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

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 R 2 =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.