Preparation and Crystal Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole

Caira, Mino R.; Alkhamis, Khouloud A.; Obaidat, Rana

doi:10.1002/jps.10541

Cited by 93 publications

(114 citation statements)

References 7 publications

(22 reference statements)

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“…Differential scanning calorimetry (DSC) has been recently often used in analysis of medicaments [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. For many years it has been an important tool in the study of drug polymorphism [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Thermal study of four irradiated imidazoline derivatives in solid state

Marciniec

Kozak

Naskrent

et al. 2007

J Therm Anal Calorim

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Four imidazoline derivatives: antazoline (AN), naphazoline (NN), tymazoline (TM), xylometazoline (XM), in the form of hydrochlorides in solid phase have been subjected to high energy e-beam irradiation from an accelerator (~10 MeV) at a dose varied from 25 to 200 kGy. The effects of the irradiation have been assessed by DSC, X-ray diffraction, FTIR, EPR and TLC.The standard sterilisation dose of 25 kGy has been found to produce changes in the properties of one derivative (XM), two other ones (AN and TM) have been found sensitive to doses >100 kGy, whereas NN has been resistant to irradiation in the whole range studied (25-200 kGy). EPR results indicated that the changes taking place in the therapeutic substances studied are related to radical formation. The irradiation induced changes in colour, a decrease or increase in the melting point, changes in the XRD pattern, small changes in the shape of FTIR peaks and the presence of radiolysis products. The XM compounds cannot be sterilised by irradiation because of the radiation induced changes in its physico-chemical properties.

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Section: Introductionmentioning

confidence: 99%

Thermal study of four irradiated imidazoline derivatives in solid state

Marciniec

Kozak

Naskrent

et al. 2007

J Therm Anal Calorim

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“…10) Three anhydrate polymorphic forms, one monohydrate and several solvates of fluconazole, have been prepared and characterized. [11][12][13][14][15][16][17][18][19][20] However, there has been no published research involving the characterization of fluconazole polymorphs using SSNMR spectroscopy. Consequently, we investigate the characterization of two fluconazole polymorphs, anhydrate forms I and II prepared by the supercritical antisolvent (SAS) process using SSNMR spectroscopy to obtain the structural differences in molecular level between fluconazole polymorphs.…”

mentioning

confidence: 99%

Solid-State Carbon NMR Characterization and Investigation of Intrinsic Dissolution Behavior of Fluconazole Polymorphs, Anhydrate Forms I and II

Park

Kim

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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NotePolymorphism is defined as the occurrence of different crystalline forms of the same pure compound in which the molecules have different arrangement and/or conformation. 1)Many drugs are able to be crystallized in several polymorphic forms, each having a different energy and thereby differing in physicochemical and mechanical properties such as melting point, solubility, stability, heat of fusion, density, refractive index, compression behavior and hygroscopicity. 2)Supercritical fluid (SCF) based technologies are currently valid tools among various crystallization techniques to control the polymorphic form of pharmaceuticals.3) The differences of properties such as solubility may have implications for absorption of the active drug from its dosage form. These concerns have led to an increased regulatory interest in the solid-state properties. 4,5) Solid state NMR (SSNMR) spectroscopy is also an essential technique for the solid state characterization of pharmaceuticals. The SSNMR spectroscopy not only differentiates between polymorphic forms of a pharmaceutical, but also intimately probes the structural aspects of polymorphic form. 6) Furthermore, solid state proton relaxation time (T 1 ) studies can also provide useful information on molecular motion in the solid state. 7)Intrinsic dissolution test is a one of the attempt to measure the solubility of a metastable polymorph which can undergo a phase transformation to the more stable phase during dissolving procedure. In fact, equilibrium solubility may not be very relevant for study of polymorphs if polymorphs are physically unstable in the aqueous environment. Instead, intrinsic dissolution rate (IDR) and kinetic solubility may be more relevant parameters to consider while studying the oral absorption of polymorphs. 2,8,9) Fluconazole is designated chemically as 2,4-difluoroa,a 1 -bis(1H-1,2,4-triazol-L-ylmethyl) benzyl alcohol ( Fig. 1) and is the first of a new subclass of synthetic triazole antifungal agent.10) Three anhydrate polymorphic forms, one monohydrate and several solvates of fluconazole, have been prepared and characterized.11-20) However, there has been no published research involving the characterization of fluconazole polymorphs using SSNMR spectroscopy. Consequently, we investigate the characterization of two fluconazole polymorphs, anhydrate forms I and II prepared by the supercritical antisolvent (SAS) process using SSNMR spectroscopy to obtain the structural differences in molecular level between fluconazole polymorphs. General solid state characterization such as differential scanning calorimetry (DSC), Powder X-ray diffraction (PXRD), fourier transform infrared (FT-IR) and Raman spectroscopy were also performed. Furthermore, kinetic solubility and intrinsic dissolution tests in aqueous solution were performed to investigate the solubility profiles and dissolution properties of fluconazole polymorphs. ExperimentalMaterials Micronized fluconazole (99.0% purity) was kindly provided Hwail Pharm. Co., Ltd. (Korea). The CO 2 used was 99.9% p...

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“…Discussion 2-(2,4-Difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol (HFlu) is one of the first-line popular drugs used to treat invasive infections [1]. 5-Ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (IMaz) is an imidazole compound used as aselective herbicide [2].…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of bis[2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol]-bis[5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinato]manganese(II), Mn(C13H12F2N6O)2(C15H18N3O3)2

Zhuang¹,

Yin²,

Li³

et al. 2010

Zeitschrift Für Kristallographie - New Crystal Structures

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C 56 H 60 F 4 MnN 18 O 8 ,triclinic, P1 (no. 2), a =9.7450(6) Å, b =11.2747(6) Å, c =15.2325(8) Å, a =79.072(4)°, b =78.248(4)°, g =65.073(3)°, V =1475.7 Å 3 , Z =1, Source of materialAn ethanol solution of 2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol (Fluconazole, HFlu, 0.05 mmol) and 5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (Imazethapyr, Imaz, 0.05 mmol) were added to asolution of manganese chloride (0.2 mmol) in water (10 ml). Then a purple solution was obtained. The crystals were obtained by evaporating the solution at room temperature for several days. Elemental analysis -found: C, 53.79 %; H, 5.16 %; N, 20.26 %; calculated for C 56H60F4MnN18O8:C ,5 3.84 %; H, 5.13 %; N, 20.19 %. Experimental detailsThe isopropyl, methyl, N12 and O5 of the imidazole ring of the Imaz are disordered with occupancy of 0.5/0.5. . 5-Ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid (IMaz) is an imidazole compound used as aselective herbicide [2]. Both of them would be an interesting candidate to construct coordination polymers, since it combines the features required for coordination to metal ions through nitrogen atoms and oxygen atoms for extended intermolecular interactions. Thus, the HFlu and Imaz ligands are potential to construct adiversity of coordination architectures upon the metal complexation. The crystal structure of the title complex consists of divalent manganese cation coordinated by six Na toms. Two Na toms originate from two triazole of two different HFlu molecules and the other four Natoms are from two different imazethapyr anions (two Natoms from two pyridyl rings and the other two Natoms from two oxo-imidazole rings). The lengths of Ni-Nbonds are in the range of 2.220(2) -2.304(1) Å.The associated angles range from 71.54(5)°to 180.00(5)°.Itindicates that manganese(II) has ad istorted octahedral coordination. The pyridinyl ring C2-C3-C4-C5-C6-N3 and the triazole ring N2-C17-N9-Z. Kristallogr. NCS 225 (2010) 213-215

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Preparation and Crystal Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole

Cited by 93 publications

References 7 publications

Thermal study of four irradiated imidazoline derivatives in solid state

Thermal study of four irradiated imidazoline derivatives in solid state

Solid-State Carbon NMR Characterization and Investigation of Intrinsic Dissolution Behavior of Fluconazole Polymorphs, Anhydrate Forms I and II

Crystal structure of bis[2-(2,4-difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)propan-2-ol]-bis[5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinato]manganese(II), Mn(C13H12F2N6O)2(C15H18N3O3)2

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