Quantification of active pharmaceutical ingredients and polymorphs in tablets by spectroscopic means
Hennigan, Michelle Celine
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Active pharmaceutical ingredients (APIs) can exist in various solid state forms including polymorphs, solvates, and hydrates. In the case of polymorphs each form can possess its own unique physical properties and chemical stability which in turn can directly affect the efficacy of the API. It is clear that accurate characterisation and quantification of the precise solid state form present within a formulation is of vital concern for safety and regulatory affairs. It is therefore important to study and compare which analytical technologies are most appropriate to address these issues. Powder X-ray diffraction (PXRD) is considered to be the golden standard in the differentiation of polymorphs as a difference in crystal structure signifies the presence of an alternate form. However this technique is not amenable to quick on-line analysis. Vibrational spectroscopies provide useful tools as they are rapid, non-destructive and non-contact where they can be employed in, on and at-line. In this body of work the abilities of near infra-red (NIR) and Raman spectroscopies in combination with chemometric methods for the identification and quantification of low levels of API and polymorph contaminants present in model tablet formulations were investigated. For active quantification a simple model tablet system comprised of a model API, 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile, ROY, in a matrix of excipients was utilised. The tablets were then analysed using PXRD, NIR, backscattering Raman (BRS) and transmission Raman (TRS) spectroscopies. The data was pre-processed using a variety of methods. The data was then used to develop a range of calibration models for predicting ROY concentration with the best accuracy of ~0.3% RMSEP (root mean square error of prediction) being achieved with NIR and Transmission Raman spectroscopies. Polymorph and polymorph contaminant within formulations studies were concerned with the polymorphs of piracetam. A simple binary polymorphic system consisting of mixtures of varying proportions of Form II and III of piracetam were prepared and analysed by PXRD, NIR and Raman. Univariate and multivariate analysis was performed on the PXRD data and although multivariate chemometric analysis provided better error values of prediction for the level of polymorphs within the mixtures, it did not perform as well as the NIR based multivariate model which was found to demonstrate the best accuracy overall. BRS models were poor due to the inherent sub-sampling associated with this technique. For the polymorph contaminant work, low levels of polymorphic contaminant of Form II piracetam were incorporated into tablets containing 10% API loading of Form III piracetam in the range of 0.1 to 10% of the total tablet. Transmission Raman and NIR were comparable with limits of detection ~ 0.6% FII in tablets. Transmission Raman spectroscopy overcomes the limitation of sub-sampling and fluorescence that is often associated with the conventional backscattering Raman and is a technology ripe for utilisation in a process analytical technology context within the pharmaceutical industry.