Drug–Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment

Thorat, Shridhar H.; Sahu, Sanjay Kumar; Patwadkar, Manjusha V.; Badiger, Manohar V.; Gonnade, Rajesh G.

doi:10.1002/jps.24651

Cited by 46 publications

(39 citation statements)

References 36 publications

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“…However, the original defects of the parent drugs are still there (discussed below). In this way, drug-drug pharmaceutical salts present an alternative method that is expected to overcome the problems associated with traditional combination drugs since they offer a way to dramatically alter physicochemical properties (Bag et al, 2014;Thorat et al, 2015;Gopi et al, 2016;Putra et al, 2016;Peng et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

Jia

Gong

2019

Acta Crystallogr C

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A drug–drug anhydrous pharmaceutical salt containing tolbutamide {systematic name: 3‐butyl‐1‐[(4‐methylbenzene)sulfonyl]urea, TOL, C12H18N2O3S} and metformin (systematic name: 1‐carbamimidamido‐N,N‐dimethylmethanimidamide, MET, C4H11N5) was created based on antidiabetic drug combinations to overcome the poor pharmaceutical properties of the parent drugs. Proton transfer and the proportion of the two components were confirmed by 1H NMR spectroscopy and single‐crystal X‐ray diffraction analysis. Comprehensive characterization of the new pharmaceutical salt crystal, 2‐[(dimethylamino)(iminiumyl)methyl]guanidine (butylcarbamoyl)[(4‐methylbenzene)sulfonyl]azanide, C4H12N5+·C12H17N2O3S−, was performed and showed enhancement of the pharmaceutical properties, such as lower hygroscopicity and greater accelerated stability than the parent drug MET, and higher solubility and dissolution rate than TOL. The property alterations were correlated with the crystal packing features and potential hydrogen‐bonding sites through observed changes in the crystal structures.

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Section: Introductionmentioning

confidence: 99%

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

Jia

Gong

2019

Acta Crystallogr C

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“…Form I is converted into the trihydrate form in aqueous solution. Shridhar and co-workers in their study observed a crystal-to-crystal transition of form II to the more stable form I and mentioned that the metastable form is not a useful alternative form of Gefitinib (Thorat et al, 2014(Thorat et al, , 2015. Hence, the quest for solving the problem of the solubility of Gefitinib and an investigation of the polymorphism of this drug is still a major challenge in the pharmaceutical industry.…”

Section: Introductionmentioning

confidence: 99%

Exploring a solvated dimer of Gefitinib: a quantitative analysis

et al. 2018

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Gefitinib or Iressa is an orally administered anilinoquinazoline used in cancer chemotherapy for the treatment of lung and breast cancer. It is reported to exist in two polymorphic forms, a stable form I and a metastable form II. Both of the forms belong to the triclinic P-1 space group. In this work, we report the crystallization of Gefitinib to form a methanol solvate [systematic name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine methanol hemisolvate, CHClFNO·0.5CHOH] that was theoretically and experimentally investigated. The unit cell is composed of two independent Gefitinib molecules (A and B) that form a stable molecular complex with methanol in the crystal lattice. To understand the crystal lattice stabilization, a combination of techniques, namely X-ray diffraction, IR spectroscopy, thermogravimetric/differential scanning calorimetry (TG-DSC), Hirshfeld surface analysis and CLP-PIXEL methods were used. The analysis of the crystal structure of this dimer revealed a three-dimensional isostructurality with the already reported form II. The A and B molecules are connected via trifurcated C-H...O and N-H...O hydrogen bonding. In addition, the presence of the methanol molecule stabilizes the crystal structure via C-H...O, N-H...O and C-H...Cl interactions between the two monomers. The IR analysis of the dimer has shown characteristic fingerprint values when compared to the commercial form. The TG-DSC analysis of the solvated dimer is in good agreement with the patent reporting cocrystals of Gefitinib. Finally, theoretical calculations by the CLP-PIXEL method and Hirshfeld surface and two-dimensional (2D) fingerprint plot analysis were carried out in order to quantify the different intermolecular interactions and their energies in the crystal packing.

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“…Drug-drug molecular salts have been exploited as new crystal forms of active pharmaceutical ingredients [3]. Flavonoids are natural occurring polyphenolic compounds with health-prolonging effects such as antioxidant, antitumor and anti-inflammatory properties [4].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C₃₇H₃₅N₁O₁₀

Zhang

Lou

Huang

et al. 2017

Zeitschrift Für Kristallographie - New Crystal Structures

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Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C 37 The asymmetric unit of the title crystal structure is shown in the figure. Tables 1 and 2 contain details on crystal structure and measurement conditions and a list of the atoms including atomic coordinates and displacement parameters. Source of materialPalmatine chloride (systematic name: 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium chloride; 387 mg, 1 mmol) was dissolved in absolute methanol (30 mL) and NaOH (40 mg, 1 mmol) was added under stirring conditions. Genistein (systematic name: 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one; 270 mg, 1 mmol) was then added. The mixture was stirred for 8 h and then filtered. The yellow powder was further recrystallized in absolute methanol and yellow block crystals were obtained after several days. Experimental detailsThe structure was solved by direct methods and refined on F 2 by full-matrix least-squares methods using the SHELXTL program package [1]. Hydrogen atoms bound to carbon atoms were located geometrically with U iso (H) = 1.2 Ueq(C) or 1.5 Ueq(C). Hydrogen atoms bonded to oxygen were located by difference maps and the displacement factors were freely refined.

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Drug–Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment

Cited by 46 publications

References 36 publications

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

Exploring a solvated dimer of Gefitinib: a quantitative analysis

Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C₃₇H₃₅N₁O₁₀

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Drug–Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment

Cited by 46 publications

References 36 publications

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

A tolbutamide–metformin salt based on antidiabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

Exploring a solvated dimer of Gefitinib: a quantitative analysis

Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C37H35N1O10

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Crystal structure of 2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium 5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-olate methanol solvate, C₃₇H₃₅N₁O₁₀