Cocrystal Formation Research Articles

Molecular structures, solubility and pharmaceutical reactivities of flurbiprofen-based co-crystals: A DFT study

Pharmaceutical co-crystal has attracted increasing attention from researchers due to its potential to regulate the physicochemical properties of active pharmaceutical ingredient (API). Herein, three pharmaceutical co-crystals containing the API- flurbiprofen (FBP) and co-crystal formers (CCFs)- benzamide (BZA), picolinamide (Pic), salicylamide (SA) were constructed theoretically. The density functional theory (DFT) method was used to systematically investigate the structural parameters and chemical activities of these three co-crystals. The electrostatic potentials, Infrared and Raman spectra, binding energies, solvent energies, frontier molecular orbital energies, Hirshfeld surface analysis and global reactivity descriptors were investigated for both monomers and co-crystal systems. Moreover, the intermolecular interactions between the API and CCFs and Molecular Docking were also studied. Results show that the API combines with the CCFs together via the intermolecular hydrogen bond interactions. After co-crystallization with three CCFs, the water solubility and activity of FBP are enhanced, among which FBP-Pic shows the most excellent properties. Interestingly, FBP is more prone to form interaction with Butyrylcholinesterase (BChE) protein after forming co-crystal with Pic. This work could provide valuable reference and guidance for further research and application of pharmaceutical co-crystal in flurbiprofen.

Variable stoichiometry and a salt-cocrystal intermediate in multicomponent systems of flucytosine: structural elucidation and their impact on stability.

New cocrystals and a salt-cocrystal intermediate system involving the antifungal drug flucytosine (FCY) and various coformers including caffeic acid (CAF), 2-chloro-4-nitrobenzoic acid (CNB), hydroquinone (HQN), resorcinol (RES) and catechol (CAL), are reported. The crystal structures of the prepared multicomponent systems were determined through SC-XRD analysis and characterized by different solid-state techniques. All FCY multicomponent systems crystallize in anhydrous form with different stoichiometric ratios. The cocrystals FCY-HQN, FCY-RES and FCY-CAL crystallize in 2:0.5, 2:0.5 and 3:2 stoichiometric ratios respectively. In contrast, FCY-CAF and FCY-CNB crystallize in a 1:1 stoichiometric ratio. The FCY-CAF cocrystal is formed via an acid-pyrimidine heterosynthon. Due to the partial proton transfer from the acid group of CNB to FCY, a three-point homosynthon is observed between two FCY molecules and the molecules interact via an N-H...O hydrogen bond between FCY and CNB. In FCY phenolic cocrystals, a single-point O-H...O hydrogen bond is observed. The formation of cocrystals and salt-cocrystal intermediate was further confirmed by difference Fourier map analysis and bond angle differences. Except for FCY-CAL, all the multicomponent systems were reproduced in the bulk scale for further characterization. A detailed Crystal Structural Database search was carried out on the multicomponent systems of FCY with acid coformers and we evaluated the formation of cocrystals/salt based on the ΔpKa values, the difference in the bond distances and bond angles. Additionally, the prepared multicomponent systems exhibited hydration stability for one month under accelerated conditions [40 (2)°C and relative humidity 90-95 (5)%].

CL‐20/4,5‐MDNI crystal growth and morphology under different conditions: A molecular dynamics simulation

AbstractCL‐20/4,5‐MDNI exists in two cocrystal forms with different stoichiometric ratios of 1:1 and 1:3. The properties (such as blast performance, thermal performance, sensitivity, and density) of the two cocrystals are significantly different, but both cocrystals are expected to become new high‐energy insensitive explosives and have good applications. The AE model and molecular dynamics were used to simulate the crystal morphology and important crystal planes of 1:1 and 1:3 CL‐20/4,5‐MDNI under vacuum conditions, as well as in five solvents and different temperatures. 1:1 CL‐20/4,5‐MDNI has five main growth crystal planes of (002), (102), (111), (020) and (021), of which (002) has the largest proportion. 1:3 CL‐20/4,5‐MDNI has six main growth crystal planes of (001), (010), (011), (100), (101) and (111), of which (001) accounts for the largest proportion. The crystal morphology aspect ratio of 1:3 CL‐20/4,5‐MDNI in acetonitrile and 1:1 CL‐20/4,5‐MDNI in methanol are 1.936 and 1.680, respectively. The results were consistent with the experiments, which has certain guiding significance for CL‐20/4,5‐MDNI to obtain a crystal morphology closer to spherical shape.

Predicting co-crystal structures of N-halide phthalimides with 3,5-dimethylpyridine.

Crystal structure prediction (CSP) calculations were carried out to examine potential formation of co-crystals between N-halide phthalimides (Cl, Br or I) and 3,5-dimethylpyridine (35DMP). The co-crystal structure of N-bromophthalimide (nbp) with 35DMP (nbp-35DMP) is known, and the generated co-crystal structure of rank 1 is identical to experimental structure (VELXES). For the unknown crystal structure of N-iodophthalimide (nip), structure of rank 1 is suggested as a likely co-crystal structure. On the other hand, our calculations suggest the improbability of co-crystal formation between ncp and 35DMP. The CSP findings indicate that strong N-X...N interactions consistent with similar experimental structures in the Cambridge Structural Database play a major role in crystal structures of the studied compounds.

Preparation and solid-state characterization of two novel berberine chloride cocrystals with benzene derivatives

In this study, two novel salt-cocrystals of berberine chloride (BCl) with structurally similar benzene derivatives, i.e., 3-hydroxybenzoic acid (3HBA) and isophthalic acid (IA), were prepared. Their solid-state properties were characterized by complementary techniques, including single-crystal and powder X-ray diffractometry, thermogravimetric-differential scanning calorimetry, Fourier-transformed infrared spectroscopy, and dynamic moisture sorption analysis. Both cocrystals had lower hygroscopicity than BCl. An analysis of the properties of these cocrystals along with a previously published berberine chloride-resorcinol cocrystal suggests that a greater number of hydroxyl groups in these cocrystal formers may favor faster dissolution, measured by both intrinsic dissolution rate and powder dissolution.

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.

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.

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.

Trimesic Acid as a Building Block for Ternary and Quaternary Salts and Salt Cocrystals.

In the field of cocrystals, the synthon-based design of two-component crystals is well established and the interest is now shifting toward higher order cocrystals as the next challenge. Carboxylic acids form a robust synthon with pyridyl coformers and interact with 2-aminopyrimidines through a pair of strong, charge-assisted hydrogen bonds. In this work we describe the formation of higher order salts and salt cocrystals of trimesic acid using 2,4-diaminopyrimidine (pyrimethamine, trimethoprim) and pyridyl (4,4'-bipyridine, 1,2-di(4-pyridyl)ethylene, 1,3-di(4-pyridyl)propane, 4-phenylpyridine) coformers. We report the single crystal structures of five binary, eight ternary and three quaternary systems with the compositions AB, A2B, A3B, A2BC, A3BC, A2BC1.5, ABC1.5, A1 2A2B, ABC1C,2 A2BC1C2 0.5, and A1A2BC where A is a 2,4-diaminopyrimidine cation, B is the mono-, di- or trianion of trimesic acid and C is a pyridine. We also show that the ternary and quaternary salts and salt cocrystals can be prepared in bulk quantities by liquid-assisted grinding.

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 cocrystal as a promising approach to enhance BCA’s therapeutic potential.

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.

Developing a switch “OFF-ON” fluorescent probe for detection of melamine based on doubly-protected red emissive copper nanoclusters mediated by Hg2+ ions

Melamine, often used as an adulterant in infants’ formula due to its high protein content, can be harmful when ingested in large amounts, leading to the formation of cyanurate-melamine co-crystals in infants and potentially causing kidney damage. In this study, we introduce a fluorescent method for the selective and reliable detection of melamine in milk and infants’ formula. The fluorescent probe comprises copper nanoclusters (Cu NCs) functionalized with thiosalicylic acid (TSA) and polyvinylpyrrolidone (PVP) as double-protecting ligands. Upon the addition of Hg2+, the fluorescence emission of TSA-PVP@Cu NCs is diminished due to static quenching. Subsequently, the fluorescence emission of the TSA-PVP@Cu NCs + Hg2+ probe is restored upon the introduction of melamine, facilitated by the coordination interaction between melamine and Hg2+ and the formation of a stable chelate between them. Under optimized conditions, the fluorescence emission was recorded initially for the TSA-PVP@Cu NCs + Hg2+ probe (F°) and after melamine addition (F). The (F/F°) ratio increased with rising melamine concentrations within the range of 0.025–65 µM. The detection limit, calculated using a signal-to-noise ratio of 3, was determined to be 8.0 nM. The TSA-PVP@Cu NCs + Hg2+ probe was successfully employed to detect melamine in milk and infants’ formula, yielding acceptable recovery percentages and relative standard deviations. These results underscore the reliability and efficacy of the proposed probe for the fluorometric detection of melamine in real-world samples.

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.

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.