Journal articles: '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.

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Topić, Filip, Katarina Lisac, Mihails Arhangelskis, Kari Rissanen, Dominik Cinčić, and Tomislav Friščić. "Cocrystal trimorphism as a consequence of the orthogonality of halogen- and hydrogen-bonds synthons." Chemical Communications 55, no. 93 (2019): 14066–69. http://dx.doi.org/10.1039/c9cc06735c.

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Trimorphic cocrystals, i.e. multi-component molecular crystals with three polymorphic structures, are exceedingly rare. First example of a trimorphic halogen-bonded cocrystal, reported here, shows a critical role for the interaction orthogonality.

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12

Sun, Shanhu, Haobin Zhang, Jinjiang Xu, Hongfan Wang, Shumin Wang, Zhihui Yu, Chunhua Zhu, and Jie Sun. "Design, preparation, characterization and formation mechanism of a novel kinetic CL-20-based cocrystal." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 75, no. 3 (May 9, 2019): 310–17. http://dx.doi.org/10.1107/s2052520619002816.

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2,4,6,8,10,12-Hexanitrohexaazaisowurtzitane (CL-20)-based cocrystals have gained increasing attention as a means of obtaining insensitive high explosives. However, the design of ideal candidates for these cocrystals remains difficult. This work compares the crystal energies of the CL-20–dinitrobenzene (DNB) and CL-20–2,4,6-trinitrotoluene (TNT) cocrystals with those of the respective pure coformers. The results indicate that the cocrystal formation is driven by the differences in the energies of the cocrystals and the coformers. Furthermore, analysis via Hirshfeld surfaces and two-dimensional fingerprint plots confirms that the O...O, O...H, O...N and C...O interactions were the main force for stabilizing the CL-20-based cocrystal structure. Based on these findings, a novel energetic–energetic cocrystal of CL-20–2,4,6-trinitrophenol (TNP) was designed and prepared by means of a rapid method for solvent removal. The crystal structure was investigated via powder X-ray diffraction methods, solid-state nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy. The results revealed that the O—H...O hydrogen bonding interaction between the phenolic hydroxyl group of TNP and nitro groups of CL-20, as well as nitro...π, nitro...nitro and ONO2...π(N)NO2 interactions, based on the benzene ring and nitro groups, are the main interactions occurring in the cocrystal.

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Dudek, Marta K., Ewelina Wielgus, Piotr Paluch, Justyna Śniechowska, Maciej Kostrzewa, Graeme M. Day, Grzegorz D. Bujacz, and Marek J. Potrzebowski. "Understanding the formation of apremilast cocrystals." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 75, no. 5 (September 7, 2019): 803–14. http://dx.doi.org/10.1107/s205252061900917x.

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Apremilast (APR), an anti-psoriatic agent, easily forms isostructural cocrystals and solvates with aromatic entities, often disobeying at the same time Kitaigorodsky's rule as to the saturation of possible hydrogen-bonding sites. In this paper the reasons for this peculiar behavior are investigated, employing a joint experimental and theoretical approach. This includes the design of cocrystals with coformers having a high propensity towards the formation of both aromatic–aromatic and hydrogen-bonding interactions, determination of their structure, using solid-state NMR spectroscopy and X-ray crystallography, as well as calculations of stabilization energies of formation of the obtained cocrystals, followed by crystal structure prediction calculations and solubility measurements. The findings indicate that the stabilization energies of cocrystal formation are positive in all cases, which results from strain in the APR conformation in these crystal forms. On the other hand, solubility measurements show that the Gibbs free energy of formation of the apremilast:picolinamide cocrystal is negative, suggesting that the formation of the studied cocrystals is entropy driven. This entropic stabilization is associated with the disorder observed in almost all known cocrystals and solvates of APR.

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Sathisaran, Indumathi, and Sameer Dalvi. "Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium." Pharmaceutics 10, no. 3 (July 31, 2018): 108. http://dx.doi.org/10.3390/pharmaceutics10030108.

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Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

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MacGillivray, L. R., A. N. Sokolov, D. K. Bucar, and P. Kaushik. "Functional molecular cocrystals." Acta Crystallographica Section A Foundations of Crystallography 63, a1 (August 22, 2007): s41. http://dx.doi.org/10.1107/s0108767307099084.

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Sun, Shanhu, Haobin Zhang, Jinjiang Xu, Shumin Wang, Hongfan Wang, Zhihui Yu, Lang Zhao, Chunhua Zhu, and Jie Sun. "The competition between cocrystallization and separated crystallization based on crystallization from solution." Journal of Applied Crystallography 52, no. 4 (July 8, 2019): 769–76. http://dx.doi.org/10.1107/s1600576719008094.

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The competition between cocrystallization and separated crystallization in a solvent was explored via X-ray diffraction and high-performance liquid chromatography methods in different solvents and by considering the solvent evaporation rate. The results revealed that the solvent system and solvent evaporation rate can affect the nucleation order of the cocrystal and coformers in the solution. In fact, solubility tests in different solvents confirmed that the solubility plays a key role in the cocrystal formation process. Furthermore, the width of the metastable zone influenced the solute nucleation order and was a decisive factor in the cocrystal formation process when the solvent evaporation rate was varied. Cocrystals could therefore be obtained by adjusting the solvents and solvent evaporation rate. The preparation of kinetic 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane–2,4,6-trinitrophenol cocrystals via rapid solvent evaporation proves the practicability of this theory.

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Álvarez-Vidaurre, Raquel, Alfonso Castiñeiras, Isabel García-Santos, and Rocío Torres-Iglesias. "Interactions between Isoniazid and α-Hydroxycarboxylic Acids." Chemistry Proceedings 3, no. 1 (November 14, 2020): 73. http://dx.doi.org/10.3390/ecsoc-24-08355.

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The present study refers to the preparation of isonicotinic acid hydrazide (isoniazid (INH)) cocrystals with two α-hydroxycarboxylic acids. The interaction of glycolic acid (H2ga) or dl-mandelic acid (H2ma) resulted in the formation of cocrystals, or salts of composition, as isoniazid−glycolic acid cocrystal (INH)·(H2ga) (1) and isoniazid−dl-mandelic acid salt cocrystal [HINH]+[Hma]−·(H2ma) (2), when reacted with isoniazid. An N’-(propan-2-ylidene)isonicotinic hydrazide hemihydrate, (pINH)·1/2(H2O) (3), was also prepared by condensation of isoniazid with acetone in the presence of glycolic acid. The prepared compounds were well characterized by elemental analysis and spectroscopic methods, and their three-dimensional molecular structure was determined by single-crystal X-ray crystallography. Hydrogen bonds involving carboxylic acid occur consistently with the pyridine ring N atom of the isoniazid and its derivatives. The remaining hydrogen-bonding sites on the isoniazid backbone vary on the basis of the steric influences of the derivative group. These are contrasted in each of the molecular systems.

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Jones, William, W. D. Samuel Motherwell, and Andrew V. Trask. "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement." MRS Bulletin 31, no. 11 (November 2006): 875–79. http://dx.doi.org/10.1557/mrs2006.206.

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AbstractPharmaceutical cocrystals are crystalline molecular complexes containing therapeutic molecules. They represent an emerging class of pharmaceutical materials offering the prospect of optimized physical properties. This article highlights important opportunities and challenges associated with the design and synthesis of pharmaceutical cocrystals. Cocrystallization is first placed into context with the more established approaches to physical property optimization of polymorph, hydrate, and salt selection. A directed, intermolecular-interaction-based approach to cocrystal design is described. The enhancement of specific physical properties, such as dissolution rate and physical stability, is illustrated by summarizing several recent reports. Synthetic approaches to cocrystallization are considered; in particular, the selectivity and screening-related opportunities afforded by solid-state grinding and solvent-drop grinding methods are discussed. Finally, an outlook on future developments summarizes the growth potential in this field, especially with regard to targeted, informatics-driven cocrystal screening approaches.

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Wasim, Muhammad, Abdul Mannan, Muhammad Hassham Hassan Bin Asad, Muhammad Imran Amirzada, Muhammad Shafique, and Izhar Hussain. "Fabrication of Carbamazepine Cocrystals: Characterization, In Vitro and Comparative In Vivo Evaluation." BioMed Research International 2021 (March 15, 2021): 1–9. http://dx.doi.org/10.1155/2021/6685806.

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Carbamazepine (CBZ) is an antiepileptic drug having low bioavailability due to its hydrophobic nature. In the current study, efforts are made to investigate the effect of dicarboxylic acid coformer spacer groups (aliphatic chain length) on physicochemical properties, relative humidity (RH) stability, and oral bioavailability of CBZ cocrystals. Slurry crystallization technique was employed for the preparation of CBZ cocrystals with the following coformers: adipic (AA), glutaric (GA), succinic (SA), and malonic acid (MA). Powder X-ray diffractometry and Fourier-transform infrared spectroscopy confirmed cocrystal preparation. Physicochemical properties, RH stability, and oral bioavailability of cocrystals were investigated. Among the prepared cocrystals, CBZ-GA showed maximum solubility as well as improved dissolution profile (CBZ-GA > CBZ-MA > CBZ-AA > pure CBZ > CBZ-SA) in ethanol. Maximum RH stability was shown by CBZ-AA, CBZ-SA, and CBZ-MA. In vivo studies confirmed boosted oral bioavailability of cocrystals compared to pure CBZ. Furthermore, in vivo studies depicted the oral bioavailability order of cocrystals as CBZ-GA > CBZ-MA > Tegral® > CBZ-AA > CBZ-SA > pure CBZ. Thus, pharmaceutical scientists can effectively employ cocrystallization technique for tuning physicochemical properties of hydrophobic drugs to achieve the desired oral bioavailability. Overall, results reflect no consistent effect of spacer group on physicochemical properties, RH stability, and oral bioavailability of cocrystals.

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Kloda, Matouš, Irena Matulková, Ivana Císařová, Petra Becker, Ladislav Bohatý, Petr Němec, Róbert Gyepes, and Ivan Němec. "Cocrystals of 2-Aminopyrimidine with Boric Acid—Crystal Engineering of a Novel Nonlinear Optically (NLO) Active Crystal." Crystals 9, no. 8 (August 3, 2019): 403. http://dx.doi.org/10.3390/cryst9080403.

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Crystal engineering of novel materials for nonlinear optics (NLO) based on 2-aminopyrimidine yielded two molecular cocrystals with boric acid—trigonal (P3221 space group) 2-aminopyrimidine—boric acid (3/2) and monoclinic (C2/c space group) 2-aminopyrimidine—boric acid (1/2). In addition to crystal structure determination by single crystal X-ray diffraction, the cocrystals were characterized by powder X-ray diffraction and vibrational spectroscopy (FTIR and FT Raman). Large single crystals of the non-centrosymmetric cocrystal 2-aminopyrimidine—boric acid (3/2) were grown to study the optical properties and determine the second harmonic generation (SHG) efficiency (using 800 nm fundamental laser line) of powder samples.

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Liu, Yan, Chongwei An, Jin Luo, and Jingyu Wang. "High-density HNIW/TNT cocrystal synthesized using a green chemical method." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 74, no. 4 (July 23, 2018): 385–93. http://dx.doi.org/10.1107/s2052520618008442.

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The main challenge for achieving better energetic materials is to increase their density. In this paper, cocrystals of HNIW (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane, often referred to as CL-20) with TNT (2,4,6-trinitrotoluene) were synthesized using ethanol in a green chemical method. The cocrystal was formulated as C13H11N15O18 and possesses a higher density (1.934 g cm−3) than published previously (1.846 g cm−3). This high-density cocrystal possesses a new structure, which can be substantiated by the different types of hydrogen bonds. The predominant driving forces that connect HNIW with TNT in the new cocrystal were studied at ambient conditions using single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform–infrared spectroscopy and Raman spectroscopy. The results reveal that the structure of the new HNIW/TNT cocrystals consists of three one-dimensional hydrogen-bonded chains exploiting the familiar HNIW–TNT multi-component supramolecular structure, in which two hydrogen-bonded chains are between —NO2 (HNIW) and —CH (TNT), and one hydrogen-bonded chain is between —CH (HNIW) and —NO2 (TNT). The changes to the electron binding energy and type of element in the new cocrystal were traced using X-ray photoelectron spectroscopy. Meanwhile, the physicochemical characteristics alter after cocrystallization due to the hydrogen bonding. It was found that the new HNIW/TNT cocrystal is more thermodynamically stable than HNIW. Thermodynamic aspects of new cocrystal decomposition are investigated in order to explain this observation. The detonation velocity of new HNIW/TNT cocrystals is 8631 m s−1, close to that of HNIW, whereas the mechanical sensitivity is lower than HNIW.

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Xie, Yifei, Penghui Yuan, Tianyu Heng, Lida Du, Qi An, Baoxi Zhang, Li Zhang, Dezhi Yang, Guanhua Du, and Yang Lu. "Insight into the Formation of Cocrystal and Salt of Tenoxicam from the Isomer and Conformation." Pharmaceutics 14, no. 9 (September 19, 2022): 1968. http://dx.doi.org/10.3390/pharmaceutics14091968.

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Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different tautomers exist in different crystalline forms. TNX is such a compound and has three tautomers. TNX always exists as the zwitterionic form in cocrystals. When the salt is formed, TNX exists in the enol form, which exhibits two conformations depending on whether a proton is gained or lost. Currently, the crystal structure of the keto form is not in the Cambridge Structural Database (CSD). Based on the analysis of existing crystal structures, we derived a simple rule for what form of TNX exists according to the pKa value of the cocrystal coformer (CCF) and carried out validation tests using three CCFs with different pKa values, including p-aminosalicylic acid (PAS), 3,5-dinitrobenzoic acid (DNB), and 2,6-dihydroxybenzoic acid (DHB). The molecular surface electrostatic potential (MEPS) was combined with the pKa rule to predict the interaction sites. Finally, two new cocrystals (TNX-PAS and TNX-DNB) and one salt (TNX-DHB) of TNX were obtained as expected. The differences between the cocrystals and salt were distinguished by X-ray diffraction, vibration spectra, thermal analysis, and dissolution measurements. To further understand the intermolecular interactions in these cocrystals and salt, the lattice energy and energy decomposition analysis (EDA) were used to explain them from the perspective of energy. The results suggest that the melting point of the CCF determines that of the cocrystal or salt, the solubility of the CCF itself plays an important role, and the improvement of the solubility after salt formation is not necessarily better than that of API or its cocrystals.

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Xu, Jia, Qin Shi, Yanan Wang, Yong Wang, Junbo Xin, Jin Cheng, and Fang Li. "Recent Advances in Pharmaceutical Cocrystals: A Focused Review of Flavonoid Cocrystals." Molecules 28, no. 2 (January 6, 2023): 613. http://dx.doi.org/10.3390/molecules28020613.

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Cocrystallization is currently an attractive technique for tailoring the physicochemical properties of active pharmaceutical ingredients (APIs). Flavonoids are a large class of natural products with a wide range of beneficial properties, including anticancer, anti-inflammatory, antiviral and antioxidant properties, which makes them extensively studied. In order to improve the properties of flavonoids, such as solubility and bioavailability, the formation of cocrystals may be a feasible strategy. This review discusses in detail the possible hydrogen bond sites in the structure of APIs and the hydrogen bonding networks in the cocrystal structures, which will be beneficial for the targeted synthesis of flavonoid cocrystals. In addition, some successful studies that favorably alter the physicochemical properties of APIs through cocrystallization with coformers are also highlighted here. In addition to improving the solubility and bioavailability of flavonoids in most cases, flavonoid cocrystals may also alter their other properties, such as anti-inflammatory activity and photoluminescence properties.

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Roy, Monalisa, Keyao Li, Madiha Nisar, Lawrence W. Y. Wong, Herman H. Y. Sung, Richard K. Haynes, and Ian D. Williams. "Varying degrees of homostructurality in a series of cocrystals of antimalarial drug 11-azaartemisinin with salicylic acids." Acta Crystallographica Section C Structural Chemistry 77, no. 6 (May 6, 2021): 262–70. http://dx.doi.org/10.1107/s2053229621004460.

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The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one, C15H23NO4) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C7H5BrO3), 4-bromo- (4-BrSalA, C7H5BrO3) and 3,5-dibromosalicylic acid (3,5-Br2SalA, C7H4Br2O3)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P21) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br2SalA cocrystals retain the highly preserved 21 stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br2SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O—H...O=C hydrogen bonds of 2.54 Å in the cocrystals.

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Bolla, Geetha, Vladimir Chernyshev, and Ashwini Nangia. "Acemetacin cocrystal structures by powder X-ray diffraction." IUCrJ 4, no. 3 (March 8, 2017): 206–14. http://dx.doi.org/10.1107/s2052252517002305.

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Cocrystals of acemetacin drug (ACM) with nicotinamide (NAM),p-aminobenzoic acid (PABA), valerolactam (VLM) and 2-pyridone (2HP) were prepared by melt crystallization and their X-ray crystal structures determined by high-resolution powder X-ray diffraction. The powerful technique of structure determination from powder data (SDPD) provided details of molecular packing and hydrogen bonding in pharmaceutical cocrystals of acemetacin. ACM–NAM occurs in anhydrate and hydrate forms, whereas the other structures crystallized in a single crystalline form. The carboxylic acid group of ACM forms theacid–amide dimer three-point synthonR32(9)R22(8)R32(9) with three differentsynamides (VLM, 2HP and caprolactam). The conformations of the ACM molecule observed in the crystal structures differ mainly in the mutual orientation of chlorobenzene fragment and the neighboring methyl group, beinganti(type I) orsyn(type II). ACM hydrate, ACM—NAM, ACM–NAM-hydrate and the piperazine salt of ACM exhibit the type I conformation, whereas ACM polymorphs and other cocrystals adopt the ACM type II conformation. Hydrogen-bond interactions in all the crystal structures were quantified by calculating their molecular electrostatic potential (MEP) surfaces. Hirshfeld surface analysis of the cocrystal surfaces shows that about 50% of the contribution is due to a combination of strong and weak O...H, N...H, Cl...H and C...H interactions. The physicochemical properties of these cocrystals are under study.

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26

Wróblewska, Aneta, Justyna Śniechowska, Sławomir Kaźmierski, Ewelina Wielgus, Grzegorz D. Bujacz, Grzegorz Mlostoń, Arkadiusz Chworos, Justyna Suwara, and Marek J. Potrzebowski. "Application of 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide as Coformer in Formation of Pharmaceutical Cocrystals." Pharmaceutics 12, no. 4 (April 15, 2020): 359. http://dx.doi.org/10.3390/pharmaceutics12040359.

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Two, well defined binary crystals with 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide (HIMO) as coformer and thiobarbituric acid (TBA) as well barbituric acid (BA) as Active Pharmaceutical Ingredients (APIs) were obtained by cocrystallization (from methanol) or mechanochemically by grinding. The progress of cocrystal formation in a ball mill was monitored by means of high-resolution, solid state NMR spectroscopy. The 13C CP/MAS, 15N CP/MAS and 1H Very Fast (VF) MAS NMR procedures were employed to inspect the tautomeric forms of the APIs, structure elucidation of the coformer and the obtained cocrystals. Single crystal X-ray studies allowed us to define the molecular structure and crystal packing for the coformer as well as the TBA/HIMO and BA/HIMO cocrystals. The intermolecular hydrogen bonding, π–π interactions and CH-π contacts responsible for higher order organization of supramolecular structures were determined. Biological studies of HIMO and the obtained cocrystals suggest that these complexes are not cytotoxic and can potentially be considered as therapeutic materials.

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Evtushenko, Diana N., Sergey G. Arkhipov, Alexander V. Fateev, Tatyana I. Izaak, Lidia A. Egorova, Nina A. Skorik, Olga V. Vodyankina, and Elena V. Boldyreva. "A cocrystal of L-ascorbic acid with picolinic acid: the role of O—H...O, N—H...O and C—H...O hydrogen bonds and L-ascorbic acid conformation in structure stabilization." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 76, no. 6 (November 3, 2020): 967–78. http://dx.doi.org/10.1107/s2052520620012421.

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A new 1:1 cocrystal (L-Asc–Pic) of L-ascorbic acid (vitamin C) with picolinic acid was prepared as a powder and as single crystals. The crystal structure was solved and refined from single-crystal X-ray diffraction (SCXRD) data collected at 293 (2) and 100 (2) K. The samples of the L-Asc–Pic cocrystal were characterized by elemental (HCNS) analysis and titrimetric methods, TG/DTG/DSC, and IR and Raman spectroscopy. The asymmetric unit comprises a picolinic acid zwitterion and an L-ascorbic acid molecule. The stabilization energy of intermolecular interactions involving hydrogen bonds, the vibrational spectrum and the energies of the frontier molecular orbitals were calculated using the GAUSSIAN09 and the CrystalExplorer17 programs. The charge distribution on the atoms of the L-Asc–Pic cocrystal, L-ascorbic acid itself and its 12 known cocrystals (structures from Version 5.40 of the Cambridge Structural Database) were calculated by the methods of Mulliken, Voronoi and Hirshfeld charge analyses (ADF) at the bp86/TZ2P+ level of theory. The total effective charges and conformations of the L-ascorbic acid molecules in the new and previously reported cocrystals were compared with those of the two symmetry-independent molecules in the crystals of L-ascorbic acid. A correlation between molecular conformation and its effective charge is discussed.

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Devogelaer, Jan-Joris, Hugo Meekes, Elias Vlieg, and René de Gelder. "Cocrystals in the Cambridge Structural Database: a network approach." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 75, no. 3 (May 18, 2019): 371–83. http://dx.doi.org/10.1107/s2052520619004694.

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To obtain a better understanding of which coformers to combine for the successful formation of a cocrystal, techniques from data mining and network science are used to analyze the data contained in the Cambridge Structural Database (CSD). A network of coformers is constructed based on cocrystal entries present in the CSD and its properties are analyzed. From this network, clusters of coformers with a similar tendency to form cocrystals are extracted. The popularity of the coformers in the CSD is unevenly distributed: a small group of coformers is responsible for most of the cocrystals, hence resulting in an inherently biased data set. The coformers in the network are found to behave primarily in a bipartite manner, demonstrating the importance of combining complementary coformers for successful cocrystallization. Based on our analysis, it is demonstrated that the CSD coformer network is a promising source of information for knowledge-based cocrystal prediction.

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29

Balakrishnan, C., M. Manonmani, S. Rafi Ahamed, G. Vinitha, S. P. Meenakshisundaram, and R. M. Sockalingam. "Supramolecular cocrystals of O—H...O hydrogen-bonded 18-crown-6 with isophthalic acid derivatives: Hirshfeld surface analysis and third-order nonlinear optical properties." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 76, no. 2 (March 19, 2020): 241–51. http://dx.doi.org/10.1107/s2052520620001821.

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Two cocrystals of 18-crown-6 with isophthalic acid derivatives, 5-hydroxyisophthalic acid and trimesic acid, have been successfully grown by the slow evaporation solution growth technique. Crystal structures of (18-crown-6)·6(5-hydroxyisophthalic acid)·10(H2O) (I) and (18-crown-6)·2(trimesic acid)·2(H2O) (II) elucidated by single crystal X-ray diffraction reveal that both cocrystals pack the centrosymmetric triclinic space group P{\overline 1}. The molecules are associated by strong/weak hydrogen bonds, π...π and H...H stacking interactions. Powder X-ray diffraction analyses, experimental and simulated from single-crystal diffractogram data have been matched. The vibrational patterns in FT–IR spectra are used to identify the functional groups. The band gap energy is estimated by the application of the Kubelka–Munk algorithm. Hirshfeld surfaces derived from X-ray diffraction analysis reveal the type of molecular interactions and their relative contributions. The constructed supramolecular assembly of crown ether cocrystal is thoroughly described. Both cocrystals exhibit a significant third-order nonlinear optical response and it is observed that (I) possesses a significant first-order molecular hyperpolarizability whereas it is negligible for (II).

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30

Xue, Na, Yutao Jia, Congwei Li, Binnan He, Caiqin Yang, and Jing Wang. "Characterizations and Assays of α-Glucosidase Inhibition Activity on Gallic Acid Cocrystals: Can the Cocrystals be Defined as a New Chemical Entity During Binding with the α-Glucosidase?" Molecules 25, no. 5 (March 5, 2020): 1163. http://dx.doi.org/10.3390/molecules25051163.

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Cocrystallization with co-former (CCF) has proved to be a powerful approach to improve the solubility and even bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, it is still uncertain whether a cocrystal would exert the pharmacological activity in the form of a new chemical entity, an API-CCF supramolecule. In the present study, gallic acid (GA)-glutaric acid and GA-succinimide cocrystals were screened. The solubility, dissolution rate and oral bioavailability of the two cocrystals were evaluated. As expected, AUCs of GA-glutaric acid and GA-succinimide cocrystals were 1.86-fold and 2.60-fold higher than that of single GA, respectively. Moreover, experimental evaluations on α-glucosidase inhibition activity in vitro and theoretical simulations were used to detect whether the two cocrystals would be recognized as a new chemical entity during binding with α-glucosidase, a target protein in hypoglycemic mechanisms. The enzyme activity evaluation results showed that both GA and glutaric acid displayed α-glucosidase inhibition activity, and GA-glutaric acid cocrystals showed strengthened α-glucosidase inhibition activity at a moderate concentration, which is attributed to synergism of the two components. Molecular docking displayed that the GA-glutaric acid complex deeply entered the active cavity of the α-glucosidase in the form of a supramolecule, which made the guest-enzyme binding configuration more stable. For the GA and succinimide system, succinimide showed no enzyme inhibition activity, however, the GA-succinimide complex presented slightly higher α-glucosidase inhibition activity than that of GA. Molecular docking simulation indicated that the guest molecules entering the active cavity of the α-glucosidase were free GA and succinimide, not the GA-succinimide supramolecule.

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Karothu, Durga Prasad, Ilma Jahović, Gligor Jovanovski, Branko Kaitner, and Panče Naumov. "Ionic cocrystals of molecular saccharin." CrystEngComm 19, no. 30 (2017): 4338–44. http://dx.doi.org/10.1039/c7ce00627f.

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Ionic cocrystals of molecular saccharin, one of the most commonly used artificial low-calorie sweeteners, where saccharin exists as a neutral species and an ion in the same crystal were synthesized and structurally characterized.

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32

Wang, Na, Xin Huang, Lihang Chen, Jinyue Yang, Xin Li, Jiayuan Ma, Ying Bao, Fei Li, Qiuxiang Yin, and Hongxun Hao. "Consistency and variability of cocrystals containing positional isomers: the self-assembly evolution mechanism of supramolecular synthons of cresol–piperazine." IUCrJ 6, no. 6 (October 9, 2019): 1064–73. http://dx.doi.org/10.1107/s2052252519012363.

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The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O—H...N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.

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Rahmani, Maryam, Vijith Kumar, Julia Bruno-Colmenarez, and Michael J. Zaworotko. "Crystal Engineering of Ionic Cocrystals Sustained by Azolium···Azole Heterosynthons." Pharmaceutics 14, no. 11 (October 28, 2022): 2321. http://dx.doi.org/10.3390/pharmaceutics14112321.

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Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B−A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B−C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31–46 kJ mol−1. The azolium-triazole ICC (A+B−C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.

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Javoor, Manjunath, Pradip Mondal, and Deepak Chopra. "Cocrystals: A Review of Recent Trends in Pharmaceutical and Material Science Applications." Material Science Research India 14, no. 1 (June 17, 2017): 09–18. http://dx.doi.org/10.13005/msri/140103.

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Over the last two decades, the design of multicomponent molecular crystals or cocrystals has grown out to be an interesting and promising area of research in pharmaceuticals and material science. Cocrystallization is at the interface of crystal engineering and supramolecular chemistry and allows us to vary the physicochemical properties of solids according to the need, through manipulation of various intermolecular interactions. In this short review, we focus on some recent reports on pharmaceutical cocrystals and emerging subclasses of cocrystals, namely: Charge transfer cocrystals, Energetic cocrystals, and Ternary cocrystals and discuss about their methods of characterization and applications of importance in the industry.

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Gawade, Ashwini, Ashwin Kuchekar, Sanjay Boldhane, and Akshay Baheti. "Improvement of Physicochemical and Solubility of Dipyridamole by Cocrystallization Technology." Journal of Drug Delivery and Therapeutics 11, no. 1-s (February 15, 2021): 43–48. http://dx.doi.org/10.22270/jddt.v11i1-s.4696.

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The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and cocrystal technology tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving physicochemical properties and dissolution behavior of DP under neutral conditions. Molecular docking method was used to identify the suitable conformer. Upon optimization of the ratio of TA to DP (molar ratio of 1:1, 1:2 and 1:3) was prepared by a solvent assisted griding method. Scanning electron microscopy images revealed that formation of DP-TA co crystals supported by supported by powder X-ray diffraction and differential scanning calorimetry analyses. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP and TA resulting in pH independent dissolution behavior of drug substance. The study confirmed the selection of proper coformer and exhibited enhanced physicochemical, solubility and stability of the Dipyridamole cocrystals. Hence, based upon results it revealed that cocrystallization helps in improving the physicochemical properties of the API. Keywords: Dipyridamole, Coformer, Molecular docking, Radar chart, solvent assisted griding, Cocrystals

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McArdle, Patrick, and Andrea Erxleben. "Sublimation – a green route to new solid-state forms." CrystEngComm 23, no. 35 (2021): 5965–75. http://dx.doi.org/10.1039/d1ce00715g.

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Aakeröy, C. B. "Constructing, deconstructing, and reconstructing molecular cocrystals." Acta Crystallographica Section A Foundations of Crystallography 63, a1 (August 22, 2007): s39. http://dx.doi.org/10.1107/s0108767307099138.

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Tojiboev, A., R. Okmanov, K. Turgunov, B. Tashkhodjaev, N. Mukarramov, and K. Shakhidoyatov. "Molecular cocrystals of peganole with peganine." Acta Crystallographica Section A Foundations of Crystallography 64, a1 (August 23, 2008): C477. http://dx.doi.org/10.1107/s0108767308084675.

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Rodríguez-Hornedo, Naír. "Cocrystals: Molecular Design of Pharmaceutical Materials." Molecular Pharmaceutics 4, no. 3 (June 2007): 299–300. http://dx.doi.org/10.1021/mp070042v.

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Brittain, Harry G. "Vibrational Spectroscopic Study of the Cocrystal Products Formed by Cinchona Alkaloids with 5-Nitrobarbituric Acid." Journal of Spectroscopy 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/340460.

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X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of cocrystal formation in the molecular complexes formed by 5-nitrobarbituric acid with four cinchona alkaloids. The cocrystal products were found to contain varying degrees of hydration, ranging from no hydration in the nitrobarbiturate-quinidine cocrystal up to a 4.5-hydrate species in the nitrobarbiturate-cinchonine cocrystal. For the nitrobarbiturate cocrystals with cinchonine, cinchonidine, and quinidine, the predominant interaction was with the quinoline ring system of the alkaloid. However, for quinine, the predominant interaction was with the quinuclidine group of the alkaloid. These properties serve to demonstrate the utility of 5-nitrobarbituric acid as a preferred reagent for chemical microscopy, since the differing range of hydrate and structural types would serve to easily differentiate the cinchona alkaloids from each other, even when different compounds contained the same absolute configurations at their dissymmetric centers.

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Mswahili, Medard Edmund, Min-Jeong Lee, Gati Lother Martin, Junghyun Kim, Paul Kim, Guang J. Choi, and Young-Seob Jeong. "Cocrystal Prediction Using Machine Learning Models and Descriptors." Applied Sciences 11, no. 3 (February 1, 2021): 1323. http://dx.doi.org/10.3390/app11031323.

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Cocrystals are of much interest in industrial application as well as academic research, and screening of suitable coformers for active pharmaceutical ingredients is the most crucial and challenging step in cocrystal development. Recently, machine learning techniques are attracting researchers in many fields including pharmaceutical research such as quantitative structure-activity/property relationship. In this paper, we develop machine learning models to predict cocrystal formation. We extract descriptor values from simplified molecular-input line-entry system (SMILES) of compounds and compare the machine learning models by experiments with our collected data of 1476 instances. As a result, we found that artificial neural network shows great potential as it has the best accuracy, sensitivity, and F1 score. We also found that the model achieved comparable performance with about half of the descriptors chosen by feature selection algorithms. We believe that this will contribute to faster and more accurate cocrystal development.

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Sun, Lingjie, Weigang Zhu, Fangxu Yang, Baili Li, Xiaochen Ren, Xiaotao Zhang, and Wenping Hu. "Molecular cocrystals: design, charge-transfer and optoelectronic functionality." Physical Chemistry Chemical Physics 20, no. 9 (2018): 6009–23. http://dx.doi.org/10.1039/c7cp07167a.

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Rajendrakumar, Satyasree, Anuja Surampudi Venkata Sai Durga, and Sridhar Balasubramanian. "Strategic synthon approach in obtaining cocrystals and cocrystal polymorphs of a high-Z′ system deferiprone – an anti-thalassemia drug." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 77, no. 6 (November 12, 2021): 946–64. http://dx.doi.org/10.1107/s205252062100980x.

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Compounds with more than one molecule in the crystallographic asymmetric unit (Z′ > 1) display a noticeably stronger propensity to form cocrystals. Deferiprone is an anti-thalassemia drug known to exhibit polymorphic behaviour. Previously, three polymorphs were reported out of which one of them exhibited Z′ > 1. In the present manuscript, a fourth polymorph of deferiprone was identified and it also possessed Z′ > 1. All the four polymorphs showed similar hydrogen bonding features and differed in crystal packing. The ability of deferiprone to crystallize as Z′ > 1 prompted us to investigate the hydrogen bonding and synthon variation upon cocrystallization of deferiprone with hydroxyl-group-containing coformers such as catechol, hydroquinone, phloroglucinol, resorcinol and pyrogallol. Crystallization attempts along with PXRD analysis aided in obtaining 11 new cocrystal structures which involve different stoichiometric cocrystals and some polymorphs. Synthon analysis, crystal packing as well as thermal behaviour were assessed and compared. The presence of multiple phases in each cocrystal system in its respective bulk powders was identified and quantified using PXRD and Rietveld analysis. Homosynthons were observed in three co-crystal systems, while a heterosynthon was observed in five systems. The combination of both homo- and heterosynthon was observed in three cocrystal systems. The phase transformation events were observed in most of the systems. In nine co-crystal systems, the melting points were observed intermediate between those of the API and the coformers.

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Lee, Min-Jeong, Srinivasulu Aitipamula, Guang J. Choi, and Pui Shan Chow. "Agomelatine–hydroquinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 75, no. 6 (November 6, 2019): 969–77. http://dx.doi.org/10.1107/s2052520619011739.

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Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine–hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063–1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)–(II) and 352 K for the pair form (II)–(III).

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Mohamed, Sharmarke, Ahmad A. Alwan, Tomislav Friščić, Andrew J. Morris, and Mihails Arhangelskis. "Towards the systematic crystallisation of molecular ionic cocrystals: insights from computed crystal form landscapes." Faraday Discussions 211 (2018): 401–24. http://dx.doi.org/10.1039/c8fd00036k.

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Tutughamiarso, Maya, Guido Wagner, and Ernst Egert. "Cocrystals of 5-fluorocytosine. I. Coformers with fixed hydrogen-bonding sites." Acta Crystallographica Section B Structural Science 68, no. 4 (July 17, 2012): 431–43. http://dx.doi.org/10.1107/s010876811202561x.

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The antifungal drug 5-fluorocytosine (4-amino-5-fluoro-1,2-dihydropyrimidin-2-one) was cocrystallized with five complementary compounds in order to better understand its drug–receptor interaction. The first two compounds, 2-aminopyrimidine (2-amino-1,3-diazine) and N-acetylcreatinine (N-acetyl-2-amino-1-methyl-5H-imidazol-4-one), exhibit donor–acceptor sites for R 2 2(8) heterodimer formation with 5-fluorocytosine. Such a heterodimer is observed in the cocrystal with 2-aminopyrimidine (I); in contrast, 5-fluorocytosine and N-acetylcreatinine [which forms homodimers in its crystal structure (II)] are connected only by a single hydrogen bond in (III). The other three compounds 6-aminouracil (6-amino-2,4-pyrimidinediol), 6-aminoisocytosine (2,6-diamino-3H-pyrimidin-4-one) and acyclovir [acycloguanosine or 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one] possess donor–donor–acceptor sites; therefore, they can interact with 5-fluorocytosine to form a heterodimer linked by three hydrogen bonds. In the cocrystals with 6-aminoisocytosine (Va)–(Vd), as well as in the cocrystal with the antiviral drug acyclovir (VII), the desired heterodimers are observed. However, they are not formed in the cocrystal with 6-aminouracil (IV), where the components are connected by two hydrogen bonds. In addition, a solvent-free structure of acyclovir (VI) was obtained. A comparison of the calculated energies released during dimer formation helped to rationalize the preference for hydrogen-bonding interactions in the various cocrystal structures.

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Lynch, Daniel E., Manpreet Singh, and Simon Parsons. "Molecular cocrystals of 2-amino-5-chlorobenzooxazole." Crystal Engineering 3, no. 1 (March 2000): 71–79. http://dx.doi.org/10.1016/s1463-0184(00)00029-0.

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Liu, Wenwen, Ru Ma, Feifei Liang, Chenxin Duan, Guisen Zhang, Yin Chen, and Chao Hao. "New Cocrystals of Antipsychotic Drug Aripiprazole: Decreasing the Dissolution through Cocrystallization." Molecules 26, no. 9 (April 21, 2021): 2414. http://dx.doi.org/10.3390/molecules26092414.

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Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.

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Kamis, Mohamad Nor Amirul Azhar, Hamizah Mohd Zaki, Nornizar Anuar, and Mohammad Noor Jalil. "Synthesis, Characterization and Morphological Study of Nicotinamide and p-Coumaric Acid Cocrystal." Indonesian Journal of Chemistry 20, no. 3 (May 9, 2020): 661. http://dx.doi.org/10.22146/ijc.45530.

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Cocrystallization is one of the potent methods used to modify the physicochemical properties of drugs. Cocrystal of nicotinamide (NIC):p-coumaric acid (COU) was synthesized by a slow evaporation method using acetonitrile. The cocrystals with different feed molar ratios (NIC:COU : 1:1, 1:2, and 2:1) were characterized using DSC, PXRD, and FTIR, which revealed the formation of different polymorphs for each feed molar ratio. A single crystal of the NIC:COU (1:1) cocrystal was analyzed using single crystal X-ray diffraction (SCD), and 1H-NMR revealed a greater cocrystal structure stability compared to the previously published cocrystal. The intermolecular hydrogen bonds, N-H···O, and O-H···O interactions played a major role in stabilizing the cocrystal structure. A molecular modeling technique was used for prediction and surface chemistry assessment of the morphology showed an elongated (along y-axis) octagonal crystal shape which was in a reasonable agreement with the experimental crystal morphology. The reduction in values of the cocrystal solubility in ethanol was supported by the DSC data and simulation of crystal facets where most the crystal facets exposed to polar functional groups. At the concentration of 31.3 µM, NIC:COU (1:1) cocrystal showed more effective DPPH scavenging with 77.06% increased activity compared to NIC at the same concentration.

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Sarmah, Kashyap Kumar, Trishna Rajbongshi, Sourav Bhowmick, and Ranjit Thakuria. "First-line antituberculosis drug, pyrazinamide, its pharmaceutically relevant cocrystals and a salt." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 73, no. 5 (September 29, 2017): 1007–16. http://dx.doi.org/10.1107/s2052520617011477.

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A few pyrazinamide (Pyz) cocrystals involving hydroxybenzoic/cinnamic acid derivatives [2,4-dihydroxybenzoic acid (24DHBA); 2,6-dihydroxybenzoic acid (26DHBA); 3,5-dihydroxybenzoic acid (35DHBA) and nutraceutical molecule ferulic acid (FRA)] and the first example of a molecular salt withp-toluenesulfonic acid (pTSA) have been prepared and characterized using various solid-state techniques. A high-temperature cocrystal polymorph of Pyz·FRA has been characterized from the endothermic peaks observed using differential scanning calorimetry. The presence of substituent groups carrying hydrogen bond donors or acceptors and their influence on supramolecular synthon formation has been investigated using a Cambridge Structural Database search. Equilibrium solubility of all the binary complexes of Pyz follows the order of their coformer solubility,i.e.Pyz+·pTSA−> Pyz·35DHBA > Pyz > Pyz·26DHBA > Pyz·24DHBA > Pyz·FRA. A twofold enhancement in solubility of Pyz+·pTSA−molecular salt compared with the parent drug suggests a potential drug formulation for the treatment of tuberculosis.

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Journal articles on the topic 'Molecular cocrystals'

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