- One-pot synthesis of phosphinylphosphonate derivatives and their anti-tumor evaluations
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This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).
- Deschamp, Julia,Dussart-Gautheret, Jade,Lecouvey, Marc,Legigan, Thibaut,Migianu-Griffoni, Evelyne,Monteil, Maelle
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- Investigation of Physical Properties of Disodium Etidronate Tetrahydrate and Application of Phosphorus K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy
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Purpose: Disodium etidronate is a bisphosphonate, compounds that are widely used in the treatment of bone disorders such as osteoporosis and Paget’s disease. We investigated the physical properties of disodium etidronate tetrahydrate crystal, form I. Methods: We used X-ray powder diffraction (XRPD), thermal analysis, dynamic vapor sorption (DVS), X-ray single crystal structure analysis, and phosphorus K-edge X-ray absorption near-edge structure (XANES) spectroscopy for the first time. Results: XRPD and thermal analyses demonstrated that form I was dehydrated and transformed to an amorphous form, to a crystalline form II, and finally to a form III by heating. DVS measurements revealed that the amorphous form, form II, and form III were rehydrated to form I by humidification, and form I was stable even at 0% relative humidity. These results indicate that form I is the most stable solid-state under ambient conditions and is suitable as an API for manufacture in solid formulations. The phosphorus K-edge XANES spectra differed among form I, the amorphous form, and form II, which may be ascribed to the difference in the coordinate bond schemes between the phosphate moieties and sodium ions. The results demonstrated that the phosphorus K-edge XANES spectroscopy could be applied to the identification or the discrimination of crystal forms of the APIs containing phosphate moieties. Conclusions: Acquired information about physical properties are crucial for manufacturing of solid formulations of disodium etidronate. XANES spectroscopy is a promising alternative method for evaluating the solid-state forms of APIs.
- Ito, Naoya,Hashizuka, Takahiko,Ito, Masataka,Suzuki, Hironori,Noguchi, Shuji
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p. 2147 - 2155
(2021/12/22)
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- Optimized synthesis of etidronate
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The synthesis of Etidronate (as the disodium salt) by the reaction of acetic acid with phosphorus trichloride/phosphorus acid in methanesulfonic acid was studied and optimized. We showed that it is enough to use 3.2 equivalents of the phosphorus trichlori
- Kovacs, Rita,Nagy, David Illes,Gruen, Alajos,Balogh, Gyoergy Tibor,Garadnay, Sandor,Greiner, Istvan,Keglevich, Gyoergy
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p. 733 - 737
(2013/12/04)
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- METHOD FOR PRODUCING PURE DISODIUM PAMIDRONATE
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Biphosphonates and especially disodium pamidronate are becoming more and more important for the therapy of a wide variety of diseases. Pure and stable disodium pamidronate is a prerequisite for the manufacture of the respective pharmaceutical formulations. In the literature, there is a controversy on the stability of the various hydrates of disodium 10 pamidronate. The present invention presents a facile, easy to scale-up method of producing disodium pamidronate pentahydrate of high purity and high stability, at yield >90 %. This method avoids any steps that may introduce impurities. It is based on the fact that pamidronic acid can be transferred into its diammonium salt at high concentration, at room temperature. This highly concentrated solution is converted into the disodium salt via ion-exchange, at conditions that maintain the high concentration. The ion-exchange step simultaneously eliminates any undesired divalent or trivalent cations. The disodium salt can be directly crystallized in the eluate of the ion-exchange column, without the need of further concentration and/or addition of any alcohol, by only lowering the temperature down to 5°C.
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Page/Page column 10
(2008/06/13)
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