Polymorphism in metformin embonate salt – recurrence of dimeric and tetrameric guanidinium–carboxylate synthons

Nanubolu, Jagadeesh Babu; Sridhar, Balasubramanian; Ravikumar, K.; Sawant, Kamlesh D.; Naik, Triveni Ashok; Patkar, Laxmikant N.; Cherukuvada, Suryanarayan; Sreedhar, B.

doi:10.1039/c3ce26986h

Cited by 26 publications

(14 citation statements)

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“…In this context, we explored the preparation of [MET] 2 [SUC] 2 by melt mixing of 1 in the presence of dehydrated Na 2 [SUC] 2 . In this case, we are interested in replacing the anion Clbased on the concepts of the crystal engineering and using melting procedures [7], exploiting the well-known ability of the carboxylate and guanidinium groups to form charged-assisted hydrogen bonding in solid state (Scheme 1) [8].…”

Section: Introductionmentioning

confidence: 99%

“…al. [8] ten metforminium (H-MET + ) salts with different anions have been deposited at the Cambridge Structural Database CSD [9]. Five of them including the monocation H-MET + (two hydrochloride polymorphs, bromide, nitrate and one acetate salts) and five more having the metformin dication (H 2 -MET 2+ , oxalate, sulfate, perchlorate, squarate and calixiarenesulfonate salts).…”

Section: Introductionmentioning

confidence: 99%

“…Five of them including the monocation H-MET + (two hydrochloride polymorphs, bromide, nitrate and one acetate salts) and five more having the metformin dication (H 2 -MET 2+ , oxalate, sulfate, perchlorate, squarate and calixiarenesulfonate salts). Nanubolu also discusses the formation of two polymorphs of the salt [MET] 2 [EMB] (EMB 2-= embonate) [8]. In addition, the formation of the salt [MET][SAL] (SAL -= salicylate) [10], and the drug-drug salt [MET][GLI] containing two antidiabetic agents in the same solid phase (GLI, glicazide is a drug of the sulfonylurea-type) have been recently reported [11].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Metforminium Succinate by Melting. Crystal Structure, Thermal, Spectroscopic and Dissolution Properties

et al. 2017

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The reaction by melt mixing at 220 °C of the antihyperglycemic drug metformin hydrochloride 1 with dehydrated sodium succinate yields efficiently the organic salt [MET]2[SUC] 2 (H-MET+= metforminium and SUC2- = succinate). Solid state CPMAS NMR 13C spectroscopy experiments, powder X-ray diffraction and FT-IR results support the formation of the pharmaceutical salt 2 in good yields. Besides, the charged-assisted hydrogen bonding interactions of type N-H…-O(carboxylate) were thoroughly analyzed by single crystal X-Ray diffraction techniques. Thus, the pharmaceutical salt 2 possesses considerable thermal differences when compared to the pure starting reagents. In addition, intrinsic dissolution rate experiments in buffered aqueous solutions at pH= 6.8 showed a sustained-release behavior of the drug in 2 with a constant value of Kint = 0.885 mg/min * cm2.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of Metforminium Succinate by Melting. Crystal Structure, Thermal, Spectroscopic and Dissolution Properties

et al. 2017

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“…298 2298 2298 2298 2a (Å) 17.4278(18) 10.9035 527.754 1010.5258 717.798 56.1426 136.1552 10b (Å) 6.5075(8) 14.2541 (6) 8.0001 (16) 7.3870 65.3302 1522.952 410.232(2)…”

Section: Resultsmentioning

confidence: 99%

Salts and Co-crystals of Theobromine and their phase transformations in water

Sanphui

Nangia

2014

J Chem Sci

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Theobromine, a xanthine derivative analogous to caffeine and theophylline, is an effective central nervous system stimulant. It has lower aqueous solubility than caffeine and theophylline. Salts of theobromine with hydrochloric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid were prepared using liquid-assisted grinding (LAG). Proton transfer from the strong acid to the weak base imidazole N resulted in N +-H• • • O − hydrogen-bonded supramolecular assemblies of theobromine salts. The mesylate salt is polymorphic with amide N-H• • • O dimer and catemer synthons for the theobromine cations. A variable stoichiometry for phosphate salts (1:3 and 1:2.5) were observed with the latter being more stable. All new salts were characterized by FT-IR, PXRD, DSC and finally single crystal X-ray diffraction. In terms of stability, these salts transformed to theobromine within 1 h of dissolution in water. Remarkably, the besylate and tosylate salts are 88 and 58 times more soluble than theobromine, but they dissociated within 1 h. In contrast, theobromine co-crystals with gallic acid, anthranilic acid and 5-chlorosalicylic acid were found to be stable for more than 24 h in the aqueous slurry conditions, except malonic co-crystal which transformed to theobromine within 1 h. Water mediated phase transformation of theobromine salts and co-crystal may be due to the incongruency (high solubility difference) between the components. These results suggest that even though traditional salts are highly soluble compared to co-crystals, co-crystals can be superior in terms of stability.

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“…The Me 2 N–C–N–C backbone adopts the U conformation in the thermodynamic phase A (Me 2 NCNC torsion angle value of 53.7°), whereas the form of an S backbone is observed in the metastable polymorph B (Me 2 NCNC torsion angle value of 129.1°). The calculated minima are near 50° and 160°, respectively [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N′-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions

et al. 2020

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A new organic salt of metformin, an antidiabetic drug, and N,N′-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption–desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA−, as well as its structure in the solid, is herein reported for the first time. Regular O(δ−)∙∙∙C(δ), O(δ−)∙∙∙N+ and bifacial O(δ−)∙∙∙C(δ)∙∙∙O(δ−) of n→π * charge-assisted interactions are herein described in H2MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.

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Polymorphism in metformin embonate salt – recurrence of dimeric and tetrameric guanidinium–carboxylate synthons

Cited by 26 publications

References 65 publications

Synthesis of Metforminium Succinate by Melting. Crystal Structure, Thermal, Spectroscopic and Dissolution Properties

Synthesis of Metforminium Succinate by Melting. Crystal Structure, Thermal, Spectroscopic and Dissolution Properties

Salts and Co-crystals of Theobromine and their phase transformations in water

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N′-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions

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