Characterization of Polymorphs of a Novel Quinolinone Derivative, TA-270 (4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone).

Abstract

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone, Fig. 1) is a newly developed antiallergy compound. TA-270 inhibits the immediate-and late-airway responses, pulmonary inflammatory cell accumulation, and airway hypersensitiveness.1) There are several useful reviews on the pharmaceutical applications of polymorphs, [2][3][4][5][6] and the study of polymorphism of newly developed compounds is important. A polymorphism is a solid material with at least two different molecular arrangements giving distinct crystal species. There can be large differences in their physical properties and also differences in bioavailability. 7,8) Several techniques for solid state measurements have been reported in the study of polymorphs: microscopy, infrared (IR) spectroscopy, 9) differential scanning calorimetry (DSC), [10][11][12] powder X-ray diffractometry, 13,14) and solid state NMR spectroscopy. [15][16][17][18][19][20][21] In the present study, the characterization of various crystalline forms of TA-270 was examined as a preformulation study. To confirm the molecular state of the polymorphic forms, powder X-ray diffractometry, thermal analysis, IR spectroscopy and solid state 13 C-NMR spectroscopy were performed. The intrinsic dissolution rate of each form was analyzed based on the rotating disk method. In vivo studies were also performed using Male Cr:CD strain rats. ExperimentalMaterials TA-270 was synthesized by the synthetic department of Dainippon Ink and Chemicals, Inc. and the purity of the compound was above 99 %. The a, b and d polymorphic forms were prepared by recrystallization from acetonitrile, ethanol, and acetone, respectively. The amorphous form was prepared by milling the b-form with a vibrating mill (CMT MGF, TI-300). All other chemicals and solvents were of analytical reagent grade.Powder X-Ray Diffraction The powder X-ray diffraction pattern was measured with an X-ray diffractometer (Model RINT Ultima, Rigaku Denki). The conditions of measurement were as follows: target Cu, monochrometer graphite, voltage 40 kV and current 30 mA, with a scanning speed of 2°/min.Thermal Analysis DSC thermograms were obtained by a differential scanning calorimeter (Model DSC7, Perkin-Elmer). The measurements were made using an aluminum sample pan (sample weights were 6-10 mg) under a nitrogen atmosphere at a scanning speed of 5 or 20°C/min. Temperature scale was calibrated by an Indium standard.Thermogravimetry (TG) curves were obtained with a thermogravimeter (Model TGA7, Perkin-Elmer ).IR Spectroscopy IR spectra were obtained with a Fourier transform (FT)-IR spectrometer (Perkin Elmer Spectrum One) using a diffuse reflectance technique. 22)Dissolution Rate Measurement The intrinsic dissolution rate was determined according to the rotating disk method under the following conditions: 2%w/v Tween80-pH 8.0 phosphate buffer (37°C), stirring rate of 100 rpm. A disk (diameter: 8 mm) was prepared by compressing a 100 mg sample under a pressure of 196 MPa in a hydraulic press. It was confirmed by powder X-ray...

NMR studies of organic polymorphs & solvates

“…In practice, a great range of methods have been used to obtain the amorphous forms for which 13 C NMR spectra have been reported. These include melt-quenching, 45,63,132 ball milling, [181][182][183] freeze-drying, 184,185 desolvation 45 and solvent evaporation. [186][187][188] In some cases, 139,189 the provenance is apparently not mentioned.…”

Crystal forms of rifaximin and their effect on pharmaceutical properties

“…4 The impact of polymorphism on bioavailability has already been reported for chloroamphenicol, 5 phenylbutazone, 6 amobarbital 7 and a quinolinone derivative. 8 More recent examples include doxazosin, 9 tranilast, 10 clopidogrel, 11 celecoxib, 12 ketorolac, 13 fuconazole, 14 piroxicam, 15 and theophylline. 16 Modification of polymorphism can occur, sometimes unexpectedly, during the manufacturing process, [17][18][19][20] emphasising the importance of knowing and being able to control the crystal form, particularly in the case of pharmaceutical compounds.…”

N-{2-[3-(3-Formyl-2-oxoquinolin-1(2H)-yl)prop-1-ynyl]phenyl}acetamide

“…The usefulness of 2-quinolone framework has been well demonstrated in the development of a broad range of pharmacologically active compounds including antibacterial, antiulcer, anti HIV, anti-allergic, anti-inflammatory and antifungal agents [1][2][3][4][5][6][7]. In continuation of our efforts to identify novel small molecules of potential pharmacological interest, we have recently reported the synthesis and PDE4 inhibitory properties of 2-quinolone derivatives [8].…”