In situ high-throughput study of drug polymorphism under controlled temperature and humidity using FT-IR spectroscopic imaging K.L.A. Chan a , S.G. Kazarian a, * , D. Vassou b , V. Gionis b , G.D. Chryssikos b a Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK b Theoretical & Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vass. Constantinou Avenue, Athens 11635, Greece Received 14 April 2006; received in revised form 24 July 2006; accepted 24 July 2006 Available online 12 September 2006 Abstract Fourier transform infrared (FT-IR) spectroscopic imaging in combination with a controlled humidity cell was applied to simultaneously monitor crystallisation of several binary mixtures of two drugs under identical environment. The effect of relative humidity was studied on samples of binary mixtures of nifedipine and nitrendipine with different molar ratios as well as on amorphous nitrendipine. All samples were arranged in array format on the surface of BaF 2 window for simultaneous imaging using an infrared focal plane array detector. The effect of sample thickness on the analysis of imaging results was addressed using novel approach to create images. The thickness-independent images have been obtained by plotting the distribution of the wavenumber corresponding to the peak maximum of the n(N–H) vibrational mode which is sensitive to the formation of the various crystalline polymorphs. The FT-IR spectroscopic imaging approach described in this work can be utilised in further high-throughput studies of many samples under controlled environment. # 2006 Elsevier B.V. All rights reserved. Keywords: FT-IR spectroscopy; FTIR; Crystallisation; Spectroscopic imaging; Polymorphism 1. Introduction Polymorphism is important to the pharmaceutical industry because it has a direct impact on the physical properties of drugs such as solubility in water and bioavailability [1,2]. Vibrational spectroscopy has been recognised as a powerful method for the characterisation and study of the different solid states of drugs [3]. Polymorphic transitions can be studied in situ by infrared and Raman micro-spectroscopy combined with a controlled environment unit [4,5]. This approach becomes even more powerful when coupled with imaging capabilities and combined with a controlled environment cell [6,7]. Spectroscopic imaging based on Raman or near-IR spectro- scopic techniques can be also used for the study of polymorphic transition processes. The choice between these and the present mid-infrared approach in the study of dynamic processes is determined by a number of factors including the selection rules that apply in each case, the availability of band assignments, the signal to noise ratio and the speed of data acquisition, the field of view, etc. However, the field of view and measurement speed of Raman imaging are typically smaller and slower compared to mid-IR imaging, while near-IR imaging allows for the use of thicker samples and the study of bulk phenomena but is often lacking detailed assignments of the observed vibrational bands. With the new advancement in mid-infrared array detectors, such as the focal plane array (FPA) detector for FT-IR imaging [8], the spatial distribution of structurally different components can be captured within seconds. A typical 64 Â 64 FPA detector consists of 4096 small detector elements. Each of these elements acquires an infrared spectrum from different locations within the sample. The spatial differentiation of various structural characteristics of the sample is enabled by applying specific spectroscopic criteria to the individual spectral components and plotting them as two-dimensional images [9]. The advantages of imaging are not only limited to the spatial information collected in each measurement, it can also be used as a tool for the parallel analysis of multiple samples. This high- throughput technology is a valuable tool for the development of new products and the fast optimisation of new formulations [10]. However, the simultaneous FT-IR characterisation of many samples within the small imaging area of an FT-IR www.elsevier.com/locate/vibspec Vibrational Spectroscopy 43 (2007) 221–226 * Corresponding author. E-mail address: s.kazarian@imperial.ac.uk (S.G. Kazarian). 0924-2031/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.vibspec.2006.07.015