Cocrystal Formation Research Articles

Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine-Triazole Groups in Stable Crystal Form.

Ensitrelvir is a nonpeptide 3CL protease inhibitor used for coronavirus disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable (Form I), acetonate (Form II), stable (Form III), and hydrate (Form IV), have been analyzed as pharmaceutical crystals. Their rank order of solubility is Form I > IV > III. Form III is the stable crystal with a significantly lower solubility than that predicted from its log P value of 2.7. Here, single-crystal structural analysis revealed strong intermolecular interactions between the triazine (acidic) and triazole (basic) groups of Form III not Forms I and IV. Multicomponent crystals were also designed to improve the solubility by altering the intermolecular interactions in Form III. Slurry conversion with equal molar ratios of ensitrelvir and fumaric acid successfully induced the formation of a novel cocrystal (Form V). Fumaric acid inhibited the triazine-triazole interactions, and dissolution of Form V was approximately 8- and 13-fold higher than that of Form III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited an approximately 16-fold higher flux value than that of Form III. Therefore, alterations in intermolecular interactions via cocrystallization significantly enhance the dissolution and permeation of ensitrelvir.

Graph Neural Networks with Multi-features for Predicting Cocrystals using APIs and Coformers Interactions.

Active pharmaceutical ingredients (APIs) have gained direct pharmaceutical interest, along with their in vitro properties, and thus utilized as auxiliary solid dosage forms upon FDA guidance and approval on pharmaceutical cocrystals when reacting with coformers, as a potential and attractive route for drug substance development. However, screening and selecting suitable and appropriate coformers that may potentially react with APIs to successfully form cocrystals is a time-consuming, inefficient, economically expensive, and labour-intensive task. In this study, we implemented GNNs to predict the formation of cocrystals using our introduced API-coformers relational graph data. We further compared our work with previous studies that implemented descriptor-based models (e.g., random forest, support vector machine, extreme gradient boosting, and artificial neural networks). All built graph-based models show compelling performance accuracies (i.e., 91.36, 94.60 and 95. 95% for GCN, GraphSAGE, and RGCN respectively). RGCN demonstrated effectiveness and prevailed among the built graph-based models due to its capability to capture intricate and learn nuanced relationships between entities such as non-ionic and non-covalent interactions or link information between APIs and coformers which are crucial for accurate predictions and representations. These capabilities allows the model to adeptly learn the topological structure inherent in the graph data.

Cocrystallization‐Induced Red Ultralong Organic Phosphorescence

AbstractOrganic cocrystals formed through multicomponent self‐assembly have attracted significant interest owing to their clear structure and tunable optical properties. However, most cocrystal systems suffer from inefficient long‐wavelength emission and low phosphorescence efficiency due to strong non‐radiative processes governed by the energy gap law. Herein, an efficient long‐lived red afterglow is achieved using a pyrene (Py) cocrystal system incorporating a second component (NPYC4) with thermally activated delayed fluorescence (TADF) and ultralong organic phosphorescence (UOP) properties. The cocrystal (NPYC4‐Py) not only inherits the excellent luminescence of its monomeric counterparts, but also exhibits unique dual‐mode characteristics, including persistent TADF and UOP emission with a high quantum yield of 58 % and a lifetime of 362 ms. The precise cocrystal stacking distinctly reveals that intermolecular interactions lock the cocrystal formation and weaken the intermolecular π‐π interactions between NPYC4 and Py, thereby stabilizing the excited triplet excitons. Furthermore, the favorable energy level of NPYC4 acts as a bridge, reducing the energy gap between the S1 and T1 states for Py, therefore activating its red phosphorescence from Py. This research provides direct insights into achieving efficient red UOP through co‐crystallization.

Theoretical Study on Intramolecular Hydrogen Bonds of Flavonoid Cocrystals.

This study investigates the role of intramolecular hydrogen bonds in the formation of cocrystals involving flavonoid molecules, focusing on three active pharmaceutical ingredients (APIs): chrysin (CHR), isoliquiritigenin (ISO), and kaempferol (KAE). These APIs form cocrystals with different cocrystal formers (CCFs) through intramolecular hydrogen bonding. We found that disruption of these intramolecular hydrogen bonds leads to decreased stability compared to molecules with intact bonds. The extrema of molecular electrostatic potential surfaces (MEPS) show that flavonoid molecules with disrupted intramolecular hydrogen bonds have stronger hydrogen bond donors and acceptors than those with intact bonds. Using the artificial bee colony algorithm, dimeric structures of these flavonoid molecules were explored, representing early-stage structures in cocrystal formation, including API-API, API-CCF, and CCF-CCF dimers. It was observed that the number and strength of dimeric interactions significantly increased, and the types of interactions changed when intramolecular hydrogen bonds were disrupted. These findings suggest that disrupting intramolecular hydrogen bonds generally hinders the formation of cocrystals. This theoretical study provides deeper insight into the role of intramolecular hydrogen bonds in the cocrystal formation of flavonoids.

Prioritizing Computational Cocrystal Prediction Methods for Experimental Researchers: A Review to Find Efficient, Cost-Effective, and User-Friendly Approaches

Pharmaceutical cocrystals offer a versatile approach to enhancing the properties of drug compounds, making them an important tool in drug formulation and development by improving the therapeutic performance and patient experience of pharmaceutical products. The prediction of cocrystals involves using computational and theoretical methods to identify potential cocrystal formers and understand the interactions between the active pharmaceutical ingredient and coformers. This process aims to predict whether two or more molecules can form a stable cocrystal structure before performing experimental synthesis, thus saving time and resources. In this review, the commonly used cocrystal prediction methods are first overviewed and then evaluated based on three criteria: efficiency, cost-effectiveness, and user-friendliness. Based on these considerations, we suggest to experimental researchers without strong computational experiences which methods and tools should be tested as a first step in the workflow of rational design of cocrystals. However, the optimal choice depends on specific needs and resources, and combining methods from different categories can be a more powerful approach.

Insights into pharmaceutical co-crystallization using coherent Raman microscopy

Formulating active pharmaceutical ingredients (APIs) as co-crystals requires a thorough understanding of co-crystallization behavior under different process conditions. This study employs two forms of coherent Raman microscopy, narrowband coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) with spectral focusing, to study co-crystallization via liquid-assisted ball milling. Indomethacin and nicotinamide served as the model API and co-former, and the results were compared with established analytical methods. Narrowband CARS, with univariate peak position analysis, was useful to visualize co-crystal formation, but suffered some degree of signal mixing that affected component identification. Hyperspectral SRS imaging, combined with classical least squares multivariate analysis, separated the different components with high confidence and proved to be a robust and rapid tool to qualitatively and quantitatively image co-crystallization. The coherent Raman imaging results explained divergent co-crystallization endpoints obtained with the conventional solid-state analysis methods. CARS and SRS microscopies also revealed the presence of otherwise undetected trace forms. Finally, we also demonstrated the dramatic reversal of partial co-crystal formation during milling, depending on ethanol content. Overall, the study demonstrates the added value coherent Raman microscopy can provide for analysis of co-crystallization processes.

Solubility and Dissolution Improvement of Paramethoxycinnamic Acid (PMCA) Induced by Cocrystal Formation using Caffeine as a Coformer

Para-methoxy cinnamic acid (pMCA) is a derivative compound of ethyl p-methoxycinnamate that could be obtained in nature. pMCA has excellent pharmacological properties. However, in their application as a drug, pMCA has poor water solubility. In this present research, we try to increase the water solubility of pMCA using the cocrystal formation (cocrystallization) strategy. Here, we use caffeine as a coformer that can interact very well with pMCA via non-covalent bonding and Van der Waals interaction to achieve cocrystal formation. The cocrystal samples were successfully synthesized using various synthesis techniques; physical mixture, solvent evaporation, and microwave radiation methods. It shows that the solubility of the samples synthesized using microwave-assisted and solvent evaporation increases about 3.30 and 3.12 times, respectively, whereas the dissolution rate profile increases 2.50 and 2.39 times, respectively, compared to pure APMS. Our findings explain the importance of the cocrystal formation strategy to enhance the solubility of active material pMCA. This strategy can also be used as a standard formulation of a new drug system with excellent solubility and dissolution which is very important for the pharmaceutical industry.

Cocrystallization-Induced Red Ultralong Organic Phosphorescence.

Organic cocrystals formed through multicomponent self-assembly have attracted significant interest owing to their clear structure and tunable optical properties. However, most cocrystal systems suffer from inefficient long-wavelength emission and low phosphorescence efficiency due to strong non-radiative processes governed by the energy gap law. Herein, an efficient long-lived red afterglow is achieved using a pyrene (Py) cocrystal system incorporating a second component (NPYC4) with thermally activated delayed fluorescence (TADF) and ultralong organic phosphorescence (UOP) properties. The cocrystal (NPYC4-Py) not only inherits the excellent luminescence of its monomeric counterparts, but also exhibits unique dual-mode characteristics, including persistent TADF and UOP emission with a high quantum yield of 58% and a lifetime of 362 ms. The precise cocrystal stacking distinctly reveals that intermolecular interactions lock the cocrystal formation and weaken the intermolecular π-π interactions between NPYC4 and Py, thereby stabilizing the excited triplet excitons. Furthermore, the favorable energy level of NPYC4 acts as a bridge, reducing the energy gap between the S1 and T1 states for Py, therefore activating its red phosphorescence from Py. This research provides direct insights into achieving efficient red UOP through co-crystallization.

Synthesis, characterization, in silico and in vitro assessment of 2-aminopyridine nicotinamide cocrystal as a new agent for breast cancer therapy

Breast cancer is the leading cause of cancer-related death among women globally, in spite of major advances in diagnosis and treatment. 2-Aminopyridine Nicotinamide (2APNA) cocrystal was synthesized and cocrystal formation was confirmed through powder XRD. Computational investigations in structural fields and spectroscopic parameters were conducted and compared with the experimental results. Comparing the optimized geometrical characteristics, it was observed that molecular properties of 2APNA closely match the previously reported experimental data. FT-IR and FT-Raman spectroscopic analysis revealed the theoretical wavenumbers agree better with recorded data and in UV–visible absorption a single peak was recorded at 247 nm showing n → π* transition. The 2APNA's stability, reactive nature, charge relocations were studied through quantum chemical calculation such as FMO, MEP, NBO, NLO and Mulliken charge analysis. The topological features of cocrystal 2APNA was examined through ELF, LOL and RDG studies. The anti-apoptotic protein BCL-2 was selected as a target in molecular docking analysis and the results expressed 2APNA's binding score as -8.2 kcal/mol. In vitro studies confirmed that 2APNA has 2APNA demonstrated an enhanced cell death in MCF-7 cells with the IC50 concentration of 56.58 µg/mL and decreased the expression of BCL-2, thus resulting in apoptotic cell death. These results indicated that 2APNA possess a potent anticancer property for the treatment of breast cancer.

Effect of conformational landscape on the polymorphism and monomorphism of tizanidine cocrystallization outcomes

Molecular conformational diversity plays a crucial role in both polymorphic nucleation and cocrystal formation during the cocrystallization process. However, the relationship between molecular conformation and cocrystallization polymorphism is not well-explored. Herein, the impact of molecular conformational landscapes on cocrystallization outcomes was investigated using tizanidine (TZND) as model compound. Four coformers, namely maleic acid (MA), salicylic acid (SA), p-hydroxybenzoic acid (pHBA), and heptanedioic acid (HDA), were employed and five salt forms were developed for the first time. Compared with TZND, all five salts showed significantly improved water solubility and dissolution rate. The cocrystallization behavior of TZND varied with each coformer: MA exhibited solvent-dependent polymorphism, while SA, pHBA, and HDA showed solvent-independent monomorphism. Crystal structure and conformational analyses revealed the conformational variation of TZND across different cocrystallization outcomes. Molecular dynamics simulations and quantum chemical calculations demonstrated that the interplay between solvent effects and coformer interactions determines the dominant conformations of TZND. The cocrystallization nucleation process was also examined, and the molecular mechanism that explains both polymorphism and monomorphism in the cocrystallization of TZND was proposed.

Biochanin-A co-crystal formulation improves bioavailability and ameliorates cerulein-induced pancreatitis by attenuating the inflammation

Co-crystallization of a therapeutic ingredient with an appropriate co-former is a powerful technique to augment the physicochemical and pharmacokinetic properties and the effectiveness of Active Pharmaceutical Ingredients (APIs). Biochanin A (BCA), a flavonoid with medicinal potential, is limited by poor solubility and low oral bioavailability. This study aimed to design and develop a novel BCA-nicotinamide cocrystal as BCC to enhance BCA’s oral bioavailability and explore its therapeutic potential for ameliorating cerulein-induced acute pancreatitis (CIAP) by elucidating the target identification utilizing tissue/serum metabolite profiles. The cocrystal was designed by the supramolecular synthon approach and characterized by single-crystal X-ray diffraction that confirms a robust three-dimensional hydrogen-bonded network of BCA and Nicotinamide (NCT) in the crystal. FT-IR and DSC were used to analyze the cocrystal’s intermolecular interactions and thermal behavior. BCC exhibited enhanced solubility and drug release compared to BCA alone, resulting in enhanced oral bioavailability and pancreatic tissue concentration. Comparing BCC to BCA in the CIAP model, BCC therapy remarkably reduced cerulein-induced pancreatitis, evidenced by significant reductions in inflammation, acinar cell atrophy, and amylase levels in pancreatic tissues. Further, the cocrystal formulation also down-regulated the oxidative stress markers, inflammatory cytokines and macrophage-related proteins. The study has identified distinct metabolomic signatures linked with AP with the help of Orbitrap Exploris mass spectrometry, which could pave the way for creating focused diagnostic tools for a better prognosis. In conclusion, these results offer new insights into exploring mechanistic pathways associated with specific biomarkers and underscore BCC cocrystals as a promising approach to enhance BCA’s therapeutic potential.

Influence of solvent selection and RESS processing conditions on formation of a praziquantel-malonic acid cocrystal in supercritical CO2

Praziquantel (PZQ) is an anthelmintic drug with low solubility, therefore cocrystallization and particle size reduction is desirable to improve bioavailability. In this study, a PZQ-malonic acid cocrystal was micronized by rapid expansion of supercritical solution (RESS). Due to low solubility in scCO2, four cosolvents were screened as RESS modifiers. While addition of acetone or THF yielded mixtures of PZQ and its cocrystal, MeOH and EtOH produced pure cocrystal. Impact of pressure (15–30 MPa), temperature (35–55 °C), and cosolvent loading (3–10 volumes) on phase-purity, yield, and particle size were investigated. Adding cosolvent to RESS facilitated dissolution of cocrystal formers in scCO2 and crystallization of the cocrystal with yields up to 68.5 wt% and particle size as low as 600 nm. Results show that for APIs with low solubility in scCO2, cosolvent-modified RESS is a suitable approach for simultaneous crystallization and micronization.

Development and Evaluation of Flurbiprofen-Ferulic Acid Co-crystal With Enhanced Solubility and Dissolution Rate.

Flurbiprofen, a BCS class II NSAID, was combined with GRAS molecules to create new co-crystal forms using crystal engineering techniques such as solvent drop grinding and evaporation. Analysis with XRD, DSC, and FTIR confirmed purity and co-crystal formation. X-ray crystal data revealed hydrogen bonding and interactions, while DSC showed changes in thermal behavior. The co-crystals, particularly the flurbiprofen-ferulic acid co-crystals, had increased solubility and faster dissolution than pure drug.

Recent advances in pharmaceutical cocrystals of theophylline.

Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline's additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.

Current Perspectives on Development and Applications of Cocrystals in the Pharmaceutical and Medical Domain.

In recent years, the design of pharmaceutical cocrystals has garnered significant attention. The process of cocrystallization offers a remarkable opportunity to develop drug products with enhanced properties such as improved stability, solubility, hygroscopicity, dissolution rate, and bioavailability. This detailed review delves into this evolving area, thereby exploring its relevance in pharmaceutical formulation by defining cocrystals and their practical applications and also by discussing methods for their preparation as well as characterization. It also contrasts traditional and innovative techniques for cocrystal formation. Historically, cocrystals have been synthesized using methods like solvent evaporation, grinding, and slurry techniques; however, each has its own set of limitations under specific conditions. The latest trends in cocrystal formation lean toward more advanced approaches such as spray-drying, hot melt extrusion, and supercritical fluid technology, as well as the cutting-edge technique of laser irradiation. The aim behind developing new methods is not just to address the limitations of traditional cocrystallization techniques but also to streamline the process by introducing simpler steps and enabling a continuous production workflow for cocrystal products. In general, this full-length review article offers a report on various techniques available for the creation of pharmaceutical cocrystals, along with the methods for their evaluation. Moreover, it includes reporting developments and diverse applications of cocrystals along with the commercially available cocrystals in the pharmaceutical as well as medical domains.

Preparation and Molecular Dynamic Simulation of Superfine CL-20/TNT Cocrystal Based on the Opposite Spray Method.

In view of the current problems of slow crystallization rate, varying grain sizes, complex process conditions, and low safety in the preparation of CL-20/TNT cocrystal explosives in the laboratory, an opposite spray crystallization method is provided to quickly prepare ultrafine explosive cocrystal particles. CL-20/TNT cocrystal explosive was prepared using this method, and the obtained cocrystal samples were characterized by electron microscopy morphology, differential thermal analysis, infrared spectroscopy, and X-ray diffraction analysis. The effects of spray temperature, feed ratio, and preparation method on the formation of explosive cocrystal were studied, and the process conditions of the pneumatic atomization spray crystallization method were optimized. The crystal plane binding energy and molecular interaction forces between CL-20 and TNT were obtained through molecular dynamic simulation, and the optimal binding crystal plane and cocrystal mechanism were analyzed. The theoretical calculation temperature of the binding energy was preliminarily explored in relation to the preparation process temperature of cocrystal explosives. The mechanical sensitivity of ultrafine CL-20/TNT cocrystal samples was tested. The results showed that choosing acetone as the cosolvent, a spraying temperature of 30 °C, and a feeding ratio of 1:1 was beneficial for the formation and growth of cocrystal. The prepared CL-20/TNT cocrystal has a particle size of approximately 10 μm. The grain size is small, and the crystallization rate is fast. The impact and friction sensitivity of ultrafine CL-20/TNT cocrystal samples were significantly reduced. The experimental process conditions are simple and easy to control, and the safety of the preparation process is high, providing certain technical support for the preparation of high-quality cocrystal explosives.

Construction and Preparation of the Novel ADN/CL-20 Cocrystal via Directional Hydrogen Bonding Design for Turning Hygroscopicity.

Ammonium dinitramide (ADN), as a novel and environmentally friendly oxidizer, has strong hygroscopicity when exposed to high-humidity air, which seriously hinders its application in solid propellants. Modification of oxidizers by cocrystallization is an effective strategy to improve the hygroscopicity of energetic components. In this paper, the theoretical simulation of ADN/CL-20 cocrystals was developed via a directional hydrogen bonding design to establish a cocrystal with improved hygroscopicity. Intermolecular interaction analyses reveal that hydrogen bonds and van der Waals interactions synergistically lead to the formation of cocrystals. The ADN/CL-20 cocrystal was prepared experimentally by the spray drying self-assembly technique, and the corresponding thermal analysis and sensitivity properties were conducted to illustrate the thermal stability and high safety. Furthermore, the critical relative humidity (CRH) measurement was carried out to evaluate the hygroscopicity of the cocrystal, exhibiting a certain degree of antihygroscopic effect with a CRH of 65%. The hydrogen bonds formed between ADN and CL-20 saturate the ammonium ions of ADN, further preventing ADN from absorbing water molecules in the air. The ADN/CL-20 cocrystal has high specific impulse characteristics (Isp: 272.6 s). Accordingly, this work clearly demonstrates that the ADN/CL-20 cocrystal is expected to be used in a solid propellant to make up for the deficiency of the ADN oxidizer.

Formulation and optimization of olanzapine-carboxylic acid cocrystals orodispersible tablets: In-vitro/ In-vivo study

Oromucosal delivery of olanzapine (OLZ) is an optimal strategy to overcome low oral bioavailability as well as improve medication adherence. However, its poor aqueous solubility may hinder its absorption through the buccal mucosa. The aim of the study is to enhance OLZ solubility and dissolution via cocrystal formation, followed by incorporation into an orodispersible tablet (ODT) based on an effervescent mixture and crospovidone as a superdisintegrant mixture. OLZ was cocrystallized with different carboxylic acids using slow solvent evaporation, and the optimal cocrystal formula was subjected to solid state characterization. Central composite design (CCD) was used in the modeling and optimization of the ODT independent variables (amounts of crospovidone and effervescent mixture). The optimized OLZ cocrystal ODTs were subjected to microenvironmental pH, stability, and in-vivo studies. The results revealed that the OLZ:itaconic acid at 1:1 M ratio showed a 7.86 fold increase in OLZ solubility and 86.71 ± 1.07 % dissolution efficiency (DE60 %) with FTIR, XRPD, and DSC diffractograms that confirmed the cocrystal formation. The optimized OLZ cocrystal ODTs exhibited hardness of 3.6 ± 0.1 kg/cm2, disintegration time of 11.66 ± 1.52 s, wetting time of 36.33 ± 2.51 s, and 94.26 ± 2.77 % OLZ released within 15 min with a DE60 % of 91.65 ± 0.98 %. Finally, the optimized OLZ cocrystal ODTs showed a significant (p < 0.01) higher Cmax and AUC with a relative bioavailability of 139.08 % compared to the Schisolazine©10 mg ODTs. These results suggest that OLZ:itaconic acid cocrystal incorporated into an ODT containing a superdisintegrant mixture of effervescence mixture and crospovidone is a potential approach for enhancement of oromucosal delivery of OLZ.

Kinetics of the mechanically induced ibuprofen-nicotinamide co-crystal formation by in situ X-ray diffraction.

Mechanochemistry is drawing attention from the pharmaceutical industry given its potential for sustainable material synthesis and manufacture. Scaling mechanochemical processes to industrial level remains a challenge due to an incomplete understanding of their underlying mechanisms. We here show how time-resolved in situ powder X-ray diffraction data, coupled with analytical kinetic modelling, provides a powerful approach to gain mechanistic insight into mechanochemical reactions. By using the ibuprofen-nicotinamide co-crystal mechanosynthesis as a benchmark system, we investigate the behaviour of the solids involved and identify the factors that promote the reaction. As mechanochemical mechanisms become increasingly clear, it promises to become a breakthrough in the industrial preparation of advanced pharmaceuticals.

Spectroscopic and computational investigations of isostructural phase transitions in urea 4-carboxyanilinium nitrate having trapped disordered-nitrate ions

Urea 4-carboxyanilinium nitrate (U4-CAN) and its functional groups deuterated counterpart dU4-CAN were studied using infrared vibrational spectroscopy and computational analysis. Using the known frequencies of the parent components the infrared vibrational frequencies of U4-CAN and dU4-CAN were assigned. FTIR study was carried out to understand how the intra-and inter-molecular interactions in the parent components are affected by U4-CAN co-crystal formation. U4-CAN undergoes isostructural phase transition at 359.1 K. Hence FTIR spectra of U4-CAN were also recorded at different temperature in the range 293 K to 368 K. The interesting observation seen with temperature dependent spectra was:(i) the spectral band intensity increased with increasing temperature and (ii) the peak position of almost all bands did not change in the entire temperature range studied. This results corroborate with the reported structural data of U4-CAN were in it is found that the structural phase transition is isostructural. Hence the crystal structure in the range 293 K to 368 K has same space group and differ only in few hydrogen bond interactions. In order to carry out various theoretical calculation of U4-CAN, the crystallographically obtained structure at 293 K was optimized by density functional theory (DFT) with B3LYP/6–311 G basis set. The theoretical calculated vibration spectra were similar to the experimentally obtained FTIR data. The fingerprint plot of U4-CAN obtained using CrystalExplorer 21 software indicated that the most prominent interaction corresponds to the short O···H contact. Noncovalent interaction (NCL) study indicated that the U4-CAN complex has steric, van der Waals and hydrogen bond interactions and the NH⋅⋅⋅⋅⋅O hydrogen bond interaction between NH3+/ NH2 moieties and NO3- was the strongest. From QTAIM calculation the strongest hydrogen bond interaction in U4-CAN complex was for NH.....O and NH.....N interactions.