New Technology for the Investigation of Water Vapor Sorption–Induced Crystallographic Form Transformations of Chemical Compounds: A Water Vapor Sorption Gravimetry– Dispersive Raman Spectroscopy Coupling  Martin Philipp Feth, Jörg Jurascheck, Michael Spitzenberg, Jürgen Dillenz, Günter Bertele, Herbert Stark  Journal of Pharmaceutical Sciences  Volume 100, Issue 3, Pages 1080-1092 (March 2011) DOI: 10.1002/jps.22317 Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 1 Chemical structure of SAR474832. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 2 Experimental setup of the water sorption gravimetry (SPS11/23-10μ from Projekt Messtechnik, Ulm, Germany)–dispersive Raman spectrometer (RXN1 equipped with a 6-mm PhAT Raman probe, Kaiser Optical Systems Ltd., Ann Arbor, Michigan) coupling. Scheme of the Raman spectrometer–SPS11/23-10μ coupling (picture on the left), the PhAT Raman probe head is mounted on the glass cover plate of the SPS machine (picture on the left). Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 3 Crystalline form 1 of the active pharmaceutical ingredient (a) Water sorption gravimetric curves (desorption and sorption at 25°C), (b) Raman peak position versus relative humidity plot (wavenumber range: 1022–1034cm−1) during desorption and sorption of water. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 4 Contour plots of the Raman–water sorption gravimetric experiment (25°C) on crystalline form 1 of the active pharmaceutical ingredient (start of experiment: 40% r.h.): (a) first desorption cycle and (b) first sorption cycle. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 5 Comparison of the Raman spectra (at equilibrium conditions) of crystalline form 1 of the active pharmaceutical ingredient during desorption and sorption of water (refer to the water sorption experiment shown in Fig. 3) in the wavenumber range 720 to 1500cm−1. The Raman signals used for the peak position analysis, shown in Figure 3 and Figure 6, are marked with arrows. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 6 Raman peak position versus relative humidity plot (wavenumber range: 839–844cm−1) during desorption and sorption of water (refer to the water sorption experiment shown in Fig. 3). Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 7 Phase diagram of the solid hydrate phases of SAR474832 (forms 1, 2, and 3) showing dependence of relative humidity. Form 1 (2.25eq. water), form 2 (1eq. water), and form 3 (1.5eq. water). Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 8 Crystallographic species (forms 1, 2, and 3 of the active pharmaceutical ingredient) distribution plots of the water sorption experiment (shown in Fig. 3) determined by multivariate curve resolution analysis of the Raman spectra (wavenumber range of the simulation: 830–1650cm−1) at equilibrium. For an easier comparison, a factor of 100% was added to the portion values of form 3. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 9 X-ray amorphous active pharmaceutical ingredient (produced by lyophilization) (a) water sorption gravimetric curves (desorption and sorption at 25°C), (b) crystallographic species (form 1 and amorphous form) distribution plots of the water sorption experiment, shown in part (a), determined by multivariate curve resolution analysis of the Raman spectra (wavenumber range of the simulation: 750–1650cm−1) at equilibrium. For an easier comparison, a factor of 100% was added to the portion values of form 1. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 10 Comparison of the Raman spectra (at equilibrium conditions) of X-ray amorphous material during the desorption and sorption of water (refer to the water sorption experiment shown in Fig. 9 a) in the wavenumber range 720 to 1500cm−1. The Raman signal used for the peak position analysis, shown in Figure 12 (a), is marked with an arrow. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 11 (a) Contour plot of the Raman spectra during the recrystallization process of X-ray amorphous active pharmaceutical ingredient (API) into form 1 between 90% and 95% r.h (refer to Fig. 12 a, time period: 100–300min). (b) Overlay of the Raman spectra during the recrystallization process of X-ray amorphous API into form 1 between 90% and 95% r.h (refer to Fig. 9 a, time period: 100–300min). Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions

Figure 12 (a) Raman peak position (wavenumber range: 882–889cm−1) of the time-resolved recrystallization experiment (induced by water sorption at 25°C), time versus humidity plot, and time versus sample net-to-weight change plot. (b) Crystallographic species (amorphous form and form 1 of the active pharmaceutical ingredient) distribution plots of the time-resolved recrystallization (induced by water sorption) experiment (25°C) determined by multivariate curve resolution analysis of the Raman spectra (wavenumber range of the simulation: 750–1650cm−1) at equilibrium and from the time versus humidity plot. Journal of Pharmaceutical Sciences 2011 100, 1080-1092DOI: (10.1002/jps.22317) Copyright © 2011 Wiley Periodicals, Inc. and the American Pharmacists Association Terms and Conditions