Ethenzamide Research Articles

Ti-MOG derived TiO2 facet heterojunction rich in C/Ti3+/Ov for adsorption-photocatalytic removal of pharmaceutical pollutants from water

Developing efficient, stable, and broad-spectrum responsive photocatalysts is an effective way to degrade pharmaceutical pollutants in water. In this work, using concentrated hydrochloric acid (HCl) as a modulator, titanium metal–organic gel (Ti-MOG) was prepared and used as a template for calcination in air to obtain anatase TiO2 facet heterojunction rich in C/Ti3+/oxygen vacancy (Ov) (MOG-TiO2), which has a hierarchical porous structure, large specific surface area, and highly dispersed active site. Compared to P25, P25 + C and MIL-125(Ti) derived TiO2 (MOF-TiO2), MOG-TiO2 exhibited obviously enhanced adsorption-photocatalytic performance for tetracycline (TC) and low concentrations ethenzamide (ETH) under broad-spectrum light irradiation. The photocatalytic degradation efficiency of ETH by MOG-TiO2 reached 92.8, 100 and 98.7 % within 240, 60 and 6 min under Vis, UV and VUV light illumination, respectively, which were much higher than those of P25 (62.7, 33.2 and 73.0 %), P25 + C (61.7, 31.2 and 72.5 %) and MOF-TiO2 (79.2, 86.8 and 88.7 %). Furthermore, concentrated HCl promoted the formation of Ti3+/Ov in MOG-TiO2, which was conducive to the improvement of its photocatalytic performance. MOG-TiO2 also displayed great adsorption-photocatalytic stability and reusability. Moreover, the biotoxicity of TC toward E. coli DH5a obviously decreased after photocatalytic degradation. Based on the TiO2 facet heterojunction rich in C/Ti3+/Ov and the generation of hole, hydroxyl radicals, and superoxide radicals, the possible photocatalytic degradation mechanism of MOG-TiO2 was proposed. Overall, this work provides insights into constructing a novel hierarchical porous carbon-doped facet heterojunction photocatalyst for efficient pharmaceutical contaminants removal.

A New Look at the Mechanism of Cocrystal Formation and Coformers Exchange in Processes Forced by Mechanical and/or Thermal Stimuli - ex situ and in situ Studies of Low-Melting Eutectic Mixtures.

Three different devices: ball mill, hot stage melting, and magic angle spinning (MAS) NMR rotor were used for the preparation of ethenzamide (ET) cocrystals with glutaric acid (GLU), ethylmalonic acid (EMA) and maleic acid (MAL) as coformers. In each case, well-defined binary systems (ET:EMA, ET:GLU, ET:MAL) were obtained. The common features of the two solvent free methods of cocrystal formation (grinding, melting) are presented on the basis of arguments obtained by solid state NMR spectroscopy. Thermal analysis (Differential Scanning Calorimetry) proved that the eutectic phase arises over a wide range of molar ratios of components for each of the binary systems. NMR techniques, supported by theoretical calculations, allowed to provide details about the pathway of the reaction mechanism with atomic accuracy. It was found that the formation of ET cocrystals is a complex process that requires five steps. Each step has been recognized and described. Variable temperature 1D and 2D MAS NMR experiments allowed to track physicochemical processes taking place in a molten state. Moreover, it was found that in a multicomponent mixture consisting of all four components, ET, EMA, GLU, and MAL, ET in the molten phase behaves as a specific selector choosing only one partner to form binary cocrystals according to energy preferences. The process of exchange of coformers in binary systems during grinding, melting, and NMR measurements is described. The stabilization energies (Estab ) and molecular electrostatic potential (MEP) maps computed for the cocrystals under discussion and their individual components rationalize the selection rules and explain the relationships between individual species.

Investigation into polymorphism within ethenzamide-ethylmalonic acid cocrystal using Raman and terahertz vibrational spectroscopy

Two cocrystal polymorphs of ethenzamide (ETZ) and ethylmalonic acid (EMA) were synthesized by solvent evaporation. Crystal structure analysis revealed that the main amide − carboxyl heterosynthon in ETZ-EMA cocrystal Form I and Form II are the same, but the crystal structure of these two polymorphs are different. Terahertz (THz) and Raman vibrational spectroscopy were used to characterize ETZ, EMA, ETZ-EMA cocrystal polymorph Form I and Form II respectively. The experimental results showed that ETZ, EMA, ETZ-EMA cocrystal Form I and ETZ-EMA cocrystal Form II exhibited completely different characteristic peaks. Both THz and Raman vibrational spectroscopy can be used to distinguish ETZ-EMA cocrystal Form I from Form II. Furthermore, the investigation of phase transition induced by temperature and solid-state grinding was also performed. In the temperature phase transition experiments, when the powder sample was heated to a temperature range of 80–82 °C, the metastable ETZ-EMA cocrystal Form I transformed into the more stable ETZ-EMA cocrystal Form II. Solid-state grinding analysis revealed that the results of the ETZ-EMA cocrystal polymorph synthesis in grinding experiments depended on the polarity of the solvents used. Grinding without solvent or with high polarity solvents tended to result in the stable ETZ-EMA cocrystal Form II. Moreover, the metastable ETZ-EMA cocrystal Form I would transform into Form II after further grinding process. These results demonstrate that THz and Raman vibrational spectroscopy have high sensitivity and accuracy in the detection of both cocrystal synthesis and cocrystal polymorph phase transitions.

Amorphization of Ethenzamide and Ethenzamide Cocrystals-A Case Study of Single and Binary Systems Forming Low-Melting Eutectic Phases Loaded on/in Silica Gel.

The applicability of different solvent-free approaches leading to the amorphization of active pharmaceutical ingredients (APIs) was tested. Ethenzamide (ET), an analgesic and anti-inflammatory drug, and two ethenzamide cocrystals with glutaric acid (GLU) and ethyl malonic acid (EMA) as coformers were used as pharmaceutical models. Calcinated and thermally untreated silica gel was applied as an amorphous reagent. Three methods were used to prepare the samples: manual physical mixing, melting, and grinding in a ball mill. The ET:GLU and ET:EMA cocrystals forming low-melting eutectic phases were selected as the best candidates for testing amorphization by thermal treatment. The progress and degree of amorphousness were determined using instrumental techniques: solid-state NMR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. In each case, the API amorphization was complete and the process was irreversible. A comparative analysis of the dissolution profiles showed that the dissolution kinetics for each sample are significantly different. The nature and mechanism of this distinction are discussed.

Improving the Powder Properties of an Active Pharmaceutical Ingredient (Ethenzamide) with a Silica Nanoparticle Coating for Direct Compaction into Tablets

To improve the powder properties of active pharmaceutical ingredients (APIs), we coated APIs with silica nanoparticles using a dry process that allowed for direct compression into tablets. The dry coating performed with different apparatuses (a batch-type high-speed shear mixer (Mechanomill) and a continuous conical screen mill (Comil)) and properties of the resulting dry-coated APIs were compared. Ethenzamide (ETZ), which has low powder flowability, was selected as the host particle to be improved and the colloidal silicas Aerosil 200 and R972 were used as the guest particles. Both coating processes and types of silica nanoparticles improved the powder flowability (angle of repose) of ETZ under unstressed conditions. Inverse gas chromatography demonstrated that dry coating with silica nanoparticles reduced the surface free energy and improved the homogeneity of the surface energy distribution of ETZ particles. Under the stress conditions of a shear cell test, the Mechnomill-based treatment improved the powder flowability of ETZ from that of untreated ETZ; however, the Comil-based treatment did not improve the flowability. The mechanical shear force exerted by Comil was apparently insufficient for interactions between host and guest particles. However, the properties of tableted ETZ were enhanced even when the silica nanoparticles were coated using Comil.

Pharmaceutical Cocrystals of Ethenzamide: Molecular Structure Analysis Based on Vibrational Spectra and DFT Calculations.

Pharmaceutical cocrystals can offer another advanced strategy for drug preparation and development and can facilitate improvements to the physicochemical properties of active pharmaceutical ingredients (APIs) without altering their chemical structures and corresponding pharmacological activities. Therefore, cocrystals show a great deal of potential in the development and research of drugs. In this work, pharmaceutical cocrystals of ethenzamide (ETZ) with 2,6-dihydroxybenzoic acid (26DHBA), 2,4-dihydroxybenzoic acid (24DHBA) and gallic acid (GA) were synthesized by the solvent evaporation method. In order to gain a deeper understanding of the structural changes after ETZ cocrystallization, terahertz time domain spectroscopy (THz-TDS) and Raman spectroscopy were used to characterize the single starting samples, corresponding physical mixtures and the cocrystals. In addition, the possible molecular structures of ETZ-GA, ETZ-26DHBA and ETZ-24DHBA cocrystals were optimized by density functional theory (DFT). The results of THz and Raman spectra with the DFT simulations for the three cocrystals revealed that the ETZ-GA cocrystal formed an O−H∙∙∙O hydrogen bond between the -OH of GA and oxygen of the amide group of the ETZ molecule, and it was also found that ETZ formed a dimer through a supramolecular amide–amide homosynthon; meanwhile, the ETZ-26DHBA cocrystal was formed by a powerful supramolecular acid–amide heterosynthon, and the ETZ-24DHBA cocrystal formed the O−H∙∙∙O hydrogen bond between the 4-hydroxy group of 24DHBA and oxygen of the amide group of the ETZ molecule. It could be seen that in the molecular structure analysis of the three cocrystals, the position and number of hydroxyl groups in the coformers play an essential role in guiding the formation of specific supramolecular synthons.

Co-crystals of ethenzamide with 2-nitrobenzoic acid - Conformational analysis, MD simulations and DFT investigations

In crystal engineering and pharmaceutical chemistry, co-crystals have a wide range of applications. Ethenzamide (EA) is found to form co-crystal with 2-nitrobenzoic acid (NBA). Geometry properties like stability energy, charge distribution, bond length, electronic properties and thermodynamic characteristics have been analyzed. The C–H⋯O hydrogen bond involves C–H of EA and oxygen of NBA. Configuration with the angle, N3–C4–C5–C6 gives the lowest energy conformation. Partition coefficient value suggests that EA-NBA has pharmaceutics behavior. RMSD values show the simulation's relative stability and the complexes, remained stable throughout.

Dry mechanochemical synthesis of ethenzamide and saccharin 1:1 cocrystal and their evaluation using powder X-ray diffraction and FT-MIR and NIR spectroscopy

The purpose of this study was to evaluate effects of dry mechanochemical synthesizes on ethenzamide (EZ) and saccharin (SA) mixture. EZ and SA mixture were evaluated after grinding by mid and near infrared spectroscopy, powder X-ray diffraction (PXRD) and thermal analysis. During the grind, EZ and SA mixture was transformed into their 1:1 cocrystal form. Measurement time course data was applied to multi variate analysis of principal component analysis (PCA). Their cocrystallization could decompose two steps reactions. At first, EZ crystal transform into amorphous phase and their amorphous react with SA molecules after them, hydrogen bond networks were constructed and produce cocrystal was suggested. Combination PCA and several measurement data enable to extract useful chemical information.

Mechanosynthesis of Eutectics of Anti‐Inflammatory Drug Ethenzamide – A Comparison with Analogous Cocrystals

AbstractMechanochemical milling of ethenzamide (ETZ), a nonsteroidal anti‐inflammatory drug, with substituted aromatic carboxylic acids as well as anti‐tuberculosis drug pyrazinamide (PZA) resulted in the formation of eutectics. Although a large number of cocrystals as well as polymorphic cocrystals are reported for ETZ, for the first time we have synthesized six eutectics including an instance of a drug‐drug eutectic system. Supramolecular synthon energy calculations validate the formation of eutectic mixtures over cocrystals with coformers considered in our study.

Experimental measurement and thermodynamic modelling of ethenzamide solubility in three binary solvent systems

The solid–liquid phase equilibrium of ethenzamide (ETZ), a classic anti-inflammatory drug, in binary solvent systems was experimentally investigated and simulated. The equilibrium solubility of ETZ in binary solvent mixtures of methanol + acetonitrile, ethanol + acetonitrile, and isopropanol + acetonitrile was determined via a gravimetric method at temperatures ranging from 293.15 K to 323.15 K at atmospheric pressure (0.1 MPa). In all binary solvent systems, the solubility of ETZ increases with the increasing of temperature at a given solvent composition, but it initially increased and then decreased with the increase in alcohol composition (good solvent). Additionally, the Jouyban-Acree, van’t Hoff-Jouyban-Acree, Apelblat-Jouyban-Acree, and Ma models were utilized to correlate the experimental data. Results showed that the Jouyban-Acree model achieved the best correlation performance. Molecular dynamic simulation and radial distribution function analysis revealed the cooperation effect originating from solute-solvent and solvent–solvent interactions, which explained the dissolution behaviors of ETZ in various solvent mixtures. Calculations of dissolution thermodynamic properties, including enthalpy, Gibbs free energy, and entropy, revealed that the dissolution behavior of ETZ was an endothermic and entropy-driven process. This study provides insights into modulating ETZ crystallization and in understanding solid–liquid phase equilibrium behaviors in mixed solvent systems.

Ethenzamide Exerts Protective Effects against Ibuprofen-Induced Gastric Mucosal Damage in Rats by Suppressing Gastric Contraction.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage, in which gastric hypermotility has been reported to play a primary role. The antipyretic analgesic drug ethenzamide (ETZ) is widely used in combination with other NSAIDs and, in a recent study, was found to possess 5-hydroxytriptamine (5HT)2B receptor antagonistic activity. Therefore, the inhibition of gastric contraction via 5HT2B receptor blockade by ETZ might contribute to ETZ's protective effect against NSAIDs-induced gastric mucosal damage. In the present study, we examined the effects of ETZ on gastric contraction and ibuprofen (IBP)-induced gastric mucosal damage in rats. We found that ETZ suppressed both 5HT- and α-methyl-5HT (5HT2 receptor agonist)-induced contractions of rat-isolated gastric fundus in a concentration-dependent manner. This suppressive effect of ETZ was not seen for either high-KCl- or acetylcholine-induced contractions. Furthermore, ETZ was confirmed to decrease ibuprofen-induced gastric mucosal damage in a dose-dependent manner in rats. Similarly, clonidine is known to reduce gastric motility, and methysergide (a 5HT2 receptor antagonist) is known to inhibit 5HT-induced contractions of the gastric fundus, which also decreases IBP-induced gastric mucosal damage, respectively. Although further research on other possible sites or mechanisms of action would be needed, these results suggest that ETZ exerts a protective effect against IBP-induced gastric mucosal damage and that suppressing the gastric contraction may play an important role in the gastroprotective effect of ETZ.

Mixed micellization of bile salts and transglycosylated stevia and enhanced binding and solubility of non-steroidal anti-inflammatory drugs using mixed micelle

This research investigated the efficacy of mixed micellar systems as an innovative chemical means of improving the binding properties of poorly water-soluble drugs. The formulations based on the mole fraction were used to prepare mixed micelles using anionic sodium deoxycholate (NaDC) or sodium cholate (NaC), and nonionic transglycosylated stevia (Stevia–G). Surface tension and dynamic light scattering (DLS) assessed the characteristic of the NaDC–Stevia–G and NaC–Stevia–G mixed micelles. Rubingh approach evaluated the interaction parameter (−βm), which demonstrated synergistic interaction between the anionic and non-ionic surfactant. Mixed micelle was used to assess the binding constant (Kb) and solubility of non-steroidal anti-inflammatory drugs, ethenzamide (ETZ), and ibuprofen (IBF). Kb values increased, but the mean occupancy (i) of ETZ and IBF per micelle decreased by increasing αStevia–G 0.1 to 0.9, predicting a shift in occupancy of drugs from Palisade to Stern layer. At αStevia–G 0.9 the maximum solubility of ETZ and IBF was 7.50 and 2.60 mmolL−1 for NaDC–Stevia–G and 5.60 and 1.70 mmolL−1 for NaC–Stevia–G. To get a better comprehension about micellization behavior and preferential interaction of the drugs under study, quantum chemical calculations and molecular dynamic (MD) simulations were performed. The MD analysis assessed that the poorly water-soluble drugs demonstrated strong binding in the presence of NaDC–Stevia–G as compared to NaC–Stevia–G mixed micelle. Ultimately, in pharmaceutical applications, mixed micelle of bile salts-Stevia-G can be used as an effective drug solubilizing agent.

Ethenzamide Exerts Analgesic Effect at the Spinal Cord <i>via</i> Multiple Mechanisms of Action Including the 5HT<sub>2B</sub> Receptor Blockade in the Rat Formalin Test

Ethenzamide (ETZ), an antipyretic analgesic categorized as a non-steroidal anti-inflammatory drug (NSAID), is widely used as an OTC drug in combination with other NSAIDs. However, its site of action and mechanism underlying its analgesic action have not yet been fully elucidated. In this study, we performed in vitro pharmacological assays to identify the mechanism underlying the analgesic action of ETZ, and also conducted the rat formalin test to investigate its analgesic effect and site of action. Of the 85 receptors, ion channels, transporters and enzymes tested, we found that ETZ binds to the 5-hydroxytryptamine (5HT)2B receptor in concentration-dependent manner with modest inhibitory effects on monoamine oxidase-A and transient potential vanilloid 1 channel. The 5HT2B receptor antagonist activity of ETZ was also confirmed in a cellular functional assay. Furthermore, the drug exerted no inhibitory effects on cycrooxygenase-1 and -2. In the rat formalin test, oral administration of ETZ significantly reduced the nociceptive responses of the second phase and also the number of c-Fos-expressing cells in the spinal dorsal horn, in a dose-dependent manner. Moreover, intrathecal administration of ETZ significantly reduced the nociceptive responses. These results suggest that the analgesic effect of ETZ is exerted at least in the spinal cord, and the effect would be attributed to multiple mechanisms of action including 5HT2B receptor blockade.

A Novel Binary Supercooled Liquid Formulation for Transdermal Drug Delivery.

The aim of this study was to prepare binary supercooled liquid (SCL) by intermolecular interaction and apply this formulation to transdermal drug delivery. Ketoprofen (KET) and ethenzamide (ETH) were selected as binary SCL component. Thermal analysis of physical mixtures of KET and ETH showed decreases in melting points and glass transition below room temperature, thereby indicating formation of KET-ETH SCL. Intermolecular interactions between KET and ETH in the SCL were evaluated from Fourier transform (FT)-IR spectra. KET-ETH SCL maintained SCL state at 25°C with silica gel over 31 d and at 40°C/89% relative humidity (RH) over 7 d. KET SCL and KET-ETH SCL showed similar permeability of KET for hairless mice skin, which was two-fold higher than that of KET aqueous suspension. Our findings suggest that the SCL state could enhance the skin permeation of drugs and the binary SCL formed by intermolecular interaction could also improve the stability of the SCL. The binary SCL system could become a new drug form for transdermal drug delivery.

Mixed micelles of the antihistaminic cationic drug diphenhydramine hydrochloride with anionic and non-ionic surfactants show improved solubility, drug release and cytotoxicity of ethenzamide

This study aimed to apply mixed drug–surfactant micelles to enhance the solubility and reduce the cytotoxicity of poorly water-soluble active pharmaceuticals. Nanosized drug–surfactant formulations were prepared using antihistaminic cationic drug diphenhydramine hydrochloride (DCP) with anionic sodium deoxycholate (SDC) and non-ionic transglycosylated stevia (Stevia-G) surfactants. Surface tension and fluorescence methods were used to evaluate mixed micellization in an aqueous medium. The negative interaction parameters (βm) values of the drug-surfactant mixed micelle showed the strong attractive interactions of DCP with SDC and Stevia-G. The applicability of the drug-surfactant mixed micelle for enhancing the binding constant (logKb), partition coefficient (logKm) and molar solubilization ration (MSR) of the non-steroidal anti-inflammatory drug, ethenzamide (ETZ) was evaluated. The %EE of ETZ in DCP at αDCP = 1.0 was higher than that of SDC and Stevia-G, reflecting the formation of a hydrogen bond between ETZ and DCP. The controlled released of ETZ in PBS at pH 7.4 was approximately 10% from both mixed micelles after 55 h. In addition, cell viabilities in the presence of ETZ and SDC were reduced to 48% and 40% at 0.5 and 3.0 mM, respectively, indicating their high cytotoxicity. By contrast, cell viability was >90% in the presence of mixed micelles of DCP–SDC and DCP–Stevia-G with αDCP = 0.9 at 3.0 mM, suggesting low cytotoxicity. These data show that nanosized mixed micelles facilitate the passage of these two drugs through the cell membranes, thereby leading to their improved uptake into the target cells.

Structural Characterization and Pharmaceutical Properties of Three Novel Cocrystals of Ethenzamide With Aliphatic Dicarboxylic Acids

Ethenzamide (ET) was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover materials of improved physicochemical properties, that is, higher solubility and better stability. Three novel cocrystals of ET with glutaric, malonic, and maleic acids were obtained by neat grinding and slow evaporation from solution. The purpose of the study was to notice the changes in the geometry and interactions of ET molecule in crystalline phase introduced by different acid and relate them to physicochemical properties of pure ET. Therefore, the crystal structure of the cocrystals was determined by single crystal X-ray diffraction analysis. The powder samples were characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and 13C and 15N solid-state nuclear magnetic resonance spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave calculations of chemical shielding constants. The high stability of cocrystals during direct compression was proved. The solubility in simulated gastric fluids for studied cocrystals appeared to be approximately 1.6 times-fold higher than ET. The dissolution rates of all ET cocrystals were not faster than the pure drug, but after 240 min, more drugs were released.

Cocrystal of nutraceutical sinapic acid with Active Pharmaceutical Ingredients ethenzamide and 2-chloro-4-Nitrobenzoic acid: Equilibrium solubility and stability study

Sinapic acid (SNP) is a nutraceutical compound of hydroxybenzoic acid derivative which possesses anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-anxiety activity properties. In the present work, two cocrystals of SNP with two active drug ingredients such as Ethenzamide (ETZ) and 2-chloro-4-nitrobenzoic acid (CNB) are reported. Both the cocrystals were synthesized via simple solvent evaporation method and the crystal structures were characterized by Single Crystal X-ray Diffraction (SC-XRD) techniques. The cocrystals were formed via robust acid-amide heterosynthon and acid-acid homosynthon between SNP and drug molecules. Both the cocrystals were crystallized in monoclinic crystal system with P 21/c space group. The synthesized cocrystals were further characterized by DSC, PXRD, FT-IR, and 1H NMR techniques. The solubility study in purified distilled water and in 0.1 N HCl solution demonstrate that there was no increment in the solubility of drug molecules in the cocrystals in both purified water and in 0.1 N HCl solution. The synthesized cocrystal exhibited six months stability at ambient conditions (∼25 °C, 60–65% RH).

Pharmaceutical properties of two ethenzamide-gentisic acid cocrystal polymorphs: Drug release profiles, spectroscopic studies and theoretical calculations

The aim of this study was to evaluate the stability and solubility of the polymorphic forms of the ethenzamide (ET) – gentisic acid (GA) cocrystals during standard technological processes leading to tablet formation, such as compression and excipient addition. In this work two polymorphic forms of pharmaceutical cocrystals (ETGA) were characterized by 13C and 15N solid-state nuclear magnetic resonance and Fourier transformed infrared spectroscopy. Spectroscopic studies were supported by gauge including projector augmented wave (GIPAW) calculations of chemical shielding constants.Polymorphs of cocrystals were easily identified and characterized on the basis of solid-state spectroscopic studies. ETGA cocrystals behaviour during direct compressionand tabletting with excipient addition were tested. In order to choose the best tablet composition with suitable properties for the pharmaceutical industry dissolution profile studies of tablets containing polymorphic forms of cocrystals with selected excipients were carried out.

Pharmaceutical Co-Crystal of Flufenamic Acid: Synthesis and Characterization of Two Novel Drug-Drug Co-Crystal

Two novel pharmaceutical co-crystals of anti-inflammatory drug flufenamic acid (FFA) with 2-chloro-4-nitrobenzoic acid (CNB) and ethenzamide (ETZ) have been synthesized by solvent evaporation method as well as by solvent drop-assisted grinding method. The synthesized co-crystals were characterized thoroughly by various spectroscopic methods and crystal structures were determined by single-crystal x-ray diffraction technique. In FFA-CNB co-crystal, robust supramolecular acid-acid homosynthon was observed. FFA-ETZ co-crystal is formed via robust supramolecular acid-amide heterosynthon. In FTIR spectra, a significant shift in the carbonyl stretching frequency was observed for the co-crystals due to the presence of intermolecular hydrogen bond. 1H nuclear magnetic resonance study suggests the presence of hydrogen bond in the solution state of FFA-ETZ co-crystal; however, it was absent for FFA-CNB co-crystal. Solubility study in Millipore water revealed that the solubility of FFA is increased by 2-fold when it is in the form of FFA-CNB co-crystal and no increment in the solubility of FFA was observed in FFA-ETZ co-crystal. About 5-fold increment in the solubility of FFA was observed in both the co-crystals in 0.1 N HCl (pH 1) solution. The synthesized co-crystals were found to be non-hygroscopic at ∼75% relative humidity and stable for a period of 6 months at ambient temperature (∼25°C).

Crystal structure landscape of ethenzamide: a physicochemical property study

Pharmaceutical cocrystals/cocrystal hydrate of ethenzamide (ETZ) with various hydroxy-acid coformers namely 2,4-dihydroxybenzoic acid (24DHBA), 3,5-dihydroxybenzoic acid (35DHBA), ferulic acid (FRA, nutraceutical molecule) and 35DHBA dihydrate (1:3:2) were synthesised using solution crystallisation as well as mechanical grinding. All the multi-component systems were characterised using various solid-state characterisation techniques such as single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and FT-IR spectroscopy. Structural analysis reveals that the position of the hydroxyl group governs the hydrogen bond synthon present in the cocrystals/cocrystal hydrate system. ETZ·24DHBA has an unusual amide–amide catemer synthon and is 3D isostructural to the reported ETZ·4HBA cocrystal. The solubility study shows that the ETZ·35DHBA cocrystal is 13 times more soluble in water compared to pure ETZ. The solubility order of ETZ cocrystals along with pure ETZ can be represented as ETZ·35DHBA > ETZ·24DHBA > ETZ > ETZ·FRA, and follows the trend of the coformer's solubility.