Morton, Mark; (2008) Low-Level Pharmaceutical Analysis of Drugs and Impurities by Near-infrared Spectroscopy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Standard definitions of limit of detection (3σ) and limit of quantification (10σ) used for separative techniques have rarely been applied to near-infrared spectroscopy (NIRS). Fundamental differences between NIRS and these separative techniques limit the applicability of these standard methods. This thesis demonstrated detection and quantification by NIRS at key stages of pharmaceutical manufacture (standard reference materials, raw materials, tablets, API manufacture) and suggested more pertinent definitions of the LOD (6σ) and LOQ (% RSEP). Grinding and dissolution of the matrix to produce more uniform particles between that and the analyte studied were investigated (direct measurement, wavelength distance, two-point method, OLSR, SLR, PLSR). The resulting effect after optimisation of key parameters such as wavelength region selection, number of samples, sample distribution, pre-treatments and selection of vials were measured. Evaluations of different manufacturers' instruments and their effects on each method resulted in selection of the PLSR calibration method. Each PLSR calibration was studied by comparison between the standard error of calibration and prediction (SEC and SEP) and the net analytical signal (NAS) and the effects of relative sensitivities from co-impurities assessed. Loading identification of the resulting PLSR calibrations assessed the specificity of these calibrations and the effects of heteroscedasticity were minimised by applying WLSR and logarithmic transformations. These techniques allowed detection of impurities at the 6σ level, such as erythromycin B and erythromycin C within erythromycin A (0.80 and 1.36% w/w) and erythromycin ethyl succinate (0.40 and 0.92% w/w). Low-level detection was also obtained within a manufacturing process of 5-desosaminyl-6-0-methyl erythronolide within water (0.13% w/v) and clarithromycin in 3N HCl (0.17% w/v) and the active levothyroxine sodium (0.26% w/w) within a finished product Elthyrone® was successfully obtained and quantified.

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