide new insight for the design of lipid based nanostructured materials in ionic liquids with atypical properties.

Roles of hydrogen bonding interactions and hydrophobic effects on enhanced water structure in aqueous solutions of amphiphilic organic molecules

Insights into the solute-induced water structural transformations are essential to understand the role of water in biological and chemical reaction processes. Herein, the structural changes in water induced by amphiphilic organic molecules were investigated using concentration-dependent derivative Raman spectroscopy (DRS) combined with two-dimensional Raman correlation spectroscopy (2D Raman-COS). We shall restrict our attention in this work to binary mixtures of water with dimethyl sulfoxide (DMSO), acetone, and isopropanol (IPA), all of which have similar chemical structures. The spectral changes in O:H and OH stretching modes illustrate that the solute molecules induce an enhancement of the water structure in dilute solutions, where the enhanced degree of water structure is closely related to the size of the dipole moment of organic molecules. In addition, the transformations of solute-induced water-specific structures were evaluated by 2D Raman-COS, which shows that the strong hydrogen bond (H-bond) structure of water is more sensitive to organic molecules and induces a transition to the weak H-bond structure of water.

Roles of hydrogen bonding interactions and hydrophobic effects on enhanced water structure strength in aqueous alcohol solutions

The structure and dynamics of water in aqueous alcohol solutions were explored using two-dimensional Raman correlation spectroscopy (2D Raman-COS) combined with the density functional theory (DFT). The spectral changes in the H–O–H bending and O:H stretching modes demonstrated that ethanol and n-propanol induced an enhancement of the water structure compared to methanol. The extent of this effect was related to the length of the alkyl chain. Comparative studies with aqueous ethylene glycol solution revealed that an enhanced water structure stemmed mainly from hydrophobic effects rather than hydrogen bonding (H-bonding) interactions. Alcohol-induced water-specific structural transitions were further analyzed using 2D Raman-COS, which showed that the free OH and strong H-bond structure of water respond preferentially to changes in alcohol content, inducing a transition in the weak H-bond structure of water. In addition, the 2D Raman-COS results indicated that the CH3 stretching mode of alcohol responds preferentially to variations in water content compared to other C–H vibrational modes. Finally, the details of the alcohol-induced water structural transitions were calculated using DFT. The 2D Raman-COS combined with DFT calculations provided insight into alcohol-induced water structural transitions and can be easily extended to other studies of water-organic chemistry.

Analysis of Co-Crystallization Mechanism of Theophylline and Citric Acid from Raman Investigations in Pseudo Polymorphic Forms Obtained by Different Synthesis Methods.

Designing co-crystals can be considered as a commonly used strategy to improve the bioavailability of many low molecular weight drug candidates. The present study has revealed the existence of three pseudo polymorphic forms of theophylline-citric acid (TP-CA) co-crystal obtained via different routes of synthesis. These forms are characterized by different degrees of stability in relation with the strength of intermolecular forces responsible for the co-crystalline cohesion. Combining low- and high-frequency Raman investigations made it possible to identify anhydrous and hydrate forms of theophylline-citric acid co-crystals depending on the preparation method. It was shown that the easiest form to synthesize (form 1'), by milling one hydrate with an anhydrous reactant, is very metastable, and transforms into the anhydrous form 1 upon heating or into the hydrated form 2 when it is exposed to humidity. Raman investigations performed in situ during the co-crystallization of forms 1 and 2 have shown that two different types of H-bonding ensure the co-crystalline cohesion depending on the presence of water. In the hydrated form 2, the cohesive forces are related to strong O-H … O H-bonds between water molecules and the reactants. In the anhydrous form 1, the co-crystalline cohesion is ensured by very weak H-bonds between the two anhydrous reactants, interpreted as corresponding to π-H-bonding. The very weak strength of the cohesive forces in form 1 explains the difficulty to directly synthesize the anhydrous co-crystal.