Publications (3)

  • Yimei Bao · Xiaopeng Mo · Xiaoying Xu · [...] · Haoyun An
    [Show abstract] [Hide abstract] ABSTRACT: Bis(4-fluorobenzyl)trisulfide, fluorapacin, has been extensively developed as a promising new anticancer drug candidate. Its degradation products were identified and verified by the newly synthesized compounds bis(4-fluorobenzyl)disulfide (A) and bis(4-fluorobenzyl)tetrasulfide (B) which were resulted from the disproportionation of fluorapacin under forced conditions. A stability-indicating HPLC method was used for the stability evaluation of active pharmaceutical ingredient (API) fluorapacin and finished pharmaceutical product (FPP) under various conditions. High recovery (99.57%) of API was found after three freeze-thaw cycle processes of fluorapacin FPP. Susceptibility of fluorapacin to oxidative degradation was studied by treating fluorapacin and FPP in 30% hydrogen peroxide aqueous solution, and the result verified the oxidative stability of fluorapacin. However, treatment of this drug candidate under strong light (4500 Lx ± 500 Lx) for 10 days showed substantial effect on the recovery of fluorapacin, especially from fluorapacin FPP. Strong acid (1.0 M, HCl) did not affect the recovery of fluorapacin while strong basic condition (1.0 M, NaOH) accelerated the disproportionation of fluorapacin to its related substances A and B. The stability of fluorapacin in its aqueous media at a pH range of 2.0-10.0 for up to 6 h was further investigated, and 4.0-8.0 was found to be the most stable pH range. Fluorapacin and FPP were exposed to the elevated temperatures of 40 and 60 °C for 10 days without obvious impact on their stability. The thermal stability of fluorapacin API and FPP under constant humidity with light protection was also thoroughly investigated under accelerated (40 ± 2 °C, RH 75 ± 5%, 6 months) and long-term (25 ± 2 °C, RH 60 ± 10%, 24 months) conditions. There was no significant change except minor color change of fluorapacin FPP. Therefore, fluorapacin has excellent stability as a potential drug candidate for further clinical development investigation.
    Article · Aug 2008 · Journal of Pharmaceutical and Biomedical Analysis
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    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this research was to investigate the physical characteristics and crystalline structure of bis(p-fluorobenzyl)trisulfide, a new anti-tumor agent. Methods used included X-ray single crystal diffraction, X-ray powder diffraction (XRPD), Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC) and thermogravimetric (TG) analyses. The findings obtained with X-ray single crystal diffraction showed that a monoclinic unit cell was a = 12.266(1) A, b = 4.7757(4) A, c = 25.510(1) A, beta = 104.25(1) degrees ; cell volume = 1,448.4(2) A(3), Z = 4, and space group C2/c. The XRPD studies of the four crystalline samples, obtained by recrystallization from four different solvents, indicated that they had the same diffraction patterns. The diffraction pattern stimulated from the crystal structure data is in excellent agreement with the experimental results. In addition, the identical FT-IR spectra of the four crystalline samples revealed absorption bands corresponding to S-S and C-S stretching as well as the characteristic aromatic substitution. Five percent weight loss at 163.3 degrees C was observed when TG was used to study the decomposition process in the temperature range of 20-200 degrees C. DSC also allowed for the determination of onset temperatures at 60.4(1)-60.7(3) degrees C and peak temperatures at 62.1(3)-62.4(3) degrees C for the four crystalline samples studied. The results verified that the single crystal structure shared the same crystal form with the four crystalline samples investigated.
    Full-text Article · Feb 2008 · AAPS PharmSciTech
  • [Show abstract] [Hide abstract] ABSTRACT: A simple isocratic and stability-indicating HPLC method was developed and validated for the quantitative determination of anti-tumor agent fluorapacin and its pharmaceutical preparation. A Spherisorb ODS II C(18) (250 mm x 4.6 mm, 5 microm) column was eluted with a mobile phase consisting of acetonitrile/water (85:15, v/v). The analyses were performed at 40+/-1 degrees C with a flow rate of 1.0 mL/min and UV detection at 218 nm. The calibration curve was linear over a concentration range of 160-240 microg/mL with the correlation coefficient of 0.9997. The LOD and LOQ were determined to be 1.4 and 7.0 ng/mL, respectively. Average recoveries were 98.27% and 100.40% for fluorapacin API and its drug product with corresponding relative standard deviations (R.S.D.) of 0.41% and 0.30%, respectively. Good repeatability (precision and intermediate precision), accuracy and tolerability were obtained with R.S.D. of <1.0%. This specific and reliable method has been successfully applied for quality control of fluorapacin API and drug product.
    Article · Feb 2008 · Journal of Pharmaceutical and Biomedical Analysis