Academic literature on the topic 'Molecular cocrystals'
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Journal articles on the topic "Molecular cocrystals"
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Yang, Shiying, Qiwen Liu, Weiwen Ji, Qi An, Junke Song, Cheng Xing, Dezhi Yang, Li Zhang, Yang Lu, and Guanhua Du. "Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation." Molecules 27, no. 6 (March 21, 2022): 2022. http://dx.doi.org/10.3390/molecules27062022.
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Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.
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Wan, Mei, Jiyuan Fang, Jiadan Xue, Jianjun Liu, Jianyuan Qin, Zhi Hong, Jiusheng Li, and Yong Du. "Pharmaceutical Cocrystals of Ethenzamide: Molecular Structure Analysis Based on Vibrational Spectra and DFT Calculations." International Journal of Molecular Sciences 23, no. 15 (August 1, 2022): 8550. http://dx.doi.org/10.3390/ijms23158550.
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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.
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González-González, Juan Saulo, Ana María Monserrat Martínez-Santiago, Francisco Javier Martínez-Martínez, María José Emparán-Legaspi, Armando Pineda-Contreras, Marcos Flores-Alamo, and Héctor García-Ortega. "Cocrystals of Isoniazid with Polyphenols: Mechanochemical Synthesis and Molecular Structure." Crystals 10, no. 7 (July 2, 2020): 569. http://dx.doi.org/10.3390/cryst10070569.
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Isoniazid is used as anti-tuberculosis drug which possesses functional groups capable of forming hydrogen bonds. A series of cocrystals of isoniazid (INH) with polyphenolic coformers such as catechol (CAT), orcinol (ORC), 2-methylresorcinol (MER), pyrogallol (PYR), and phloroglucinol (PLG) were prepared by solvent-assisted grinding. Powder cocrystals were characterized by infrared (IR) spectroscopy and X-ray powder diffraction. The crystal structure of the cocrystals revealed the unexpected hydration of the INH-MER cocrystal and the preference of the (phenol) O–H∙∙∙N (pyridine) and (terminal) N-H∙∙∙O (phenol) heterosynthons in the stabilization of the structures. The supramolecular architecture of the cocrystals is affected by the conformation and the substitution pattern of the hydroxyl groups of the polyphenols.
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Manin, Alex N., Denis E. Boycov, Olga R. Simonova, Tatyana V. Volkova, Andrei V. Churakov, and German L. Perlovich. "Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study." Pharmaceutics 14, no. 9 (September 6, 2022): 1881. http://dx.doi.org/10.3390/pharmaceutics14091881.
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Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM].
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Mir, Niyaz A., Ritesh Dubey, and Gautam R. Desiraju. "Four- and five-component molecular solids: crystal engineering strategies based on structural inequivalence." IUCrJ 3, no. 2 (January 5, 2016): 96–101. http://dx.doi.org/10.1107/s2052252515023945.
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A synthetic strategy is described for the co-crystallization of four- and five-component molecular crystals, based on the fact that if any particular chemical constituent of a lower cocrystal is found in two different structural environments, these differences may be exploited to increase the number of components in the solid. 2-Methylresorcinol and tetramethylpyrazine are basic template molecules that allow for further supramolecular homologation. Ten stoichiometric quaternary cocrystals and one quintinary cocrystal with some solid solution character are reported. Cocrystals that do not lend themselves to such homologation are termed synthetic dead ends.
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Patel, Diksha J., and Prashant K. Puranik. "Pharmaceutical Co-crystal : An Emerging Technique to enhance Physicochemical properties of drugs." International Journal of ChemTech Research 13, no. 3 (2020): 283–90. http://dx.doi.org/10.20902/ijctr.2019.130326.
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Major constraints in development of new product are poor aqueous solubility, stability and low oral bioavailability, low permeability. As majority of drugs marketed worldwide are administered by oral route and about 40% -50% of the new molecular entities were never invade into the market because of such biopharmaceutical issues.So issues related to poor physiochemical property of an active pharmaceutical ingredient (API) can be resolved using cocrystallization approach.Crystallization emerge as potential technique for enhancement of solubility of poorly aqueous soluble drugs also helps to improve physicochemical with preserving the pharmacological properties of the API . Cocrystals are solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates/hydrates nor simple salts. It is multicomponent system in which one component is API and another is called coformer. Coformer selection is the main challenging step during cocrystal synthesis , so various screening methods for the selection of coformers was explained . This article also summarizes differences between cocrystals with salts, solvates and hydrates along with the implications and limitations of cocrystals .It also provides a brief review on different methods of cocrystal formation and characterization techniuqes of cocrystals. Lastly this article highlights 85 synthetic and 14 herbal cocrystals along with its method of preparation and coformers used.
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Emami, Shahram, Mohammadreza Siahi-Shadbad, Khosro Adibkia, and Mohammad Barzegar-Jalali. "Recent advances in improving oral drug bioavailability by cocrystals." BioImpacts 8, no. 4 (May 31, 2018): 305–20. http://dx.doi.org/10.15171/bi.2018.33.
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Introduction: Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Methods: In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. Results: Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. Conclusions: Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human.
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Dubey, Ritesh, Niyaz A. Mir, and Gautam R. Desiraju. "Quaternary cocrystals: combinatorial synthetic strategies based on long-range synthon Aufbau modules (LSAM)." IUCrJ 3, no. 2 (January 5, 2016): 102–7. http://dx.doi.org/10.1107/s2052252515023957.
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A synthetic strategy is outlined whereby a binary cocrystal may be developed in turn into a ternary and finally into a quaternary cocrystal. The strategy hinges on the concept of the long-range synthon Aufbau module (LSAM) which is a large supramolecular synthon containing more than one type of intermolecular interaction. Modulation of these interactions may be possible with the use of additional molecular components so that higher level cocrystals are produced. We report six quaternary cocrystals here. All are obtained as nearly exclusive crystallization products when four appropriate solid compounds are taken together in solution for crystallization.
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Tutughamiarso, Maya, and Ernst Egert. "Cocrystals of 5-fluorocytosine. II. Coformers with variable hydrogen-bonding sites." Acta Crystallographica Section B Structural Science 68, no. 4 (July 17, 2012): 444–52. http://dx.doi.org/10.1107/s0108768112029977.
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Two flexible molecules, biuret and 6-acetamidouracil, were cocrystallized with 5-fluorocytosine to study their conformational preferences. In the cocrystal with 5-fluorocytosine (I), biuret exhibits the same conformation as in its hydrate. In contrast, 6-acetamidouracil can adopt two main conformations depending on its crystal environment: in crystal (II) the trans form characterized by an intramolecular hydrogen bond is observed, while in the cocrystal with 5-fluorocytosine (III), the complementary binding induces the cis form. Three cocrystals of 6-methylisocytosine demonstrate that complementary binding enables the crystallization of a specific tautomer. In the cocrystals with 5-fluorocytosine, (IVa) and (IVb), only the 3H tautomer of 6-methylisocytosine is present, whereas in the cocrystal with 6-aminoisocytosine, (V), the 1H tautomeric form is adopted. The complexes observed in the cocrystals are stabilized by three hydrogen bonds similar to those constituting the Watson–Crick C·G base pair.
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Rajkumar, Madhu, and Gautam R. Desiraju. "Quaternary and quinary molecular solids based on structural inequivalence and combinatorial approaches: 2-nitroresorcinol and 4,6-dichlororesorcinol." IUCrJ 8, no. 2 (January 11, 2021): 178–85. http://dx.doi.org/10.1107/s2052252520016589.
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A synthetic strategy for the formation of stoichiometric quaternary and nonstoichiometric quinary solids is outlined. A series of 2-nitroresorcinol-based quaternary cocrystals were developed from binary precursors in two conceptual stages. In the first stage, ternary solids are synthesized based on the structural inequivalence at two recognition sites in the binary. In the second stage, the ternary is homologated into a stoichiometric quaternary based on the same concept. Any cocrystal without an inequivalence becomes a synthetic dead end. The combinatorial approach involves lower cocrystal systems with different structural environments and preferred synthon selection from a synthon library in solution. Such are the stepping stones for the isolation of higher cocrystals. In addition, a quaternary cocrystal of 4,6-dichlororesorcinol is described wherein an unusual synthon is observed with two resorcinol molecules in a closed loop with two different ditopic bases. The concept of the virtual synthon in binaries with respect to isolated ternaries is validated for the 4,6-dichlororesorcinol system. It is possible that only some binary systems are amenable to homologation into higher cocrystals. The reasons for this could have to do with the existence of preferred synthon modules, in other words, the critical components of the putative higher assembly that cannot be altered. Addition of the third and fourth component might be more flexible, and the choices of these components, possible from a larger pool of chemically related molecules.
Dissertations / Theses on the topic "Molecular cocrystals"
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Lynch, Daniel Eric. "Molecular cocrystals of carboxylic acids." Thesis, Queensland University of Technology, 1994.
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Ong, Tien Teng. "Crystal Engineering of Molecular and Ionic Cocrystals." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3270.
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Solubility enhancement of poorly-soluble active pharmaceutical ingredients (APIs) remains a scientific challenge and poses a practical issue in the pharmaceutical industry. The emergence of pharmaceutical cocrystals has contributed another dimension to the diversity of crystal forms available at the disposal of the pharmaceutical scientist. That pharmaceutical cocrystals are amenable to the design principles of crystal engineering means that the number of crystal forms offered by pharmaceutical cocrystals is potentially greater than the combined numbers of polymorphs, salts, solvates and hydrates for an API. The current spotlight and early-onset dissolution profile ("spring-and-parachute" effect) exhibited by certain pharmaceutical cocrystals draw attention to an immediate question: How big is the impact of cocrystals on aqueous solubility? The scientific literature and in-house data on pharmaceutical cocrystals that are thermodynamically stable in water are reviewed and analyzed for trends in aqueous solubility and melting point between the cocrystal and the cocrystal formers. There is poor correlation between the aqueous solubility of cocrystal and cocrystal former with respect to the API. The log of the aqueous solubility ratio between cocrystal and API has a poor correlation with the melting point difference between cocrystal and API. Structure-property relationships between the cocrystal and the cocrystal formers remain elusive and the actual experiments are still necessary to investigate the desired physicochemical properties.
Crystal form (cocrystals, polymorphs, salts, hydrates and solvates) diversity is and will continue to be a contentious issue for the pharmaceutical industry. That the crystal form of an API dramatically impacts its aqueous solubility (a fixed thermodynamic property) is illustrated by the histamine H2-receptor antagonist ranitidine hydrochloride and HIV protease inhibitor ritonavir. For more than a century, the dissolution rate of a solid has been shown to be directly dependent on its solubility, cçterîs paribus. A century later, it remains impossible to predict the properties of a solid, given its molecular structure. If delivery or absorption of an API are limited by its aqueous solubility, aqueous solubility then becomes a critical parameter linking bioavailability and pharmacokinetics of an API. Since the majority of APIs are Biopharmaceutical Classification System (BCS) Class II (low solubility and high permeability) compounds, crystal form screening, optimization and selection have thus received more efforts, attention and investment. Given that the dissolution rate, aqueous solubility and crystal form of an API are intricately linked, it remains a scientific challenge to understand the nature of crystal packing forces and their impact upon physicochemical properties of different crystal forms. Indeed, the selection of an optimal crystal form of an API is an indispensable part of the drug development program. The impact of cocrystals on crystal form diversity is addressed with molecular and ionic targets in ellagic acid and lithium salts. A supramolecular heterosynthon approach was adopted for crystal form screening. Crystal form screening of ellagic acid yields molecular cocrystals, cocrystal solvates/hydrates and solvates. Crystal form screening of lithium salts (chloride, bromide and nitrate salts) afforded ionic cocrystals and cocrystal hydrates.
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Thompson, Laura. "Synthesis and structure determination of molecular cocrystals." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4007/.
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Research into cocrystals is just a small field within crystallography, though the significant rise of investigation into cocrystals has made it an exciting area of research. This thesis initially introduces the phenomenon of cocrystals, including the design, formation, structure solution and the properties of cocrystals. This thesis presents a number of new multi-component crystalline adducts that have been synthesised using dicarboxylic acids as coformers with isonicotinamide, nicotinamide or adenine. The first results chapter discusses a number of molecular adducts that contain distinct hydrogen bonding networks and includes the discovery of a new polymorph and the potential of adenine to tautomerise. The following two results chapters focus on molecular structures of nicotinamide and isonicotinamide with the dicarboxylic acids in which trends in crystal packing, cocrystal property studies and twisting of the acid backbone are discussed in detail. In conjunction with the crystal structure and property studies, several powder X-ray diffraction datasets were collected from a synchrotron source. The final results chapter shows that a cocrystal structure, such as nicotinamide : succinic acid, can be solved without the need of single crystal X-ray diffraction data.
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Panikkattu, Sheelu. "Designing molecular solids with structural control and tunable physical properties using co-crystallization techniques." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/16247.
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Doctor of PhilosophyDepartment of Chemistry
Christer Aakeröy
Physical properties of bulk solids are typically governed by the molecular arrangement of individual building blocks with respect to each other in the crystal lattice. Thus the ability to synthesize molecular crystals with pre-organized connectivities allows for the rational design of functional solids with desirable and tunable physical properties. A thorough understanding of the various intermolecular interactions that govern the solid-state architectures is an important pre-requisite for the rational design of molecular solids. In order to understand the role of molecular geometric complementarity in the design of solid-state architectures, we explored the structural landscape of two isomeric pyridine based acceptors (3N and 4N) with binding sites oriented along different directions, i.e. parallel and at angle of 60° respectively, with a series of even chain diacid (colinear binding sites) and odd chain diacid (binding sites oriented along 120°) using co-crystallization technique. The results obtained shows a striking correlation between the observed solid state architecture and geometric complementarity of interacting species. Combinations of 3N with odd and 4N with even chain diacid produced 1-D chains whereas 3N with even and 4N with odd chain diacid generated 0-D ring architectures. In order to exploit the possibility of fine-tuning physical properties using co-crystallization techniques, solubility measurements were performed on 3N and 4N co-crystals with the diacids. The results show that the solubilities of 3N and 4N in the co-crystal form were very different from their solubility in the pure form. Also, there was a strong correlation observed between the solubility of the co-crystals and their corresponding co-formers, i.e. diacids. To explore the dependence of crystal structure on a physical property such as melting point, we synthesized co-crystals of 3,3‟-azopyridine and 4,4‟-azopyridine with a series of even chain diacids. Structural consistency was obtained within the two groups of co-crystals. In both groups, 1-D chains were formed with the diacid as the primary building block. However, In the series of 3,3‟-azopyridine co-crystals, the co-crystal with succinic acid showed a different solid-state packing arrangement (although the primary building block was same as others) compared to the others in the same series. This difference is also reflected as a deviation in the melting point, while the others in the series showed a perfect correlation between the structural consistency and melting point behavior. It was also observed that the co-crystals of 4,4‟-azopyridine displayed higher melting points than co-crystals of 3,3‟-azopyridine which could be due to the differences in the overall packing of the crystal which is a combination of different intermolecular interactions that exist between molecules in the solid state. Using bi-functional donors (with both hydrogen and halogen bond donors on same backbone), we investigated the relative strengths of hydrogen and halogen bond donors in the presence of two isomeric acceptors, 3,3‟-azopyridine and 4,4‟-azopyridine, which exhibit geometric bias in their binding-site orientation. Based on the crystal structures, we noticed a preferential binding of hydrogen bond donors with 3,3‟-azopyridine and both hydrogen and halogen bond donors with 4,4‟-azopyridine. This shows that the two types of donors are very comparable and their binding preference is governed by the geometric complementarity between the donor-acceptor pair. Finally, we explored the scope of using co-crystallization for tuning the physical properties of two agrochemicals, cyprodinil and terbuthylazine. The crystal structures of the actives with a series of even chain diacids displayed structural consistency in the primary motifs within the two groups, while few differences were observed in the packing arrangement and secondary interactions. By forming co-crystals we were able to improve the solubility and melting point of cyprodinil, while ensuring that the hygroscopicity of the active was unaltered.
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Mukherjee, Sreya. "Applications of Molecular Modelling and Structure Based Drug Design in Drug Discovery." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6331.
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Calcium ions have important roles in cellular processes including intracellular signaling, protein folding, enzyme activation and initiation of programmed cell death. Cells maintain low levels of calcium in their cytosol in order to regulate these processes. When activation of calcium-dependent processes is needed, cells can release calcium stored in the endoplasmic reticulum (ER) into the cytosol to initiate the processes. This can also initiate formation of plasma membrane channels that allow entry of additional calcium from the extracellular milieu. The change in calcium levels is referred to as calcium flux. A key protein involved in initiation of calcium flux is Stromal Interaction Molecule 1 (STIM1), which has recently been identified as a sensor of ER calcium levels. STIM1 is an ER transmembrane protein that is activated by a drop in ER calcium levels. Upon activation, STIM1 oligomerizes with a plasma membrane protein, ORA1, to form calcium-selective plasma membrane channels. Dysregulation of calcium flux has been reported in cancers, autoimmune diseases and other diseases. STIM1 is a promising target in drug discovery due to its key role early in calcium flux. Here we review the involvement and importance of STIM1 in diseases and we discuss STIM1 as a viable target for drug discovery using computational chemistry methods to rapidly identify new molecules to target STIM1. Herein, computational techniques were used to understand the mechanistic role of STIM1 and virtual screening is in process to discover potential inhibitors of STIM1 activity. Also mutational analysis on STIM1 was performed computationally to see the effect it had on the protein computationally.
It has been found that tumor cells and tissues, compared to normal cells, have higher levels of copper and possibly other metal ions. This presents a potential vulnerability of tumor cells that can serve as a physiological difference between cancer cells and normal cells and allows design of compounds that selectively target tumor cells while sparing normal cells. Recently we have identified compounds that have potential to inhibit the proteasome in tumor cells and induce cell death by mobilizing endogenous tumor copper resulting in in cellulo activation of the compound. These compounds hence act as pro-drugs, becoming active drugs in tumor cells with high copper content but remaining essentially inactive in normal cells, thereby greatly reducing adverse effects in patients. Such use would be of significant benefit in early detection and treatment of cancers, in particular, aggressive cancers such as pancreatic cancer which is usually not detected until it has reached an advanced stage. Six compounds were identified following virtual screening of the NCI Diversity Set with our proteasome computer model followed by confirmation with a biochemical assay that showed significant inhibition of the proteasome by the compounds in the presence of copper ions. In a dose response assay, NSC 37408 (6, 7-dihydroxy-1-benzofuran-3-one), our best compound, exhibited an IC50 of 3µM in the presence of 100 nM copper.
Chagas’ Disease, a parasitic disease caused by the parasite Trypanosma Cruzi, is endemic to Latin America. The disease manifests itself in a short acute phase and a long chronic phase. Current treatments are effective only in the acute phase and are not used in the chronic phase due to toxicity of the drugs. Hence a new drug discovery approach was chosen for this disease. Cruzain is the major etiologic enzyme involved in the disease and is only present in the parasite. It is also an enzyme expressed by the parasite in both phases. Herein, a novel peptoid library containing hydromethylketones was constructed and screened against a virtual structure of cruzain. The peptoids thus found through this drug discovery effort can be used as potential drug candidates against cruzain. Computational techniques will help achieve a high degree of specificity and aid in proposing assays for determining compounds with high activity
Alzheimer disease is the most common form of dementia. Its pathogenesis incorporates many potential targets for treatment. Among the targets identified, Apolipoprotein E4 (apoE4) is especially interesting due to its catalytic role in the degradation and clearance of amyloid beta (Aβ), a risk factor for Alzheimer disease. ApoE exists in 3 isoforms which directly impact its functionality in the body. There are characteristic structural differences between them. In ApoE4 ionic interactions exist between Arg-61 and Glu-255 residues, unlike the other isoforms. Hence interruption of this interaction by inhibitors may change the structure of apoE4 to a more linear structure as observed in the other isoforms. Virtual screening of the NCI diversity set on an energy minimized protein virtual structure was performed to identify potential small molecule inhibitors and to gain further understanding of interactions that can be targeted to inhibit this protein. From the top ligands in the NCI diversity set, a peptide library was designed to target the protein.
Previous research has indicated that liquid assisted grinding (LAG) is efficient and reliable for cocrystal formation when compared to solvent crystallization and dimethyl formamide is the best solvent for grinding. Herein, we report the comparison of four screening processes: Slurry, solvent crystallization, LAG and dry grinding. Thirty-eight crystal forms containing the Narom··· COOH, Narom···OH supramolecular heterosynthons were screened in the process, and it was observed that slurry methodology is as efficient and reliable in forming cocrystals as solution crystallization. Twenty-four new crystal forms were also isolated herein. LAG was found to be more efficient as compared to dry grinding and was successful in the formation of twenty-five crystal forms of the thirty-eight screened. Dimethyl formamide still remains the best solvent for LAG. All our slurry experiments were performed in water and it was found that water can be used reliably for this method for compounds within a wide range of solubility, thereby increasing the versatility and usability of this method for future screening procedures.
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Weston, Laura. "Computational characterisation of organic molecules for electronic applications and an experimental study of cocrystals for electronic devices." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/computational-characterisation-of-organic-molecules-for-electronic-applications-and-an-experimental-study-of-cocrystals-for-electronic-devices(0d1a24ea-3241-40cf-bafa-6be179ba4c26).html.
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A range of small molecules of interest for use in organic semiconductor devices were studied computationally. Trends in geometry, absorption spectra, molecular orbitals, electrostatic potentials, reorganisation energies were studied. Results suggest that, as with acenes, the performance of non-linear cata-condensed polyaromatic hydrocarbons improves as number of fused benzene rings increases. The torsion in these molecules did not appear to have a large impact on the conjugation across the core and little effect on the absorption spectra, although it did affect the reorganisation energies on which charge mobilities depend. Computational studies of mobilities of anthradithiophene molecules were broadly able to reproduce trends seen experimentally and emphasised the importance of crystal morphology. Experimental work was also carried out to search for cocrystals between anthradithiophene derivatives. Many examples were found with some mixtures forming different cocrystals at different mixture ratios. These results were rationalised by a computational study that showed molecules which had a similar binding energy were more likely to be able to form cocrystals. Cocrystal devices were fabricated and 3 out of 7 showed a larger mobility than devices made out of its constituent materials alone. The best of these had a mobility 65% higher than a device made out of the constituent material with the largest mobility. An energy decomposition analysis was carried out on a novel thallophilic system, a complex of thallium with a neutral β-triketimine ligand which was found to form dimers with close Tl-Tl interactions. Calculations show the electrostatic interaction to be repulsive for the dimer with no counter ions, but attractive when 3,5-bistrifluoromethylphenyl borate counter ions are included. This suggests the metallophilic interaction is counter ion-mediated, requiring the anions to provide favourable electrostatics, even in the case of spatially diffuse and distant counter ions such used here. To enable the studies described here software was written for simulating absorption spectra. An implementation into the Gaussian Suite of programs of an energy decomposition scheme and its extension to include an empirical dispersion correction was also carried out.
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Forbes, Safiyyah. "Hydrogen-bond driven supramolecular chemistry for modulating physical properties of pharmaceutical compounds." Diss., Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/3756.
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Khan, E., A. Shukla, Niten B. Jadav, Richard Telford, A. P. Ayala, P. Tandon, and Venu R. Vangala. "Study of molecular structure, chemical reactivity and H-bonding interactions in the cocrystal of nitrofurantoin with urea." 2017. http://hdl.handle.net/10454/13220.
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YesThe cocrystal of nitrofurantoin with urea (C8H6N4O5)·(CH4N2O), a non-ionic supramolecular complex, has been studied. Nitrofurantoin (NF) is a widely used antibacterial drug for the oral treatment of infections of the urinary tract. Characterization of the cocrystal of nitrofurantoin with urea (NF–urea) was performed spectroscopically by employing FT-IR, FT- and dispersive-Raman, and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. With the purpose of having a better understanding of H-bonding (inter- and intra-molecular), two different models (monomer and monomer + 3urea) of the NF–urea cocrystal were prepared. The fundamental vibrational modes were characterized depending on their potential energy distribution (PED). A combined experimental and theoretical wavenumber study proved the existence of the cocrystal. The presence and nature of H-bonds present in the molecules were ascertained using quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. As the HOMO–LUMO gap defines the reactivity of a molecule, and this gap is more for the API than the cocrystal, this implies that the cocrystal is more reactive. Global descriptors were calculated to understand the chemical reactivity of the cocrystal and NF. Local reactivity descriptors such as Fukui functions, local softness and electrophilicity indices were analysed to determine the reactive sites within the molecule. The comparison between NF–urea (monomer) and NF showed that the cocrystal has improved overall reactivity, which is affected by the increased intermolecular hydrogen bond strength. The docking studies revealed that the active sites (C[double bond, length as m-dash]O, N–H, NO2, N–N) of NF showed best binding energies of −4.89 kcal mol−1 and −5.56 kcal mol−1 for MUL and 1EGO toxin, respectively, which are bacterial proteins of Escherichia coli. This cocrystal could potentially work as an exemplar system to understand H-bond interactions in biomolecules.
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Shukla, A., E. Khan, K. Srivastava, K. Sinha, P. Tandon, and Venu R. Vangala. "Study of hydrogen bonding interactions and chemical reactivity analysis of nitrofurantoin–3-aminobenzoic acid cocrystal using quantum chemical and spectroscopic (IR, Raman, 13C SS-NMR) approaches." 2017. http://hdl.handle.net/10454/12402.
Full textAbstract:
YesInvestigations of structural reactivity, molecular interactions and vibrational characterization of pharmaceutical drugs are helpful in understanding their behaviour. The aim of this study is to determine the molecular, electronic and chemical properties of the antibiotic drug nitrofurantoin (NF), after cocrystallisation with 3-aminobenzoic acid (3ABA) and to understand how those changes lead to variation of properties in the cocrystal NF–3ABA. NF–3ABA formation is explained by stabilization via the hydrogen-bond network between NF and 3ABA molecules. It is thoroughly characterized by IR, Raman and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. The results of IR, Raman, and 13C NMR analyses showed that imide N–H23 and C12[double bond, length as m-dash]O of NF interact with the acid C[double bond, length as m-dash]O and –OH groups in 3-ABA, respectively. Therefore the IR, Raman, and 13C NMR spectra verified the formation of N–H⋯O and O–H⋯O hydrogen bonds. To study hydrogen bonding interactions theoretically in NF–3ABA, two functionals B3LYP and wB97X-D have been used. A comparison is made between the results obtained by B3LYP and those predicted at the wB97X-D level. It is found that wB97X-D is best applied density functional theory (DFT) functional to describe the hydrogen bonding interactions. The strength and nature of hydrogen bonding in NF–3ABA have been analysed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. To validate the results obtained by QTAIM theory and to study the long-range forces, such as van der Waals interactions, the steric effects in NF–3ABA, the reduced density gradient (RDG) and the isosurface have been plotted using Multiwfn software. QTAIM and isosurface analysis suggested that the hydrogen bonding interactions present in NF–3ABA are moderate in nature. The calculated HOMO–LUMO energy gap shows that NF–3ABA is more active than NF and 3ABA. Chemical reactivity descriptors are calculated to understand the various aspects of pharmacological sciences. Chemical reactivity parameters show that NF–3ABA is softer and chemically more reactive than NF. The results suggest that cocrystals can be a feasible alternative for positively changing the targeted physicochemical properties of an active pharmaceutical ingredient (API).
V. R. Vangala acknowledges the financial support of the Royal Society of Chemistry for mobility grant (2015/17).
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Shukla, A., E. Khan, K. Srivastava, K. Sinha, P. Tandon, and Venu R. Vangala. "Study of molecular interactions and chemical reactivity of the nitrofurantoin-3-aminobenzoic acid cocrystal using quantum chemical and spectroscopic (IR, Raman,13C SS-NMR) approaches." 2017. http://hdl.handle.net/10454/17779.
Full textAbstract:
NoInvestigations of structural reactivity, molecular interactions and vibrational characterization of pharmaceutical drugs are helpful in understanding their behaviour. The aim of this study is to determine the molecular, electronic and chemical properties of the antibiotic drug nitrofurantoin (NF), after cocrystallisation with 3-aminobenzoic acid (3ABA) and to understand how those changes lead to variation of properties in the cocrystal NF–3ABA. NF–3ABA formation is explained by stabilization via the hydrogen-bond network between NF and 3ABA molecules. It is thoroughly characterized by IR, Raman and CP-MAS solid-state 13C NMR techniques, along with quantum chemical calculations. The results of IR, Raman, and 13C NMR analyses showed that imide N–H23 and C12[double bond, length as m-dash]O of NF interact with the acid C[double bond, length as m-dash]O and –OH groups in 3-ABA, respectively. Therefore the IR, Raman, and 13C NMR spectra verified the formation of N–H⋯O and O–H⋯O hydrogen bonds. To study hydrogen bonding interactions theoretically in NF–3ABA, two functionals B3LYP and wB97X-D have been used. A comparison is made between the results obtained by B3LYP and those predicted at the wB97X-D level. It is found that wB97X-D is best applied density functional theory (DFT) functional to describe the hydrogen bonding interactions. The strength and nature of hydrogen bonding in NF–3ABA have been analysed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. To validate the results obtained by QTAIM theory and to study the long-range forces, such as van der Waals interactions, the steric effects in NF–3ABA, the reduced density gradient (RDG) and the isosurface have been plotted using Multiwfn software. QTAIM and isosurface analysis suggested that the hydrogen bonding interactions present in NF–3ABA are moderate in nature. The calculated HOMO–LUMO energy gap shows that NF–3ABA is more active than NF and 3ABA. Chemical reactivity descriptors are calculated to understand the various aspects of pharmacological sciences. Chemical reactivity parameters show that NF–3ABA is softer and chemically more reactive than NF. The results suggest that cocrystals can be a feasible alternative for positively changing the targeted physicochemical properties of an active pharmaceutical ingredient (API).
Royal Society of Chemistry for the mobility grant (2015/17); DST (New Delhi) under the DST purse programme; UGC under the BSR meritorious fellowship scheme; DST, India under the Indo-Brazil project
Books on the topic "Molecular cocrystals"
1
Gruss, Michael, and Carsten Schauerte. Solid State Development of Pharmaceutical Molecules: Salts, Cocrystals, and Polymorphism. Wiley & Sons, Limited, John, 2020.
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Mannhold, Raimund, Helmut Buschmann, Michael Gruss, and J¿rg Holenz. Solid State Development and Processing of Pharmaceutical Molecules: Salts, Cocrystals, and Polymorphism. Wiley & Sons, Incorporated, John, 2021.
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Gruss, Michael. Solid State Development and Processing of Pharmaceutical Molecules: Salts, Cocrystals, and Polymorphism. Wiley & Sons, Incorporated, John, 2021.
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4
Mannhold, Raimund, Helmut Buschmann, Michael Gruss, and J¿rg Holenz. Solid State Development and Processing of Pharmaceutical Molecules: Salts, Cocrystals, and Polymorphism. Wiley & Sons, Incorporated, John, 2021.
Find full textBook chapters on the topic "Molecular cocrystals"
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Aitipamula, Srinivasulu. "Polymorphism in Molecular Crystals and Cocrystals." In Advances in Organic Crystal Chemistry, 265–98. Tokyo: Springer Japan, 2015. http://dx.doi.org/10.1007/978-4-431-55555-1_14.
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Wang, Yu, Weigang Zhu, Huanli Dong, Xiaotao Zhang, Rongjin Li, and Wenping Hu. "Organic Cocrystals: New Strategy for Molecular Collaborative Innovation." In Molecular-Scale Electronics, 229–62. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-030-03305-7_8.
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Gavezzotti, Angelo. "Multi-molecular asymmetric units and cocrystals: Symmetry violation." In Theoretical and Computational Chemistry, 169–99. Elsevier, 2021. http://dx.doi.org/10.1016/b978-0-12-823747-2.00009-3.
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