Development of sampling methods for Raman analysis of solid dosage forms of therapeutic and illicit drugs

The results of a study aimed at determining the most important experimental parameters for automated, quantitative analysis of solid dosage form pharmaceuticals (seized and model ‘ecstasy’ tablets) are reported. Data obtained with a macro-Raman spectrometer were complemented by micro-Raman measurements, which gave information on particle size and provided excellent data for developing statistical models of the sampling errors associated with collecting data as a series of grid points on the tablets’ surface. Spectra recorded at single points on the surface of seized MDMA–caffeine–lactose tablets with a Raman microscope (lex = 785 nm, 3 μm diameter spot) were typically dominated by one or other of the three components, consistent with Raman mapping data which showed the drug and caffeine microcrystals were ca 40 μm in diameter. Spectra collected with a microscope from eight points on a 200 μm grid were combined and in the resultant spectra the average value of the Raman band intensity ratio used to quantify the MDMA: caffeine ratio, mr, was 1.19 with an unacceptably high standard deviation, sr, of 1.20. In contrast, with a conventional macro-Raman system (150 μm spot diameter), combined eight grid point data gave mr = 1.47 with sr = 0.16. A simple statistical model which could be used to predict sr under the various conditions used was developed. The model showed that the decrease in sr on moving to a 150 μm spot was too large to be due entirely to the increased spot diameter but was consistent with the increased sampling volume that arose from a combination of the larger spot size and depth of focus in the macroscopic system. With the macro-Raman system, combining 64 grid points (0.5 mm spacing and 1–2 s accumulation per point) to give a single averaged spectrum for a tablet was found to be a practical balance between minimizing sampling errors and keeping overhead times at an acceptable level. The effectiveness of this sampling strategy was also tested by quantitative analysis of a set of model ecstasy tablets prepared from MDEA–sorbitol (0–30% by mass MDEA). A simple univariate calibration model of averaged 64 point data had R2 = 0.998 and an r.m.s. standard error of prediction of 1.1% whereas data obtained by sampling just four points on the same tablet showed deviations from the calibration of up to 5%. Copyright  2004 John Wiley & Sons, Ltd.