Caffeine Cocrystals Research Articles

Investigation of the Mechanism of Cocrystal Formation at the Polarized Liquid-Liquid Interface

The cocrystals of two reagents of mismatch solubility, hydrophilic caffeine and lipophilic 1-hydroxy-2-naphthoic acid, were obtained at a water-oil interface. 1 By analysing the product collected at the phase interface by X-ray diffraction and Raman spectroscopy, we confirmed that we obtained the molecular cocrystals of caffeine and 1-hydroxy-2-naphthoic acid, free of starting reagents and solvents. Polarisation of the interface allowed the electrochemical control of the cocrystallisation process: for non-polarised interfaces, a mixture of phase I and II cocrystals were obtained, whereas cocrystals of phase I were formed when a high interfacial potential was applied. The difference between the polymorphs obtained in the absence or in the presence of interfacial polarisation is attributed to the different cocrystallisation mechanisms. In the absence of interfacial polarisation, caffeine and 1-hydroxy-2-naphthoic acid are cocrystallising through an interfacial process. When the interface is positively polarised, cationic form of caffeine is transferred to the organic phase, the complex with naphthoic acid is formed and the proton is released. The pH increased after cocrystallisation, suggesting that the liberated H+ remained in the organic phase. On the contrary, in the absence of polarisation or in the case of low interfacial potential the protons are remaining in the aqueous phase what resulted in a decrease in pH after cocrystallisation process. We demonstrated an indirect evidence of the transfer of caffeine upon chemical polarization of the interface. We observed almost no deposits in the organic phase by analysing it with a scanning electron microscope.We investigated here the mechanism behind the formation of cocrystals by using the polarized interface between two immiscible electrolyte solutions (ITIES).2 For the purpose of this study, the two solutions have been placed in contact3 : one being an aqueous solution of caffeine, as a model drug substance, and the second being organic solution of 1-hydroxy-2-naphthoic acid (cocrystal component) and the salt inducing the suitable imposed potential difference. The formation of the caffeine: 1-hydroxy-2-naphthoic acid complex was studied by changing the salts present in the aqueous phase, the chemical compounds imposing potential in organic phase, varying the organic solvents and the temperature at the liquid-liquid interface. The cocrystals collected at the interface were analysed by X-ray diffraction (XRD), scanning electron microscopy (SEM) and low frequency Raman spectroscopy. We studied the proportions of polymorphic phases as a function of changing conditions. To understand the mechanism behind the caffeine transfer and the formation of different forms of polymorphic crystals at the water-oil interface, Electrochemical Noise Experiments4 have been carried out. A four-electrode system was used to apply zero volts between the working electrode and the counter electrode and then measuring the current and the potential versus the reference electrode. Such a setup allows the measurement of potential and current as the function of time simultaneously. We could thus follow the phenomena that are taking place at the interface. The measurements were carried out by varying the cations (tetraalkylammoniums, Li+, K+) in aqueous and organic phase as well as the anions (derivatives of tetrakis(phenyl-borate) in organic phase). The experimental results were supported by theoretical equations and applied to the system containing caffeine.This novel strategy of cocrystallization, was followed by the investigation of other coformers (3-hydroxy-2-naphthoic acid) and drugs (cocrystals of ketoprofen with amino acids and carboxylic acids) in order to validate the method. Such an electrocrystallization process at the ITIES will open new opportunities for the formation of drugs cocrystals. M. Kaliszczak et al., CrystEngComm (2022) doi: 10.1039/D1CE01281A.Z. Samec, Pure Appl. Chem., 76, 2147–2180 (2004).S. J. Diez et al., Cryst. Growth Des., 18, 3263–3268 (2018).I. B. Obot, I. B. Onyeachu, A. Zeino, and S. A. Umoren, J. Adhes. Sci. Technol., 33, 1453–1496 (2019).

Trimesic acid–Theophylline and Isopthalic acid–Caffeine Cocrystals: Synthesis, Characterization, Solubility, Molecular Docking, and Antimicrobial Activity

The preparation of cocrystals from active pharmaceutical ingredients (APIs) and biologically relevant coformers offers the opportunity of obtaining compounds with more desirable physicochemical and...

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study.

Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C17H14BrN3O2S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH3OH) and ethanol (C2H5OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, C8H10N4O2) and nicotinamide (C6H6N2O), polymorphs with urea (CH4N2O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT-IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid-triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid-triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid-triazole heterosynthon is replaced by an acid-amide synthon. Among the urea cocrystal polymorphs, Form I (P-1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P21/c, 2:2), both acid-amide heterosynthons and urea-urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad-urea Form I (43-fold) > lesinurad-caffeine (20-fold) > lesinurad-allopurinol (12-fold) ≃ lesinurad-nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

Stability of co‐crystals of caffeine with gallic acid in presence of coformers

AbstractCaffeine forms interactive complexes with several compounds. The formation and stability of caffeine's cocrystals with competing coformers has been investigated in terms of Gibbs free energy of coformer replacement from the solubility values and solubility product of co‐crystals at a given temperature. The feasibility of replacement was checked experimentally, and analysis was done by XRD, FTIR, and DSC technique. The Gibbs free energy of coformer replacement at other temperatures was predicted by using solubility values with Gibbs‐Helmholtz equation and correlating experimental solubility of coformer via nonrandom two‐liquid (NRTL) model of liquid mixtures in terms of activity coefficient and thereby predicting the coformer solubility at other temperatures. The NRTL parameters for catechin, citric acid, oxalic acid, and gallic acid have been estimated. The thermodynamic approach to determine the coformer replacement is found to be in line with the experimental results.Practical applicationsCooling of tea infusion leads to solid sediment formation called as tea cream, because of formation of many stable complexes of tea components. Several parameters such as temperature, concentration, and chemical composition, affect the formation of tea cream. Tea infusion contains caffeine along with different acids such as gallic acid, oxalic acid, and tannic acid, which can form stable co‐crystals. This study attempts to estimate the stability of the cocrystals of caffeine in the presence of different acidic coformers as a function of temperature and thus prediction and minimization of tea cream formation.

Crystallization at Solvent Interfaces Enables Access to a Variety of Cocrystal Polymorphs and Hydrates

A crystal growth technique, interfacial cocrystallization, is demonstrated to be a simple and effective method for preparing multicomponent crystal forms. The technique is based on the generation of a liquid–liquid interface between two immiscible solutions of cocrystal-forming compounds, and its utility is demonstrated through the preparation of polymorphs and hydrates of caffeine cocrystals, involving three different hydroxy-2-naphthoic acids, including the formation of some with unexpected compositions.

Cocrystal formation by ionic liquid-assisted grinding: case study with cocrystals of caffeine

Liquid assisted grinding using imidazolium-based ionic liquids (IL-AG) was found to be effective in isolation of cocrystals and cocrystal polymorphs.

Prediction of Solid State Properties of Cocrystals Using Artificial Neural Network Modeling

Using Artificial Neural Networks (ANNs), four distinct models have been developed for the prediction of solid-state properties of cocrystals: melting point, lattice energy, and crystal density. The models use three input parameters for the pure model compound (MC) and three for the pure coformer. In addition, as an input parameter the model uses the pKa difference between the MC and the coformer, and a 1:1 MC–conformer binding energy as calculated by a force field method. Notably, the models require no data for the actual cocrystals. In total, 61 CCs (two-component molecular cocrystals) were used to construct the models, and melting temperatures and crystal densities were extracted from the literature for four MCs: caffeine, theophylline, nicotinamide, and isonicotinamide. The data set includes 14 caffeine cocrystals, 9 theophylline cocrystals, 9 nicotinamide cocrystals, and 29 isonicotinamide cocrystals. Model-I is trained using known cocrystal melting temperatures, lattice energies, and crystal densitie...

A 13C solid-state NMR investigation of four cocrystals of caffeine and theophylline.

We report an analysis of the 13C solid-state NMR chemical shift data in a series of four cocrystals involving two active pharmaceutical ingredient (API) mimics (caffeine and theophylline) and two diacid coformers (malonic acid and glutaric acid). Within this controlled set, we make comparisons of the isotropic chemical shifts and the principal values of the chemical shift tensor. The dispersion at 14.1 T (600 MHz 1H) shows crystallographic splittings in some of the resonances in the magic angle spinning spectra. By comparing the isotropic chemical shifts of individual C atoms across the four cocrystals, we are able to identify pronounced effects on the local electronic structure at some sites. We perform a similar analysis of the principal values of the chemical shift tensors for the anisotropic C atoms (most of the ring C atoms for the API mimics and the carbonyl C atoms of the diacid coformers) and link them to differences in the known crystal structures. We discuss the future prospects for extending this type of study to incorporate the full chemical shift tensor, including its orientation in the crystal frame of reference.

Caffeine Co-Crystal Mechanics Evaluated with a Combined Structural and Spectroscopic Approach

In this report caffeine (CAF) co-crystallization with a fluoro-nitrobenzoic acid (F-NBA) yields a new solid form with superior tableting performance. A primary N···H–O synthon connects the basic nitrogen of CAF with the carboxylic acid of F-NBA to result in a layered structure with supportive CH3···O interactions. Over the entire compaction pressure range of nominally 50–300 MPa, the co-crystal displayed improved tensile strength relative to the individual co-formers that demonstrated tensile strengths consistently below 2 MPa. Qualitatively we interpret this tableting improvement for the co-crystal a result of increased plasticity manifested from the layered co-crystal structure, an observation consistent with previous co-crystal studies on modified material mechanics that suggest facile slip plane activation supports improved tableting. Powder Brillouin light scattering (BLS) is further introduced as a novel tool to rapidly evaluate elastic anisotropy to complement our structural interpretation of table...

A New Method for Producing Pharmaceutical Co-crystals: Laser Irradiation of Powder Blends

In this work, a high-power CO2 laser was used to irradiate powder blends of co-crystal formers, with the specific aim of trying to cause recrystallization to a co-crystal structure. By varying the power and raster speed of the laser, it was found that sufficient thermal energy could be imparted to the powder to cause molecular rearrangement. It was possible to form co-crystals of caffeine with oxalic acid and caffeine with malonic acid. Interestingly, it was found that, to form co-crystals successfully, the coformers needed to sublime to an appreciable extent, which indicates that the mechanism of rearrangement involves interaction and nucleation in the vapor phase. Laser irradiation thus offers a new route to creation of pharmaceutical co-crystals and a potentially rapid screen for likely co-crystal formation between coforming pairs.

Solution and Solid State Study on the Recognition of Hydroxyaromatic Aldoximes by Nitrogen Containing Compounds

Structural aspects and fluorescence behaviors of a series of cocrystals of hydroxyaromatic aldoximes, namely, 2(H2NAP)·(4,4′-bipyridine), 2(H2NAP)·(HMTA), H2NAP·caffeine, and (H3OHPA)·theophylline·2H2O, where H3OHPA = 2,3-dihydroxyphenylaldoxime, H2NAP = 2-hydroxynaphthaldoxime, HMTA = hexamethylenetetramine, were studied. A difference in fluorescence behavior of oxime molecules in solution and solid states was observed. The H2NAP·caffeine cocrystals are fluorescence active in the solid state but not in solution. The combinations of H3OHPA and 4,4′-bipyridine, HMTA or caffeine in the solid state did not yield cocrystals; however, these combinations in solution caused fluorescence quenching of H3OHPA. On the other hand, a hydrated cocrystal of H3OHPA with theophylline, namely, (H3OHPA)·theophylline·2H2O, was isolated and characterized. It was found that this combination causes fluorescence quenching of 2,3-dihydroxyphenylaldoxime (H3OHPA) in the solution state but not in the solid state as a cocrystal. The fluorescence change of H3OHPA interacting with theophylline can be identified among several aldoximes such as 2-hydroxynaphthaldoxime (H2NAP), 2-hydroxyphenylaldoxime (H2PA), and 2,4-dihydroxyphenylaldoxime (H3PHPA). The synthons involved in each cocrystal are identified, and the fluorescence emission differences leading to molecular recognition are determined. The differences in fluorescent behavior among aldoximes were exploited for their identification and separation.

Stability order of caffeine co-crystals determined by co-crystal former exchange reaction and its application for the validation of in silico models.

The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA-citric acid co-crystal (CA-CI), CA-CI converted to CA-OX, suggesting that CA-OX is more stable than CA-CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA-OX≈CA-p-hydroxybenzoic acid (HY)>CA-CI>CA-malonic acid>CA-maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA-HY. The π-π stacking in CA-HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation.

Synthon Hierarchies in Crystal Forms Composed of Theophylline and Hydroxybenzoic Acids: Cocrystal Screening via Solution-Mediated Phase Transformation

Theophylline, a pharmaceutical model compound, was screened for cocrystal formation using nine (di)hydroxybenzoic acids as cocrystal formers, namely, 2-, 3-, 4-hydroxybenzoic- and 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acids. The experiments were conducted using an efficient, reliable, and fast screening method based on thermodynamically driven solution-mediated phase transformation and revealed the formation of eight cocrystals and one salt. The theophylline-based solids were identified using powder and structurally characterized via single-crystal X-ray diffraction. The obtained solids are sustained by theopylline-carboxylic acid heterosynthons, in addition to both theophylline and carboxylic acid homosynthons. The results are a part of a systematic study of xanthine-alkaloid cocrystals that aims to establish synthon hierarchies in cocrystals comprised of molecules with multiple hydrogen-bonding functional groups. Structural features and synthon hierachies are discussed and compared to those in a series of published caffeine cocrystals.

Solid-state characterization and solubility of a genistein–caffeine cocrystal

Combination of genistein and caffeine leads to a 1:1 cocrystalline phase, which was identified by means of a solvent-drop grinding experiment and isolated afterwards in a solution-evaporation approach. Obtained cocrystal was characterized by X-ray single-crystal and powder diffraction as well as investigated in terms of thermal stability and Hirshfeld surfaces. A scale-up procedure was provided by slurry technique, enabling solubility determination. Neutral forms of both compounds cocrystallize in a common P21/c space group of the monoclinic crystal system. Analysis of packing and interactions in the crystal lattice reveals formation of molecular layers, formed by O–H⋯O, O–H⋯N and C–H⋯O-type contacts between genistein and caffeine molecules, whereas stabilization of the three-dimensional crystal lattice is provided by π⋯π interactions. Dissolution studies in a 50:50 v/v ethanol–water medium revealed that the maximum solubility of the cocrystalline phase reached 0.861mg/mL after 8h, revealing some degree of enhancement as compared to parent genistein, maximum solubility of which was also reached after 8h and equalled 0.588mg/mL.

The Effects of Interactions of Dicarboxylic Acids on the Stability of the Caffeine Molecule: A Theoretical Study

Abstract The cocrystal formation leads to the improvement of the physicochemical properties of drug substances. Caffeine, as a pharmaceutical compound, forms cocrystals with dicarboxylic acids through OH(acid)···N(caffeine) and CH(caffeine)···O(acid) hydrogen bonds. In the present work, four 2:1 ternary complexes of the caffeine molecule with oxalic, malonic, maleic, and glutaric acids (as cocrystal units) were studied by computational quantum chemistry methods. Also, all ternary complexes were considered in the presence of water molecules. The energy data indicate that the caffeine–oxalic acid complex is the most stable ternary complex with respect to humidity. The results of population analysis, on the basis of the atoms-in-molecules (AIM) and the natural bond orbital (NBO) methods, are in good agreement with the energy data and experimental observations for the caffeine cocrystals.

Molecular mechanics of elastic and bendable caffeine co-crystals.

Complementing recent experimental results, here we report a computational study of remarkably flexible, elastically bendable caffeine cocrystals (cocrystal solvate 1), formed from caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB), and methanol, and compare with its unsolvated brittle form, 1 (dry). We show that 1 is able to maintain stable cocrystal structures at temperatures between 100 K and 400 K. The tensile and compressive Young's modulus of 1 are close to ~10 GPa. The ultimate strength is more than 600 MPa in tensile and 400 MPa in compressive at temperature of 100 K. The simulation results of the structural and mechanical properties of 1 are in good agreement with our previous experimental work. Notably, before the ultimate tensile stress, the stress-to-strain curves of 1 show linear behavior, but 1 (dry) show nonlinear behavior. This study might explain the remarkable elasticity of 1 and is relevant to the design of high-performance organic materials with excellent self-healing or efficient stress dissipating properties.

Microwave assisted synthesis of caffeine/maleic acid co-crystals: the role of the dielectric and physicochemical properties of the solvent

In the present work microwave radiation has been used to prepare the 1 : 1 and 2 : 1 co-crystals of caffeine and maleic acid. We obtained 1 : 1 co-crystals in the presence of water and methanol and we also see Form II of the 1 : 1 co-crystal in methanol. Co-crystallisation under microwave irradiation is shown to be controlled by the saturation of solvent at the reacting interface between the co-crystal components as well as the solvent dielectric properties.

Concomitant cocrystallization on engineered surfaces

Engineered self-assembled monolayer (SAM) substrates were successfully illustrated as a high throughput polymorph screening method for cocrystals. In this study, we have obtained new polymorphs of the cocrystals of caffeine and oxalic acid (2 : 1 molar ratio). This is evidenced by the Raman spectra, which showed new peaks at 1076, 1588 and 1602 cm−1. In addition, the XRD diffraction pattern exhibited a new peak at 30.0°, further confirming the presence of new polymorphs.

Syntheses, structural characterization, and DPPH radical scavenging activity of cocrystals of caffeine with 1- and 2-naphthoxyacetic acids

Caffeine:1-naphthoxyacetic acid [(caf)(1-naa)] and caffeine:2-naphthoxyacetic acid [(caf)(2-naa)] cocrystals have been synthesized and single crystals were grown by slow evaporation technique. The structures of the grown crystals were elucidated using single crystal X-ray diffraction analysis. Both the cocrystals belong to the monoclinic crystallographic system with space group P21/c, Z=4, and α=γ=90°, whereas β=111.4244(18)° for [(caf)(1-naa)] and β=109.281(6)° for [(caf)(2-naa)]. The crystal packing is predominantly stabilized by hydrogen bonding and π–π stacking interactions. The presence of unionized –COOH functional group in both the cocrystals was identified by FTIR spectral analysis. Thermal behavior and stability of both the cocrystals were studied by TGA/DTA analyses. Solvent-free formation of these cocrystals was confirmed by powder X-ray diffraction analyses. The theoretical energy of cocrystals showed that the formers have higher energy than cocrystals 1 and 2. DPPH radical scavenging activity of cocrystals 1 and 2 is slightly greater than the formers.

Microfluidic Approach to Cocrystal Screening of Pharmaceutical Parent Compounds

We describe a microfluidic approach to screen for the formation of cocrystalline solid forms of pharmaceutical parent compounds (PCs). Saturated solutions of PCs and of cocrystal formers dissolved in a variety of solvents are precisely metered in arrays of 48 wells to enable the combinatorial mixing of all possible combinations. Key characteristics of the microfluidic approach, including small quantities (∼240 μg/48 conditions), the ability to generate and screen 48 unique conditions per chip, and the ability to identify solid forms on-chip via Raman spectroscopy, enable solid form screening very early in the drug development process. In contrast, current approaches require on the order of ∼240 mg for 48 conditions, thus delaying solid form screening to later stages of the drug development. Sequential screening experiments using caffeine as the model compound were conducted to validate the on-chip approach reported here. Preliminary screens were executed to identify conditions with the highest propensity for crystallization and to identify the cocrystal formers (CCFs) resulting in formation of cocrystals via on-chip Raman spectroscopy. Next, the identified, promising conditions were replicated to confirm reproducibility and consistency of the on-chip outcomes. Nine cocrystals of caffeine were identified in this way.