Validation of a UV spectrophotometric method for the determination of copper and platinum with dithizone

Abstract

The measurement of metal catalyst residues in the synthesis of pharmaceutical products establishes whether concentration levels are below the maximum allowed concentration limits. The synthesis of the antifungal active ingredient Terbinafine HCl involves two metal catalysts, copper(II) and platinum. The method chosen for measuring copper and platinum was the dithizone method. The metal-dithizone complexes formed, termed dithizonates, are strongly coloured and are soluble in dichloromethane, the organic solvent used for this analysis. Thus, a mixed colour procedure was carried out, recording absorbance at 611nm, where excess dithizone gives an absorption peak and monitoring copper and platinum(II) dithizonates at 545nm and 720nm respectively. The optimum conditions for extraction of the metal-dithizone complexes were investigated. Copper(II) dithizonate extraction is favoured in fairly acidic media ( ~ pH5) while platinum(II) dithizonate was best extracted in very acidic media, in 1MH2S04 and 0 .5M HCl. Equilibration was reached after shaking for 2.5 minutes for copper(II) dithizonate and a shaking time of 2 minutes was required for complete extraction of platinum(II) dithizonate. The labilising agent stannous chloride was used to allow efficient extraction of the platinum by reducing any platinum(IV) to platinum(II) and forming a more labile complex with SnCb - as ligand. The copper-dithizone method was found to obey Beer's Law between a range of 0.10.7µgmL-1 while for platinum, the range was between 0.1-3 µgmL-1. Linearity results obtained during the validation procedure, showed that very high correlation coefficients (>O 99) were prod11ced for the copper ca1ibration line at 611nm and at 720nm for the platinum calibration line. Further validation results revealed that only the copper dithizone method at 611nm and the platinum-dithizone method at 720nm show suitable specificity, precision, reproducibility and accuracy. This shows that both methods have been validated. Furthermore, RSD values obtained were less than 10% and were accepted as being suitable for validation. Ultraviolet/visible spectrophotometry results were compared to those obtained using a standard graphite furnace atomic absorption spectrophotometric (GF AAS) method, and both methods proposed concentration values below the detection limit. Using UV spectrophotometry, the detection limit for copper was found to be 0.037mgL-1 while that for platinum was found to be 0.093mgL-1. This implies that the Terbinafine HCl samples analysed using both the copper and platinum dithizone methods were found to have metal concentrations below the maximum concentration limit values (15mgkg-1 for copper and 5mgkg-1 for platinum (EMEA, 2002)) as defined by quality and safety-based criteria. A single analytical method for measuring copper and platinum in a single solution is possible for routine applications. It is also a comparatively less expensive and faster method than atomic absorption spectrophotometry with acceptable limits of detection.