Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals

Dandela, Rambabu; Tothadi, Srinu; Marelli, Udaya Kiran; Nangia, Ashwini

doi:10.1107/s2052252518014057

Cited by 18 publications

(16 citation statements)

References 45 publications

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“…Beginning with binary cocrystals, we have recently reported the successful design of a six‐component molecular solid using both interaction‐based and solid solution‐based strategies . This approach has been subsequently used by others …”

Section: Figurementioning

confidence: 99%

From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

Paul

Desiraju

2019

Angew Chem Int Ed

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Formation of a stoichiometric quaternary cocrystal consisting of resorcinol (RES), tetramethylpyrazine (TMP), phenazine (PHE) and pyrene (PYR) is described. A closed tetrameric resorcinol‐heterocycle synthon, unusual in that it has two different linker bases rather than just one, is observed in this four‐component solid. The tetrameric synthon is formed by two RES molecules and the two pyridine bases TMP and PHE. The stoichiometric quaternary cocrystal grows in an epitaxial fashion on the surfaces of a RES.PHE binary cocrystal which is initially obtained from the mother liquor. By indexing the common crystal faces of the binary and quaternary cocrystals, and noting that no ternary solid is obtained, a plausible mechanism has been proposed for the formation of this rare supramolecular architecture.

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Section: Figurementioning

confidence: 99%

From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

Paul

Desiraju

2019

Angew Chem Int Ed

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“…This knowledge can be utilized to improve the physicochemical properties of active pharmaceutical ingredients (APIs) in the pharmaceutical industry. , It is important to know the nature of solid forms of APIs, whether they are salts or cocrystals. There is a complete proton transfer from the acid to the base − in salts, whereas in cocrystals the proton is retained on the acid − and for the salt–cocrystal continuum, the proton is between the acid and the base (quasi proton state). ,− , Characterization techniques such as single-crystal X-ray diffraction (SC-XRD) and solid-state nuclear magnetic resonance (ss-NMR) have been reported to define the binary adduct systems as salts or cocrystals. , SC-XRD is able to show the proton position, albeit less accurately in comparison to neutron diffraction. However, obtaining single crystals of drug salts and cocrystals is not always easy, with amorphous solids posing a limitation to the use of diffraction-based techniques.…”

Section: Introductionmentioning

confidence: 99%

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Tothadi

Shaikh

Gupta

et al. 2021

Crystal Growth & Design

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X-ray photoelectron spectroscopy (XPS) is used to understand the nature of acid–base crystalline solids, to know whether the product is a salt (proton transfer, O–···H–N+) or a cocrystal (neutral adduct, O–H···N). The present study was carried out to explore if intermediate states of proton transfer from COOH to nitrogen (the proton resides between hydrogen bonded to O and N, O···H···N, quasi state) can be differentiated from a salt (complete proton transfer, N+–H··· O–) and cocrystal (no proton transfer, O–H···N) using N 1s XPS spectroscopy. The intermediate states of proton transfer arise when the pK a difference between the acid and the conjugate base is between −1 and 4, −1 < ΔpK a < 4, a situation common with COOH and pyridine functional groups present in drug molecules and pharmaceutically acceptable coformers. Complexes of pyridine N bases with aromatic COOH molecules in nine salts/cocrystals were cocrystallized, and their N 1s core binding energies in XPS spectra were measured. The proton state was analyzed by single-crystal X-ray diffraction for confirmation. Three new complexes were crystallized and analyzed by XPS spectra (without knowledge of their X-ray structures), to assess the predictive ability of XPS spectra in differentiating salt–cocrystal intermediate states against the extremities. The XPS results were subsequently confirmed by single-crystal X-ray data. Complexes of 3,5-dinitrobenzoic acid and isonicotinamide in 1:1 and 1:2 ratios exist as a salt and a salt–cocrystal continuum, respectively, as shown by the N 1s core binding energies. The proton states of the crystalline solids by XPS are in good agreement with the corresponding crystal structures. Other complexes, such as those of 3,5-dinitrobenzoic acid with 1,2-bis(4-pyridyl)ethylene, exhibit a salt–cocrystal continuum, maleic acids with 1,2-bis(4-pyridyl)ethylene and acridine are salts, 2-hydroxybenzoic acid and acridine is a salt, and the complex of 3,5-dinitrobenzoic acid and 3-hydroxypyridine is a salt and salt–cocrystal continuum, while fumaric acids with 1,2-bis(4-pyridyl)ethylene and acridine are cocrystals. Furthermore, three new acid–base complexes of 3,5-dinitrobenzoic acid with phenazine, 4-hydroxypyridine, and 4-cyanopyridine were studied initially by XPS and then confirmed by X-ray diffraction. In summary, since the N 1s binding energies cluster in a narrow range as cocrystals (398.7–398.9 eV) and salts (400.1–401.1 eV), it is clearly possible to differentiate between cocrystals and salts, but the salt–cocrystal continuum values in XPS spectra are clustered in an intermediate range of cocrystals and salts but overlap with those of cocrystal or salt binding energies.

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“…Any synthetic strategy towards higher cocrystals should be of high supramolecular yield and without contamination from by-products such as binaries and pure compounds. A very limited number of stoichiometric quaternaries (less than 20) have been obtained to date (Bhogala & Nangia, 2008;Dandela et al, 2018;Dubey et al, 2016;Mir et al, 2016;Paul et al, 2018;Paul & Desiraju, 2019). All quaternary cocrystals thus far obtained by our group are based on either structural inequivalences or a combinatorial approach.…”

Section: Introductionmentioning

confidence: 99%

Quaternary and quinary molecular solids based on structural inequivalence and combinatorial approaches: 2-nitroresorcinol and 4,6-dichlororesorcinol

Rajkumar

Desiraju

2021

Int Union Crystallogr J

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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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Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals

Cited by 18 publications

References 45 publications

From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Quaternary and quinary molecular solids based on structural inequivalence and combinatorial approaches: 2-nitroresorcinol and 4,6-dichlororesorcinol

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