Finding a reliable limit of detection in the NIR determination of residual moisture in a freeze-dried drug product.

The validation of an analytical method in the pharmaceutical industry follows strictly regulated guidelines. The introduction of multivariable calibration methods requires a revision of these recommendations, since some of them are contradictory regarding the limit of detection (LOD). This work compares the LOD values obtained using pseudounivariate and multivariate procedures in the PLS-NIR determination of residual moisture content (RMC) in a freeze-dried drug. As NIR has proved to be more precise than Karl-Fischer at low RMC values, LOD has been estimated by ordinary and by orthogonal least squares regression. The precision of the RMC determination in approx. 2000 industrial vials was used as an indirect evidence of the reliability of the LOD values obtained. The effect of reducing the number of calibration samples and increasing the RMC values have also been studied. No significant differences were observed using a number of calibration samples ≥ 20. Based on our findings, when the size of the calibration sample set is high and the range of RMC values is close to the limit, the LOD estimated with the ICH formula and using orthogonal regression should be recommended. If water content moves away, the ICH formula should be replaced by the LODOS equation as a practical, reliable and simple procedure.

Fast assessment of the surface distribution of API and excipients in tablets using NIR-hyperspectral imaging.

The inclusion of hyperspectral imaging systems in the manufacturing and development of pharmaceutical products is allowing a successful improvement in the quality control of solid dosage forms. The correct distribution not only of active pharmaceutical ingredient (API) but also of the rest of excipients is essential to assure the correct behavior of the tablet when ingested. This is especially relevant in tablets with low content of potent APIs, in which the prescribed intake dosage frequently corresponds to half-a-tablet. Therefore, the aim of this work is to study the surface distribution of the compounds in tablets with low API content. The proposed procedure includes the scanning of the tablet surface using near infrared hyperspectral spectroscopy in association with multivariate curve resolution (MCR) techniques to obtain selective pictures for each individual compound and to allow the fast assessment of their distribution in the measured surface. As an example, a set of commercial Lorazepam tablets (approximately 1% mass fraction of API, and four excipients) were analyzed. The results obtained show the capacity of the proposed methodology as an expedite approach to evaluate the uniformity of the contents between and within tablets. A method to estimate the homogeneity distribution of API in the two halves of the tablet is also proposed.