Halogen bonded cocrystals of active pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline in combination with haloperfluorinated compounds

Choquesillo-Lazarte, Duane; Nemec, Vinko; Cinčić, Dominik

doi:10.1039/c7ce01252g

Cited by 34 publications

(41 citation statements)

References 46 publications

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“…Where large quantities of halogen-bonded materials are desired (>100 mg), crystallization methods requiring solvent evaporation or solvent diffusion can be tedious to perform, often requiring many days or perhaps weeks to achieve the desired product in sufficient quantity. Mechanochemistry has been shown to be a favorable route for the halogen bond synthon, 54,59,60,61,62 offering a scalable and rapid method of preparing halogen-bonded cocrystals, 63,64 all without the need of large volumes of solvents. However, mechanochemistry by ball milling 65 has the inconvenience of yielding powdered products, requiring further manipulations in order to prepare a sample for SCXRD.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Cosublimation: A Rapid Route Toward Otherwise Inaccessible Halogen-Bonded Architectures

Szell

Gabriel

Caron‐Poulin

et al. 2018

Crystal Growth & Design

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Several synthetic techniques are available for the preparation of halogen-bonded adducts, including traditional solvent-evaporation methods and mechanochemistry. With the intention of reducing solvent usage and experimental times, we establish cosublimation as a synthetic technique for preparing halogen-bonded cocrystals, focusing on the C–I···N motif involving nitrogen-containing heterocycles. We selected four common halogen-bond donors (I2, 1,4-diiodobenzene, 1,4-diiodotetrafluorobenzene, 1,3,5-trifluoro-2,4,6-triiodobenzene) and four halogen-bond acceptors (2,3,5,6-tetramethylpyrazine, 1,4-diazabicyclo[2.2.2]octane, 2,2′-bipyridyl, 1-adamantanecarbonitrile), by virtue of their range in volatility, and explored all 16 combinations via the following methods: solvent evaporation, overnight cosublimation in a sealed glass tube using a two-zone furnace, and expedited cosublimation in a vacuum sublimation apparatus. We show that the raw crystals obtained from overnight cosublimation are of suitable quality for single-crystal X-ray diffraction, resulting in five new crystal structures, two of which are, currently, unobtainable through other methods. Of these new structures, the first halogen bond to the nitrile group of 1-adamantanecarbonitrile is reported, resulting in the formation of a supramolecular rotor in a spinning top configuration as evidenced by 13C and 15N solid-state NMR spectroscopy. Strikingly, the cosublimation approach overcomes an anticooperative halogen-bonding effect to produce fully saturated cocrystals of the tritopic halogen bond donor 1,3,5-trifluoro-2,4,6-triiodobenzene with 1,4-diazabicyclo[2.2.2]octane. Finally, we show that cosublimation can be used to rapidly prepare and purify bulk samples using a vacuum sublimation apparatus, enabling the scalable preparation of halogen-bonded cocrystals within 10 to 30 min using common laboratory equipment. The methods described here enable a broad exploration of the polymorphic landscape and may be extended to the facile preparation of other classes of cocrystals.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Cosublimation: A Rapid Route Toward Otherwise Inaccessible Halogen-Bonded Architectures

Szell

Gabriel

Caron‐Poulin

et al. 2018

Crystal Growth & Design

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“…Choquesillo-Lazarte et al [ 247 ] has investigated the nature of halogen bonding interactions observed in pharmaceutical cocrystals of pyrazinamide, lidocaine and pentoxifylline with perfluorinated halogen-bond donors namely 1,4-diiodotetrafluorobenzene (tfib) and 1,4-dibromotetrafluorobenzene [ 247 ]. The halogen bonding interaction observed in lidocaine-1,4-diiodotetrafluorobenzene (2:1) and lidocaine-1,4-dibromotetrafluorobenzene (2:1) cocrystals are shown in Figure 16 .…”

Section: Influence Of Intermolecular Interactions On Cocrystallizamentioning

confidence: 99%

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

2018

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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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Section: Introductionmentioning

confidence: 99%

“…To a prevailing degree, however, when noncovalent interactions are concerned, hydrogen bonding (HB) [19] is implied [20]. Considering that over the last decade, the halogen bond (XB) [21] has emerged as an effective tool for crystal engineering [22][23][24][25][26][27][28][29] and designing supramolecular constructs [30][31][32], it is surprising that literature reports on the utility of XB in engineering new API crystal forms has been relatively scarce [20,[33][34][35][36]. Our recent engagement in crystal engineering based on XB in metal complexes [37][38][39][40][41][42][43][44][45] prompted us to consider exploring new opportunities for filling the above void and applying the XB approach towards identifying novel API crystal forms.…”

Section: Introductionmentioning

confidence: 99%

“…Contrary to our expectations at the time, instead of a co-crystal, we obtained an intriguing salt form, nevirapinium pentaiodide hydrate, which was investigated by crystallography to reveal the presence of numerous HBs and an unusual I 4 -I -•••O=C interionic XB. In continuation of these efforts, NVP was co-crystallized with 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB), an XB donor that has already been employed in the co-crystal formation for such biologically active compounds as nicotine [62], pyrazinamide, lidocaine and pentoxifylline [20]. Additionally, we used 1,3-diiodobenzene (1,3-DIB), a rarely employed [63] XB donor.…”

Section: Introductionmentioning

confidence: 99%

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New Crystal Forms for Biologically Active Compounds. Part 1: Noncovalent Interactions in Adducts of Nevirapine with XB Donors

et al. 2019

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Stabilization of specific crystal polymorphs of an active pharmaceutical ingredient is crucial for preventing uncontrollable interconversion of various crystalline forms, which affects physicochemical properties as well as physiological activity. Co-crystallization with various excipients is an emerging productive way of achieving such stabilization in the solid state. In this work, we identified an opportunity for co-crystallization of antiviral drug nevirapine (NVP) with a classical XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB), as well as 1,3-diiodobenzene (1,3-DIB), which has been seldom employed as an XB donor to date. In the X-ray structures of NVP·1,4-FIB and NVP·1,3-DIB co-crystals, different hydrogen and halogen bonding modes were detected and further investigated via DFT calculations as well as topological analysis of the electron density distribution within the framework of the QTAIM method at the M06/DZP-DKH level of theory. Estimated energies of these supramolecular contacts vary from 0.6 to 5.7 kcal/mol.

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Halogen bonded cocrystals of active pharmaceutical ingredients: pyrazinamide, lidocaine and pentoxifylline in combination with haloperfluorinated compounds

Abstract: Six novel halogen-bonded cocrystals of active pharmaceutical ingredients with 1,4-diiodo- and 1,4-dibromotetrafluorobenzene have been synthesized.

Cited by 34 publications

References 46 publications

Cosublimation: A Rapid Route Toward Otherwise Inaccessible Halogen-Bonded Architectures

Cosublimation: A Rapid Route Toward Otherwise Inaccessible Halogen-Bonded Architectures

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

New Crystal Forms for Biologically Active Compounds. Part 1: Noncovalent Interactions in Adducts of Nevirapine with XB Donors

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